​ Trials

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Study Description

The purpose of Phase 1b of this study is to:

• Asses the safety, tolerability and activity of carfilzomib, alone and in combination with induction chemotherapy, in children with relapsed or refractory acute lymphoblastic leukemia (ALL).
• Determine the maximum tolerated dose (MTD) and to recommend a phase 2 dose of carfilzomib in combination with induction chemotherapy.

The purpose of Phase 2 of this study is to compare the rate of complete response (CR) of carfilzomib in combination with vincristine, dexamethasone, PEG asparaginase, daunorubicin (VXLD) at the end of induction therapy to an appropriate external control.

Inclusion Criteria

Phase 1b Key Inclusion Criteria:

1. Age 21 years or younger at the time of initial ALL diagnosis and age > 1 year at the time of study treatment initiation.

2. Subjects must have a diagnosis of relapsed or refractory ALL with ≥ 5% blasts in the bone marrow (M2 or M3 disease), with or without extramedullary disease.

   -To be eligible, subjects must have had 1 or more prior therapeutic attempts, defined as:

   • Early first relapse (< 36 months from original diagnosis) after achieving a CR (B-ALL) or first relapse any time following the original diagnosis after achieving a CR (T-ALL)
   • First refractory bone marrow relapse occurring any time after original diagnosis after achieving a CR (ie, ≥1 failed attempt to induce a second remission) OR
   • Relapse after achieving a CR following the first or subsequent relapse (i.e., ≥ 2 relapses) OR
   • Failing to achieve a CR from original diagnosis after at least 1 induction attempt
3. Subjects must have fully recovered from the acute toxic effects of all previous chemotherapy, immunotherapy, or radiotherapy treatment before enrollment.
4. Subjects must have a serum creatinine level that is ≤ 1.5 × institutional upper limit of normal (ULN) according to age. If serum creatinine level is > 1.5 × ULN, the subject must have a calculated creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m2.

5. Adequate liver function, defined as both of the following:

   • Total bilirubin ≤ 1.5 × institutional ULN except in the presence of Gilbert Syndrome
   • Alanine aminotransferase (ALT) ≤ 5 × institutional ULN
6. Performance status: Karnofsky or Lansky scores ≥ 50 for subjects > 16 years old or ≤ 16 years old, respectively.

Phase 2 Inclusion Criteria:

1. Subject's legally acceptable representative has provided informed consent when the subject is legally too young to provide informed consent and the subject has provided written assent based on local regulations and/or guidelines prior to any study-specific activities/procedures being initiated.
2. Age ≥ 1 month to < 21 years. Subjects ≥ 18 years must have had their original diagnosis at < 18 years of age.
3. Subjects must be diagnosed with relapsed or refractory relapsed ALL.
4. Subjects must have a documented first remission, ≤ 5% blasts in the bone marrow (M1 bone marrow) and no evidence of extramedullary disease.

5. T-cell ALL with bone marrow relapse (defined as ≥ 5% leukemia blasts in bone marrow) or refractory relapse with or without extramedullary disease.

   OR B-cell ALL bone marrow relapse or refractory relapse (defined as ≥ 5% leukemia blasts in bone marrow) after having received a targeted B-cell immune therapy as treatment for a prior relapse (eg, blinatumomab, inotuzumab or a CAR-T therapy) with or without extramedullary disease. Subjects that receive blinatumomab for treatment of MRD positive disease during first remission do not qualify.

6. Adequate liver function: bilirubin ≤ 1.5 x upper limit of normal (ULN), alanine aminotransferase (ALT) ≤ 5 x ULN.
7. Adequate renal function: serum creatinine ≤ 1.5 x ULN or glomerular filtration rate (GFR) ≥ 70 ml/min/1.73m^2; or for children < 2 years of age ≥ 50 ml/min/1.73m^2.
8. Adequate cardiac function: shortening fraction > 30% or ejection fraction ≥ 50%.
9. Karnofsky (subjects ≥ 16 years of age) or Lansky (subjects 12 months to < 16 years of age) performance status ≥ 50%.
10. Subjects must have fully recovered from the acute toxic effects of all previous chemotherapy, immunotherapy, or radiotherapy treatment before enrollment (for example: recovery from gastrointestinal toxicity may occur more rapidly than less reversible organ toxicities such as sinusoidal obstruction syndrome or non-infectious pneumonitis, for serious prior toxicities recommended discussion with Amgen medical monitor).
11. Life expectancy of ≥ 6 weeks per investigator's judgement at time of screening.

Exclusion Criteria

Phase 1b Key Exclusion Criteria:

1. Known allergy to any of the drugs used in the study (Subjects who have had a previous allergy to PEG-asparaginase and if able, may receive Erwinia asparaginase at the investigator's discretion)
2. Known allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib)
3. Left ventricular fractional shortening < 30%
4. History of ≥ Grade 2 pancreatitis
5. Active graft-versus-host disease requiring systemic treatment
6. Positive culture for or other clinical evidence of infection with bacteria or fungus within 14 days of the initiation of study treatment
7. Down Syndrome

8. Prior therapy restrictions:

   • Subjects must have completed therapy with granulocyte-colony stimulating factor (G-CSF) or other myeloid growth factors at least 7 days before study treatment initiation, or at least 14 days before study treatment initiation, if pegylated myeloid growth factors were administered.
   • Subjects must have completed any type of active immunotherapy (e.g., tumor vaccines) at least 42 days before study treatment initiation.
   • Subjects must have received the last dose of a non-monoclonal antibody biologic agent at least 7 days before study treatment initiation.
   • At least 3 antibody half-lives must have elapsed since the last dose of monoclonal antibody (e.g., 66 days for rituximab and 69 days for epratuzumab) before subjects may initiate study treatment.
   • Subjects must not have received other antineoplastic agents with therapeutic intent, excluding hydroxyurea and antimetabolites administered as part of maintenance chemotherapy, within 7 days prior to study treatment initiation.
9. Hepatitis B infection with positive hepatitis B DNA

Phase 2 Exclusion Criteria:

