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Study Description

The purpose of this study is to assess the safety and tolerability of epcoritamab in pediatric participants with relapsed/refractory aggressive mature B-cell neoplasms and young adult participants with Burkitt's or Burkitt-like lymphoma/leukemia. Adverse events and change in disease activity will be assessed.

Epcoritamab is an investigational drug being developed for the treatment of relapsed/refractory aggressive mature B-cell neoplasms. Participants will receive subcutaneous (SC) of epcoritamab. Approximately 15 pediatric participants with a diagnosis of relapsed/refractory aggressive mature B-cell neoplasms and and young adult participants, ages of 18-25, with a diagnosis of Burkitt's or Burkitt-like lymphoma/leukemia will be enrolled at 50 sites globally.

Participants will receive subcutaneous epcoritamab in 28-day cycles. Participants will be followed for a minimum of 3 years after enrollment.

Inclusion Criteria

• Participants >= 1 and < 18 years old at time of primary diagnosis with Burkitt's or Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma (DLBCL), or other aggressive mature (CD20+) B-cell lymphomas. Participants up to 25 years of age with Burkitt's or Burkitt-like lymphoma/leukemia are also eligible.
• Disease pathologically confirmed (tumor tissue) by local testing.

• Relapsed or primary refractory disease meeting any of the following criteria:

  • Progressive disease at any time during second-line chemoimmunotherapy (CIT).
  • Best response of stable disease (SD) after a minimum of 2 cycles of second-line CIT.
  • Best response of partial response (PR) after a minimum of 3 cycles of second-line CIT.
  • Complete Response (CR) after a minimum of 3 cycles of second-line CIT therapy but unfit or ineligible for consolidation with cell therapy.
  • Not in CR and unable to initiate or tolerate (i.e., must discontinue) second-line CIT.
  • Have received cell therapy (allogeneic or autologous transplant or chimeric antigen receptor T-cell (CAR-T) therapy) as consolidation but have not obtained or maintained a CR.
• Recovery from toxic effects of prior chemoimmunotherapy.
• Performance status by Lansky (< 16 years old at evaluation) or Karnofsky (>= 16 years old at evaluation) score >= 50 or Eastern Cooperative Oncology Group (ECOG) score <= 2 .
• Adequate bone marrow, hepatic, and renal function.

Other inclusion criteria may apply

Exclusion Criteria

• Known central nervous system (CNS) involvement by lymphoma at screening as confirmed by screening magnetic resonance imaging (MRI)/computed tomography (CT)/positron emission tomography (PET) brain scans (participants with evidence of CNS disease only in the cerebrospinal fluid (CSF) will be eligible).
• Other malignancy requiring therapy.
• Currently receiving anti-cancer therapy, including chemotherapy (excluding intrathecal therapy), radiotherapy, small molecules, monoclonal antibodies, cell therapy, or other investigational agents.

Other exclusion criteria may apply

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Centres

Study Description

This is a single-arm, non-randomized study of re-irradiation of diffuse intrinsic pontine glioma (DIPG)

Study therapy will consist of radiation therapy (RT) given over 17 treatment days (for 30.6 Gy in fractions of 1.8 Gy) or 20 treatment days (for 36 Gy in 1.8 Gy fractions), depending on the time from completion of the first course of RT. Treatment days will generally be weekdays, not including statutory holidays.

Inclusion Criteria

All of these criteria must be met for a patient to be eligible for this study:

1. The patient is 17 years of age or younger at the time of first or second relapse or progression of DIPG
2. The patient has no evidence of metastases on cranial or spinal MR imaging
3. The patient has received RT in the past, given to a total cumulative dose of <60 Gy; prior radiation using opposed lateral fields, conformal 3-D fields, IMRT or using protons is acceptable
4. At least 180 days have elapsed from the last day of primary RT for DIPG
5. The patient has recovered from all acute and subacute toxicities of prior RT and of chemotherapy, if chemotherapy was utilized in the past
6. The patient has been off all anti-tumour therapy for at least 14 days
7. The patient has a Lansky score of 40% or higher
8. The patient has a life expectancy anticipated to be at least 8 weeks with treatment using re-irradiation, with or without dexamethasone
9. The patient has no uncontrolled medical condition (e.g., seizures, diabetes, infection) that would interfere with the delivery of rRT
10. The patient agrees to not enroll on any other clinical trial of an anti-tumour intervention
11. The patient agrees to report and have recorded the use of all medications taken during ReRAD therapy, from the time of diagnosis of progression or recurrence, then through and after completion of, ReRAD therapy; this includes the use of complementary, alternative and dietary therapies
12. The patient is treated at a site where the study is approved by the local ethics board
13. Males and females of child-bearing potential must agree to use effective birth control measures during rRT
14. Consent, and, if applicable, assent, has been obtained according to institutional standards

Exclusion Criteria

If the patient fulfills any of these criteria, then he or she will not be eligible for the study:

1. Females who are pregnant, due to risks from rRT on the developing fetus.
2. Any patient with a condition that prohibits the planned delivery of rRT as prescribed in this study.
3. Patients who are receiving any other clinical trial of an anti-tumour intervention

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Study Description

Relapse of AML is driven by chemotherapy resistant stem cells. One mechanism of chemotherapeutic resistance in AML is the overexpression of the protein B-cell lymphoma 2 (BCL-2), an anti-apoptotic protein which sequesters intracellular activators of apoptosis. Venetoclax is a selective, potent, orally bioavailable, small molecule inhibitor of B-cell lymphoma (BCL)-2 that restores programmed cell death in cancer cells.

This is a trial for children, adolescents and young adults with 2nd relapsed AML or 1st relapsed AML unable to receive additional anthracycline.

This is randomized trial of venetoclax in combination with intensive chemotherapy (fludarabine/cytarabine/gemtuzumab ozogamicin) for the first two cycles that would inform and evaluate if this agent is an effective option for this population to improve its poor prognosis. Participants can receive up to two cycles of induction chemotherapy before hematopoietic stem cell transplantation (HSCT). Participants benefiting from treatment and who are not able to proceed to HSCT have the possibility to continue to receive azacitidine in monotherapy (Arm A, control arm) or in combination with venetoclax (Arm B, experimental arm).

