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Study Description

The purpose of this study is to evaluate the investigational drug, silmitasertib (a pill taken by mouth), in combination with FDA approved drugs for solid tumors. An investigational drug is one that has not been approved by the U.S. Food & Drug Administration (FDA), or any other regulatory authorities around the world for use alone or in combination with any drug, for the condition or illness it is being used to treat.

The goals of this part of the study are:

• Establish a recommended dose of silmitasertib in combination with chemotherapy
• Test the safety and tolerability of silmitasertib in combination with chemotherapy in subjects with cancer
• To determine the activity of study treatments chosen based on:
• How each subject responds to the study treatment
• How long a subject lives without their disease returning/progressing

Inclusion Criteria

• Age: Less than 30 years old at initial diagnosis
• Pathology All subjects must have a confirmed diagnosis of tumor type. Phase I: Relapsed/refractory solid tumors: Neuroblastoma, Ewing Sarcoma, Osteosarcoma, Rhabdomyosarcoma, Liposarcoma
  • Phase II: 
    • Relapsed/refractory Neuroblastoma
    • Relapsed/refractory Ewing sarcoma
• Tumor assessment: Disease assessment is required for eligibility and must be done after last dose of previous therapy and prior to first dose of study drug.
• Disease Status: Relapsed/Refractory Neuroblastoma Relapsed disease defined as neuroblastoma that was previously in remission after standard therapy (at least 4 cycles of aggressive multi-drug induction chemotherapy, with or without radiation and surgery, followed by immunotherapy, or according to a standard high-risk treatment/neuroblastoma protocol) and has now relapsed and is in any number of relapses. Refractory disease defined as High-risk neuroblastoma (as defined by INRG) that failed to achieve CR after at least 4 cycles of aggressive multi-drug induction chemotherapy, progression during upfront therapy or with disease remaining after standard immunotherapy. 
  • International Neuroblastoma Risk Group Staging System (INRG) High Risk NB defined as one of the following:
    • Any age with International Neuroblastoma Risk Group (INRG) Stage L2, MS, or M with MYCN amplification
    • Age ≥ 547 days and INRG Stage M regardless of biologic features
    • Any age initially diagnosed with INRG Stage L1 MYCN amplified NBL who have progressed to Stage M without systemic chemotherapy
    • Age ≥ 547 days of age initially diagnosed with INRG Stage L1, L2, or MS who have progressed to Stage M without systemic chemotherapy
  • Relapsed/refractory Sarcoma Subjects that have relapsed following standard of care therapy or having progressed during standard of care therapy. Standard of care therapy for sarcoma includes multi-agent chemotherapy with local control consisting of either surgery or radiation therapy.
• Measurable or evaluable disease, including at least one of the following:
  • Measurable tumor by CT or MRI
  • MIBG or PET that is positive for disease
  • Bone Marrow biopsy/aspirate that is positive for disease
• Timing from prior therapy:
  • Subjects must have fully recovered from the acute toxic effects of all prior anti- cancer therapy and be within the following timelines:
    • Myelosuppressive chemotherapy: Must not have received within 2 weeks of enrollment onto this study.
    • Small Molecule Inhibitors (anti-neoplastic agent): At least 2 weeks from the completion of therapy with a small molecule inhibitor.
    • Immunotherapy: At least 4 weeks since the completion of any type of immunotherapy, e.g. tumor vaccines, CAR-T cells, anti-GD2 Monoclonal antibodies (ex. naxitamab, dinutuximab, etc.).
    • Radiotherapy: At least 30 days since the last treatment except for radiation delivered with palliative intent to a non-target site.
    • Stem Cell Transplant:
      • Allogeneic: No evidence of active graft vs. host disease
      • Allogeneic/Autologous: ≥ 2 months must have elapsed since transplant.
    • MIBG Therapy: At least 6 weeks since treatment with MIBG therapy.
• Subjects must have a Lansky or Karnofsky Performance Scale score of >/= 50.
• Subjects must have adequate organ function at the time of enrollment:
  • Cardiac: Subjects must have a QTcF ≤ 480 msc.
  • Hematological: Hematological recovery as defined by ANC ≥750/μL
  • Liver: Adequate liver function as defined by AST and ALT <5x upper limit of normal
  • Renal: Subjects must have adequate renal function defined as an estimated Glomerular Filtration rate (eGFR) as calculated from the Bedside Schwartz equation (in units of mL/min/1.73 m2) or via radioisotope GFR ≥ 70. The Bedside Schwartz equation is: [(0.413) X (Height in cm)] / SCr
• Subjects of childbearing potential must have a negative serum pregnancy test. Subjects of childbearing potential must agree to use effective measures to avoid pregnancy.
• Written informed consent in accordance with institutional and FDA guidelines must be obtained from all subjects (or subjects' legal representative).

Exclusion Criteria

• Investigational Drugs: Subjects who are currently receiving another investigational drug are excluded from participation.
• Anti-cancer Agents: Subjects who are currently receiving other anticancer agents are not eligible. Subjects must have fully recovered from the hematological and bone marrow suppression effects of prior therapy.
• Subjects who are currently receiving Vitamin K antagonists (warfarin).
• Subjects who are currently receiving the class of lipid-lowering medications HMG-CoA reductase inhibitors (statins).
• Infection: Subjects who have an uncontrolled infection are not eligible until the infection is judged to be well controlled in the opinion of the investigator.
• Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study, or in whom compliance is likely to be suboptimal, should be excluded.
• Subjects with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the subject's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results.
• Subjects with any of the following gastrointestinal disorders:
  • Active malabsorption (e.g. short gut) syndrome.
  • Uncontrolled diarrhea (excess of 4 stools/day)
  • Gastritis, ulcerative colitis, Chron's disease or hemorrhagic coloproctitis
  • History of gastric or small bowel surgery involving any extent of gastric or small bowel resection
• Lactating subjects are not eligible unless they have agreed to not breastfeed their infants. There is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the nursing subject with silmitasertib. (NOTE: breast milk cannot be stored for future use while the nursing subject is being treated on study.)
• Subjects with a history of any other malignancy.

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Study Description

This is a pilot study to determine feasibility of adding intrathecal (IT) chemotherapy and maintenance therapy after high dose chemotherapy for treatment of newly diagnosed HR-EBTs in patients less than 6 years of age. Patients meeting all inclusion criteria will receive 3 cycles of multiagent chemotherapy induction (vinCRIStine, cyclophosphamide, CISplatin, etoposide) with IT cytarabine and hydrocortisone, and 3 cycles of consolidation with CARBOplatin, thiotepa, and autologous stem cell rescue (as per CCG 99703). Maintenance chemotherapy will then be given immediately after the completion of consolidation therapy and consist of risk-stratified oral chemotherapy using either "Maintenance A" (48 weeks) using tamoxifen and retinoic acid or "Maintenance B" (54 weeks) using metronomic isotretinoin, celecoxib, etoposide, temozolomide, and cyclophosphamide. Both arms of maintenance will receive monthly IT topotecan.

Following the end of treatment, patients will be scheduled for a follow-up visit every 3 months for 24 months to evaluate PFS and OS. Approximately 15 patients will be recruited as part of this clinical study.