1. Prior treatment with carfilzomib.
2. Prior treatment with a proteasome inhibitor (other than carfilzomib) within < 3 months of enrollment or to which a subject did not respond (response is defined as bone marrow with < 5% blasts).
3. Treatment with a chemotherapy regimen including a vinca alkaloid, steroid, L-asparaginase, and anthracycline combination with or without other chemotherapy agents within 2 months of enrollment (eg VXLD, VPLD, R3).
4. Intolerance, hypersensitivity, or inability to receive any of the chemotherapy components of the VXLD regimen. An exception is allowed for allergy to asparaginase products if Erwinia Asparaginase is unable to be administered, or if PEG-Asparaginase or Erwinia Asparaginase are not available in the country, these subjects may still be included.
5. Autologous HSCT within 6 weeks prior to start of study treatment.
6. Allogeneic HSCT within 3 months prior to start of study treatment.
7. Active GVHD requiring systemic immune suppression.
8. < 30 days from discontinuation of immune suppressive therapy administered for the treatment of acute or chronic GVHD.
9. Isolated extramedullary relapse.
10. Positive bacterial or fungal infection within 14 days of enrollment (except for documented line infection, line has been removed, and blood culture after line removal is negative for 5 days prior to first dose of induction therapy). Antibiotics may be administered for prophylaxis as per institutional standards up to and after enrollment.
11. < 3 antibody half-lives since the last dose of monoclonal antibody (eg, 66 days for rituximab, 69 days for epratuzumab, inotuzumab for 36 days), prior to first dose of investigational product.
12. Cell-based immunotherapy (eg, donor leucocyte infusion, CAR-T cells, tumor vaccines) within 42 days prior to first dose of investigational product. If the Amgen medical monitor agrees, an exception may be granted to the 42-day requirement for subjects with rapidly rising peripheral or bone marrow blast counts.
13. Down's syndrome.
14. Presence of another active cancer.
15. History of grade ≥ 2 pancreatitis within 6 months to screening.
16. Unresolved toxicities from prior anticancer therapy, defined as not having resolved to CTCAE version 4.03 grade 1 or to levels dictated in the eligibility criteria apart from alopecia or toxicities from prior anticancer therapy that are considered irreversible and do not trigger another exclusion criterion (defined as having been present and stable for > 4 weeks).
17. Antitumor therapy (chemotherapy, investigational agents, molecular-targeted therapy) within 7 days of day 1 of induction. Exception: hydroxyurea to control peripheral blood leukemic cell counts is allowed until start of investigational product.
18. Active viral infection, including but not limited to CMV, Hepatitis B infection with positive serum hepatitis surface antigen or hepatitis B DNA, HIV, Hepatitis C with detectable hepatitis C RNA.
19. Currently receiving treatment in another investigational device or product study, or < 14 days since ending treatment on another investigational device or product study.
20. Uncontrolled arrhythmias or screening ECG with corrected QT interval (QTc) of > 470 msec.
21. History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
22. Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional months after the last dose of any study treatment or for 12 months after last dose of cyclophosphamide if administered during optional consolidation cycle.
23. Female subjects of childbearing potential unwilling to use 1 highly effective method of contraception during treatment and for an additional 12 months after the last dose of any study treatment. Refer to Section 28 for additional contraceptive information.
24. Female subjects of childbearing potential with a positive pregnancy test assessed at Screening by a serum or urine pregnancy test.
25. Male subjects with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use a condom with spermicide during treatment and for an additional 6 months after the last dose of any study treatment, even if they have undergone a successful vasectomy.
26. Male subjects with a pregnant partner who are unwilling to practice abstinence or use a condom with spermicide during treatment, for duration of pregnancy, and for an additional 6 months after the last dose of any study treatment.
27. Male subjects unwilling to abstain from donating semen or sperm during treatment and for an additional 6 months after the last dose of any study treatment.

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Study Description

This phase II trial studies how well veliparib, radiation therapy, and temozolomide work in treating patients with newly diagnosed malignant glioma without H3K27M or BRAFV600 mutations. Poly adenosine diphosphate (ADP) ribose polymerases (PARPs) are proteins that help repair DNA mutations. PARP inhibitors, such as veliparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving veliparib, radiation therapy, and temozolomide may work better in treating patients with newly diagnosed malignant glioma without H3 K27M or BRAFV600 mutations compared to radiation therapy and temozolomide alone.

Inclusion Criteria

• Stratum 1 (IDH wild-type): Patients must be >= 3 years of age and =< 21 years of age at the time of enrollment
  • Please note Stratum 1 was closed to accrual on January 24, 2020
• Stratum 2 (IDH mutant): Patients must be >= 3 years of age and =< 25 years of age at the time of enrollment
• Patients must have eligibility confirmed by rapid central pathology and central molecular screening reviews performed on APEC14B1:
  • Newly-diagnosed high-grade glioma such as anaplastic astrocytoma or glioblastoma
  • Negative results for H3 K27M by immunohistochemistry (IHC)
  • Negative results for BRAFV600 mutation by next-generation sequencing (NGS)
• Patients must have histological verification of diagnosis. Patients with M+ disease (defined as evidence of neuraxis dissemination) are not eligible. Cerebrospinal fluid (CSF) cytology is not required but may be obtained if clinically indicated prior to study enrollment. If cytology is positive, the patient would be considered to have metastatic disease and would, therefore, be ineligible
• Pre-operative and post-operative brain magnetic resonance imaging (MRI) with and without contrast must be obtained. The requirement for a post-operative MRI is waived for patients who undergo biopsy only. A spine MRI is not required, but may be obtained if clinically indicated. If the spine MRI is positive, the patient would be considered to have M+ disease (defined as neuraxis dissemination) and would be ineligible
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age
• Peripheral absolute neutrophil count (ANC) >= 1,000/uL (within 7 days prior to enrollment)
• Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to enrollment)
• Hemoglobin >= 8.0 gm/dL (can be transfused) (within 7 days prior to enrollment)
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 OR a serum creatinine based on age/gender as follows (within 7 days prior to enrollment):
  • 3 to < 6 years: 0.8 (male and female) maximum serum creatinine (mg/dL)
  • 6 to < 10 years: 1 (male and female) maximum serum creatinine (mg/dL)
  • 10 to < 13 years: 1.2 (male and female) maximum serum creatinine (mg/dL)
  • 13 to < 16 years: 1.5 (male), 1.4 (female) maximum serum creatinine (mg/dL)
  • >= 16 years: 1.7 (male), 1.4 (female) maximum serum creatinine (mg/dL)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment)
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L
• Patients with seizure disorder may be enrolled if seizures are well-controlled (i.e., patients must not have required rescue medications for uncontrolled seizures within 14 days prior to enrollment)
• Patients must be enrolled and protocol therapy must be projected to begin no later than 31 days after definitive surgery (Day 0). If a biopsy only was performed, the biopsy date will be considered the date of definitive surgery. For patients who have a biopsy or incomplete resection at diagnosis followed by additional surgery, the date of the last resection will be considered the date of definitive surgery
• 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