Inclusion Criteria

• Participants must have enrolled on APAL2020SC, NCT Number: NCT04726241 prior to enrollment on ITCC-101/APAL2020D. (This is only applicable for participants in USA/Canada/Australia/New Zealand sites/LLS territory).
• Participants must be ≥ 29 days of age and ≤ 21 years of age at enrollment.
• Participants must have one of the following:
  • Children, adolescents, and young adults with acute myeloid leukemia without FLT3/internal tandem duplication (ITD) mutation in:
    • Second relapse, who are sufficiently fit to undergo another round of intensive chemotherapy
    • First relapse who per investigator discretion cannot tolerate additional anthracycline containing chemotherapy.
• Participants must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2 (≥ 50% Lansky or Karnofsky score)
• Participants must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to start of protocol treatment:
  • Cytotoxic chemotherapy: Must not have received cytotoxic chemotherapy within 14 days prior to start of protocol treatment, except for corticosteroids, low dose cytarabine or hydroxyurea that can be given up to 24 hours prior to start of protocol treatment.
  • Intrathecal cytotoxic therapy: No wash-out time is required for participants having received any combination of intrathecal cytarabine, methotrexate, and/or hydrocortisone.
  • Antibodies: ≥ 21 days must have elapsed from infusion of last dose of an antibody-drug conjugate before start of protocol treatment. For unmodified antibodies or T cell engaging antibodies, 2 half-lives must have elapsed before start of protocol treatment. Any toxicity related to prior antibody therapy must be recovered to Grade ≤ 1.
  • Interleukins, Interferons and Cytokines (other than Hematopoietic Growth Factors): ≥ 21 days after the completion of interleukins, interferon or cytokines (other than Hematopoietic Growth Factors) before start of protocol treatment.
  • Hematopoietic growth factors: ≥ 14 days after the last dose of a long-acting growth factor (e.g., pegfilgrastim) or ≥7 days for short-acting growth factor before start of protocol treatment.
  • Radiation therapy (RT) (before start of protocol treatment):
    • ≥ 14 days have elapsed for local palliative RT (small port);
    • ≥ 84 days must have elapsed if prior craniospinal RT or if ≥ 50% radiation of pelvis;
    • ≥ 42 days must have elapsed if other substantial bone marrow (BM) radiation.
  • Stem Cell Infusions (before start of protocol treatment):
    • ≥ 84 days since allogeneic (non-autologous) bone marrow or stem cell transplant (with or without total body irradiation [TBI]) or boost infusion (any stem cell product; not including donor lymphocyte infusion [DLI])
    • No evidence of active graft versus host disease (GVHD).
  • Participants who are receiving cyclosporine, tacrolimus or other agents to treat or prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant are not eligible for this trial. Participants must be off medications to treat or prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant for at least 14 days prior to enrollment
  • Cellular Therapy: ≥ 42 days after the completion of donor lymphocyte infusion (DLI) or any type of cellular therapy (e.g., modified T cells, natural killer [NK] cells, dendritic cells, etc.) before start of protocol treatment.
  • Participants with prior exposure to venetoclax are eligible in this trial
• Adequate organ function:
  • Adequate Renal Function defined as:
    • Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 60ml/min/1.73 m^2, or
    • Normal serum creatinine based on age/sex
  • Adequate Liver Function defined as:
    • Direct bilirubin < 1.5 x upper limit of normal (ULN), and
    • Alkaline phosphatase ≤ 2.5 x ULN, and
    • Serum glutamic pyruvic transaminase (SGPT) alanine aminotransferase (ALT) ≤ 2.5 x ULN. If liver abnormality is due to radiographically identifiable leukemia infiltrate, the participant will remain eligible.
  • Cardiac performance: Minimum cardiac function defined as:
    • No history of congestive heart failure in need of medical treatment
    • No pre-treatment diminished left ventricular function on echocardiography (shortening fraction [SF] < 25% or ejection fraction [EF] < 40%)
    • No signs of congestive heart failure at presentation of relapse.
• Participant, parent or guardian must sign and date informed consent and pediatric assent (when required), prior to the initiation of screening or study specific procedures, according to local law and legislation.

Exclusion Criteria

• Participants who in the opinion of the investigator may not be able to comply with the study requirements of the study, are not eligible.
• Participants with Down syndrome.
• Participants with Acute promyelocytic leukemia (APL) or Juvenile myelomonocytic leukemia (JMML).
• Participants with isolated CNS3 disease or symptomatic CNS3 disease.
• Participants with malabsorption syndrome or any other condition that precludes enteral administration of venetoclax.
• Participants who are currently receiving another investigational drug (GO is not considered investigational in this study).
• Participants with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known congenital bone marrow failure syndrome.
• Participants with known prior allergy to any of the medications used in protocol therapy.
• Participants with documented active, uncontrolled infection at the time of study entry.
• No known human immunodeficiency virus (HIV) infection.
• Post menarchal female participants with positive pregnancy test.
• Concomitant Medications
  • Participants who have received strong and moderate CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St. John's wort within 7 days of the start of study treatment.
  • Participants who have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit within 3 days of the start of study treatment.
  • Participants who have hypersensitivity to the active substance or to any of the excipients listed in summary of product characteristics (SPC).
• Pregnancy or Breast-Feeding:
  • Participants who are pregnant or breast-feeding.
  • Participants of reproductive potential may not participate unless they have agreed to use a highly effective contraceptive method per clinical trials facilitation group (CTFG) guidelines for the duration of study therapy and for 6 months after the completion of all study therapy.
  • Male participants must use a condom during intercourse and agree not to father a child or donate sperm during therapy and for the duration of study therapy and for 4 months after the completion of all study therapy.