Patients aged between 0 and 6 years old at the time of enrollment will be eligible. This study will only enrol patients with high risk Central Nervous System Embryonal Brain Tumors (CNS-EBTs) with histologic and/or molecular confirmation of diagnosis for ATRT intrinsic to the brain and spinal cord, group 3 and group 4 MB, pineoblastoma, CNS neuroblastoma, ETMR, including embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma and ETMR not otherwise specified), medulloepithelioma, CNS embryonal tumor with rhabdoid features (INI-1 intact) and CNS embryonal tumor, not otherwise specified.

Response to treatment will be evaluated using the modified RAPNO (Response Assessment in Pediatric Neuro-Oncology) 1.

This study will also explore the genetic landscape of CNS HR-EBTs. Our biological study will include genomic analyses of tumor and CSF with use of epigenomic analyses (methylation profiling) arrays, Nanostring sub-typing studies, Next generation sequencing analyses for DNA and/or RNA.

Inclusion Criteria

• Tumor Tissue Sample
• Age: Patient must be aged ≥ 0 years to ≤ 6 years at the time of definitive confirmation of histologic diagnosis of eligible CNS tumor.
• Diagnoses. Participants must have Central nervous system (CNS) HR-EBT including atypical teratoid rhabdoid tumour (ATRT), group 3 and group 4 medulloblastoma (MB), pineoblastoma, CNS neuroblastoma, embryonal tumor with multi-layered rosettes (ETMR including embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma and ETMR not otherwise specified), medulloepithelioma, CNS embryonal tumor with rhabdoid features (INI-1 intact) and CNS embryonal tumor, not otherwise specified. Metastatic disease included. Any extent of resection included.
• Cranial and Spine MRI. A baseline MRI brain and spine with and without contrast is required for all patients. cranial MRI (with and without gadolinium) must be done pre-operatively. Post-operatively, cranial MRI (with and without gadolinium) must be done.
• Lumbar Puncture (LP) CSF for cytopathology (strongly recommended but not mandatory; if medically feasible). A baseline LP CSF cytology either pre-operatively or post-operatively at least 10 days after definitive surgery for all patients if medically feasible (This is not mandatory and will not make the patient ineligible).
• Life expectancy: Patients must have a life expectancy of greater than 8 weeks from diagnosis.
• Performance level: Patients must have a performance status corresponding of a Lansky score ≥ 50.
• Organ Function Requirements: Participants must have normal organ and marrow function as defined below:
  • Adequate renal function defined as:
    • Creatinine clearance (12-24-hour urine collection) or radioisotope glomerular filtration rate (GFR) ≥ 60 ml/min/1.73m2
  • Adequate cardiac function defined as:
    • Shortening fraction of ≥ 27% by echocardiogram, or
    • Ejection fraction of ≥ 47% by radionuclide angiogram.
  • Adequate pulmonary function defined as:
    • No evidence of dyspnea at rest and a pulse oximetry > 94% on room air.
  • Adequate Bone Marrow Function defined as:
    • Peripheral absolute neutrophil count (ANC) > 1000/μL
    • Platelet Count > 100,000/μL (without transfusion for 3 days)
    • Hemoglobin greater than 8 gm/dL (may have received red blood cell (RBC) transfusions)
  • Adequate liver function defined as:
    • Total bilirubin ≤ 1.5X upper limit of normal (ULN) within normal institutional limits for age (patients with documented Gilbert's Disease may be enrolled with Study Chair approval and total bilirubin ≤ 2.0 × ULN)
    • Alanine Aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 100 U/L

Other inclusion and exclusion criteria may apply. 

Exclusion Criteria

• Patients who are receiving any other conventional anti-cancer agents or investigational agents.
• Patients who received previous therapy including radiotherapy or chemotherapy other than corticosteroids.
• Presence of another malignancy, except if the other primary malignancy is neither currently clinically significant nor requiring active intervention.
• Concomitant medications restrictions: Concurrent use of enzyme inducing anticonvulsants (e.g. phenytoin, phenobarbital, and carbamazepine), selected strong inhibitors of cytochrome P450 3A4 include azole antifungals, such as fluconazole, voriconazole, itraconazole, ketoconazole, and strong inducers include drugs such as rifampin, phenytoin, phenobarbitol, carbamazepine, and St. John's wort or CYP450 3A4 stimulators or inhibitors.
• Other uncontrollable medical disease: Patient has a severe and uncontrollable medical disease (i.e., uncontrolled diabetes, hyperglycemia, chronic renal disease or active uncontrolled infection), has chronic liver disease (i.e., chronic active hepatitis and cirrhosis), hypercholesterolemia (serum cholesterol >300 mg/dL), intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, active hyperparathyroidism, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients who have a known diagnosis of human immunodeficiency virus (HIV) infection, hepatitis B or C.
• Ineligible diagnoses for study entry by neuropathology: This includes sonic hedgehog (SHH) and wingless (WNT) MBs, all ependymomas, all choroid plexus carcinomas, all high grade glial and glio-neuronal tumors, all diffuse midline gliomas, all primary CNS germ cell tumors, all primary CNS sarcomas, all primary or metastatic CNS lymphomas and solid leukemic lesions (chloromas, granulocytic sarcomas).
• The participant or parent(s)/guardian(s) cannot comply with the study visit schedule and other protocol requirements, in the investigator's opinion.

Other inclusion and exclusion criteria may apply. 

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Study Description

This phase III trial compares the effect of vinorelbine with vincristine, dactinomycin, and cyclophosphamide (VAC) followed by vinorelbine and cyclophosphamide versus VAC followed by vinorelbine and cyclophosphamide for the treatment of high risk rhabdomyosarcoma. Chemotherapy drugs, such as vinorelbine, vincristine, dactinomycin, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving vinorelbine and VAC may kill more tumor cells. Adding maintenance therapy (vinorelbine and cyclophosphamide) after VAC therapy, with or without vinorelbine, may help get rid of the cancer and/or lower the chance that the cancer comes back.

PRIMARY OBJECTIVE:

I. To compare event-free survival (EFS) of patients with high-risk rhabdomyosarcoma (HR-RMS) treated with vinorelbine, dactinomycin and cyclophosphamide (VINO AC) followed by 24 weeks of vinorelbine and oral cyclophosphamide (VINO-CPO) maintenance therapy to that of patients treated with vincristine, dactinomycin and cyclophosphamide (VAC) followed by 24 weeks of VINO-CPO maintenance therapy.

SECONDARY OBJECTIVES:

I. To assess the safety and feasibility of administering VINO-AC in newly diagnosed patients with HR-RMS.

II. To describe the toxicity experience of patients with HR-RMS treated with VINO-AC compared to VAC.

III. To compare overall survival (OS) of patients with HR-RMS treated with VINO AC followed by 24 weeks of VINO-CPO maintenance therapy to that of patients treated with VAC followed by 24 weeks of VINO-CPO maintenance therapy.

IV. To compare objective radiologic response rates at week 12 between patients with HR-RMS treated with VINO-AC to those treated with VAC.