Other inclusion and exclusion criteria may apply and will be discussed with you by the study doctor

Exclusion Criteria

• Patients with the following histologies:
  • Diffuse astrocytoma (grade 2)
  • Oligodendrogliomas (any grade)
  • Pleomorphic xanthoastrocytoma (PXA, any grade)
• Patients with primary tumor location of brainstem or spinal cord
• Patients with M+ disease (defined as neuraxis dissemination either by imaging or by cytology)
• Patients with treatment-related acute myeloid leukemia (AML) (t-AML)/myelodysplastic syndrome (MDS) or with features suggestive of AML/MDS
• Prior allogenic bone marrow transplant or double umbilical cord blood transplantation
• Patients must not have received any prior tumor-directed therapy including radiation therapy, chemotherapy (tumor-directed therapy), molecularly targeted agents, or immunotherapy for the treatment of HGG other than surgical intervention and/or corticosteroids
• Lumbar CSF cytology is not required, but may be performed if clinically indicated prior to study enrollment. If lumbar CSF cytology is positive, the patient is considered to have M+ disease and is ineligible
  • Note: False positive cytology can occur within 10 days of surgery
• Patients with gliomatosis cerebri type 1 or 2
• Patients who are not able to receive protocol specified radiation therapy
• Patients must not be currently receiving other anti-cancer agents
• Patients with known constitutional mismatch repair deficiency syndrome (CMMR-D)/biallelic mismatch repair deficiency (bMMRD)
• Female patients who are pregnant are ineligible due to risks of fetal and teratogenic adverse events as seen in animal/human studies
• Lactating females are not eligible unless they have agreed not to breastfeed their infants
• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained
• Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation and for 6 months after the last dose of protocol-specified chemotherapy

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Study Description

A Phase I open-label, multicentre study to determine the RP2D of olaparib monotherapy in the paediatric population, and to evaluate the safety, tolerability, PK, PDx and preliminary efficacy of olaparib monotherapy in paediatric patients from ≥6 months to <18 years of age at enrolment, with relapsed or refractory solid or primary CNS tumours (excluding lymphoid malignancies) for whom there are no standard treatment options. It is anticipated that eligible patients fulfilling all of the inclusion criteria and none of the exclusion criteria, will include but will not be limited to those with osteosarcoma, rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcoma, Ewing Sarcoma, neuroblastoma, medulloblastoma and glioma.

Inclusion Criteria

• Provision of Informed Consent
• Male and female patients who are ≥6 months to <18 years of age at consent
• Pathologically confirmed relapsed or refractory solid or primary CNS tumours (excluding lymphoid malignancies), with a HRR deficiency/gene mutation, and for whom there are no standard treatment options. Eligible patients may include but not be limited to those with osteosarcoma, rhabdomyosarcoma, non rhabdomyosarcoma soft tissue sarcoma, Ewing Sarcoma, neuroblastoma, medulloblastoma and glioma
• For dose finding phase only: recruitment will be open to all patients with HRR deficiency, based on a local test. For the signal identification phase: recruitment will be open only to patients with documented evidence of a deleterious or suspected deleterious germline or tumour HRR gene mutation that meets the AZ HRR rules
• A formalin fixed, paraffin embedded (FFPE) tumour sample from the primary cancer (all patients) suitable for central HRR testing and a blood sample (patients ≥2 years old) for central germline BRCA testing must be provided for each patient
• For all non-neuroblastoma tumours, patients must have at least 1 radiographical assessable lesion (measurable and/or non-measurable). For neuroblastoma tumours, patients must have radiographical assessable disease with at least 1 lesion (measurable and/or non measurable) OR disease evidenced by uptake of meta-iodobenzylguanidine- (MIBG) or fluorodeoxyglucose positron emission tomography (FDG-PET) scans
• Adequate performance status, organ, and marrow function and adequate weight to obtain blood samples for both safety laboratory assessments and PK analysis.
• Ability to swallow tablets

Exclusion Criteria

• Patients with MDS/AML or with features suggestive of MDS/AML
• Patients unable to swallow orally administered medication
• Unresolved toxicity from previous anticancer therapy
• Unstable or untreated CNS disease (i.e., symptomatic uncontrolled brain metastases or untreated spinal cord compression)
• Previous treatment with a PARP inhibitor, including olaparib
• Receipt of any radiotherapy for cancer treatment (except for palliative reasons) within 30 days prior to first dose of study treatment or receipt of last dose of an approved (marketed) anticancer therapy (chemotherapy, targeted therapy, biologic therapy, monoclonal antibodies, etc) within 21 days prior to the first dose of study treatment
• Concomitant use of known strong or moderate CYP3A inhibitors or concomitant use of known strong or moderate CYP3A inducers
• Whole blood transfusions in the last 120 days prior to screening (packed red blood cells and platelet transfusions are acceptable)

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

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Study Description

The purpose of the phase 1 portion (dose escalation) of the study will be to establish an optimally safe and biologically active recommended phase 2 dose (RP2D) and/or to determine maximum tolerated dose (MTD) for gilteritinib in sequential combination with fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG). The purpose of the phase 2 portion (dose expansion) is to determine complete remission (CR) rates and composite complete remission (CRc) rates after two cycles of therapy. The study will also assess safety, tolerability and toxicities of gilteritinib in combination with FLAG, evaluate FLT3 inhibition, assess pharmacokinetics (PK), perform serial measurements of minimal residual disease, obtain preliminary estimates of 1-year event free survival (EFS) and overall survival (OS) rate and assess the acceptability as well as palatability of the formulation.

One cycle is defined as 28 days of treatment. A participant completing 2 cycles in phase 1 or 2 will have the option to participate in long term treatment (LTT) with gilteritinib (for up to 2 years).

Inclusion Criteria

• Subject is aged ≥ 6 months and < 21 years of age at the time of signing informed consent and/or assent, as applicable.