Additional criteria to receive a gemtuzumab ozogamicin infusion:

Gemtuzumab ozogamicin should not be given:

• to participants with history of veno-occlusive disease (VOD)/Sinusoidal obstruction syndrome (SOS) grade 4
• to participants with history of VOD/SOS grade 3
• to participants with CD33 negative leukemic blasts (determined at local lab)

Note that these participants are eligible for the study but will not be treated with gemtuzumab ozogamicin.

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Study Description

A Phase II pilot trial will estimate survival after a non-TBI based conditioning regimen in patients diagnosed with B-acute lymphoblastic leukemia (ALL) who are pre-allogeneic hematopoietic cell transplantation (HCT) next-generation-sequence (NGS) minimal residual disease (MRD) negative.

The relationship of NGS-MRD status to survival in children, adolescents, and young adults with B-ALL undergoing any approach to allogeneic HCT will be explored in a larger cohort (treatment [phase II] and observational arms of the study).

The primary objective is to estimate 2-year event free survival (EFS) in pre-HCT NGS-MRD negative patients with B-ALL undergoing a non-TBI based conditioning regimen through a multi-center prospective trial. The accrual period is 3 years.

Patients that are NGS-MRD negative with B-ALL may be eligible for the Treatment Arm, which is myeloablative non-TBI conditioning with busulfan, fludarabine, and thiotepa followed -matched related, unrelated, and umbilical cord blood transplants. Patients that are NGS-MRD positive will be followed on the observational arm for outcome.

Study sampling will include NGS-MRD bone marrow (BM) aspirate and peripheral blood (PB) samples collected [same day when possible] pre-HCT (within 4 weeks), and post-HCT on days 42 ± 14, 100 ± 20, and 365 ± 60; PB samples only will also be collected day 180± 60 and 270± 60; day +30, day +100, and 1-year post-HCT. NGS-MRD peripheral blood sample only at 6 months and 9 months post-HCT; (Blast specimen at time of diagnosis or relapse is required for NGS-MRD testing).

Inclusion Criteria

Inclusion Criteria for the Observational Arm:

Any patient with ALL who undergoes Myeloablative HCT including any of the following:

• Patients who are pre-HCT NGS-MRD positive.
• Patients <1 year old who are pre-HCT NGS-MRD negative.
• Patients who are pre-HCT NGS-MRD negative (CR1/CR2) who received inotuzumab ozogamicin therapy before proceeding to HCT.
• Patients who are pre-HCT NGS-MRD negative and will be receiving haploidentical HCT.
• Patients who are pre-HCT NGS-MRD negative in CR2 with history of CNS relapse.
• Patients who have received blinatumomab, but are >CR2 prior to HCT.
• Patients who have received CART-T cellular therapy, but are >CR2 prior to HCT.
• Patients with pre-HCT NGS-MRD negative in ≥ CR3.
• Any T-ALL and MPAL patients undergoing first allogeneic HCT
• Any patient who is pre-HCT NGS-MRD negative and eligible for participation in the treatment arm but family does not consent for treatment arm or treating physician believe it is in the patient best interest not to enroll on the treatment arm

Inclusion Criteria for the Treatment Arm:

• Pre-HCT NGS-MRD negative
• Age ≥ 1 year and ≤ 25 years
• Disease status: B-ALL in first (CR1) or second remission (CR2)
• No prior allogeneic hematopoietic stem cell transplant.
• Patients in CR1 or CR2 after blinatumomab treatment.
• Patients in CR1 or CR2 after CAR-T cellular therapy.
• Karnofsky Index or Lansky Play-Performance Scale ≥ 60 % on pre-transplant evaluation. Karnofsky scores must be used for patients > 16 years of age and Lansky scores for patients < 16 years of age.
• Able to give informed consent if > 18 years, or with a legal guardian capable of giving informed consent if < 18 years.
• Adequate organ function (within 4 weeks of initiation of preparative regimen), defined as:
• Pulmonary: FEV1, FVC, and corrected DLCO must all be ≥ 50% of predicted by pulmonary function tests (PFTs). For children who are unable to perform for PFTs due to age, the criteria are: no evidence of dyspnea at rest and no need for supplemental oxygen.
• Renal: Creatinine clearance or radioisotope GFR ≥ 60 mL/min/1.73 m2 or a serum creatinine based on age/gender.
• Cardiac: Shortening fraction of ≥ 27% by echocardiogram or radionuclide scan (MUGA) or ejection fraction of ≥ 50% by echocardiogram or radionuclide scan (MUGA), choice of test according to local standard of care.
• Hepatic: SGOT (AST) or SGPT (ALT) < 5 x upper limit of normal (ULN) for age. Conjugated bilirubin < 2.5 mg/dL, unless attributable to Gilbert's Syndrome.

Exclusion Criteria

• CR2: exclude patients with history of CNS relapse (i.e. in CR2 with history of CNS isolated or combined relapse; CNS 2 will also be considered as CNS 3 for this purpose) from the treatment arm of study (can be enrolled on the observational arm).
• Patients who have received inotuzumab treatment prior to allogeneic HCT are NOT eligible for the study treatment arm. Inotuzumab treatment may increase the risk of VOD/SOS for any allogeneic HCT recipient, but could potentiate the risk for with busulfan-based myeloablation (study-directed non-TBI conditioning). All inotuzumab-treated patients are eligible for the observational arm (HCT center standard of care).
• Patients receiving non-myeloablative conditioning are not allowed on the observational arm (reduced toxicity conditioning with Flu/Mel/Thio is allowed on the observational arm).
• Pregnant or lactating females are ineligible as many of the medications used in this protocol could be harmful to unborn children and infants.
• Patients with HIV or uncontrolled fungal, bacterial or viral infections are excluded. Patients with history of fungal disease during induction therapy may proceed if they have a significant response to antifungal therapy with no evidence or minimal evidence of non-progressive disease remaining by CT evaluation.
• Patients with active CNS leukemia or any other active site of extramedullary disease at the time of enrollment are not permitted.
• T-ALL and MPAL patients are only allowed on the observational arm.
• Patients with genetic disorders (generally marrow failure syndromes) prone to secondary AML/ALL with known poor outcome are not eligible (Fanconi Anemia, Kostmann Syndrome, Dyskeratosis Congenita, etc).