V. To determine whether the addition of 24 weeks of VINO-CPO maintenance therapy improves EFS in patients with HR-RMS when compared to historical controls.

EXPLORATORY OBJECTIVE:

I. To collect serial blood samples and tumor tissue for banking at baseline, during treatment, at the end of therapy, and at the time of progression for future tumor and liquid biopsy studies.

OUTLINE: Patients are randomized to 1 of 2 arms.

• ARM A: Patients receive vincristine sulfate intravenously (IV) on days 1, 8 and 15 of cycles 1-4, 7, 8, 11, and 12, and day 1 of cycles 6, 9, 10, 13, and 14. Patients also receive dactinomycin IV over 1-15 minutes on day 1 of cycles 1-5 and 8-14, and cyclophosphamide IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on weeks 13 and 40.
• ARM B: Patients receive vinorelbine tartrate IV over 6-10 minutes on days 1 and 8, vincristine sulfate IV on day 15, dactinomycin IV over 1-15 minutes on day 1 of cycles 1-5 and 8-14, and cyclophosphamide IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on weeks 13 and 40.

MAINTENANCE: All patients receive vinorelbine tartrate IV over 6-10 minutes on days 1, 8, and 15, and cyclophosphamide orally (PO) on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for year 1, every 4 months for years 2-3, and every 6 months for year 4.

Inclusion Criteria

• Patients must be =< 50 years of age at the time of enrollment
• Patients with newly diagnosed RMS of any subtype, except adult-type pleomorphic, based upon institutional histopathologic classification are eligible to enroll on the study based upon Stage, Group, and age, as below. FOXO1 fusion status must be determined by week 4 (day 28) of therapy. RMS types included under embryonal RMS (ERMS) include those classified in the 1995 International Classification of Rhabdomyosarcoma (ICR) as ERMS (classic, spindle cell, and botryoid variants), which are reclassified in the 2020 World Health Organization (WHO) Classification as ERMS (classic, dense and botryoid variants) and spindle cell/sclerosing RMS (encompassing the historical spindle cell ERMS variant and the newly recognized sclerosing RMS variant). Classification of alveolar RMS (ARMS) in the 2020 WHO Classification is the same as in the ICR and includes classic and solid variants
  • ERMS
    • Stage 4, group IV, >= 10 years of age
  • ARMS
    • Stage 4, group IV Patients will be eligible to remain on protocol therapy based upon stage, group, and age
• Bone marrow metastatic disease is based on morphologic evidence of RMS based on hematoxylin and eosin (H&E) stains. In the absence of morphologic evidence of marrow involvement on H&E, patients with bone marrow involvement detected ONLY by flow cytometry, reverse transcriptase (RT)-polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), or immunohistochemistry will NOT be considered to have clinical bone marrow involvement for the purposes of this study
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
  • Age; Maximum serum creatinine (mg/dL)
  • 1 month to < 6 months; 0.4 mg/dL (male); 0.4 mg/dL (female)
  • 6 months to < 1 year; 0.5 mg/dL (male); 0.5 mg/dL (female)
  • 1 to < 2 years; 0.6 mg/dL (male); 0.6 mg/dL (female)
  • 2 to < 6 years; 0.8 mg/dL (male); 0.8 mg/dL (female)
  • 6 to < 10 years; 1 mg/dL (male); 1 mg/dL (female)
  • 10 to < 13 years; 1.2 mg/dL (male); 1.2 mg/dL (female)
  • 13 to < 16 years; 1.5 mg/dL (male); 1.4 mg/dL (female)
  • >= 16 years; 1.7 mg/dL (male); 1.4 mg/dL (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
  • If there is evidence of biliary obstruction by tumor, then total bilirubin must be < 3 x ULN for age
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Additional inclusion and exclusion criteria may apply 

Exclusion Criteria

• Patients with evidence of uncontrolled infection are not eligible
• RMS that is considered a second malignancy and previous cancer(s) that were treated with chemotherapy and/or radiation. Surgical resection alone of previous cancer(s) is allowed
• Patients with central nervous system involvement of RMS as defined below:
  • Malignant cells detected in cerebrospinal fluid
  • Intra-parenchymal brain metastasis separate and distinct from primary tumor (i.e., direct extension from parameningeal primary tumors is allowed).
  • Diffuse leptomeningeal disease
• Patients who have received any chemotherapy (excluding steroids) and/or radiation therapy for RMS prior to enrollment.
  • Note: the following exception:
    • Patients requiring emergency radiation therapy for RMS. These patients are eligible, provided they are consented to ARST2031 prior to administration of radiation
  • Note: Patients who have received or are receiving chemotherapy or radiation for non-malignant conditions (e.g. autoimmune diseases) are eligible. Patients must discontinue chemotherapy for non-malignant conditions prior to starting protocol therapy
• Vincristine and vinorelbine are sensitive substrates of CYP450 3A4 isozyme. Patients must not have received drugs that are moderate to strong CYP3A4 inhibitors and inducers within 7 days prior to study enrollment
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation

Additional inclusion and exclusion criteria may apply 

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Study Description

Brief Summary:

This partially randomized phase II/III trial studies how well, in combination with surgery, cisplatin and combination chemotherapy works in treating children and young adults with hepatoblastoma or hepatocellular carcinoma. Drugs used in chemotherapy, such as cisplatin, doxorubicin, fluorouracil, vincristine sulfate, carboplatin, etoposide, irinotecan, sorafenib, gemcitabine and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving combination chemotherapy may kill more tumor cells than one type of chemotherapy alone.

Detailed Description:

PRIMARY OBJECTIVES:

I. To reduce therapy associated toxicity for patients with non-metastatic hepatoblastoma (HB) and hepatocellular carcinoma (HCC) without adversely affecting long term outcomes.

II. To determine the event-free survival (EFS) in patients with HB whose tumor is completely resected at diagnosis and either receive no adjuvant chemotherapy (completely resected well differentiated fetal [WDF] histology HB) or 2 cycles of standard dose cisplatin monotherapy (completely resected non-well differentiated fetal histology HB - 100 mg/m^2/cycle given 3 weeks apart). (Group A) III. To demonstrate that 4 to 6 cycles of interval compressed lower dose cisplatin monotherapy (80 mg/m^2/cycle; 320-480 mg/m^2 total) is adequate for low risk HB. (Group B) IIIa. In patients who are resected after 2 cycles of cisplatin monotherapy, to compare EFS following a randomized comparison of 2 versus 4 post-operative cycles of cisplatin monotherapy. (Group B) IIIb. In patients whose tumors are deemed unresectable after 2 cycles of cisplatin monotherapy, to determine the proportion of tumors rendered completely resectable by an additional 2 or 4 cycles of chemotherapy. (Group B) IV. To compare in a randomized fashion, EFS in patients with intermediate risk HB treated with 6 cycles of cisplatin/5-fluorouracil/vincristine/doxorubicin (C5VD) chemotherapy versus 6 cycles of interval compressed cisplatin monotherapy (100 mg/m^2/dose). (Group C) V. To determine the EFS in patients with HCC whose tumor is completely resected at diagnosis who receive no adjuvant chemotherapy (completely resected HCC arising in the context of underlying liver disease) or 4 cycles of cisplatin/doxorubicin (PLADO) (completely resected de novo HCC). (Group E) VI. To improve the EFS of patients with high risk HB by treating them with interval compressed cisplatin and doxorubicin based induction regimen followed by response-adapted consolidation therapy. (Group D) VIa. In patients whose metastatic disease resolves with the administration of Societe Internationale d'Oncologie Pediatrique (SIOPEL) 4 Induction therapy, to determine if the promising pilot results observed in SIOPEL 4 can be validated in a large international study. (Group D1) VIb. In patients whose metastatic disease does not resolve with the administration of SIOPEL 4 Induction therapy, to determine in a randomized comparison which post induction treatment (irinotecan and vincristine sulfate [vincristine] alternating with carboplatin and doxorubicin or carboplatin and etoposide alternating with carboplatin and doxorubicin) results in superior outcomes. (Group D Arm CE & Arm VI) VII. In patients with unresectable/metastatic HCC at diagnosis, to determine whether the addition of gemcitabine and oxaliplatin (GEMOX + sorafenib) to a cisplatin, doxorubicin and sorafenib backbone improves chemotherapy response, resectability and survival. (Group F)

