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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.

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Study Description

The participants of this study will be children, adolescents, and young adults with residual osteosarcoma, which cannot be removed completely through surgery.

Participants will have achieved a partial response or stable disease at the end of conventional chemotherapy. Osteosarcoma is cancer of the bone. The cancer cells make immature bone cells, known as osteoid.

Osteosarcoma is very rare, but it is the most common type of bone cancer in children and teens. It is most common in teens and young adults.

In this study, participants will receive either cabozantinib and best supportive care or the best supportive care alone. Best supportive care will be provided at the investigator's discretion and according to institutional guidelines.

It includes antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management (including radiotherapy), etc. but does not include tumor specific therapy.

Cabozantinib will be taken by mouth (orally), as a tablet, once a day. Cabozantinib will be provided to participants who tolerate it for as long as their disease does not progress. Participants in the study receiving best supportive care alone may switch to treatment with cabozantinib and best supportive care if their disease progresses and if other eligibility criteria are met.

Participants may withdraw consent to participate at any time.

The estimated duration of the study for participants is 24 months, however a participant could remain in the study longer if demonstrating treatment benefit.

Inclusion Criteria

• Participants must be ≥5 and ≤30 years of age at the time of study entry.
• Histologically or cytologically confirmed diagnosis of high-grade osteosarcoma as defined by a local pathologist
• Participants with unresectable residual disease after standard chemotherapy treatment at diagnosis or first relapse (treated with systemic chemotherapy). A minimum of 4 cycles of systemic chemotherapy (or minimum of 2 cycles if chemotherapy was stopped early due to toxicity) must have been received.
• Measurable residual or evaluable disease by RECIST version 1.1. Participants will be considered with evaluable disease if they have only non-measurable disease as per RECIST version 1.1 criteria.
• Absence of Progressive Disease (PD) (defined by the investigator according to RECIST version 1.1) at study entry. Note, the two most recent radiological evaluations (e.g. computerised tomography (CT) or magnetic resonance imaging (MRI) scan) including the one following completion of chemotherapy should be available later to facilitate BIRC review.
• Chemotherapy must be the last anticancer treatment received by participants before study entry and must have been completed at least 4 weeks but no longer than 2 months before randomization.
• Participants must have recovered to Grade ≤1, except for alopecia, ototoxicity, and Grade ≤2 peripheral neuropathy, per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0) from the acute toxic effects of all prior anticancer therapy at study entry, unless AEs are clinically non significant and/or stable on supportive therapy, per investigator clinical judgment.
• Life expectancy >6 months.
• Performance level: participants must have a Lansky or Karnofsky performance status score of ≥70 corresponding to Eastern Cooperative Oncology Group (ECOG) categories 0-1.
• Adequate organ and marrow function.
• Adequately controlled blood pressure (BP) with or without antihypertensive medications.
• Male and/or female (according to their reproductive organs and functions assigned by chromosomal complement) (FDA 2016)
• Contraception and barriers as well as pregnancy testing is required as appropriate for the age and sexual activity of pediatric participants and as required by local regulations.
• All participants (typically ≥18 years) and/or their parents or legal guardians must sign a written informed consent and assent must be obtained from minor participants according to local guidelines.

Exclusion Criteria

• Low grade osteosarcoma and periosteal osteosarcoma
• Previous treatment with cabozantinib or another Mesenchymal-epithelial transition (MET)/hepatocyte growth factor (HGF) inhibitor (e.g., tivantinib, crizotinib).
• Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks or 5 half-lives of the agent, whichever is longer, before first dose of study intervention.
• Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study intervention (or washout of at least 5 half-lives, whichever is shorter).
• Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery or major surgery e.g., removal or biopsy of brain metastasis) and stable for at least 4 weeks prior to randomization. Eligible participants must be neurologically asymptomatic and without systemic corticosteroid treatment at the time of randomization. Note: Participants with a known seizure disorder who are receiving non-enzyme inducing anticonvulsants and have well-controlled seizures on a stable dose of anti-convulsant may be enrolled.
• Participants who have an uncontrolled/active infection requiring systemic therapy.
• Participants who are unable to swallow intact tablets.
• Participants with uncontrolled, significant intercurrent or recent illness.
• Previously identified allergy or hypersensitivity to components of the study treatment formulations.
• Any other active malignancy at time of first dose of study intervention or diagnosis of another malignancy within 3 years prior to first dose of study intervention that requires active treatment.
• Pregnancy or breast-feeding.
• Participants who in the opinion of the investigator may not be able to comply with the requirements of the study are not eligible
• Major surgery (eg, orthopaedic surgery, removal or biopsy of brain metastasis) within 8 weeks before randomization. Complete wound healing from major surgery must have occurred 4 weeks before randomization and from minor surgery (eg, simple excision, tooth extraction) at least 10 days before randomization. Participants with clinically relevant ongoing complications from prior surgery are not eligible.

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Study Description

Brief Summary:

Quizartinib is an experimental drug. It is not approved for regular use. It can only be used in medical research.

Children or young adults with a certain kind of blood cancer (FLT3-ITD AML) might be able to join this study if it has come back after remission or is not responding to treatment.

Detailed Description:

The medical condition being investigated is relapsed or refractory AML in participants aged ≥1 month to ≤21 years with Feline McDonough Sarcoma (FMS)-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) mutations (FLT3-ITD AML), following failure of front-line intensive chemotherapy.

