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MDM2 Inhibitor AMG-232 in Treating Patients With Recurrent or Newly Diagnosed Glioblastoma

Descriptive Information
Brief Title † MDM2 Inhibitor AMG-232 in Treating Patients With Recurrent or Newly Diagnosed Glioblastoma
Official Title † Phase 0/I Study of AMG 232 Concentrations in Brain Tissue in Patients With Recurrent Glioblastoma and of AMG 232 in Combination With Radiation in Patients With Newly Diagnosed Glioblastoma and Unmethylated MGMT Promoters
Brief Summary This phase 0/I trial studies the side effects and best dose of MDM2 inhibitor AMG-232 in treating patients with glioblastoma that is newly diagnosed or has come back. MDM2 inhibitor AMG-232 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed Description PRIMARY OBJECTIVES: I. Determine the concentration and variability in concentration of MDM2 inhibitor AMG-232 (AMG 232) in brain and brain-associated tissue in patients with recurrent glioblastoma (GBM). (Part 1) II. Determine the maximum tolerated dose (MTD) of AMG 232 given in combination with standard radiation following surgery for patients with newly diagnosed GBM harboring unmethylated MGMT promoters and wild-type TP53. (Part 2) SECONDARY OBJECTIVES: I. Determine the safety and toxicity of AMG 232 in patients with recurrent GBM. (Part 1) II. Assess the variability of AMG 232 concentration in tumor enhancing versus (vs.) infiltrative tissue. (Part 1) III. Assess the pharmacodynamic effect of AMG 232 on p21 elevation. (Part 1) IV. Determine the safety of AMG 232 at the concurrent MTD in combination with the recommended phase 2 dose (RP2D) of AMG 232 as monotherapy for patients with newly diagnosed GBM harboring unmethylated MGMT promoters and wild-type TP53. (Part 2) V. Assess AMG 232 exposure and correlations with PD effect PD effect on p21 elevation. (Part 2) VI. Assess pharmacodynamic (PD) effect on MIC-1 elevation in serum. (Part 2) OUTLINE: This is a phase 0, intratumoral pharmacokinetic (PK)/ pharmacodynamic (PD) study of MDM2 inhibitor AMG-232 followed by a phase I dose-escalation study. PART I: Patients with recurrent glioblastoma receive MDM2 inhibitor AMG-232 orally (PO) once daily (QD) for 2 days. Within 3-6 hours of the last dose, patients undergo standard of care surgery. Upon recovery (within 30 days), patients with TP53 wild-type tumors continue to receive MDM2 inhibitor AMG-232 PO QD on days 1-7. Courses repeat every 21 days in absence of disease progression or unacceptable toxicity. PART II: Within 6 weeks of standard of care surgery, patients with newly diagnosed glioblastoma undergo radiation therapy daily during weeks 1-6. Patients also receive MDM2 inhibitor AMG-232 PO once weekly for 6 weeks or 3 times weekly on days 2, 3, and 5 for 6 weeks or 2 times weekly on days 2 and 4 for 6 weeks during radiation therapy. PART II (EXPANSION COHORT): Patients receive MDM2 inhibitor AMG-232 PO QD on days 1-7. Courses repeat every 21 days in absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 2 months for the first two years from the off-treatment date, and then every 6 months until death.
Study Phase Phase 1
Study Type † Interventional
Study Design †
Primary Outcome Measure † MTD of MDM2 inhibitor AMG-232 when combined with concomitant radiation therapy (Part 2)
Secondary Outcome Measure † Incidence of adverse events assessed by CTCAE version 4.0 (Part 1)
Condition † Glioblastoma Gliosarcoma Recurrent Glioblastoma TP53 wt Allele Unmethylated MGMT Promoter
Intervention † OtherLaboratory Biomarker Analysis
Study Arms / Comparison Groups Treatment (MDM2 inhibitor AMG-232) PART I: Patients with recurrent glioblastoma receive MDM2 inhibitor AMG-232 orally PO QD for 2 days. Within 3-6 hours of the last dose, patients undergo standard of care surgery. Upon recovery (within 30 days), patients with TP53 wild-type tumors continue to receive MDM2 inhibitor AMG-232 PO QD on days 1-7. Courses repeat every 21 days in absence of disease progression or unacceptable toxicity. PART II: Within 6 weeks of standard of care surgery, patients with newly diagnosed glioblastoma undergo radiation therapy daily during weeks 1-6. Patients also receive MDM2 inhibitor AMG-232 PO once weekly for 6 weeks or 3 times weekly on days 2, 3, and 5 for 6 weeks or 2 times weekly on days 2 and 4 for 6 weeks during radiation therapy. PART II (EXPANSION COHORT): Patients receive MDM2 inhibitor AMG-232 PO QD on days 1-7. Courses repeat every 21 days in absence of disease progression or unacceptable toxicity.