  • For phase 2: Enrollment of subjects from 6 months to less than 1 year and 1 year to less than 2 years will be dependent on the establishment of recommended phase 2 dose (RP2D) in the respective for age groups during phase 1.

• Subject has a diagnosis of acute myeloid leukemia (AML) according to The French-American-British (FAB) classification with ≥ 5% blasts in the bone marrow, with or without extramedullary disease (except subjects with active central nervous system [CNS] leukemia).

  • In the phase 1 portion of the study, subject must be in first or greater relapse or refractory to induction therapy with no more than 1 attempt at remission induction.
  • For the phase 2 portion of the study, subject must be in first relapse.

• Subject has fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

  • Myelosuppressive chemotherapy:

    • For subject who relapses while receiving cytotoxic therapy, at least 21 days must have elapsed since the completion of cytotoxic therapy and prior to screening.
    • Cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of systemic protocol therapy (cycle 1 day -1). Subject may also receive low dose cytarabine (100 mg/m^2 per dose once daily for 5 days) for cytoreduction until 24 hours prior to cycle 1 day -1.
    • Subject who has received other FLT3 inhibitors (e.g., lestaurtinib, sorafenib, etc) is eligible for this study.
  • Hematopoietic growth factors: at least 7 days must have elapsed since the completion of therapy with a growth factor and prior to screening.
  • Biologic (anti-neoplastic agent): at least 7 days must have elapsed since the completion of therapy with a biologic agent and prior to screening. For agents that have known adverse events (AEs) occurring beyond 7 days after administration, this period must be extended beyond the time during which AEs are known to occur.

  • X-ray treatment (XRT):

    • 14 days must have elapsed for local palliative XRT for CNS chloromas and prior to screening; no washout period is necessary for other chloromas;
    • Prior to screening, 90 days must have elapsed if the subject had a prior traumatic brain injury or has received craniospinal XRT.
• For subject undergoing hematopoietic stem cell transplant (HSCT), at least 90 days must have elapsed since HSCT and subject must not have active graft-versus-host disease (GVHD).
• Subject has Karnofsky score ≥ 50 (if the subject is of ≥ 16 years of age) or Lansky score of ≥ 50 (if the subject is < 16 years of age). A score < 50 is acceptable if related to the subject's leukemia.

• Subject must meet the following criteria as indicated on the clinical laboratory tests.

  • Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x upper limit normal (ULN) for age
  • Total serum bilirubin ≤ 1.5 x ULN for age
  • Serum creatinine ≤ 1.5 x ULN for age or an estimated glomerular filtration rate of > 60 mL/min/1.73 m^2.

• A female subject is eligible to participate if she is not pregnant and at least 1 of the following conditions applies:

  • Not a woman of childbearing potential (WOCBP) OR
  • WOCBP who agrees to follow the contraceptive guidance throughout the treatment period and for at least 180 days after the final study drug administration.
• Female subject must agree not to breastfeed starting at Screening, and throughout the study period and for 60 days after the final study drug administration.
• Female subject must not donate ova starting at Screening and throughout the study, and for 180 days after the final study drug administration.
• A male subject with female partner(s) of childbearing potential must agree to use contraception during the treatment period and for at least 180 days after the final study drug administration. (in United Kingdom, Germany and Canada)
• A male subject must not donate sperm during the treatment period and for at least 120 days after the final study drug administration.
• Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for 180 days after the final study drug administration. (United Kingdom, Germany and Canada)
• Subject and subject's parent(s) or legal guardian agrees not to participate in another interventional study while on treatment.
• In United Kingdom, Germany and Canada: Live Vaccines - At least 6 weeks must have elapsed since the administration of the last dose of a live vaccine and prior to the initiation of study treatment (cycle 1, day -1)
• Phase 1: Subject is positive for FLT3 (ITD and/or tyrosine kinase domain [TKD]) mutation in bone marrow or blood as determined by the local institution.
• Phase 2: Subject is positive for the FLT3 (ITD) mutation in bone marrow or blood as determined by the local institution.

Exclusion Criteria

• Subject has active CNS leukemia.

• Subject has uncontrolled or significant cardiovascular disease, including:

  • Diagnosed or suspected congenital long QT syndrome or any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes (TdP)); any history of arrhythmia will be discussed with the sponsor prior to subject's entry into the study
  • Prolonged Fridericia's Correction Formula (QTcF) interval on pre-entry electrocardiogram (ECG) (≥ 450 ms)
  • Any history of second or third degree heart block (may be eligible if the subject currently has a pacemaker)
  • Heart rate < 50 beats/minute on pre-entry ECG
  • Uncontrolled hypertension
  • Complete left bundle branch block
• Subject 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 subject needs to be off pressors and have negative blood cultures for 48 hours.
• Subject is receiving or plans to receive concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.
• Subject has active clinically significant graft-versus-host disease (GVHD) or is on treatment with systemic corticosteroids and is receiving > 0.5 mg/kg of prednisone (or equivalent) daily dose for GVHD.
• Subject has active malignant tumors other than AML.
• Subject has any significant concurrent disease, illness, psychiatric disorder or social issue that would compromise subject safety or compliance; interfere with consent, study participation, follow-up or interpretation of study results.
• Subject has hypokalemia and/or hypomagnesemia at Screening (defined as values below institutional lower limit of normal [LLN]). Repletion of potassium and magnesium levels during the screening period is allowed.
• Subject requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP)3A/P-glycoprotein (P-gp).
• Subject is known to have human immunodeficiency virus infection.
• Subject has active hepatitis B or C, or other active hepatic disorder.
• Subject must wait for at least 5 half-lives after stopping therapy with any investigational agent and before starting gilteritinib.
• In United Kingdom, Germany and Canada: Subject has a known or suspected hypersensitivity to gilteritinib, cytarabine, fludarabine, granulocyte colony-stimulating factor (G-CSF) or any components of the formulation used.

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Study Description

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

This phase I trial studies the side effects and best dose of volitinib in treating patients with primary central nervous system (CNS) tumors that have come back (recurrent) or does not respond to treatment (refractory). Volitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and recommend a phase II dose of volitinib (savolitinib) administered orally daily in children with refractory, progressive or recurrent primary CNS tumors.

II. To define and describe the toxicities of savolitinib in children with refractory, progressive, or recurrent primary CNS tumors.