The trial will be conducted in multiple phases. An independent data monitoring committee (DMC) will protect the rights, safety, and well-being of participants by monitoring the progress and results. The DMC will comprise qualified physicians and scientists who are not Investigators in the study and not otherwise directly associated with the Sponsor and will be convened at the end of Phase 1.

A. Dose Escalation/De-escalation Phase:

Number of participants is determined by age group. Participants will be enrolled by dose-level to determine the recommended Phase 2 dose (RP2D) of quizartinib for pediatric participants that provides similar exposure to adult patients treated at the target adult dose of 60 mg orally once daily.

B. Dose-Expansion Phase:

Participants will receive the RP2D of quizartinib for their respective age group.

During both dose escalation and dose expansion phases, participants will receive:

Re-Induction Therapy

• Intrathecal (IT) triple chemotherapy prophylaxis prior to and between cycles
• In re-induction Cycles 1 and 2, fludarabine/cytarabine (FLA) followed by quizartinib as a single agent

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Period:

After re-induction therapy, participants will be evaluated for eligibility to undergo allogeneic hematopoietic stem cell transplant (HSCT). Eligible participants may receive a single 28-day cycle of consolidation therapy (standard of care chemotherapy with or without quizartinib) if an allogeneic HSCT is not available immediately. The options for consolidation therapy are as follows:

• High intensity chemotherapy with quizartinib, or
• Low intensity chemotherapy alone, or
• Low intensity therapy with quizartinib as a single agent

Continuation Therapy:

Participants in remission after HSCT, or who are not eligible for HSCT but achieve at least a partial remission (PR) after re-induction, will receive up to 12 continuous 28-day cycles of quizartinib continuation therapy at the same dose received during re-induction in the dose expansion phase.

Long-term Follow-up:

The long-term follow-up phase begins upon completion of 12 cycles of quizartinib Continuation Therapy or permanent discontinuation of quizartinib at any time. After completion of the 30-day safety follow-up visit, subsequent visits will occur at the following frequencies to assess survival and anti-leukemic treatments:

• every 3 months for the first 2 years, and then
• once a year thereafter until the last participant enrolled has been followed for three years from the date of enrollment

Inclusion Criteria

• Has diagnosis of AML according to the World Health Organization (WHO) 2008 classification with >5% blasts in bone marrow, with or without extramedullary disease
• Is in first relapse or refractory to first-line high-dose chemotherapy with no more than 1 attempt (1 to 2 cycles of induction chemotherapy) at remission induction - prior HSCT is permitted
• Has presence of the FLT3-ITD activating mutation in bone marrow or peripheral blood as defined in the protocol
• Is between 1 month and 21 years of age at the time the Informed Consent/Assent form is signed
• Has protocol-defined adequate performance status score
• Has fully recovered from the acute clinically significant toxicity effects of all prior chemotherapy, immunotherapy, or radiotherapy, per protocol guidelines
• Has protocol-defined adequate renal, hepatic and cardiac functions
• If of reproductive potential, is permanently sterile or agrees to use highly effective birth control upon enrollment, during the period of therapy, and for 6 months following the last dose of study drug or cytarabine, whichever is later
• If female of child-bearing potential, tests negative for pregnancy and agrees not to breast feed
• Participant/legal representative is capable of understanding the investigational nature of the study, potential risks, and benefits, and the patient (and/or legal representative) signs a written assent/informed consent
• Meets protocol-specified guidelines before inclusion in the continuation therapy phase

Exclusion Criteria

• Has been diagnosed with isolated central nervous system relapse, certain kinds of leukemia, or with myeloid proliferations related to Down syndrome
• Has uncontrolled or pre-defined significant cardiovascular disease as detailed in the protocol
• Has systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. The patient must be off vasopressors and have negative blood cultures for at least 48 hours prior to the start of systematic protocol therapy.
• Has known active clinically relevant liver disease (e.g., active hepatitis B or active hepatitis C)
• Has known history of human immunodeficiency virus (HIV)
• Has history of hypersensitivity to any of the study medications or their excipients
• Is receiving or is anticipated to receive concomitant chemotherapy, radiation, or immunotherapy other than as specified in the protocol
• Has any significant concurrent disease, illness, psychiatric disorder or social issue that would compromise subject safety or compliance, interfere with consent/assent, study participation, follow up, or interpretation of study results
• Is currently participating in another investigative interventional procedure (observational or long-term interventional follow-up is allowed)
• Is otherwise considered inappropriate for the study by the Investigator

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Study Description

Patients with relapsed or refractory leukemia or lymphoma are often refractory to further chemotherapy. In this study, the investigators will attempt to use T cells obtained directly from the patient, which can be genetically engineered to express a chimeric antigen receptor (CAR). The CAR used in this study can recognize CD22, a protein expressed on the surface of leukemia and lymphoma cells. The phase 1 part of this study will determine the safety and appropriate dose level of these CAR T cells, and the phase 2 part of the study will determine how effective this CAR T cell therapy is. Both patients who have never had prior CAR T cell therapy and those who have had prior CAR T cell therapy may be eligible to participate in this study.