Publications *

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information
Recruitment Status † Other
Estimated Enrollment † 92
Start Date † October 27, 2017
Completion Date June 30, 2019
Primary Completion Date June 30, 2019
Eligibility Criteria † Inclusion Criteria: - Patients must have a Karnofsky performance status >= 60% (i.e. the patient must be able to care for himself/herself with occasional help from others) - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Hemoglobin >= 9 g/dL - Total bilirubin == 60 ml/min/1.73 m^2 - Activated partial thromboplastin time (aPTT)/PTT == five years - Patients must be maintained on a stable corticosteroid regimen (no increase for 5 days) prior to the start of treatment - Patients must be able to swallow oral medications - PART 1 PATIENTS (SURGICALLY ELIGIBLE RECURRENT GBM) - Part 1 patients must have prior histologically proven glioblastoma that is progressive or recurrent following radiation therapy +/- chemotherapy - Part 1 patients must be undergoing repeat surgery that is clinically indicated as determined by their care providers - Part 1 patients must have a tumor tissue form indicating availability of archived tissue from initial resection at diagnosis of glioblastoma completed and signed by a pathologist - Part 1 patients may have an unlimited number of prior therapy regimens - Part 1 patients must have recovered from severe toxicity of prior therapy; the following intervals from previous treatments are required to be eligible: - 12 weeks from the completion of radiation - 6 weeks from a nitrosourea chemotherapy or mitomycin C - 3 weeks from a non-nitrosourea chemotherapy - 4 weeks from any investigational (not FDA-approved) agents - 2 weeks from administration of a non-cytotoxic, Image result for Food and Drug Administration (FDA)-approved agent, except bevacizumab/VEGFR inhibitors (e.g., erlotinib, hydroxychloroquine, etc.) - 6 weeks from bevacizumab/VEGFR inhibitors - PART 2 PATIENTS (NEWLY DIAGNOSED GBM) - Part 2 patients must have histologically confirmed glioblastoma or gliosarcoma - Part 2 patients must have recovered from the immediate post-operative period - Part 2 patients must have tumor MGMT methylation status of unmethylated. Results of routinely used methods for MGMT methylation testing (e.g. mutagenically separated polymerase chain reaction [MSPCR] or quantitative PCR) are acceptable - Part 2 patients must show evidence of wild-type (WT) p53 as assessed by central deoxyribonucleic acid (DNA) sequencing - Part 2 patients must not have received prior radiation therapy, chemotherapy, immunotherapy or therapy with biologic agent (including immunotoxins, immunoconjugates, antisense, peptide receptor antagonists, interferons, interleukins, tumor infiltrating lymphocytes [TIL], LAK or gene therapy), or hormonal therapy for their brain tumor; glucocorticoid therapy is allowed - Patients may not use herbal or non-traditional medications while receiving AMG 232 therapy; all herbal medicines (e.g., St. John's wort), vitamins, and supplements consumed by the subject within the 30 days prior to receiving the first dose of AMG 232 should be reviewed by the principal investigator - Treatment with medications known to cause QTc interval prolongation within 7 days of study day 1 is not permitted unless approved by the sponsor; use of ondansetron is permitted for treatment of nausea and vomiting - Patients may not be on warfarin, factor Xa inhibitors and direct thrombin inhibitors; Note: low molecular weight heparin and prophylactic low dose warfarin are permitted; prothrombin time (PT)/PTT must meet the inclusion criteria; subjects taking warfarin must have their INR followed closely Exclusion Criteria: - Patients receiving any other investigational agents are ineligible - Part 1 patients who have not recovered to
Gender All
Ages 18 Years - N/A
Accepts Healthy Volunteers No
Contacts ††
Location Countries † United States
Administrative Information
NCT ID † NCT03107780
Organization ID NCI-2017-00568
Secondary IDs †† NCI-2017-00568, ABTC-1604, ABTC-1604, UM1CA137443
Responsible Party Sponsor
Study Sponsor † National Cancer Institute (NCI)
Collaborators ††
Investigators † Principal Investigator: Brian Alexander, National Cancer Institute (NCI)
Information Provided By
Verification Date April 2017
First Received Date † April 10, 2017
Last Updated Date April 23, 2017
† Required WHO trial registration data element.
†† WHO trial registration data element that is required only if it exists.
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