EXPLORATORY OBJECTIVES:

I. To determine if the Childhood Hepatic tumor International Consortium (CHIC) hepatoblastoma risk stratification analysis of very low risk (Group A), low risk (Group B), intermediate risk (Group C) and high risk (Group D) groups stratifies patients allowing appropriate utilization of varying intensity chemotherapy regimens and surgical resection strategies.

II. To define the prognostic relevance of a positive microscopic margin in Group A-D resected HB specimens.

III. To define the frequency of histologically detectable multifocal lesions in liver explants and resected specimens in which multifocal disease was detected at diagnosis and disappeared on cross sectional imaging following treatment with chemotherapy.

IV. To define the prognostic relevance in HB of a 'small cell undifferentiated' tumor component and percentage of tumor necrosis in post chemotherapy specimens.

V. To determine the prognostic impact on EFS and overall survival (OS) of biopsy technique in liver tumors unresectable at diagnosis.

VI. To determine the 3-year EFS and OS of HB patients who undergo liver transplantation vs extreme resection in Group C and D patients.

VII. To determine the 3-year EFS and OS of Group D patients who undergo pulmonary metastasectomy.

VIII. To determine the 3-year EFS and OS of patients who undergo liver transplantation for HCC.

IX. To determine the frequency of relapse in non-metastatic HCC in children treated by liver transplantation versus conventional resection.

X. To determine the concordance of Pretreatment Extent of Disease (PRETEXT) and Post-treatment Extent of disease (POSTTEXT) based surgical guidelines and the surgical intervention performed.

XI. To collect for future analysis, HB and HCC tumor specimens that can be molecularly characterized to validate newly identified molecular and immunohistochemical biomarkers correlating with known clinical prognostic factors and outcome.

XII. To evaluate the hepatoblastoma molecular risk-predictive model (HB-MRP) to risk stratify hepatoblastoma patients in the context of the current AHEP1531 trial.

XIII. To collect for future analysis samples to assess the pharmacogenomics (PG) related to cisplatin therapy in pediatric and adolescent liver tumor patients and correlate PG with Boston Grading Scale for ototoxicity.

XIV. To collect for future analysis samples such that novel biomarkers of renal toxicity (urine neutrophil gelatinase-associated lipocalin [NGAL], cystatin C and Kim1) from cisplatin therapy can be correlated with pharmacogenomics, other associated toxicities, and outcomes.

XV. To determine which system (Children's Oncology Group [COG] PRETEXT, SIOPEL PRETEXT, or a new hybrid definition of PRETEXT) of the annotation factors for V, P, E, F and R provides the best prognostic information for determining response to chemotherapy, guiding risk based therapy, predicting surgical resectability, and EFS.

XVI. To determine the concordance between institutional and expert panel review assessment of PRETEXT and POSTTEXT stage in an international cooperative group setting.

OUTLINE:

GROUP A (VERY LOW RISK HB): Patients are assigned to 1 of 2 groups.

GROUP A1 (WDF): Patients undergo observation.

GROUP A2 (NON-WDF): Patients receive cisplatin (CDDP) intravenously (IV) over 6 hours on day 1 following surgery. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

GROUP B (LOW RISK HB): Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients are then assigned to 1 of 2 groups

GROUP B1 (RESECTABLE): Patients receive 2 cycles of cisplatin, undergo surgery, then are randomized to 1 of 2 arms (2 vs 4 additional cycles of cisplatin).

GROUP B1 ARM 4-CDDP: Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 4 total cycles (2 pre-surgery, 2 post-surgery) in the absence of disease progression or unacceptable toxicity.

GROUP B1 ARM 6-CDDP: Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 total cycles(2 pre-surgery, 4 post-surgery) in the absence of disease progression or unacceptable toxicity.

GROUP B2 (UNRESECTABLE): Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 total cycles (4 pre-surgery, 2 post-surgery). Patients with resectable tumors undergo surgery, then all patients continue with 2 additional cycles of cisplatin.

GROUP C (INTERMEDIATE RISK HB): Patients are randomized to 1 of 2 arms.

GROUP C ARM CDDP: Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after cycle 2 or 4.

GROUP C ARM C5VD: Patients receive cisplatin IV over 6 hours on day 1, 5-fluorouracil IV over 1-15 minutes, vincristine sulfate IV over 1 minute on days 1, 8, and 15 and doxorubicin IV over 1-15 minutes on days 1 and 2. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after cycle 2 or 4.

GROUP D (HIGH RISK HB): SIOPEL-4 IV INDUCTION: Patients receive cisplatin IV over 6 hours on days 1, 8, and 15 (for cycles 1 and 2) and days 1 and 8 (for cycle 3) and doxorubicin IV over 1-15 minutes on days 8 and 9 (for cycles 1 and 2) and days 1 and 2 (for cycle 3). Cycles 1 and 2 are 28 days; cycle 3 is 21 days. Patients are then assigned to 1 of 2 arms.

GROUP D1: CONSOLIDATION THERAPY: Patients with lung complete remission (either with chemotherapy and/or surgery) receive carboplatin IV over 1 hour on day 1 and doxorubicin IV over 1-15 minutes on days 1 and 2. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity.

GROUP D2: Patients with residual metastatic disease are randomized to 1 of 2 arms.

GROUP D2 ARM CE: Patients receive carboplatin IV over 1 hour on days 1 and 2, doxorubicin IV over 1-15 minutes on days 1 and 2 during cycles 1, 3 and 5, and carboplatin IV over 1 hour and etoposide IV over 2 hours on day 1 and 2 of cycles 2, 4 and 6. Treatments repeat every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

GROUP D2 ARM VI: Patients receive carboplatin IV over 1 hour on days 1 and 2 and doxorubicin IV over 1-15 minutes on days 1 and 2 during cycles 1, 3 and 5. Patients also receive vincristine sulfate IV over 1 minute on days 1 and 8 and irinotecan IV over 60-90 minutes once daily (QD) on days 1 to 5 of cycles 2, 4 and 6. Treatments repeat every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

GROUP E (RESECTED HCC): Patients are assigned to 1 of 2 groups.