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Study Description

ACTEMRA (tocilizumab) is an IL-6 receptor antagonist used for the treatment of adult Rheumatoid Arthritis as well as Polyarticular (PJIA) and Systemic (SJIA) Juvenile Idiopathic Arthritis. In this Phase II, the drug will be used to treat pediatric patients diagnosed with recurrent Adamantinomatous Craniopharyngioma including patients who have undergone surgery and/or radiation therapy.

Adamantinomatous Craniopharyngioma (ACP) is a highly debilitating pediatric brain tumor that lacks medical anti-tumor therapies. Current therapy, which depends largely on surgery and radiation, is associated with poor quality of life and becomes more challenging and risky in the setting of recurrent disease. Recent discoveries regarding the biological characteristics of ACP indicate that available agents, including IL-6 pathway blockers may have efficacy in the control of ACP. We hypothesize that the IL6- receptor antagonist ACTEMRA (tocilizumab) will be safe and effective at inducing tumor response in children with residual ACP.

In this study, up to 38 patients will receive tocilizumab at the dose approved for pediatric Systemic Juvenile Idiopathic Arthritis (< 30 kg: 12 mg/kg IV every 2 weeks; ≥30 kg: 8 mg/kg IV every 2 weeks). Therapy may continue for up to two years (26 cycles).

It will be a multi-center Phase 2 trial with two strata for patients aged >1 year and <25 years with unresectable ACP who may have been previously treated with radiation (Stratum 1, 18 patients) or without radiation (Stratum 2, 18 patients).

Inclusion Criteria

1. Age: Patients must be ≥ 12 months and ≤ 25 years of age at the time of study enrollment.
2. Diagnosis: Patients with histologically-confirmed adamantinomatous craniopharyngioma (ACP) Histologic confirmation of ACP may be made on solid tumor or, if no solid tumor can be safely obtained, cyst fluid with classic ACP characteristics of thick, cholesterol-rich, greenish-brown liquid in the context of imaging features consistent with craniopharyngioma, including lobulated, cystic/solid mass with calcifications that originates in the sellar/suprasellar region.
3. Disease Status: Patients must have measurable disease.
   • Stratum 1: Patients with progressive or recurrent ACP who demonstrate cystic and/or solid recurrence or progression at least 6 months post completion of radiation therapy
   • Stratum 2: Patients with measurable ACP who have undergone surgery but have NOT previously undergone irradiation (but may have received prior systemic or intracystic therapy). Progressive disease is allowed but not required.
4. Performance Level: Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of age (See Appendix I). Note: Neurologic deficits in patients with CNS tumors must have been stable for at least 7 days prior to study enrollment. 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.
5. Prior Therapy: Patients must have recovered or stabilized from the acute toxic effects of prior treatments
   • Biologic (anti-neoplastic agent): At least 7 days must have elapsed after the last (systemic or intracystic) dose of 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
   • Immunotherapy: At least 42 days after the completion of any type of systemic immunotherapy, e.g. tumor vaccines.
   • Monoclonal antibodies: At least 21 days after the last dose of a monoclonal antibody.
   • Radiation therapy: Patients must have had their last (conventional or hypofractionated) fraction of: a) Focal irradiation > 6 months prior to enrollment and b) No prior craniospinal irradiation is permitted.
   • Corticosteroids: Patients receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment
   • Myelosuppressive systemic therapy: At least 21 days must have elapsed after the last systemic myelosuppressive therapy.
   • Surgery: At least 6 weeks must have elapsed since surgery.
6. Organ Function Requirements
   • Adequate Bone Marrow Function Defined as:
     • Peripheral absolute neutrophil count (ANC) ≥1000/mm3
     • Platelet count ≥100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
     • Hemoglobin >8 g/dL (may be transfused)
   • Adequate Renal Function Defined as:
     • Creatinine clearance or radioisotope GFR > 70ml/min/1.73 m2 or
     • A serum creatinine based on (Schwartz et al. J. Peds, 106:522, 1985) age/gender as follows: 1 to < 2 years: maximum serum creatinine 0.6 mg/dL for males and females. 2 to < 6 years: maximum serum creatinine 0.8 mg/dL for males and females. 6 to < 10 years: maximum serum creatinine 1.0 mg/dL for males and females. 10 to < 13 years: maximum serum creatinine 1.2 mg/dL for males and females. 13 to < 16 years: maximum serum creatinine 1.5 mg/dL for males and 1.4 mg/dL for females. ≥ 16 years: maximum serum creatinine 1.7 mg/dL for males and 1.4 mg/dL for females.
   • Adequate Liver Function Defined as:
     • Total bilirubin within normal institutional limits
     • AST (SGOT) ≤ 2.5 × institutional upper limit of normal
     • ALT (SGPT) ≤ 2.5 × institutional upper limit of normal
   • Adequate Neurologic Function Defined as:
     • Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment.
     • Patients with current seizure disorders may be enrolled if seizures are well-controlled on antiepileptic therapies.
7. Informed Consent: All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.

Exclusion Criteria

1. Pregnancy or Breast-Feeding: Pregnant or breast-feeding women will not be entered on this study due to unknown risks of fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for at least 90 days after discontinuation of drug for females and at least 60 days for males. For females of childbearing potential, agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods (bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices; hormonal contraceptive methods must be supplemented by a barrier method) and agreement to refrain from donating eggs are required. For males of reproductive potential, agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm.
2. Gastrointestinal Disease: Patients with a history of serious gastrointestinal disease, including inflammatory bowel disease or gastrointestinal perforation
3. Concomitant Medications
   • Corticosteroids: Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible.
   • Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible.
   • Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible.
4. Study Specific:
   • Patients who have an uncontrolled infection are not eligible.
   • Patients who have received any live or attenuated vaccinations within three months prior to start of therapy are not eligible.
   • Any significant concurrent medical or surgical condition that would jeopardize the patient's safety or ability to complete the study, including, but not limited to, disease of the nervous, renal, hepatic, cardiac (such as symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia), pulmonary, or endocrine system
   • Patients who have a history of Human Immunodeficiency Virus, Hepatitis B Virus, Hepatitis C Virus or Tuberculosis infection are not eligible.
   • Patients who have received a prior solid organ transplantation are not eligible.
   • Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.
   • Patients who have a history of alcohol, drug, or chemical abuse within 6 months of screening.
   • Patients who have had surgery within the last 6 weeks or who have concerns for poor postsurgical wound healing.
   • Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to tocilizumab and its excipients are not eligible.

