Clinical Trials /

Testing the Ability of AMG 232 (KRT 232) to Get Into the Tumor in Patients With Brain Cancer

NCT03107780

Description:

This phase I trial studies the side effects and best dose of MDM2 inhibitor KRT-232 in treating patients with glioblastoma (brain cancer) that is newly diagnosed or has come back (recurrent). MDM2 inhibitor KRT-232 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Glioblastoma
  • Gliosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-00568
  • SECONDARY ID: NCI-2017-00568
  • SECONDARY ID: ABTC-1604
  • SECONDARY ID: ABTC-1604
  • SECONDARY ID: UM1CA137443
  • NCT ID: NCT03107780

Conditions

  • Glioblastoma
  • Gliosarcoma
  • Recurrent Glioblastoma

Interventions

DrugSynonymsArms
MDM2 Inhibitor AMG-232AMG 232, AMG-232Treatment (MDM2 inhibitor AMG-232)

Purpose

This phase 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 given concurrently with radiation therapy (RT) and
      adjuvantly 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 45 days), patients with TP53 wild-type tumors continue to
      receive MDM2 inhibitor AMG-232 PO QD on days 1-7. Cycles 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. Cycles
      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (MDM2 inhibitor AMG-232)ExperimentalPART I: Patients with recurrent glioblastoma receive MDM2 inhibitor AMG-232 PO QD for 2 days. Within 3-6 hours of the last dose, patients undergo standard of care surgery. Upon recovery (within 45 days), patients with TP53 wild-type tumors continue to receive MDM2 inhibitor AMG-232 PO QD on days 1-7. Cycles 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. Cycles repeat every 21 days in absence of disease progression or unacceptable toxicity.
  • MDM2 Inhibitor AMG-232

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/ul

          -  Platelets >= 100,000/ul

          -  Hemoglobin >= 10 g/dL (transfuse as necessary to raise levels, no transfusions within
             7 days of start)

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional ULN

          -  Alkaline phosphatase < 2.0 x ULN

          -  Creatinine =< institutional ULN

          -  Creatinine clearance >= 60 ml/min/1.73 m^2 for patients with creatinine levels above
             institutional normal

          -  Activated partial thromboplastin time (APTT)/partial thromboplastin time (PTT) =< 1.5
             x institutional ULN

          -  Corrected QT interval (QTc) =< 470 msec (based on average of screening triplicates)

          -  Patients must be able to provide written informed consent

          -  Patients must have magnetic resonance imaging (MRI) within 21 days of starting
             treatment; patients must be able to tolerate MRI with gadolinium

          -  Patients must be maintained on a stable corticosteroid regimen (no increase for 5
             days) prior to the baseline MRI

          -  Women of childbearing potential must have a negative serum pregnancy test prior to
             study entry; women of child-bearing potential must agree to use adequate contraception
             prior to study entry and for the duration of study participation through 5 weeks
             (women) after receiving the last dose of AMG 232; should a woman become pregnant or
             suspect she is pregnant while she or her partner is participating in this study, she
             should inform her treating physician immediately; men treated or enrolled on this
             protocol must also agree to use adequate contraception prior to the study, for the
             duration of study participation, and 3 months after completion of AMG 232
             administration; adequate methods of effective birth control include sexual abstinence
             (men, women); vasectomy; or a condom with spermicide (men) in combination with barrier
             methods, hormonal birth control or intrauterine device (IUD) (women); bilateral tubal
             ligation (women)

          -  Patients must have no concurrent malignancy except curatively treated basal or
             squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or
             bladder; patients with prior malignancies must be disease-free for >= five years

          -  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 Food and Drug Administration
                  [FDA]-approved) agents

               -  2 weeks from administration of a non-cytotoxic, FDA-approved agent, except
                  bevacizumab/ vascular endothelial growth factor receptor (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 polymerase chain reaction [PCR]) are
             acceptable

          -  Part 2 patient must show evidence of wild-type (WT) p53 status on somatic tissue
             specimens as assessed by 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], lymphokine-activated killer [LAK] or gene
             therapy), or hormonal therapy for their brain tumor; glucocorticoid therapy is allowed

        Exclusion Criteria:

          -  Patients receiving any other investigational agents are ineligible

          -  Part 1 patients who have not recovered to < Common Terminology Criteria for Adverse
             Events (CTCAE) grade 2 toxicities related to prior therapy are ineligible

          -  Patients with a history of hypersensitivity or allergic reactions attributed to
             compounds of similar chemical or biologic composition to AMG 232 are ineligible

          -  Patients on enzyme-inducing anti-epileptic drugs (EIAED) are not eligible for
             treatment on this protocol; patients may be on non-enzyme inducing anti-epileptic
             drugs or not be taking any anti-epileptic drugs; patients previously treated with
             EIAED may be enrolled if they have been off the EIAED for 10 days or more prior to the
             first dose of AMG 232