GROUP E1: Patients with HCC secondary to underlying hepatic disease undergo observation only.

GROUP E2 (PLADO): Patients with de novo HCC receive cisplatin IV over 6 hours on day 1 and doxorubicin IV over 1-15 minutes on days 1 and 2 following surgery. Treatments repeat every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

GROUP F (UNRESECTED AND/OR METASTATIC HCC): Patients are randomized to 1 of 2 arms.

GROUP F ARM 1 (PLADO): Patients receive cisplatin IV over 6 hours on day 1, doxorubicin IV over 1-15 minutes on days 1 and 2 and sorafenib orally (PO) twice daily (BID) on days 3-21. Treatments repeat every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients may undergo surgery, if tumors are resectable, or receive an additional 3 cycles of the treatment.

GROUP F ARM 2 (P/GEMOX): Patients receive cisplatin IV over 6 hours on day 1, doxorubicin IV over 1-15 minutes on days 1 and 2 and sorafenib PO BID on days 3-14 of cycles 1 and 3. Patients also receive gemcitabine IV over 90 minutes on day 1, oxaliplatin IV over 2 hours on day 1 and sorafenib PO on days 1-14 of cycles 2 and 4. Patients may undergo surgery, if tumors are resectable, or receive an additional 4 cycles of the treatment.

After completion of study treatment, patients are followed up for a minimum of 2 years.

Inclusion Criteria

• Patients in Group F must have a body surface area (BSA) >= 0.6 m^2
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Patients must be newly diagnosed with histologically-proven primary pediatric hepatic malignancies including hepatoblastoma or hepatocellular carcinoma, except as noted below; patients with a diagnosis of hepatocellular neoplasm, not otherwise specified, should be classified and treated per hepatoblastoma treatment arms; note that rapid central pathology review is required in some cases; please note: all patients with histology as assessed by the institutional pathologist consistent with pure small cell undifferentiated (SCU) HB will be required to have testing for INI1/SMARCB1 by immunohistochemistry (IHC) according to the practices at the institution
• Patients with histology consistent with pure SCU must have positive INI1/SMARCB1 staining

• For all Group A patients, WDF status as determined by rapid review will be used to further stratify patients to Group A1 or A2

  • For Groups B, C and D, rapid review is required if patients are either >= 8 years of age or have an alphafetoprotein (AFP) =< 100 at diagnosis
  • For all Groups E and F patients, rapid central pathology review is required

• In emergency situations when a patient meets all other eligibility criteria and has had baseline required observations, but is too ill to undergo a biopsy safely, the patient may be enrolled without a biopsy

  • Clinical situations in which emergent treatment may be indicated include, but are not limited to, the following circumstances:

    • Anatomic or mechanical compromise of critical organ function by tumor (e.g., respiratory distress/failure, abdominal compartment syndrome, urinary obstruction, etc.)
    • Uncorrectable coagulopathy

  • For a patient to maintain eligibility for AHEP1531 when emergent treatment is given, the following must occur:

    • The patient must have a clinical diagnosis of hepatoblastoma, including an elevated alphafetoprotein (AFP), and must meet all AHEP1531 eligibility criteria at the time of emergent treatment
    • Patient must be enrolled on AHEP1531 prior to initiating protocol therapy; a patient will be ineligible if any chemotherapy is administered prior to AHEP1531 enrollment
  • Note: If the patient receives AHEP1531 chemotherapy emergently PRIOR to undergoing a diagnostic biopsy, pathologic review of material obtained in the future during either biopsy or surgical resection must either confirm the diagnosis of hepatoblastoma or not reveal another pathological diagnosis to be included in the analysis of the study aims
• Patients may have had surgical resection of the hepatic malignancy prior to enrollment; all other anti-cancer therapy for the current liver lesion is prohibited

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 or

  • A serum creatinine based on age/gender as follows:

    • Age: maximum serum creatinine (mg/dL)
    • 1 month to < 6 months: 0.4 (male and female)
    • 6 months to < 1 year: 0.5 (male and female)
    • 1 to < 2 years: 06 (male and female)
    • 2 to < 6 years: 0.8 (male and female)
    • 6 to < 10 years: 1 (male and female)
    • 10 to < 13 years: 1.2 (male and female)
    • 13 to < 16 years: 1.5 (male), 1.4 (female)
    • >= 16 years: 1.7 (male), 1.4 (female)
• Total bilirubin =< 5 x upper limit of normal (ULN) for age
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 10 x upper limit of normal (ULN) for age
• Shortening fraction of >= 28% by echocardiogram (for patients on doxorubicin-containing regimens [Groups C, D, E2, and F] assessed within 8 weeks prior to study enrollment) or
• Ejection fraction of >= 47% by echocardiogram or radionuclide angiogram (for patients on doxorubicin-containing regimens [Groups C, D, E2, and F] assessed within 8 weeks prior to study enrollment)
• Group F patients only: QT/corrected QT (QTc) interval =< 450 milliseconds for males and =< 470 milliseconds for females (assessed within 8 weeks prior to study enrollment)
• Normal pulmonary function tests (including diffusion capacity of the lung for carbon monoxide [DLCO]) if there is clinical indication for determination (e.g. dyspnea at rest, known requirement for supplemental oxygen) (for patients receiving chemotherapy [Groups A, B, C, D, E2, F]); for patients who do not have respiratory symptoms or requirement for supplemental oxygen, pulmonary function tests (PFTs) are NOT required
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria

• Prior chemotherapy or tumor directed therapy (i.e. radiation therapy, biologic agents, local therapy (embolization, radiofrequency ablation, and laser); therefore, patients with a pre-disposition syndrome who have a prior malignancy are not eligible
• Patients who are currently receiving another investigational drug
• Patients who are currently receiving other anticancer agents
• Patients with uncontrolled infection
• Patients who previously received a solid organ transplant, other than those who previously received an orthotopic liver transplantation (OLT) as primary treatment of their hepatocellular carcinoma
• Patients with hypersensitivity to any drugs on their expected treatment arm
• Group C: Patients who have known deficiency of dihydropyrimidine dehydrogenase (DPD)

• Group D:

  • Patients with chronic inflammatory bowel disease and/or bowel obstruction
  • Patients with concomitant use of St. John's wort, which cannot be stopped prior to the start of trial treatment

• Group F:

  • Patients with peripheral sensitive neuropathy with functional impairment
  • Patients with a personal or family history of congenital long QT syndrome

• These criteria apply ONLY to patients who may receive chemotherapy (all groups other than Group E1):

  • Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs; a pregnancy test is required for female patients of childbearing potential
  • Lactating females who plan to breastfeed their infants

  • Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation

    • Note for Group F: patients of childbearing potential should use effective birth control during treatment with sorafenib and for at least 2 weeks after stopping treatment

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Centres

Study Description

 This study is eligible for STEP-1 funding. Find more information here. 