Other inclusion and exclusion criteria may apply.

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Study Description

The primary objective of the study is to determine the recommended phase 2 dose (RP2D) of ziftomenib in combination with chemotherapy (FLA) in children with relapsed or refractory KMT2A-r, NUP98-r, or NPM1-m acute leukemia based on safety and pharmacokinetics (PK).

Inclusion Criteria

• Age: 0-21 years (and at least 5 kg body weight), with a minimum of 80% of participants under 18 years of age.
• Diagnosis: KMT2A-r, NPM1-m, or NUP98-r acute leukemia in first or greater relapse or refractory to standard (re-) induction treatment (including HSCT). Please note that genetic alteration must be confirmed by the central laboratory, or the participant will discontinue protocol therapy.
• Eligible participants also must fulfill one of the following conditions:
  • Bone marrow relapse is defined as:
    • A single bone marrow sample showing ≥ 5% leukemic blasts by flow cytometry, fluorescence in situ hybridization (FISH) testing, or other molecular method.
      • a single bone marrow sample with at least two tests showing ≥ 1% leukemic blasts, examples of tests (confirmed by central lab) include: Flow cytometry showing leukemia ≥ 1% by multiparameter flow cytometry (MFC) confirmed by central lab
      • Karyotypic abnormality as confirmed by central cytogenetic review.
      • FISH abnormality identical to one present at diagnosis (must be above level of sensitivity of specific FISH probe; central cytogenetic review required).
      • Polymerase chain reaction (PCR) or next generation sequencing (NGS)-based demonstration of validated leukemogenic lesion (e.g., fusion, mutation) in a Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory that matches initial diagnosis and is quantifiable as ≥1% confirmed by central lab.
    • Participants with combined extramedullary and bone marrow relapse (defined as above) are eligible.
    • Participants with isolated extramedullary disease (EMD) are not eligible. EMD relapse is defined as biopsy-proven extramedullary disease without bone marrow disease after documented complete response (CR) following initial therapy. Participants with isolated central nervous system (CNS) relapse are not eligible. Participants with a combined medullary/extramedullary relapse, including CNS disease, are eligible.
    • Participants with asymptomatic CNS3 disease are eligible if they do not have isolated CNS3 extramedullary relapse.
    • For participants unable to undergo bone marrow assessment, a peripheral blood absolute blast count ≥ 1,000 cell/microliter is sufficient to diagnose relapsed or refractory disease and facilitate confirmation of required genetic alterations for protocol therapy.
  • Refractory disease/induction failure:
    • Acute myeloid leukemia (AML): The bone marrow contains ≥ 1% leukemic blasts by MFC at the end of 2 cycles of induction therapy.
    • Acute lymphoblastic leukemia (ALL)/mixed-phenotype acute leukemia (MPAL)/acute undifferentiated leukemia (AUL): The bone marrow contains ≥ 1% leukemic blasts by MFC at the end of induction and consolidation, or persistent MRD prior HSCT (defined as > 0.01%).
    • For participants unable to have bone marrow assessed, a peripheral blood absolute blast count ≥ 1,000 cell/microliter is sufficient to diagnose relapsed or refractory disease.
  • Molecular refractory disease in infant ALL, defined as MRD >0.05% after primary induction and consolidation therapy measured by MFC or PCR.
• Performance status: Participants must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2 (≥ 50% Lansky or Karnofsky score). Use ECOG for adult participants (≥18 to 21 years), Karnofsky for participants ≥16 to 18 years of age, and Lansky for participants < 16 years of age. Participants 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.
• Adequate organ function:
  • Renal function defined as: Creatinine clearance (CrCl) ≥60 mL/min (as measured by a nuclear glomerular filtration rate [GFR] scan or calculated by the Schwartz formula and normalized to a body surface area of 1.73 m^2).
  • Liver function defined as:
    • Direct bilirubin < 3 x upper limit of normal (ULN) and Serum glutamic pyruvic transaminase (SGPT) (alanine transaminase [ALT]) ≤ 5 x ULN.
    • If liver abnormality is due to radiographically identifiable leukemia infiltrate, the participant will remain eligible.
  • Cardiac function defined as: Pre-treatment left ventricular function on echocardiography: Fractional shortening (FS) ≥ 25% or ejection fraction (EF) ≥ 40%, and no signs of congestive heart failure within 4 weeks before start of screening.
• Prior therapy: Participants must have recovered from the acute toxic effects of all prior anti-cancer therapy (excluding Grade 2 toxicities that are not considered a safety risk or medically significant toxicity deemed irreversible by the Investigator) and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment.
  • Cytotoxic chemotherapy: Must not have received within 14 days or within 5 drug half-lives (whichever is longer), of entry onto this study, except for hydroxyurea or corticosteroids. Use of steroids and hydroxyurea for other purposes such as differentiation syndrome, or to premedication to prevent allergic reaction or during anesthesia is allowed.
  • Intrathecal cytotoxic therapy: No washout or waiting period is required for participants having received any combination of intrathecal cytarabine, methotrexate, and/or hydrocortisone.
  • Antibodies: ≥ 21 days must have elapsed from infusion of last dose of an antibody-drug conjugate. For unmodified antibodies or T cell engaging antibodies, 2 half-lives must have elapsed before enrollment. Any toxicity related to prior antibody therapy must be recovered back to baseline.
  • Interleukins, interferons and cytokines (other than hematopoietic growth factors): ≥ 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors).
  • Hematopoietic growth factors: ≥ 14 days after the last dose of a long-acting growth factor (e.g., peg-filgrastim) or 7 days for short-acting growth factor.
  • Radiation therapy (RT): 14 days have elapsed for local palliative RT (small port); ≥ 84 days must have elapsed if prior craniospinal RT or if ≥ 50% radiation of pelvis; ≥ 42 days must have elapsed if other substantial bone marrow (BM) radiation.
  • Stem cell infusions
    • Participants who have relapsed after allogeneic (non-autologous) BM or stem cell transplant (with or without total body irradiation [TBI]) or boost infusion (any stem cell product; not including donor lymphocyte infusion [DLI]) must be at least 84 days post HSCT and without evidence of graft versus host disease (GVHD) of any severity except: the use of topical steroids for cutaneous GVHD is allowed and stable steroid doses less than or equal to 10 mg of prednisone daily is permitted. Prednisone dose must be adjusted for body surface area (BSA) in young children. Physiologic doses of hydrocortisone for participants with adrenal insufficiency is allowed.
    • Participants who after relapse and continue to receive cyclosporine, tacrolimus or other agents to treat or prevent either GVHD post BM transplant or organ rejection post-transplant are not eligible for this trial. In the relapse setting, participants must be off medications to treat or prevent either GVHD post BM transplant or organ rejection post-transplant for at least 14 days prior to enrollment. A stable steroid dose as mentioned above is allowed.
  • Cellular therapy: ≥ 30 days after the completion of DLI or any type of cellular Therapy (e.g., modified T cells, NK cells, dendritic cells, etc.).
  • Prior exposure to a different menin inhibitor: Participants who received previous treatment with a different menin inhibitor are allowed to enrol in the study with the exception of those who experienced a severe adverse event attributable to the strong anti-proliferative/pro-differentiation effects of other menin inhibitors (such as severe differentiation syndrome). Participants who experienced a severe adverse event, which can directly be attributed to specific effects (e.g., long QT syndrome) observed with other menin inhibitors can participate in the study if they fulfill the inclusion criteria.
• Informed consent: Written, signed and dated informed consent and pediatric assent (if applicable) according to local law and legislation should be collected before start of any study procedures.
• Female participants of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment.
• Female participants with infants must agree not to breastfeed their infants while on this study.
• Contraception:
  • Participants of reproductive potential, starting from menarche and onwards, may not participate unless they have agreed to use a highly effective contraceptive method per Clinical Trial Facilitation Group (CTFG) guidelines for the duration of study therapy and for 6 months after the completion of all study therapy. For further guidance please review the CTFG website.
  • Male participants must use a condom during intercourse and agree not to father a child or donate sperm during therapy and for the duration of study therapy and for 4 months after the completion of all study therapy.
• Enrollment APAL2020SC trial (US and Canada only): Participants in the US and Canada must have enrolled in the APAL2020SC trial prior to enrollment in the APAL2020K trial.