III. To characterize the pharmacokinetics of savolitinib in children with refractory, progressive, or recurrent primary CNS tumors.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of savolitinib within the confines of a phase I study.

II. To perform a genomic analysis within the confines of a phase I study to investigate correlation between response to treatment (as measured by objective response or progression free survival [PFS]) and the presence of specific genomic alterations (e.g. MET amplification, chromosome 7q aneuploidy, MET mutation, or HGF amplification) and/or specific subgroups of disease.

OUTLINE: This is a dose-escalation study.

Patients receive volitinib orally (PO) once daily (QD). Treatment repeats every 28 days for up to 39 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, then periodically for up to 2 years.

Inclusion Criteria

• Patients with a histologically confirmed diagnosis of a primary CNS tumor (medulloblastoma, high-grade glioma, or diffuse intrinsic pontine glioma [DIPG]) that is recurrent, refractory, or progressive. All tumors must have histologic verification at either the time of diagnosis or recurrence except patients with diffuse intrinsic brain stem tumors. These patients must have radiographic or clinical evidence of progression. Patients with a recurrent, progressive, or refractory primary CNS tumor with evidence of genetic activation of the MET pathway, regardless of histology, are also eligible to the Phase I component of this study
  • Note: Refractory disease is defined as the presence of persistent abnormality on conventional magnetic resonance imaging (MRI) imaging that is further distinguished by histology (biopsy or sample of lesion) or advanced imaging, OR as determined by the treating physician and discussed with the primary investigator prior to enrollment
• Efficacy Expansion Cohort: Patients must have a recurrent, progressive, or refractory primary CNS tumor with evidence of genetic activation of the MET pathway, regardless of histology. The submitted specimen can be from diagnosis or recurrence and there is no time limit from when the specimen was obtained to enrollment onto the efficacy expansion cohort. The assessment will be performed in a Clinical Laboratory Improvement Act (CLIA) certified laboratory. MET pathway activation status must be confirmed using Food and Drug Administration (FDA) approved testing prior to enrollment. MET pathway activation is defined as:
  • MET kinase domain mutations, allelic frequency >= 5% OR
  • MET or HGF amplification, >= 6 copies OR
  • Chromosome 7 gain OR
  • MET fusion
    • If a MET aberration is identified using local testing at a Pediatric Brain Tumor Consortium (PBTC) institution, final confirmation for eligibility to the efficacy cohort will be confirmed using Memorial Sloan Kettering Cancer Center's (MSKCC's) FDA approved IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets) panel. Alternatively, if a MET aberration is identified at a PBTC site using another FDA approved panel (Foundation Medicine or Oncomine), the result will be considered sufficient for eligibility following study chair review
• Recurrent or refractory primary malignant CNS tumor patients must have adequate pre-trial frozen or formalin-fixed paraffin-embedded (FFPE) tumor material available for the required correlative studies. If target amounts of tissue or number of slides are not available, the site must obtain study chair/co-chair approval for adequacy of submitted tumor samples and prioritization of studies to be performed, prior to patient enrollment
  • Patients with DIPG who have pre-trial tumor tissue available are requested to submit tissue; however, this is not required for eligibility
• Patients must have evaluable disease to be eligible. Evaluable disease is defined as the presence of at least one lesion that can be measured accurately in at least 2 (two) dimensions
• Patients must be > 5 years and =< 21 years of age at the time of study enrollment
• Body surface area (BSA)
  • Patients enrolled on 75 mg/m^2/day (dose level 0) must have a BSA >= 1.00 m^2
  • Patients enrolled on 150 mg/m^2/day (dose level 1) must have a BSA >= 0.55 m^2
  • Patients enrolled on 240 mg/m^2/day (dose level 2) must have a BSA >= 0.67 m^2
  • Patients enrolled on 350 mg/m^2/day (dose level 3) must have a BSA >= 0.73 m^2 and =< 2.10 m^2 (the upper BSA restriction for dose level 3 applies during the dose finding phase only)
• Patients must have failed prior standard therapy for their tumor. Patients with medulloblastoma must have received radiation therapy in addition to platinum and alkylator-based chemotherapy. Patients with high-grade glioma (HGG) and DIPG must have at least received radiation therapy. Patients must have recovered from the acute treatment related toxicities (defined as =< grade 1 if not defined in eligibility criteria) of all prior chemotherapy, immunotherapy, radiotherapy or any other treatment modality prior to entering this study
• Patients must have received their last dose of known myelosuppressive anticancer therapy at least 21 days prior to enrollment or at least 42 days if it included nitrosourea
• Biologic or investigational agent (anti-neoplastic):
  • Patients must have recovered from any acute toxicity potentially related to the agent and received their last dose of the investigational or biologic agent >= 7 days prior to study enrollment
    • 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
  • Monoclonal antibody treatment and agents with known prolonged half-lives:
    • Patients must have recovered from any acute toxicity potentially related to the agent and received their last dose of the agent >= 28 days prior to study enrollment
• Patients must have had their last fraction of:
  • Craniospinal irradiation or total body irradiation or radiation to >= 50% of pelvis > 3 months prior to enrollment
  • Focal irradiation > 4 weeks prior to enrollment
• Patients must be:
  • >= 6 months since allogeneic stem cell transplant prior to enrollment with no evidence of active graft versus (vs.) host disease
  • >= 3 months since autologous stem cell transplant prior to enrollment
• Both males and females of all races and ethnic groups are eligible for this study
• Neurologic Status
  • Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment. A baseline detailed neurological exam should clearly document the neurological status of the patient at the time of enrollment on the study
  • Patients with seizure disorders may be enrolled if seizures are well controlled
  • Patients must be able to swallow whole tablets to be eligible for study enrollment
• Karnofsky performance scale (KPS for > 16 years of age) or Lansky performance score (LPS for =< 16 years of age) assessed within two weeks of enrollment must be >= 50
  • Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Absolute neutrophil count >= 1.0 x 10^9 cells/ L
• Platelets >= 100 x 10^9 cells/ L (unsupported, defined as no platelet transfusion within 7 days prior to enrollment)
• Hemoglobin >= 8 g/dL (hemoglobin should be unsupported, i.e., red blood cell transfusions are not allowed within 14 days prior to enrollment)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x the upper limit of normal (ULN) with total bilirubin =< 1x ULN OR total bilirubin > ULN - =< 1.5 x ULN with ALT and AST =< 1 x ULN
• Albumin >= 2 g/dL
• Serum creatinine based on age/gender. Patients that do not meet the criteria below but have a 24 hour creatinine clearance or glomerular filtration rate (GFR) (radioisotope or iothalamate) >= 70 mL/min/1.73 m^2 are eligible
  • Age: Maximum serum creatinine (mg/dL)
  • 2 to < 6 years: 0.8 (male and female)
  • 6 to < 10 years: 1 (male and female)
  • 10 to < 13 years: 1.2 (male and female)
  • 13 to < 16 years: 1.5 (male), 1.4 (female)
  • >= 16 years: 1.7 (male), 1.4 (female)
• International normalized ratio (INR) < 1.5 x ULN and activated partial thromboplastin time (aPTT) < 1.5 x ULN unless patients are receiving therapeutic anti-coagulation which affects these parameters
• Patients with known tumor thrombus or deep vein thrombosis are eligible if clinically stable on low molecular weight heparin for >= 2 weeks
• Cardiac function:
  • Mean resting corrected QT interval (QTc) =< 450 msec on screening obtained from 3 electrocardiograms (EKGs)
• Oxygen saturation as measured by pulse oximetry is > 93% on room air
• Patients who are receiving corticosteroids must be on a stable or decreasing dose for at least 1 week prior to enrollment
• Patients must be off all colony-stimulating factor(s) (e.g., filgrastim, sargramostim or erythropoietin) for at least 1 week prior to enrollment. Two (2) weeks must have elapsed if patients received polyethylene glycol (PEG) formulations
• Pregnancy Prevention
  • Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study
  • Women of child-bearing potential should use effective contraception from the time of enrollment until 4 weeks after discontinuing study treatment
  • Male study participants should use a condom with female partners of child-bearing potential during the study and for 4 weeks after discontinuing study treatment
  • If the female partner of a male study participant is not using effective contraception, men must use a condom during the study and for 6 months after discontinuing study treatment
  • Male study participants should avoid fathering a child and refrain from sperm donation from study start to 6 months after discontinuing study treatment
• The patient or parent/guardian is able to understand the consent and is willing to sign a written informed consent document according to institutional guidelines