Both Australia (Zero Childhood Cancer) and Canada (PROFYLE) have developed precision oncology programs for the pediatric population through which samples from childhood/adolescent cancers undergo in depth genetic profiling. OPTIMISE is a companion platform trial, which will link patients to novel targeted agents based on their tumor profile. The trial will have multiple basket arms based on the most common genetically altered pathways the investigators have identified in these childhood cancers. Each arm of the trial will be histopathology agnostic and test a rational, novel combination therapy, to maximise potential clinical benefit.

The information below is for Treatment Arm A which will be combining, for the first time, paxalisib with conventional chemotherapy in paediatric patients with high-risk malignancies.

Inclusion Criteria

• Patients must be diagnosed with a solid tumor, CNS tumor or lymphoma that has progressed despite standard therapy, or for which no effective standard therapy exists.
• Age <21 years at inclusion; patients 21 years and older may be included after approval by the Study Chair if they have a pediatric type recurrent/refractory malignancy.
• Patients must be enrolled on a precision medicine study (i.e. PROFYLE, ZERO or equivalent as agreed with Study Chair.
  • Tumour profiling should be performed as close to the time of study enrolment as possible; at a minimum profiling should have been performed on a sample obtained within 12 months prior to enrolment, or had confirmation that the targeted molecular aberration is still present from a tumour sample collected within the 12 months prior to enrolment. Patients for whom tumour profiling has been performed outside this window may only be enrolled after approval by the Study Chairs.
• Patients are eligible to enrol using existing sequencing results or other criteria such as immunohistochemistry (provided a report from a CLIA‐approved or equivalent laboratory is provided), but concurrent enrolment on a precision medicine study is still required.  
• Patients enrolled in a Phase I cohort must have either evaluable or measurable disease.
• Patients enrolled in a Phase II cohort must have measurable disease. Evaluable and measurable disease are defined by standard imaging criteria (RECIST V1.1, RAPNO or RANO) for the patient's tumor type.
• Disease evaluations, laboratory tests, and other clinical assessments that are considered standard of care may be undertaken at the patient's local oncology treatment centre with results transferred to study site for evaluation.
• Performance status: Karnofsky performance status (for patients > 16 years of age) or Lansky play score (for patients ≤ 16 years of age) ≥ 50%.
• Life expectancy ≥ 6 weeks.
• Patients must have fully recovered from the acute toxic effects of all prior anticancer therapy and must meet the following minimum duration from prior anticancer-directed therapy prior to enrolment.
• Adequate organ function.
  • Haematologic criteria:
    • Peripheral absolute neutrophil count (ANC) ≥1.0 x 109/L (unsupported) (i.e. at least 7 days post filgrastim; at least 14 days post PEG‐filgrastim (if administered)).
    • Platelet count ≥75 x 109/L (unsupported; defined as no platelet transfusions within prior 7 days).
    • Haemoglobin ≥80 g/L (transfusion is allowed).
  • Renal and hepatic function:
    • Serum creatinine ≤1.5 x upper limit of normal (ULN) for age
    • Total bilirubin ≤1.5 x ULN
    • Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤5 x ULN except in patients with documented tumour involvement of the liver who must have AST and ALT ≤10 x ULN
• Able to comply with scheduled follow-up and with management of toxicity.
• Females of childbearing potential must have a negative serum or urine pregnancy test.
• Fertile males must agree to use adequate contraception during the study and following completion of treatment.
• Provide a signed and dated informed consent form.

Additional Inclusion Criteria for Arm A

• For Cohort A1: Patients must have evaluable or measurable disease.
• For Cohort A2, Molecularly selected: Tumour must have a demonstrated pathogenic/likely pathogenic mutation in the PI3K/AKT/mTOR pathway from tumour DNA analysis, including:
  • Loss of function (LoF) in tumour suppressor genes or genes that normally act to downregulate the PI3K/AKT/mTOR pathway (PTEN, PIK3R1, TSC1, TSC2, DEPTOR)
    [Rationale: LoF variants involving these genes can lead to increased signalling of the PI3K/AKT/mTOR pathway. This includes single nucleotide variants (SNV), copy number 
    loss and structural variants (SV) leading to disruption of normal gene function.]
  • Gain of function (GoF) variants in oncogenes or genes that normally lead to upregulation of the PI3K/AKT/mTOR pathway.

• Cohort A3, Expanded drug-selection: Patients will be eligible if they have a demonstrated PI3K/AKT/mTOR pathway aberration in tumour from RNA expression analysis or proteomic analysis which would be predicted to benefit from PI3K/AKT/mTOR inhibition after discussion with the Arm A Study Chair, or demonstrated individual tumour sensitivity to a drug acting on this pathway through pre-clinical studies (in vitro and/or in vivo studies, which may include high-throughput drug screen and/or patient derived xenografts (PDX) and/or neurospheres). Patients with pathogenic/likely pathogenic mutation in relevant genes not meeting criteria for Cohort A2 will also be eligible.
• For Cohorts A2 and A3: Measurable disease as per RECIST, RAPNO or RECIL criteria. Patients with neuroblastoma will also be eligible if they have disease that is only evaluable by MIBG.
• For all Cohorts: Adequate cardiac function defined as
  • Shortening fraction of ≥27% by echocardiogram, or ejection fraction of ≥50% by gated 
    radionuclide study (MUGA); and
  • QTC <480 msec by the Fridericia formula.

Other inclusion or exclusion criteria may apply. 

Exclusion Criteria

• Patients with symptomatic CNS primary or metastatic tumors who are neurologically unstable or require increasing doses of corticosteroids or local CNS-directed therapy to control their CNS disease.
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter drug absorption of oral drugs.
• Clinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality), unstable ischemia, congestive heart failure within 12 months of screening.
• Known active viral hepatitis or human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
• Presence of any ≥Grade 2 treatment-related toxicity with the exception of alopecia, ototoxicity, lymphopenia or clinically stable peripheral neuropathy
• Major surgery within 21 days of the first dose of investigational drug.
• Known hypersensitivity to any study drug or component of the formulation.
• Pregnant or nursing (lactating) females.
• Any other concomitant serious medical condition or organ dysfunction that in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the investigational drugs.

Additional Exclusion Criteria for Arm A:

Exclusion criteria for all Cohorts:

• Patients with significant uncontrolled hyperglycaemia that in the opinion of the investigator would compromise patient safety.
• Diabetic participants who require insulin therapy.
• Patients with active pneumonitis that is clinically symptomatic. 
• Patients with a history of myocardial infarction or coronary artery disease

Other inclusion or exclusion criteria may apply. 

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Study Description

In this study subjects will receive 730 Days of oral difluoromethylornithine (DFMO) at a dose of 2500 mg/m2 BID on each day of study.