Inclusion Criteria

• Male and female subjects aged ≤ 30 years. First 2 enrolled subjects: age ≥ 18 and ≤ 30 years
• Evidence of refractory or recurrent CD22+ leukemia or lymphoma
• Able to tolerate apheresis, or subject with sufficient existing apheresis product or T cells for manufacturing investigational product.
• Life expectancy ≥ 8 weeks
• Lansky or Karnofsky, as applicable, score ≥ 50
• Recovered from acute toxic effects of all prior chemotherapy, immunotherapy, and radiotherapy, if the subject does not have a previously obtained apheresis product that is acceptable and available for manufacturing of CAR T cells
• ≥ 7 days post last chemotherapy and biologic therapy, with the exception of intrathecal chemotherapy and maintenance chemotherapy
• ≥ 7 days post last corticosteroid therapy
• ≥ 3 days post Tyrosine Kinase Inhibitor (TKI) use
• ≥ 1 day post hydroxyurea
• 30 days post most recent CAR T cell infusion
• Adequate organ function
• Adequate laboratory values, including absolute lymphocyte count ≥ 100 cells/uL
• Subjects of childbearing or child-fathering potential must agree to use highly effective contraception from consent through 12 months following infusion of investigational product on trial
• Subject and/or legally authorized representative has signed the informed consent form for this study

Exclusion Criteria

• Presence of active malignancy other than disease under study
• History of symptomatic CNS pathology or ongoing symptomatic CNS pathology
• CNS involvement of leukemia or lymphoma that is symptomatic and in the opinion of the investigator, cannot be controlled during the interval between enrollment and CAR T cell infusion
• Subjects with uniform expression of CD19 on their malignant cells who are eligible but have not attempted CD19 directed CAR T cell therapy
• For subjects having had a previous stem cell transplant: presence of active GVHD, or receiving immunosuppressive therapy for treatment or prevention of GVHD within 4 weeks prior to enrollment
• Presence of active severe infection,
• Presence of primary immunodeficiency syndrome
• Subject has received prior virotherapy
• Pregnant or breastfeeding
• Subject and/or legally authorized representative unwilling to provide consent/assent for participation in the 15-year follow-up period, required if CAR T cell therapy is administered
• Presence of any condition that, in the opinion of the investigator, would prohibit the subject from undergoing treatment under this protocol

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Study Description

This phase II trial tests effects of nivolumab in combination with chemotherapy drugs prior to radiation therapy patients with nasopharyngeal carcinoma (NPC). Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as gemcitabine and cisplatin, 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. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Researchers want to find out what effects, good and/or bad, adding nivolumab to chemotherapy has on patients with newly diagnosed NPC. In addition, they want to find out if children with NPC may be treated with less radiation therapy and whether this decreases the side effects of therapy.

Inclusion Criteria

• Patients must be ≤ 21 years of age at the time of study enrollment
• Newly diagnosed American Joint Committee on Cancer (AJCC) stage II-IV nasopharyngeal carcinoma (NPC)
  • Patients must have had histologic verification of the malignancy at original diagnosis
  • Although submission of tumor tissue for the molecular characterization initiative is not required for eligibility, it is strongly recommended
• Patients must have had histologic verification of the malignancy at original diagnosis
• Although submission of tumor tissue for the molecular characterization initiative is not required for eligibility, it is strongly recommended
• Patients must have a Lansky (for patients ≤ 16 years of age) or Karnofsky (for patients > 16 years of age) performance status score of ≥ 60%
• Peripheral absolute neutrophil count (ANC) ≥ 1000/uL (within 7 days prior to start of protocol therapy)
• Platelet count ≥ 100,000/uL (transfusion independent) (within 7 days prior to start of protocol therapy)
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m^2 or (within 7 days prior to start of protocol therapy)
• A serum creatinine based on age/gender (within 7 days prior to start of protocol therapy) 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, and (within 7 days prior to start of protocol therapy)
• Serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) ≤ 135 U/L* (within 7 days prior to start of protocol therapy)
  • Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
• Shortening fraction of ≥ 27% by echocardiogram, or
• Ejection fraction of ≥ 50% by radionuclide angiogram
• No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% if there is clinical indication for determination
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months and T-cell count above the lower limit of normal are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

Exclusion Criteria

• Patients who received prior radiotherapy to the head or neck
• Patients who received prior chemotherapy or radiation for the treatment of any cancer in the last 3 years. These patients must also be in remission
• Patients with a diagnosis of immunodeficiency
• Patients with an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive agents). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  • Note: Patients with well-controlled asthma and no need for systemic steroids for the treatment of asthma in the last 12 months will not be excluded
• Patients with a condition requiring systemic treatment with either corticosteroids (> 0.25 mg/kg (10 mg) daily prednisone equivalent) within 14 days or other immunosuppressive medications within 30 days of enrollment. Inhaled or topical steroids, and adrenal replacement steroid doses > 0.25 mg/kg (10 mg) daily prednisone equivalent, are permitted in the absence of active autoimmune disease
• Patients with a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
• Patients with detectable viral load of human immunodeficiency virus (HIV), hepatitis B or hepatitis C, or active tuberculosis
• Patients who have undergone solid organ or allogeneic hematopoietic transplant at any time
• Due to risks of fetal and teratogenic adverse events as seen in animal studies, a negative pregnancy test must be obtained in females of childbearing potential, defined as females who are post-menarchal. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Females of childbearing potential that are sexually active must agree to either practice 2 medically accepted highly-effective methods of contraception at the same time or abstain from heterosexual intercourse from the time of signing the informed consent through 5 months after the last dose of nivolumab, 6 months after the last dose of gemcitabine, and 14 months after the last dose of cisplatin, whichever is longer
• Males of childbearing potential that are sexually active must agree to either practice a medically accepted highly-effective methods of contraception or abstain from heterosexual intercourse from the time of signing the informed consent through 3 months after the last dose of gemcitabine, and 11 months after the last dose of cisplatin, whichever is longer
• Lactating females are not eligible unless they have agreed not to breastfeed their infants starting with the first dose of study therapy through 5 months after the last dose of nivolumab
• 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