Exclusion Criteria

• Participants who in the opinion of the investigator may not be able to comply with the study requirements of the study.
• Participants with Down syndrome.
• Participants with EMD are not eligible. EMD relapse is defined as biopsy proven extramedullary disease without bone marrow disease after documented CR following initial therapy.
• Participants with isolated CNS relapse are not eligible, as well as symptomatic CNS3 disease.
• Participants with acute promyelocytic leukemia (APL) or juvenile myelomonocytic leukemia (JMML).
• Participants with malabsorption syndrome or any other condition that precludes enteral administration of a menin inhibitor.
• Concomitant therapy: Gastric pH has great influence on absorption of ziftomenib; therefore, the use of proton pump inhibitors is prohibited, if necessary H2 Blockers may provide an alternative treatment option.
• Participants who are currently receiving another investigational drug.
• Participants with any known congenital bone marrow failure syndrome.
• Participants with known prior allergy to any of the medications used in protocol therapy.
• Participants with documented active, uncontrolled infection at the time of study entry.
• Active/uncontrolled known human immunodeficiency virus (HIV) infection, hepatitis B virus (HBV) and hepatitis C virus (HCV). Note: HIV testing does not need to be conducted at screening unless it is required per local guidelines or institutional standard.
• Post menarche female participants with positive pregnancy test, and a lactating female participant.
• Participant has a pre-existing disorder predisposing the participant to a serious or life-threatening infection (e.g., cystic fibrosis, congenital or acquired immunodeficiency, bleeding disorder, or cytopenia not related to the leukemia or its treatment).
• Participants must not be receiving other investigational medications (defined as medicinal products not yet approved for any indications, including alternative/herbal therapies) within 30 days of first dose of study drug or while on study.
• Significant congenital cardiovascular disease including, but not limited to conditions such as long QT syndrome, fundamental uncorrected cardiac defect (e.g., coarctation of the aorta) that poses a significant risk to the participant (ventricular septal defect or atrial septal defect are considered non-significant).
• Underlying medical condition that, in the Principal Investigator's opinion, will make the administration of study treatment hazardous or obscure the interpretation of toxicity determination or AEs.
• For fludarabine and cytarabine: Hypersensitivity to the active substance or to any of the excipients.
• Recent live vaccinations for at least 6 months.

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Centres

Study Description

This study will evaluate the safety, pharmacokinetics, and efficacy of alectinib in children and adolescents with ALK fusion-positive solid or CNS tumors for whom prior treatment has proven to be ineffective or for whom there is no satisfactory standard treatment available.