Subjects will be evaluated in 3 Cohorts:

Cohort 1: Molecular High Risk Medulloblastoma

Cohort 2: Molecular Very High Risk Medulloblastoma

Cohort 3: Relapsed/Refractory Medulloblastoma

A total of 118 subjects across all cohorts will be enrolled to ensure that there will be 107 evaluable subjects (32-39 per cohort)

Inclusion Criteria

• Age: 0-21 years of age at diagnosis
• Pathology All patients must either have a pathologically confirmed diagnosis of medulloblastoma with molecular grouping identified by either Nanostring or methylation profiling.
  • Cohort 1- Molecular High Risk:
    • Metastatic non-MYC amplified Group 3
    • Metastatic Group 4
    • Metastatic non-WNT/non-SHH (Must be non-MYC amplified)
  • Cohort 2- Molecular Very High Risk
    • Metastatic OR MYCN amplified OR TP53 mutant non-infant (>3 yrs) SHH
    • MYC amplified Group 3
    • Non-WNT, non-SHH infant (< 3 yrs)
  • Cohort 3: Relapsed/Refractory Medulloblastoma
• Pre-enrollment tumor survey:
  • Prior to enrollment on this study, a determination of mandatory disease staging must be performed:
    • Tumor imaging studies including: Brain and spine MRI
    • Lumbar Puncture only if previously positive
    • Bone Marrow aspiration/biopsy only if previously positive
    • This disease assessment is required for eligibility and preferably should be done within 2 weeks prior to first dose of study drug, but must be done within a maximum of 4 weeks before first dose of study drug.
• Disease Status: Subjects must have no evidence of disease, or stable* residual nonbulky** disease.
  • *Stable residual disease defined as non-progression over 2 separate imaging studies at least 6 weeks apart
  • **Non-bulky disease defined as maximal cross-sectional area < 3cm^2 at enrollment. Patients with leptomeningeal disease are allowed to participate on study.
• Timing from prior therapy: Enrollment (first dose of DFMO) no later than 60 days after last dose of conventional chemotherapy. Patients who have undergone high dose chemotherapy (HDCT) with autologous stem cell transplantation (SCT) are eligible if more than 45 days have elapsed since date of last SCT.
• Patients must have a Lansky or Karnofsky Performance Scale score of ≥ 50% (see Appendix II) and patients must have a life expectancy of ≥ 2 months.
• All clinical and laboratory studies for organ functions to determine eligibility must be performed within 7 days prior to first dose of study drug unless otherwise indicated below.
• Patients must have adequate organ functions at the time of registration:
  • Hematological: Hematological recovery as defined by ANC ≥750/μL, platelets ≥30 (non-transfused x 7 days)
  • Liver: Adequate liver function as defined by AST and ALT <10x upper limit of normal
  • Renal: Adequate renal function defined as (perform one of the following): Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2 or a serum creatinine based on age/gender
• Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding.
• Written informed consent in accordance with institutional and FDA guidelines must be obtained from all subjects (or patients' legal representative).

Additional inclusion and exclusion criteria may apply and will be discussed with you by the study team. 

Exclusion Criteria

• BSA of <0.25 m2
• Metastatic disease outside of CNS
• Relapsed/refractory patients who are radiation-naïve and age 5 years or older at time of enrollment
• Investigational Drugs: Subjects who are currently receiving another investigational drug are excluded from participation.
• Anti-cancer Agents: Subjects who are currently receiving other anticancer agents are not eligible. Subjects must have fully recovered from the hematological and bone marrow suppression effects of prior chemotherapy.
• Infection: Subjects who have an uncontrolled infection are not eligible until the infection is judged to be well controlled in the opinion of the investigator.
• Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study, or in whom compliance is likely to be suboptimal, should be excluded.

Additional inclusion and exclusion criteria may apply and will be discussed with you by the study team. 

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Study Description

Brief Summary:

Difluoromethylornithine (DFMO) will be used in an open label, multicenter, study in combination with etoposide for subjects with relapsed/refractory neuroblastoma.

Detailed Description:

Difluoromethylornithine (DFMO) will be used in an open label, multicenter, study in combination with etoposide for subjects with relapsed/refractory neuroblastoma.

In this study subjects will receive six 21-day cycles of Etoposide and DFMO followed by an additional 630 days of DFMO alone.

Subjects will be evaluated in 3 arms:

• Arm 1: Subjects who show no active disease after receiving any additional therapy for neuroblastoma that was refractory to standard induction/consolidation therapy.

Refractory: Subjects with progressive disease on upfront therapy OR did not have at least PR on induction OR required additional second line therapy to achieve remission who are now in first remission.

• Arm 2: Subjects who have previously relapsed and currently show no active disease (in CR2 or greater).
• Arm 3: Subjects who are relapsed or refractory with active disease.

Inclusion Criteria

• All patients must have a pathologically confirmed diagnosis of neuroblastoma, ≤ 30.99 years of age with history of relapsed/refractory neuroblastoma.
• All patients must have completed upfront therapy with at least 4 cycles of aggressive multi-drug chemotherapy.
• Specific Criteria by Arm:

Arms 1 and 2:

Subjects with no active disease:

i. No evidence of residual disease by CT/MRI and MIBG scan (or PET for patients who have a history of MIBG non-avid disease).

o Note: Patients with residual masses detected by CT/MRI may be considered in CR if their MIBG is negative or if MIBG positive and evaluated by PET and found to have negative PET scans; biopsy confirmation may be considered if there is still reasonable concern for persistent disease but is not required.

ii. No evidence of disease metastatic to bone marrow.

Arm 3:

Measurable or evaluable disease, including at least one of the following:

Measurable tumor by CT or MRI; or a positive MIBG and PET; or positive bone marrow biopsy/aspirate in at least one site.

• Timing from prior therapy: Enrollment (first dose of DFMO) no later than 60 days from last dose of the most recent therapy.

• Subjects must have fully recovered from the acute toxic effects of all prior anti- cancer chemotherapy and be within the following timelines:

  1. Myelosuppressive chemotherapy: Must not have received within 2 weeks of enrollment onto this study (6 weeks if prior nitrosourea).
  2. Hematopoietic growth factors: At least 5 days since the completion of therapy with a growth factor.
  3. Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the Study Chair.
  4. Immunotherapy: At least 6 weeks since the completion of any type of immunotherapy, e.g. tumor vaccines, CAR-T cells.
  5. Anti-GD2 Monoclonal antibodies: At least 2 weeks must have elapsed since prior treatment with a monoclonal antibody.
  6. XRT: At least 14 days since the last treatment except for radiation delivered with palliative intent to a non-target site.

  7. Stem Cell Transplant:

     1. Allogeneic: No evidence of active graft vs. host disease
     2. Allo/Auto: ≥ 2 months must have elapsed since transplant.
  8. MIBG Therapy: At least 8 weeks since treatment with MIBG therapy
• Subjects must have a Lansky or Karnofsky Performance Scale score of 60% or higher.
• Life expectancy > 2 months
• All clinical and laboratory studies for organ functions to determine eligibility must be performed within 7 days prior to first dose of study drug unless otherwise indicated below.

• Subjects must have adequate organ functions at the time of registration:

  • Hematological: Total absolute neutrophil count ANC ≥750/μL
  • Liver: Subjects must have adequate liver function as defined by AST and ALT <5x upper limit of normal (Normal=45), Bilirubin <1.5x upper limit normal (Normal=1.0). Normal PT, PTT, fibrinogen.
  • Renal: Adequate renal function defined as (perform one of the following): Creatinine clearance or radioisotope GFR 70 mL/min/1.73 m2 or greater or a serum creatinine based on age/gender
• Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding.
• Written informed consent in accordance with institutional and FDA guidelines must be obtained from all subjects (or patients' legal representative).