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Study Description

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

This is a Pilot, multicenter, open-label study of patients less than or equal to 25 years, with recurrent or progressive LGG harboring a CRAF or BRAF alteration, including BRAF V600 mutations and KIAA1549: BRAF fusions. Patients with BRAF or CRAF alterations will be identified through molecular assays as routinely performed at Clinical Laboratory Improvement Amendments (CLIA) of 1988 or other similarly certified laboratories.

The study will be conducted in two sequential phases:

Phase A: A Feasibility (combination dose finding) phase, followed by Phase B: An Efficacy phase. The maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D) of the combination as determined in Phase A would be the dose used in Phase B. The patients on Phase A who were below the MTD/RP2D would be eligible for intra-patient dose escalation to MTD/RP2D subject to criteria outlined later.

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Phase A (Feasibility Phase) - Open at SickKids

A feasibility phase will be conducted to establish the maximum tolerated dose (MTD/RP2D) of the combination of vinblastine + tovorafenib using the Rolling 6 design.

Patients will receive vinblastine and tovorafenib on Days 1, 8, 15, 22 of each cycle for a total duration of 17 cycles followed by 7 additional cycles of tovorafenib alone. One cycle of protocol therapy is 28 days.

Treatment cycles will repeat every 28 days for a total of 24 cycles in the absence of disease progression or unacceptable toxicity. Patients will undergo radiographic evaluation of their disease at the end of every third cycle, starting with the end of Cycle 3.

The RP2D of tovorafenib of 420 mg/m2 once weekly (not exceeding 600 mg) in combination with vinblastine (4mg/m2) will be used as the starting dose and will be de-escalated/escalated as per Table 4. Dose of tovorafenib will not be escalated further.

Patients will be treated on protocol therapy for a total of 24 cycles, the vinblastine and tovorafenib for a total duration of 17 cycles followed by 7 additional cycles of alone tovorafenib, unless disease progression, unacceptable toxicity occurs, or withdrawal from the study occurs. Missed doses of either vinblastine or tovorafenib will not be made up.

Phase B (Expansion/Efficacy Phase) - Not Yet Open

Once the MTD/RP2D of the combination, vinblastine + tovorafenib has been established, the expansion/efficacy phase will be initiated at the dose determined in Phase A.

Patient will receive vinblastine and tovorafenib weekly on Days 1, 8, 15, 22 of each cycle at dose determined in Phase A for a total duration of 17 cycles followed by 7 additional cycles of tovorafenib alone. One cycle of protocol therapy is 28 days.

Treatment cycles will repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients will undergo radiographic evaluation of their disease at the end of every third cycle, starting with the end of Cycle 3.

Patients will be treated on protocol therapy for a total of 24 cycles, the vinblastine and tovorafenib for a total duration of 17 cycles followed by 7 additional cycles of alone tovorafenib, unless disease progression or unacceptable toxicity occurs, unless disease progression, unacceptable toxicity or withdrawal from study occurs. Missed doses of either vinblastine or tovorafenib will not be made up.