Inclusion Criteria

• Histologically confirmed diagnosis of CNS or solid tumors harboring ALK gene fusions as determined locally by an appropriately validated assay performed in a CLIA-certified or equivalently-accredited diagnostic laboratory, or centrally by a Foundation Medicine Clinical Trial Assay (CTA) or the alternative, approved central laboratory for that region
• Disease status: prior treatment proven to be ineffective (i.e. relapsed or refractory), or for whom there is no satisfactory standard treatment available. Disease should be measurable and evaluable as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1, or Response Assessment in Neuro-oncology criteria (RANO) +/- bone marrow criteria for primary CNS tumors or International Neuroblastoma Response Criteria (INRC)
• Available tumor tissue for submission to the Sponsor from active disease, obtained subsequent to last anti-cancer therapy regiment administered and obtained prior to study enrollment, archival tumor tissue from original diagnosis, or willingness to undergo a core or excisional biopsy sample collection prior to enrollment
• For participants < 16 years old, Lansky Performance Status >/= 50%
• For participants >/= 16 years old, Karnofsky Performance Status >/= 50%
• Adequate bone marrow function as defined by the protocol within at least 28 days prior to initiation of study drug
• Participant and/or caregiver willingness and ability to complete clinical outcome assessments throughout the study using either electronic, paper, or interviewer methods
• For females of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs, as defined by the protocol
• For males who are not surgically sterile: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating sperm, as defined by the protocol

Exclusion Criteria

• Medical history of: prior use of ALK inhibitors; any gastrointestinal disorder that may affect absorption of oral medications, such as mal-absorption syndrome or status post-major bowel resection; history of organ transplant; stem cell infusions as defined by the protocol
• Substance abuse within 12 months prior to screening
• Familial or personal history of congenital bone disorders, bone metabolism alterations, or osteopenia
• Treatment with investigational therapy 28 days prior to initiation of study drug
• Liver or kidney disease as defined by the protocol
• National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grade >/=3 toxicities attributed to any prior therapy such as radiotherapy (excluding alopecia), which have not shown improvement and are strictly considered to interfere with alectinib
• Co-administration of anti-cancer therapies other than those administered in this study
• Active hepatitis B or C virus (HBV, HBC), or known HIV-positivity or AIDS-related illness
• Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the Principal Investigator, pose an unacceptable risk to the participant in this study
• Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; such conditions should be discussed with the participant before trial entry
• Planned procedure or surgery during the study except as permitted treatment as defined by the protocol
• Infection considered by the investigator to be clinically uncontrolled or of unacceptable risk to the participant upon induction of neutropenia, including participants who are, or should be, on antimicrobial agents for the treatment as active infection
• Pregnant or breastfeeding, or intending to become pregnant during the study or within 3 months after the final dose of alectinib

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Centres

Study Description

Adamantinomatous Craniopharyngioma (ACP) is a highly debilitating pediatric brain tumor that lacks medical anti-tumor therapies. Current therapy, which depends largely on surgery and radiation, is associated with poor quality of life and becomes more challenging and risky in the setting of recurrent disease. Recent discoveries regarding the biological characteristics of ACP indicate that available agents, including Mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway inhibitors may have efficacy in the control of ACP. Binimetinib is one such agent.

In this study, up to 38 patients will receive oral binimetinib at the recommended phase 2 pediatric dose (RP2D) of 32 mg/m2/dose PO every 12 hours for 4 weeks which represents one cycle. Cycles will last 28 days and treatment may continue for up to two years (26 cycles).

It will be a multi-center Phase 2 trial with two strata for patients aged >1 year and <25 years with measurable ACP who may have been previously treated with radiation (Stratum 1, 18 patients) or without radiation (Stratum 2, 18 patients).

Inclusion Criteria

• Patients must be ≥ 12 months and ≤ 25 years of age at the time of study enrollment.
• Patients with histologically-confirmed adamantinomatous craniopharyngioma (ACP) Histologic confirmation of ACP may be made on solid tumor or, if no solid tumor can be safely obtained, cyst fluid with classic ACP characteristics of thick, cholesterol-rich, greenish-brown liquid in the context of imaging features consistent with craniopharyngioma, including lobulated, cystic/solid mass with calcifications that originates in the sellar/suprasellar region.
• Disease Status: Patients must have measurable disease.
  • Stratum 1: Patients with progressive or recurrent ACP who demonstrate cystic and/or solid recurrence or progression at least 6 months post completion of radiation therapy
  • Stratum 2: Patients with measurable ACP who have undergone surgery but have NOT previously undergone irradiation (but may have received prior systemic or intracystic therapy). Progressive disease is allowed but not required.
• Performance Level: Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of age (See Appendix I). Note: Neurologic deficits in patients with CNS tumors must have been stable for at least 7 days prior to study enrollment. 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.
• Prior Therapy: Patients must have recovered or stabilized from the acute toxic effects of prior treatments
  • Biologic (anti-neoplastic agent): At least 7 days must have elapsed after the last (systemic or intracystic) dose of 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
  • Immunotherapy: At least 42 days after the completion of any type of systemic immunotherapy, e.g. tumor vaccines.
  • Monoclonal antibodies: At least 21 days after the last dose of a monoclonal antibody.
  • Radiation therapy: Patients must have had their last (conventional or hypofractionated) fraction of: a) Focal irradiation > 6 months prior to enrollment and b) No prior craniospinal irradiation is permitted.
  • Corticosteroids: Patients receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment
  • Myelosuppressive systemic therapy: At least 21 days must have elapsed after the last systemic myelosuppressive therapy.
  • Surgery: At least 6 weeks must have elapsed since surgery.
• Organ Function Requirements
  • Adequate Bone Marrow Function Defined as:
    • Peripheral absolute neutrophil count (ANC) ≥1000/mm3
    • Platelet count ≥100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
    • Hemoglobin >8 g/dL (may be transfused)
  • Adequate Renal Function Defined as:
    • Creatinine clearance or radioisotope GFR > 70ml/min/1.73 m2 or
    • A serum creatinine based on (Schwartz et al. J. Peds, 106:522, 1985) age/gender as follows:
      • 1 to < 2 years: maximum serum creatinine 0.6 mg/dL for males and females.
      • 2 to < 6 years: maximum serum creatinine 0.8 mg/dL for males and females.
      • 6 to < 10 years: maximum serum creatinine 1.0 mg/dL for males and females.
      • 10 to < 13 years: maximum serum creatinine 1.2 mg/dL for males and females.
      • 13 to < 16 years: maximum serum creatinine 1.5 mg/dL for males and 1.4 mg/dL for females.
      • ≥ 16 years: maximum serum creatinine 1.7 mg/dL for males and 1.4 mg/dL for females.
  • Adequate Liver Function Defined as:
    • Total bilirubin ≤ 1.5 × institutional upper limit of normal
    • AST (SGOT) ≤ 2.5 × institutional upper limit of normal
    • ALT (SGPT) ≤ 2.5 × institutional upper limit of normal
  • Adequate Cardiac Function Defined as:
    • Left Ventricular Ejection Fraction greater than the institutional lower limit of normal by echocardiogram
    • QTc ≤ 480 msec (by Bazett formula)
  • Adequate Neurologic Function Defined as:
    • Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment.
    • Patients with current seizure disorders may be enrolled if seizures are well-controlled on antiepileptic therapies.
  • Informed Consent: All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines