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

Exclusion Criteria

• Pregnant women or nursing mothers are excluded from this study. Female patients of childbearing potential must have a negative serum or urine pregnancy test within 24 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Pregnant women are excluded from this study because there are unknown but potential risks to an unborn baby from savolitinib. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with savolitinib, breastfeeding should be discontinued if the mother is treated with savolitinib
• Patients with a known serious active infection including, but not limited to, viral hepatitis, human immunodeficiency virus, tuberculosis
• Patients with any clinically significant unrelated systemic illness or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the patient's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results
• Patients with uncontrolled hypertension (i.e., a blood pressure [BP] > 95th percentile for age, height, and gender, patients with values above these levels must have their blood pressure controlled with medication prior to starting study drug)
  • The normal blood pressure by height, age and gender tables can be assessed in the Generic Forms section of the PBTC member's webpage
• Patients with any of the following cardiac diseases
  • Congestive heart failure (New York Heart Association >= grade 2)
  • Clinically significant cardiac arrhythmia
  • Mean resting corrected QT interval (QTc) > 450 msec on screening obtained from 3 electrocardiograms (EKGs) or
  • Factors that may increase the risk of QTc prolongation such as chronic hypokalemia not correctable with supplements, congenital or familial long QT syndrome, or
  • Family history of unexplained sudden death under 40 years of age in first-degree relatives or
  • Any concomitant medication known to prolong the QT interval and cause Torsade de Pointes. These drugs must have been discontinued prior to the start of administration of study treatment in accordance with guidance
  • Any clinically important abnormalities in rhythm, conduction or morphology of resting EKG, e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval > 250 msec.
• Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen for this trial
• Concurrent Therapy
  • Patients who are receiving any other anticancer or investigational drug therapy
  • Patients receiving strong inducers of CYP3A4, strong inhibitors of CYP3A4 or CYP1A2 or CYP3A4 substrates with a narrow therapeutic index within 2 weeks of the first dose of savolitinib (3 weeks for St John's Wort). Strong inducers of CYP3A4 and CYP3A4 substrates which have a narrow therapeutic range or CYP3A4 sensitive substrates should not be used during the trial or used with caution. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. Patient drug information handout and wallet card should be provided to patients
  • Prior or current treatment with a MET inhibitor (e.g., foretinib, crizotinib, cabozantinib, or onartuzumab)
• Patient is currently receiving any of the following herbal preparations or medications and cannot be discontinued 1 week (7 days) prior to enrollment (3 weeks for St. John's wort). These herbal medications include, but are not limited to: cannabis products, St. John's wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng
• Patient has undergone major surgical procedure =< 28 days prior to beginning study drug or a minor surgical procedure =< 7 days prior to beginning study drug. No waiting is required following port-a-cath placement
• Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity to therapy or to adhere to drug administration plan, other study procedures, and study restrictions
• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition
• Prisoners will be excluded from this study

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

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Study Description

Il s’agit d’une étude qui évaluera la tolérance, la pharmacocinétique et l’efficacité de l’alectinib chez des enfants et adolescents présentant des tumeurs solides ou du SNC avec un réarrangement du gène ALK, pour lesquels un traitement antérieur s’est avéré inefficace ou pour lesquels il n’y a pas de traitement satisfaisant disponible (les patients porteurs de lymphomes anaplasiques ne sont pas éligibles).

Inclusion Criteria

• Diagnostique confirmé histologiquement de la tumeur solide ou du SNC présentant un réarrangement du gène ALK.
• Traitement antérieur qui s’est avéré inefficace (c.-à-d. rechute ou tumeur réfractaire) ou patient pour lequel il n’y a pas de traitement satisfaisant disponible.
• La maladie doit être mesurable et évaluable comme défini par les critères RECIST v1.1 pour les tumeurs solides par les critères RANO pour les tumeurs primitives du SNC ou par les critères INRC pour les rares cas de neuroblastomes concernés.
• Tissu tumoral, disponible pour envoi au promoteur, issu de la maladie active, obtenu après la dernière thérapie anticancéreuse administrée et avant l’inclusion dans l’étude, tissu tumoral archivé provenant du diagnostique initial, ou disposé à effectuer un prélèvement d’échantillon par biopsie.