Inclusion Criteria

• Patients must be less than or equal to 25 years of age at the time of enrollment
• Progressive/Recurrent LGG (non-NF1) with documented BRAF or CRAF alteration as identified through molecular assays as routinely performed at CLIA or other similar certified laboratories.
• Diagnosis:
  • All patients must have pathological confirmation of low-grade glioma with BRAF or CRAF alteration.
  • Patient must have progressive or recurrent LGG.
  • Must have at least 1 measurable lesion, as defined by RANO-LGG criteria.
  • Eligible histologies will include all tumors considered low-grade glioma or low-grade astrocytoma (WHO grade I and II) by WHO classification of Tumors of the Central Nervous system -5th edition revised with exception of subependymal giant cell astrocytoma.
• Prior Therapy:
  • Must have received at least 1 line of systemic therapy prior (at least a vinca alkaloid and/or single agent carboplatin and/or a MEK or BRAF inhibitor) and have documented evidence of radiographic progression.
  • Patients must have fully recovered from the acute toxic effects (≤ Grade I) of all prior anticancer chemotherapy and have undergone the following washout periods, as applicable.
    • i. Myelosuppressive chemotherapy: At least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea)
    • ii. Radiation therapy (XRT): Radiation therapy to the measurable lesion(s) must be completed at least 6 months prior to administration of combination therapy. Patients who have documented radiographic progression less than 6 months from radiotherapy in 1 or more measurable lesions are eligible. At least 2 weeks after the last dose fraction of XRT to the non-target lesion.
    • iii. Investigational agent or any other anticancer therapy not defined above: At least four weeks prior to planned start of combination therapy, or five half-lives, whichever is shorter.
    • iv. Patients must have recovered from acute effects of any prior surgery. 
    • v. Chronic toxicities from prior anticancer therapy must be stable as per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grade ≤ 2, except ongoing retinopathy which must be ≤ Grade 1.
• Performance Level: a) Karnofsky (those 16 years and older) or Lansky (those younger than 16 years) performance score of at least 50. Patients who are unable to walk because of paralysis, but who are able to sit in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Tumor Tissue Sample Confirmation that an archival tumor tissue sample is available. If an archival tumor tissue sample is not available, a fresh biopsy should be performed at baseline. Submission of tumor tissue and a blood sample are mandatory and must be submitted within 14 days from enrollment onto the study and prior to initiation of treatment. Biopsy may be either at initial diagnosis or recurrence.
• Organ function: 
  • Adequate bone marrow function defined as:
    • i. Absolute neutrophil count ≥ 1000/mm3
    • ii. Platelet count (unsupported) ≥ 100 x 109/L (transfusions allowed per institutional guidelines; last transfusion > 2 weeks prior to enrollment)
    • iii. Hemoglobin (unsupported)≥ 10.0 g/dL (transfusions allowed per institutional guidelines; last transfusion > 4 weeks prior to enrollment)
    • iv. Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g., Neulasta®) or 7 days for short-acting growth factor.
  • Adequate hepatic and renal function defined as:
    • i. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age (patients with documented Gilbert's disease may be enrolled with sponsor approval and total bilirubin ≤ 2 x ULN)
    • ii. Serum glutamic-pyruvic transaminase (SGPT)/alanine aminotransferase (ALT) ≤ 2.5 x ULN
    • iii. Serum glutamic-oxaloacetic transaminase (SGOT)/aspartate transaminase (AST) ≤ 2.5 x ULN
    • iv. Serum creatinine within normal limits or estimated glomerular filtration rate ≥ 60 ml/min/1.73 m2 based on local institutional practice for determination.
  • Thyroid functions tests within institutional normal range. Patients on a stable dose of thyroid replacement therapy for a minimum of 3 weeks before starting therapy are eligible.
  • Adequate cardiac function defined as:
    • i. Left ventricular ejection fraction (LVEF) of ≥ 50% as measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan, or fractional shortening (FS) ≥ 25% (Tissot et al., 2018) as measured by ECHO, within 14 days before enrollment (while not receiving medications for cardiac function). If normal practice at the institution is to provide the LVEF result as a range of values, then the upper value of the range will be used to determine the result.
    • ii. QTc (by Fridericia's formula) < 470ms as measured by electrocardiogram (ECG) within 14 days before enrollment (while not receiving medications for cardiac function).
  • Adequate central nervous system (CNS) function defined as:
    • i. Patients with seizures should be stable and not have experienced a significant increase in seizure frequency within 14 days prior to enrollment.
    • ii. Patients with neurologic deficits should have deficits that are stable for a minimum of 14 days prior to enrollment.
    • iii. Patients receiving steroids for tumor-associated symptoms must be on a stable dose (e.g., no initial/loading dose, no increase or decrease) for 14 days prior to enrollment.
• Study specific:
  • Baseline ophthalmology assessment within 28 days of study enrollment.
  • MRI assessment within 28 days of study enrollment. MRI done for clinical indication but within the window for study would be permitted as baseline.
  • Ability to comply with treatment, laboratory monitoring, and required clinic visits for the duration of study participation.
  • Willingness of male and female patients with reproductive potential to use double effective birth control methods, defined as one used by the patient and another by his/her partner, for the duration of treatment and for 180 days following the last dose of study drug. Effective birth control methods are described in Appendix H.
  • Ability to swallow tablets or liquid, or gastric access via a nasal or gastric tube.
  • Patient is able to start treatment within 14 working days of screening.
  • Parent/guardian of child or adolescent patient has the ability to understand, agree to, and sign the study ICF and applicable pediatric assent form before initiation of any protocol related procedures; patient has the ability to give assent, as applicable, at the time of parental/guardian consent.

Exclusion Criteria

• Patient's tumor has additional previously known activating molecular alterations, other than BRAF or CRAF.
• Known or suspected diagnosis of neurofibromatosis Type 1 (NF-1) via genetic testing or current diagnostic clinical criteria.
• History of any major disease, other than the diagnosis of LGG, that might interfere with safe protocol participation.
• Patient with a history or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO), or ophthalmopathy present at baseline who would be considered a risk factor for CSR or RVO. Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor, or strabismus) will NOT be considered a significant abnormality for the purposes of this study.
• Major surgery within 14 days (2 weeks) prior to enrollment (does not include central venous access, cyst fenestration or cyst drainage, or ventriculoperitoneal shunt placement or revision).
• Clinically significant active cardiovascular disease, or history of myocardial infarction, or deep vein thrombosis/pulmonary embolism within 6 months prior to enrollment, ongoing cardiomyopathy, or current prolonged QT interval corrected for heart rate by Fridericia's formula (QTcF) interval > 470 ms based on triplicate ECG average.
• Concomitant medications that are strong inhibitors or inducers of CYP2C8 or CYP3A4 within 14 days before initiation of therapy. Concomitant medications that are substrates of BCRP with a narrow therapeutic index within 14 days before initiation of therapy
• Current enrollment in any other investigational treatment study. Participation on a concurrent observational or bio-sampling study is allowed.
• Active systemic bacterial, viral, or fungal infection.
• Nausea and vomiting ≥ National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 5.0 Grade 2 (for those not controlled by supportive care), malabsorption requiring supplementation, or significant bowel or stomach resection that would preclude adequate absorption of tovorafenib.
• Patient has CTCAE v5.0 Grade 3, creatine phosphokinase (CPK) elevation (> 5 × ULN - 10 × ULN).
• Patients who are neurologically unstable despite adequate treatment (e.g., uncontrolled seizures).
• Pregnancy or lactation.
• History of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome or Stevens Johnsons syndrome (SJS). Patients with hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any other excipient present in the pharmaceutical form of the investigational medicinal product.
• Other unspecified reasons that, in the opinion of the investigator, make the patient unsuitable for enrollment.