Exclusion Criteria

• Pregnancy or Breast-Feeding: Pregnant or breast-feeding women will not be entered on this study due to unknown risks of fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for at least 90 days after discontinuation of drug for females and at least 60 days for males. For females of childbearing potential, agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods (bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices; hormonal contraceptive methods must be supplemented by a barrier method) and agreement to refrain from donating eggs are required. For males of reproductive potential, agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm.
• Gastrointestinal Disease:
  • Patients with a history of serious gastrointestinal disease, including inflammatory bowel disease or gastrointestinal perforation
  • Patients who are unable to swallow, retain or absorb oral medications
• Concomitant Medications
  • Corticosteroids: Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible.
  • Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible.
  • Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible.
• Study Specific:
  • Patients who have an uncontrolled infection are not eligible.
  • Patients who have received any live or attenuated vaccinations within three months prior to start of therapy are not eligible.
  • Any significant concurrent medical or surgical condition that would jeopardize the patient's safety or ability to complete the study, including, but not limited to, disease of the nervous, renal, hepatic, cardiac (such as symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia), pulmonary, or endocrine system
  • Patients who have a history of Human Immunodeficiency Virus, Hepatitis B Virus, Hepatitis C Virus or Tuberculosis infection are not eligible.
  • Patients who have received a prior solid organ transplantation are not eligible.
  • Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.
  • Patients who have a history of alcohol, drug, or chemical abuse within 6 months of screening.
  • Patients who have had surgery within the last 6 weeks or who have concerns for poor postsurgical wound healing.
  • Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to tocilizumab and its excipients are not eligible.

Publications

• Foreman NK, Faestel PM, Pearson J, Disabato J, Poole M, Wilkening G, Arenson EB, Greffe B, Thorne R. Health status in 52 long-term survivors of pediatric brain tumors. J Neurooncol. 1999 Jan;41(1):47-53. doi: 10.1023/a:1006145724500.
• Goldman S, Pollack IF, Jakacki RI, Billups CA, Poussaint TY, Adesina AM, Panigrahy A, Parsons DW, Broniscer A, Robinson GW, Robison NJ, Partap S, Kilburn LB, Onar-Thomas A, Dunkel IJ, Fouladi M. Phase II study of peginterferon alpha-2b for patients with unresectable or recurrent craniopharyngiomas: a Pediatric Brain Tumor Consortium report. Neuro Oncol. 2020 Nov 26;22(11):1696-1704. doi: 10.1093/neuonc/noaa119.
• Apps JR, Carreno G, Gonzalez-Meljem JM, Haston S, Guiho R, Cooper JE, Manshaei S, Jani N, Holsken A, Pettorini B, Beynon RJ, Simpson DM, Fraser HC, Hong Y, Hallang S, Stone TJ, Virasami A, Donson AM, Jones D, Aquilina K, Spoudeas H, Joshi AR, Grundy R, Storer LCD, Korbonits M, Hilton DA, Tossell K, Thavaraj S, Ungless MA, Gil J, Buslei R, Hankinson T, Hargrave D, Goding C, Andoniadou CL, Brogan P, Jacques TS, Williams HJ, Martinez-Barbera JP. Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK/ERK pathway as a novel therapeutic target. Acta Neuropathol. 2018 May;135(5):757-777. doi: 10.1007/s00401-018-1830-2. Epub 2018 Mar 14.
• Haston S, Pozzi S, Carreno G, Manshaei S, Panousopoulos L, Gonzalez-Meljem JM, Apps JR, Virasami A, Thavaraj S, Gutteridge A, Forshew T, Marais R, Brandner S, Jacques TS, Andoniadou CL, Martinez-Barbera JP. MAPK pathway control of stem cell proliferation and differentiation in the embryonic pituitary provides insights into the pathogenesis of papillary craniopharyngioma. Development. 2017 Jun 15;144(12):2141-2152. doi: 10.1242/dev.150490. Epub 2017 May 15.
• Bendell JC, Javle M, Bekaii-Saab TS, Finn RS, Wainberg ZA, Laheru DA, Weekes CD, Tan BR, Khan GN, Zalupski MM, Infante JR, Jones S, Papadopoulos KP, Tolcher AW, Chavira RE, Christy-Bittel JL, Barrett E, Patnaik A. A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor. Br J Cancer. 2017 Feb 28;116(5):575-583. doi: 10.1038/bjc.2017.10. Epub 2017 Feb 2.
• Watanabe K, Otsu S, Hirashima Y, Morinaga R, Nishikawa K, Hisamatsu Y, Shimokata T, Inada-Inoue M, Shibata T, Takeuchi H, Watanabe T, Tokushige K, Maacke H, Shiaro K, Ando Y. A phase I study of binimetinib (MEK162) in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2016 Jun;77(6):1157-64. doi: 10.1007/s00280-016-3019-5. Epub 2016 Apr 12.
• Patel K, Allen J, Zagzag D, Wisoff J, Radmanesh A, Gindin T, Nicolaides T. Radiologic response to MEK inhibition in a patient with a WNT-activated craniopharyngioma. Pediatr Blood Cancer. 2021 Mar;68(3):e28753. doi: 10.1002/pbc.28753. Epub 2020 Oct 19. No abstract available.