Exclusion Criteria

• BSA of <0.25 m2.
• Subjects that received DFMO at a dose higher than 1000mg/m2 BID prior to this study are not eligible.
• Subjects that received a dose of DFMO in combination with etoposide are not eligible.
• Investigational Drugs: Subjects who are currently receiving another investigational drug are excluded from participation.
• Anti-cancer Agents: Subjects who are currently receiving other anticancer agents are not eligible. Subjects must have fully recovered from hematological and bone marrow suppression effects of prior chemotherapy.
• Infection: Subjects who have an uncontrolled infection are not eligible until the infection is judged to be well controlled in the opinion of the investigator.
• Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study, or in whom compliance is likely to be suboptimal, should be excluded.

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Study Description

This is a prospective, multicenter clinical trial in subjects with newly diagnosed high-risk neuroblastoma to evaluate the efficacy and safety of administering naxitamab with standard induction therapy.

All subjects will be followed for disease response, event free survival, overall survival and toxicity. Extent of disease will be measured and assessed for changes throughout the course of the study. All efficacy analyses will be performed on the evaluable population which will consist of all enrolled subjects (subjects who initiate treatment with naxitamab in combination with GM-CSF plus standard induction therapy) and who have measurable disease at baseline.

The initial chemotherapy Induction regimen will utilize sequential administration of 5 cycles of multi-agent chemotherapy. Naxitamab will be added to all 5 Induction cycles.

Subjects with an activating ALK mutation or ALK amplification will have ceritinib added to their treatment regimen as soon as results are available.

Stem cell mobilization and collection will occur after the 2nd cycle of induction.

Surgical resection of the primary tumor will ideally occur after the 4th cycle of Induction but may be delayed until after the 5th cycle of Induction if medically necessary.

Disease status evaluations will occur at the following time points: (1) pre-treatment, (2) post Cycle 2 Induction (3) Prior to surgical resection (if performed), (4) End of Induction (which includes surgery and 5 cycles of chemotherapy), and (5) End of Additional/Salvage Therapy as needed.

The current standard of care for high-risk neuroblastoma involves 5-7 cycles of induction chemotherapy with surgical removal of the tumor after 4-5 cycles of chemotherapy, followed by high-dose chemotherapy plus autologous stem cell transplant, then radiation to the primary tumor bed, followed by anti-GD2 immunotherapy and cis retinoic acid. This results in a less than 60% disease free survival for high-risk NB, a survival rate that still greatly needs improvement. Two areas in which improvements can be made include: 1) to improve response rate to induction chemotherapy and 2) to improve EFS by improving maintenance therapy to prevent relapse.

We hypothesize that the addition of anti-GD2 therapy to induction chemotherapy will result in improved end of induction responses and improved survival.

Inclusion Criteria

• Diagnosis: Subjects must have a diagnosis of neuroblastoma or ganglioneuroblastoma (nodular or intermixed) verified by histology or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites. Subjects with the following disease stages at diagnosis are eligible, if they meet the other specified criteria:

a) Subjects with newly diagnosed neuroblastoma with International Neuroblastoma Staging System (INSS) Stage 4 are eligible with the following: i. Age > 18 months (> 547 days) regardless of biologic features or ii. Age 12-18 months (365-547 days) with any of the following 3 unfavorable biologic features (MYCN amplification, unfavorable pathology and/or DNA index = 1) or iii. MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features.

b) Subjects with newly diagnosed neuroblastoma with INSS Stage 3 are eligible with the following: i. MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features or ii. Age > 18 months (> 547 days) with unfavorable pathology, regardless of MYCN status.

c) Subjects with newly diagnosed neuroblastoma with INSS Stage 2A/2B with MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features.

• Subjects must be age ≤ 21 years at initial diagnosis
• Subjects must be >12 months of age at enrollment
• Ability to tolerate Peripheral blood stem cell (PBSC) collection: No known contraindication to PBSC collection. Examples of contraindications would include a weight or size less than that determined to be feasible at the collecting institution, or a physical condition that would limit the ability of the child to undergo apheresis catheter placement (if necessary) and/or the apheresis procedure.
• Adequate Cardiac Function Defined As:
  • Shortening fraction of ≥ 27% by echocardiogram, or
  • Ejection fraction of ≥ 50% by radionuclide evaluation or echocardiogram.
• Adequate liver function must be demonstrated, defined as:
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age AND
  • ALT (SGPT) < 5 x upper limit of normal (ULN) for age
• Subjects must have adequate renal function defined as a serum creatinine based on age/gender as follows:

  • Age Maximum Serum Creatinine (mg/dL), Male/Female

    • 1 to < 2 years 0.6 0.6

    • 2 to < 6 years 0.8 0.8

    • 6 to < 10 years 1 1

    • 10 to < 13 years 1.2 1.2

    • 13 to < 16 years 1.5 1.4

    • ≥ 16 years 1.7 1.4

• A negative serum pregnancy test is required for female participants of childbearing potential (≥13 years of age or after onset of menses)
• Both male and female post-pubertal study subjects must be willing to use a highly effective contraceptive method (i.e., achieves a failure rate of <1% per year when used consistently and correctly) from the time of informed consent until 6 months after study treatment discontinuation. Such methods include: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner, sexual abstinence.
• Informed Consent: All subjects and/or legal guardians must sign informed written consent. Assent, when appropriate, will be obtained according to institutional guidelines.

Exclusion Criteria

• Subjects who are less than 1 year of age
• Subjects who are 12-18 months of age with INSS Stage 4 and all stage 3 subjects with favorable biologic features (i.e., nonamplified MYCN, favorable pathology, and DNA index > 1) are not eligible.
• Subjects who have had prior systemic therapy except for localized emergency radiation to sites of life-threatening or function-threatening disease and/or no more than 1 cycle of chemotherapy per a low or intermediate risk neuroblastoma regimen (as per P9641, A3961, ANBL0531, or similar) prior to determination of MYCN amplification status and histology.
• Treatment with immunosuppressive treatment (local steroids excluded) within 4 weeks prior to enrollment
• Inadequate pulmonary function defined as evidence of dyspnea at rest, exercise intolerance, and/or chronic oxygen requirement. In addition, room air pulse oximetry < 94% and/or abnormal pulmonary function tests if these assessments are clinically indicated.
• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study.)
• Subjects receiving any investigational drug concurrently.
• Subjects with any other medical condition, including but not limited to malabsorption syndromes, mental illness or substance abuse, deemed by the Investigator to be likely to interfere with the interpretation of the results or which would interfere with a subject's ability to sign or the legal guardian's ability to sign the informed consent, and subject's ability to cooperate and participate in the study.
• Subjects with a significant intercurrent illness (any ongoing serious medical problem unrelated to cancer or its treatment) that is not covered by the detailed exclusion criteria and that is expected to interfere with the action of investigational medicinal products (IMPs) or to significantly increase the severity of the toxicities experienced from trial treatment.