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Study Description

A study to learn about safety and find out maximum tolerable dose of palbociclib given in combination with chemotherapy (temozolomide with irinotecan or topotecan with cyclophosphamide) in children, adolescents and young adults with recurrent or refractory solid tumors (phase 1).

Neuroblastoma tumor specific cohort to further evaluate antitumor activity of palbociclib in combination with topotecan and cyclophosphamide in children, adolescents, and young adults with recurrent or refractory neuroblastoma.

Phase 2 [Closed to Enrollment] is to learn about the efficacy of palbociclib in combination with irinotecan and temozolomide when compared with irinotecan and temozolomide alone in the treatment of children, adolescents, and young adults with recurrent or refractory Ewing sarcoma (EWS). Phase 2 open-label, randomized portion of the study will randomize patients in a 2:1 ratio to receive either palbociclib in combination with irinotecan and temozolomide (Arm A) or irinotecan and temozolomide chemotherapy alone (Arm B). Randomization will be stratified using block randomization by type and time of current disease recurrence (primary refractory or 1st recurrence < 2 years versus 1st recurrence ≥ 2 years or 2nd or greater recurrence).

Inclusion Criteria

1. Histologically confirmed relapsed or refractory solid tumor as follows:

   • For dose escalation and dose determination parts: Histologically confirmed relapsed or refractory solid tumor (including CNS tumors but not lymphomas). Patients with Diffuse Intrinsic Pontine Glioma do not require histological only radiographic confirmed relapse to enroll. 
   • For dose expansion and tumor specific cohorts: Histologically confirmed relapsed or refractory solid tumor including but not limited to EWS, rhabdoid tumor, rhabdomyosarcoma, neuroblastoma, and medulloblastoma. Patients with Diffuse Intrinsic Pontine Glioma do not require histological only radiographic confirmed relapse to enroll. EWS is not eligible for TOPO and CTX tumor-specific cohorts. 
   • For randomized Phase 2 part: Histologically confirmed Ewing sarcoma. Histopathology confirmation of EWSR1-ETS or FUS-ETS rearrangement is required or availability of formalin fixed paraffin embedded (FFPE) tumor tissue sample for central testing. Patient must have relapsed or refractory disease with no known bone marrow metastases and at least evaluable disease [closed to enrollment]
2. Age ≥2 and <21 years at the time of study entry.
3. Lansky performance status ≥50% for patients ≤16 years of age, or Eastern Cooperative Oncology Group (ECOG) 0, 1 or 2 for patients >16 years of age.
4. Adequate bone marrow function.
   • Absolute neutrophil count ≥1000/mm3;
   • Platelet count ≥75,000/mm3 (transfusion independent, no platelet transfusion in past 7 days prior study entry);
   • Hemoglobin ≥8.5 g/dL (transfusion allowed).
5. Adequate renal function: Serum creatinine level based on age/gender must within protocol specified limits.
6. Adequate liver function, including:

   • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN) or ≤5 × ULN for age, if attributable to disease involvement of the liver;

   • Total bilirubin ≤1.5 × ULN for age, unless the patient has documented Gilbert's syndrome. Patients with documented Gilbert's syndrome are eligible if direct bilirubin is within normal ranges (≤ULN).

7. Patients enrolled to Phase 1 portion of the study and tumor specific cohorts must have measurable disease as defined by RECIST version 1.1 or modified RANO criteria for CNS disease or INRC for neuroblastoma. Patients with EWS enrolled to Phase 2 portion [closed] of the study are eligible with evaluable disease (eg, bone only disease with no soft tissue component).
8. Recovered to CTCAE Grade ≤1, or to baseline, from any non-hematological acute toxicities of prior surgery, chemotherapy, immunotherapy, radiotherapy, differentiation therapy or biologic therapy, with the exception of alopecia.
9. Serum/urine pregnancy test (for all girls ≥8 years of age) negative at screening and at the baseline visit.