Exclusion Criteria

• Utilisation antérieure d’inhibiteurs d’ALK.
• Trouble gastro-intestinal qui pourrait affecter l’absorption de médicaments oraux.
• Antécédent familial ou personnel d’anomalie osseuse congénitale, d’altérations du métabolisme osseux ou d’ostéopénie.
• Maladie hépatique (ALAT, ASAT ou bilirubine élevé).
• Virus actif de l’hépatite B ou C (VHB, VHC) ou positivité connue au VIH ou maladie liée au SIDA.
• Grossesse ou allaitement, ou intention de débuter une grossesse pendant l’étude.

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Study Description

The objective of this study is to evaluate the efficacy of plixorafenib in participants with locally advanced or metastatic solid tumors, or recurrent or progressive primary central nervous system (CNS) tumors harboring BRAF fusions, or in participants with recurrent high-grade glioma (HGG) harboring BRAF V600E mutation. This will be conducted as two single arm open-label subprotocols (F8394-201A; F8394-201B) under one master protocol.

Inclusion Criteria

Group A: 

• Male and female, ≥10 years of age, and weighing ≥30 kg.
• Histologic diagnosis of a solid tumor or primary CNS tumor.
• Documentation of BRAF gene fusion in tumor and/or blood detected by an analytically validated test by DNA sequencing or RNA (transcriptome) sequencing at CLIA or CLIA-equivalent laboratory or sponsor-designated central laboratory.
• Have an archival tissue sample at less than 24 months from date of screening available with sufficient tumor for central next generation sequencing (NGS) testing and biomarker analyses, or >24 months if the participant has never received targeted therapy. If an archival tissue sample is not available, a newly obtained (before treatment) tumor biopsy may be submitted instead.
• Consent to provide scan(s) prior to baseline to assess change in tumor trajectory (at least 2 preferred). For participants with LGG, every effort should be made to provide 3 to 4 pre-baseline scans to the central imaging vendor whenever feasible.
• Received all available standard therapy, is intolerant to available therapies, or the investigator has determined that treatment with standard therapy is not appropriate.
• All adverse events related to prior therapies (chemotherapy; radiotherapy; surgery) must have resolved to Grade 1 or baseline except for
  • Alopecia (Grade ≤2)
  • Sensory neuropathy (Grade ≤2)
  • Other adverse events that have resolved to Grade ≤2 that, according to the clinical judgment of the investigator, do not constitute a safety risk to the participant.

Group B: 

• Male and female, ≥10 years of age, and weighing ≥30 kg.
• Histological diagnosis of a primary CNS tumor, including but not limited to the following:
  • Adults (≥18 years) with Grade 1-4 glioma or glioneuronal tumor (including glioblastoma, anaplastic astrocytoma, high grade astrocytoma with piloid features, pilocytic astrocytoma, gliosarcoma, anaplastic pleomorphic xanthoastrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, not otherwise specified [NOS], ganglioglioma, or recurrent LGG).
  • Pediatric patients (10-17 years of age) with a Grade 3 or 4 glioma or glioneuronal tumor, including those with a prior, histologically confirmed, diagnosis of a low-grade glioma or glioneuronal tumor and now have radiographic or histopathological findings consistent with WHO [2021] Grade 3 or 4 primary CNS tumor.
  • Participants must have unresectable, locally advanced or metastatic disease that:
    • Had prior treatment with radiotherapy and/or first-line chemotherapy or concurrent chemoradiation therapy OR
    • Is intolerant to available therapies OR iii. The investigator has determined that treatment with standard therapy is not appropriate.
    • Note: Participants who have a WHO Grade 3 or 4 glioma for whom chemotherapy and/or radiotherapy is not considered standard of care may remain eligible for the study. Consult the Medical Lead to discuss and determine if participant is eligible for enrollment.
• Documented BRAF V600E mutation in tumor and/or blood detected by an analytically validated test by NGS or polymerase chain reaction (PCR) methods and locally approved assays at CLIA or CLIA-equivalent laboratory approved by sponsor or sponsor-designated central test. Sponsor review of the report is required, and testing of BRAF alteration is required at sponsor's central laboratory.
• An archival tissue sample at less than 24 months from date of screening available with sufficient tumor for central NGS testing* and biomarker analyses, or >24 month if the participant has never received a targeted therapy, or fresh biopsy is required if the archival sample is not available for retrospective confirmation test. Tissue obtained most proximal to initiating this subprotocol is preferred.
• Measurable disease based upon RANO HGG for high-grade tumors or RANO LGG for the low grade tumors, as determined by the radiographic BICR.
• All adverse events related to prior therapies (eg, chemotherapy, radiotherapy, surgery) must have resolved to Grade 1 or baseline except for:
  • Alopecia (Grade ≤2)
  • Sensory neuropathy (Grade ≤2)
  • Other adverse events that have resolved to Grade ≤2 that, according to the clinical judgment of the investigator, do not constitute a safety risk to the participant
• Participants who are receiving corticosteroid treatment must be on a stable or decreasing dose of ≤8 mg/day of dexamethasone or equivalent corticosteroid treatment for 7 days prior to first dose of study treatments.

Exclusion Criteria

Group A: 