          -  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

          -  Drugs known to be CYP3A4 substrates with narrow therapeutic windows (such as
             alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, quinidine, sirolimus,
             or terfanide) or CYP2C8 substrates are not allowed; patients must be switched to
             alternative drugs at least 14 days prior to receiving the first dose of AMG 232; those
             patients who cannot switch to alternative drugs will be excluded from the study

          -  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;
             APTT/PTT must meet the inclusion criteria; subjects taking warfarin must have their
             international normalized ratio (INR) followed closely

          -  Patients with uncontrolled intercurrent illness including, but not limited to, ongoing
             or active infection, symptomatic congestive heart failure, unstable angina pectoris,
             cardiac arrhythmia, or psychiatric illness/social situations that would limit
             compliance with study requirements, are ineligible; patients with active infection
             requiring IV antibiotics within 2 weeks of study day 1 are excluded; patients with
             myocardial infarction within 6 months of study day 1, symptomatic congestive heart
             failure (New York Heart Association [NYHA] class III and higher), unstable angina, or
             cardiac arrhythmia requiring medication are excluded

          -  Patients with gastrointestinal (GI) tract disease causing the inability to take oral
             medication, malabsorption syndrome, requirement for intravenous alimentation, prior
             surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g.,
             Crohn's disease, ulcerative colitis), are ineligible

          -  Patients with history of bleeding diathesis are ineligible

          -  Patients with positive hepatitis B surface antigen (HepBsAg), positive hepatitis total
             core antibody with negative HBsAG, or detectable hepatitis C virus ribonucleic acid
             (RNA) by a polymerase-chain reaction (PCR) assay (screening is generally done by
             hepatitis C antibody (HepCAb), followed by hepatitis C virus RNA by PCR if HepCAb is
             positive)

          -  Pregnant women are excluded from this study; breastfeeding should be discontinued if
             the mother is treated with AMG 232 through 1 week after receiving the last dose of
             study drug

          -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
             therapy are ineligible because of the potential for pharmacokinetic interactions with
             AMG 232; in addition, these patients are at increased risk of lethal infections when
             treated with marrow-suppressive therapy

          -  Patients with a planned use of Novo-TTF (Optune) are ineligible
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pharmacokinetics (PK) parameters with target inter-tumor drug concentration at >= 25 nm (Part 1)
Time Frame:Up to 3 years
Safety Issue:
Description:Part 2 of the trial will proceed only if at least one of the doses yielded a 50% PK response rate. If both doses reached 50% PK response rate, both doses will be studied in Part 2 of the trial.

Secondary Outcome Measures

Measure:Incidence of adverse events (Part 1)
Time Frame:Up to 30 days following the last dose of study drug
Safety Issue:
Description:Assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Beginning April 1, 2018 version 5.0 will be utilized for adverse event reporting). Will be used for scoring toxicity and adverse events. The severity and frequency of toxicity will be tabulated by the tested dose or doses, or combination regimens using descriptive statistics. The proportion of patients who experienced grade 3 or above toxicities will be estimated along with 95% confidence intervals by each type of toxicity.
Measure:Variability of MDM2 inhibitor AMG-232 concentration in tumor enhancing versus (vs.) infiltrative tissue (Part 1)
Time Frame:Up to 3 years
Safety Issue:
Description:Will be summarized using descriptive statistics.
Measure:p21 elevation in tissue (Part 1)
Time Frame:Up to 3 years
Safety Issue:
Description:Will be coded as binary outcome either elevated or not elevated compared to a reference value from archived tumor tissues in matched patient population. A proportion of patients with elevated p21 will be estimated using a binomial distribution along with 95% confidence interval.
Measure:Incidence of adverse events (Part 2)
Time Frame:Up to 10 weeks
Safety Issue:
Description:Assessed by CTCAE version 4.0 (Beginning April 1, 2018 version 5.0 will be utilized for adverse event reporting). Will be used for scoring toxicity and adverse events. The severity and frequency of toxicity will be tabulated by the tested dose or doses, or combination regimens using descriptive statistics. The proportion of patients who experienced grade 3 or above toxicities will be estimated along with 95% confidence intervals by each type of toxicity.
Measure:MIC-1 elevation in serum (Part 2)
Time Frame:Up to 3 years
Safety Issue:
Description:The PK variables and changes in MIC-1 will be tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) calculated for each dose level. PK parameters and MIC-1 changes will be compared across dose level using non-parametric statistical testing techniques.
Measure:MDM2 inhibitor AMG-232 exposure (Part 2)
Time Frame:Up to 3 years
Safety Issue:
Description:Assessed by liquid chromatography/tandem mass spectrometry. A full pharmacokinetic profile of AMG 232 will be proposed in this study to assess exposure-response relationships with various pharmacodynamic (PD) endpoints (i.e., MIC-1 changes, toxicity, and efficacy). Correlation with PD effect on p21 elevation will be determined.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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