Other inclusion and exclusion criteria may apply 

Exclusion Criteria

1. Phase 1 and tumor specific cohorts: For palbociclib with IRN and TMZ combination, prior treatment with a CDK4/6 inhibitor or progression while on treatment with an IRN-containing regimen that includes TMZ. Patients who have received the combination of IRN and TMZ and did not progress while on these medications are eligible. For patients enrolling in the palbociclib with TOPO and CTX combination, prior treatment with a CDK4/6 inhibitor or progression while on treatment with a TOPO-containing regimen that includes CTX. Patients who have received the combination of TOPO and CTX and did not progress while on these medications are eligible. Phase 2 portion [closed]: prior treatment with a CDK4/6 inhibitor or progression while on treatment with an IRN-containing or TMZ-containing regimen. Patients who have received IRN and/or TMZ and did not progress while on these medications are eligible.
2. Prior intolerability to IRN and/or TMZ plus/minus palbociclib with IRN and TMZ combination and prior intolerability to TOPO and/or CTX for TOPO and CTX combination. For patients enrolled in the UK, any contraindication for IRN and/or TMZ treatment, as per the local SmPC.
3. Use of strong cytochrome P450 (CYP) 3A inhibitors or inducers within 12 days of study entry. Patients who are receiving strong uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) inhibitors within 12 days of Cycle 1 Day 1 (C1D1) are not eligible for the palbociclib with IRN and TMZ combination. Patients who are receiving strong UGT1A1 inhibitors within 12 days of C1D1 are eligible for the palbociclib with TOPO and CTX combination 
4. Systemic anti cancer therapy within 2 weeks prior to study entry and 6 weeks for nitrosoureas.
5. Prior irradiation to >50% of the bone marrow
6. Participation in other studies involving investigational drug(s) within 2 weeks or 5 half lives, whichever is longer, prior to study entry.
7. Major surgery within 4 weeks prior to study entry. Surgical biopsies or central line placement are not considered major surgeries.
8. For IRN and TMZ with/without palbociclib combinations: known or suspected hypersensitivity to palbociclib, dacarbazine, IRN and/or TMZ. For combination of palbociclib with TOPO and CTX: known or suspected hypersensitivity to palbociclib, TOPO and/or CTX.
9. Patients with known symptomatic brain tumors or brain metastases and require steroids, unless they have been on a stable or on a decreasing steroid dose for >14 days.
10. Patients with previously diagnosed brain metastases are eligible if they have completed their prior treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry for these metastases for at least 14 days post radiation and 4 weeks post-surgery and are neurologically stable.
11. Hereditary bone marrow failure disorder.
12. QTc >470 msec.
13. History of clinically significant or uncontrolled cardiac disease, including:
    • History of or active congestive heart failure; if patient had congestive heart failure resolve and >1 year from resolution, patient will be considered eligible;
    • Clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation or Torsades de Pointes);
    • Diagnosed or suspected congenital or acquired prolonged QT syndrome;
    • Need for medications known to prolong the QT interval;
    • Uncorrected hypomagnesemia or hypokalemia because of potential effects on the QT interval;
    • Left ventricular ejection fraction <50% or shortening fraction <28%.
14. Recent or ongoing clinically significant gastrointestinal disorder that may interfere with absorption of orally administered drugs (eg, gastrectomy).
15. Evidence of serious active or uncontrolled bacterial, fungal or viral infection or known history of hepatitis B virus, hepatitis C virus, or human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness. Screening for viral hepatitis and HIV is under discretion of investigator unless required by local regulation.
16. Severe acute or chronic medical or laboratory test abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results, and in the judgment of the Investigator, would make the patient inappropriate for entry into this study.
17. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or patients who are Pfizer employees, including their family members, directly involved in the conduct of the study.
18. Fertile male patients or female patients of childbearing potential who are unwilling or unable to follow contraceptive requirements.
19. Pregnant or breastfeeding women.

Other inclusion and exclusion criteria may apply 

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Study Description

TAPISTRY is a Phase II, global, multicenter, open-label, multi-cohort study designed to evaluate the safety and efficacy of targeted therapies or immunotherapy as single agents or in rational, specified combinations in participants with unresectable, locally advanced or metastatic solid tumors determined to harbor specific oncogenic genomic alterations or who are tumor mutational burden (TMB)-high as identified by a validated next-generation sequencing (NGS) assay.

Participants with solid tumors will be treated with a drug or drug regimen tailored to their NGS assay results at screening.

Participants will be assigned to the appropriate cohort based on their genetic alteration(s). Treatment will be assigned on the basis of relevant oncogenotype, will have cohort-specific inclusion/exclusion criteria, and, unless otherwise specified, will continue until disease progression, loss of clinical benefit, unacceptable toxicity, participant or physician decision to discontinue, or death, whichever occurs first.

Cohort A: ROS1 fusion-positive tumors - Closed to Accrual

Participants with metastatic or advanced solid tumors, with the exception of NSCLC will receive entrectinib once daily in repeated 28-day cycles at a dose of 600 milligram per day (mg/day) for pediatric participants with a body surface area (BSA) >/= 1.51 m²

Cohort B: NTRK1/2/3 fusion-positive tumors - Closed to Accrual

Participants with metastatic or advanced solid tumors will receive entrectinib once daily in repeated 28-day cycles at a dose of 600 mg/day for adults and pediatric participants with a BSA >/= 1.51 m²

Cohort C: ALK fusion-positive tumors (excluding NSCLC) - Closed to Accrual

Participants with metastatic or advanced solid tumors, with the exception of NSCLC, will receive alectinib at a dosage of 600 mg orally twice a day (BID), taken with food, in repeated 28-day cycles.