• Participants with known co-occurring NF1 alteration and/or RAS-related mutations.
• Participants with evidence of subclonal mutations or heterogeneity that are indicative of a prior treatment effect instead of a driver mutation.
• Prior treatment with RAF/BRAF inhibitors active for Class 2 BRAF alterations for advanced unresectable or metastatic disease (including but not limited to tovorafenib [formerly known as DAY 101, TAK 580, and MLN 2480], KIN-2787, BGB-3245, and CFT1946).
  • Note: Participants with pediatric-type LGGs (molecular classification by WHO2021; diagnosed at ≤25 years of age) who had received prior treatment(s) with RAF/BRAF inhibitors are eligible for enrollment, provided there was no evidence of tumor progression on that therapy or within 4 weeks of discontinuation, based upon radiographic assessment.
• Prior treatment with a MEK inhibitor.
• Tyrosine kinase inhibitor(s) and/or targeted therapies are allowed (other than BRAF/MAPK pathway inhibitors per Exclusion Criteria 3 and 4) and will be restricted to no more than the number of lines of therapy that are consistent with standard treatment guidelines. NOTE: There is no restriction on the number of lines of chemotherapy or immunotherapy.
• Malignancy with co-occurring activating RAS mutation(s) at any time.
• Uncontrolled intercurrent illness that would limit compliance with study requirements.
• Current or planned participation in a study of an investigational agent or device.
• Have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral plixorafenib or cobicistat (such as ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, and small bowel resection).
• Are currently receiving (within 7 days of Cycle 1 Day 1) or are planning to receive during participation:
  • Agents that are known strong inducers or inhibitors of CYP3A4 (other than cobicistat). Restrictions include foods or herbal medications, including grapefruit juice and grapefruit/grapefruit related citrus fruits (eg, Seville oranges, pomelos), and St. John's Wort.
  • Agents that are contraindicated with cobicistat. Note: For participants with no other option except agents with potential drug interactions with cobicistat, but which are not contraindicated, the dose of that agent must be altered or the regimen must follow the cobicistat prescribing information and be approved by the medical monitor.

Group B: 

• Prior treatment with BRAF, ERK, and/or MEK inhibitor(s).
• Known or suspected neurofibromatosis-1 (NF-1) and/or Ras related gene alterations.
• Uncontrolled intercurrent illness that would limit compliance with study requirements.
• Active infection requiring systemic therapy.
• Current or planned participation in a study of an investigational agent or device.
• Have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral plixorafenib or cobicistat (such as ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).
• Grade ≥ 2 changes in AST, ALT, gamma-glutamyl transaminase (GGT), or bilirubin attributed to prior immune checkpoint inhibitor treatment are exclusionary, even if resolved.
• Are currently receiving (within 7 days of Cycle 1 Day 1) or are planning to receive during participation:
  • Agents that are known strong inducers or inhibitors of CYP3A4 (other than cobicistat). Restrictions include foods or herbal medications, including grapefruit juice, grapefruit/grapefruit related citrus fruits (eg, Seville oranges, pomelos), and St. John's Wort.
  • Agents that are contraindicated with cobicistat Note: For participants with no other option except agents with potential drug interactions with cobicistat, but which are not contraindicated, the dose of that agent must be altered or the regimen must follow the cobicistat prescribing information and be approved by the medical monitor.
• Progressively worsening in frequency or severity seizures indicative of rapid tumor progression, or seizures poorly controlled with available therapy.

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Study Description

This is an open-label, multicenter study to assess safety, tolerability, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and preliminary efficacy of RO7428731 administered as a monotherapy in participants with newly diagnosed or recurrent epidermal growth factor receptor variant III (EGFRvIII)-positive glioblastoma (GBM).

Experimental: Part I: Dose Escalation

Participants with newly diagnosed GBM will receive RO7428731, intravenously (IV), up to one year or until disease progression, withdrawal of consent, unacceptable toxicity, or death, whichever occurs first.

Experimental: Part II: Dose-Expansion(s)

Participants with newly diagnosed GBM will receive RO7428731, IV, in maximum of two dose expansion cohorts at a dose(s) not exceeding the maximum tolerated dose (MTD) established in Part I.

Experimental: Part III: Safety Run-in

Participants with recurrent GBM will receive RO7428731, IV in a dosing schedule determined in Part I. At the end of the Safety Run-in period, a decision will be made as to whether to open the Dose-Expansion Cohort Part IVA or open a second Safety Run-in Cohort at a lower dose.

Experimental: Part IV A: Dose-Expansions Cohort

Participants with recurrent GBM will receive RO7428731, IV at specified doses and dosing schedules.

Inclusion Criteria

Inclusion criteria for all participants:

• Life expectancy of greater than or equal to 12 weeks, in the opinion of the Investigator
• Diagnosis of GBM based on World Health Organization (WHO) classification of central nervous system (CNS) tumors, 5th edition
• Participants must have confirmed EGFRvIII-expression
• Karnofsky Performance Status (KPS) Score of >=70%
• Adequate organ functions prior to start of study treatment
• Willingness to abide by contraceptive measures for the duration of the study.

Inclusion criteria for Part I and Part II only:

• Participants whose tumors have an unmethylated (Part I and Part II) or methylated (Part I only) O6-methylguanine-DNA methyltransferase (MGMT) promotor status based on local assessment
• Participants (in Part I): Adult participants with newly diagnosed EGFRvIII-positive GBM with unmethylated MGMT promotor status who have completed standard of care therapy with surgical resection and adjuvant radiotherapy with or without concomitant temozolomide. Participants are allowed to have received any number of cycles of temozolomide maintenance. Adult participants with newly diagnosed EGFRvIII-positive GBM with methylated MGMT promotor status who have completed standard of care with surgical resection and adjuvant radiotherapy with concomitant and maintenance temozolomide or discontinued temozolomide maintenance due to reasons other than progressive disease.
• Participants (in Part II): Adult participants with newly diagnosed EGFRvIII-positive GBM with unmethylated MGMT promotor status who have completed standard of care therapy with surgical resection and adjuvant radiotherapy with or without concomitant temozolomide.

Inclusion criteria for Part III and Part IV A only:

• Documented first or second recurrence of GBM
• At least one measurable GBM lesion as per Response Assessment in Neuro-Oncology (RANO) criteria prior to initiation of study treatment.

Exclusion Criteria

Exclusion criteria for all participants:

• Participants with infratentorial tumors and tumors primarily located in or close to critical structures (e.g., brain stem)
• Presence of extracranial metastatic or leptomeningeal disease
• Known hypersensitivity to immunoglobulins or to any other component of the investigational medicinal product formulation
• Active bleeding or pathological condition that carries a high risk of bleeding, including inherited and acquired coagulopathies
• Participants unable to undergo an MRI with contrast.

Exclusion criteria for Part I and Part II only:

• Recurrent malignant gliomas
• Any prior anti-tumor treatment for GBM: tumor resection, adjuvant radiotherapy with or without concomitant temozolomide and temozolomide maintenance (Part I only) must be the only tumor-directed treatment that the participant has received for GBM.

Exclusion criteria for Part III and Part IV A only:

• More than two recurrences of GBM
• Prior anti-EGFRvIII-targeting agents (including vaccines), anti-angiogenic therapy, and/or gene therapy for the treatment of GBM and gliomas.