Cohort D: TMB-high tumors - Closed to Accrual

Participants with metastatic or advanced solid tumors will receive atezolizumab intravenously (IV) at a dose of 15 mg/kg (maximum 1200 mg) for participants aged < 18 years on Day 1 of each 21-day cycle.

Cohort E: AKT1/2/3 mutant-positive tumors - Closed to Accrual

Participants with metastatic or advanced solid tumors will receive ipatasertib orally once daily (QD). For participants 12-17 years of age, ipatasertib will be administered at the starting dose of 200 mg for participants <35 kg, 300 mg for participants >/= 35 and <45 kg, 400 mg for those >/=45 kg orally QD in repeated 28-day cycles until the participant experiences disease progression, intolerable toxicity, or withdraws consent.

Cohort F: HER2 mutant-positive tumors - Closed to Accrual

Participants with metastatic or advanced solid tumors will receive trastuzumab emtansine IV at a dose of 3.6 mg/kg every 21 days. This dosage and administration method also applies for pediatric participants 12-17 years of age.

Cohort H: PIK3CA multiple mutant-positive tumors - Closed to Accrual

Participants with metastatic or advanced solid tumors will receive GDC-0077 daily at a starting dose of 9 mg by mouth (PO) in repeated 28-day cycles. This dosage and administration method also applies for pediatric participants 12-17 years of age.

Cohort I: BRAF class II mutant or fusion-positive tumors - Closed to Accrual

Participants with BRAF class II mutant/fusion-positive tumors (adults and adolescents ≥ 40 kg) will receive 400 mg belvarafenib by mouth (PO) BID (twice a day) with adequate water (more than 200 mL). One cycle consists of 28 days. Administration of belvarafenib should occur BID on every day of each 28-day cycle.

Cohort J: BRAF class III mutant-positive tumors - Closed to Accrual

Participants with BRAF class III mutant-positive tumors (adults and adolescents ≥ 40 kg) will receive 400 mg belvarafenib by mouth (PO) BID (twice a day) with adequate water (more than 200 mL). One cycle consists of 28 days. Administration of belvarafenib should occur BID on every day of each 28-day cycle.

Cohort K: RET fusion-positive tumors - Closed to Accrual

Participants with RET fusion-positive tumors will self-administer Pralsetinib orally at home (except on clinic days) on a continuous daily dosing regimen at a dose of 400 mg/day (four 100-mg capsules per day) for adult and pediatric patients ≥ 12 and < 18 years of age. A treatment cycle consists of 4 weeks (28 days).

Inclusion Criteria

• In addition to the general inclusion criteria below, participants must meet all of the cohort-specific inclusion criteria for the respective cohort
• Briefly - for arm A, a ROS1 fusion is required; for arm B, a NTRK1/2/3 fusion is required; for arm D, a TMB >16mut/Mb is required; for arm E: specific mutations in the AKT gene are required; for arm F: specific mutations in the HER2 gene are required; for arm H, specific mutations in the PIK3CA gene are required; for arm I, a BRAF Class II mutation or fusion is required; for arm J, a BRAF Class III mutation is required; for Cohort K; a RET fusion is required. 
• Histologically or cytologically confirmed diagnosis of advanced and unresectable or metastatic solid malignancy
• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), Response Assessment in Neuro-Oncology (RANO) criteria, or International Neuroblastoma Response Criteria (INRC)
• Performance status as follows: Participants aged >= 18 years: Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2; Participantss aged 16 to < 18 years: Karnofsky score >= 50%; Participants aged < 16 years: Lansky score >= 50%
• For participants aged >= 18 and <18 years: adequate hematologic and end-organ function
• Disease progression on prior treatment, or previously untreated disease with no available acceptable treatment
• Adequate recovery from most recent systemic or local treatment for cancer
• Life expectancy >= 8 weeks
• Ability to comply with the study protocol, in the investigator's judgment
• For female participants of childbearing potential: Negative serum pregnancy test <= 14 days prior to initiating study treatment; agreement to remain abstinent or use single or combined contraception methods that result in a failure rate of < 1% per year for the period defined in the cohort-specific inclusion criteria; and agreement to refrain from donating eggs during the same period
• For male participants: Willingness to remain abstinent or use acceptable methods of contraception as defined in the cohort-specific inclusion criteria

Exclusion Criteria

• Current participation or enrollment in another therapeutic clinical trial
• Any anticancer treatment within 2 weeks or 5 half-lives prior to start of study treatment
• Whole brain radiotherapy within 14 days prior to start of study treatment
• Stereotactic radiosurgery within 7 days prior to start of study treatment
• Pregnant or breastfeeding, or intending to become pregnant during the study
• History of or concurrent serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the participant's safe participation in and completion of the study or confounds the ability to interpret data from the study
• Incomplete recovery from any surgery prior to the start of study treatment that would interfere with the determination of safety or efficacy of study treatment
• Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or higher), myocardial infarction, or cerebrovascular accident within 3 months prior to enrollment, unstable arrhythmias, or unstable angina
• History of another active cancer within 5 years prior to screening that may interfere with the determination of safety or efficacy of study treatment with respect to the qualifying solid tumor malignancy
• In addition to the general exclusion criteria above, in order to be enrolled in a treatment cohort of the study, participants must not meet any of the cohort-specific exclusion criteria

Multiple other inclusion and exclusion criteria could apply and will be reviewed by your treating team