Clinical Trial: MDM2 Inhibitor AMG-232, Carfilzomib, Lenalidomide, and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma

Study Status: Not yet recruiting
Recruit Status: Not yet recruiting
Study Type: Interventional

Official Title: A Phase 1 Dose-Escalation and Exploratory Dose Expansion Study of AMG 232 in Combination With Carfilzomib, Lenalidomide, and Dexamethasone in Relapsed and/or Refractory Myeloma

Brief Summary: This phase I trial studies the side effects and best dose of MDM2 inhibitor AMG-232 when given together with carfilzomib, lenalidomide, and dexamethasone in treating patient with multiple myeloma that has come back of has not responded to previous treatment. Drugs used in chemotherapy, such as MDM2 inhibitor AMG-232, carfilzomib, lenalidomide, and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed Summary:

PRIMARY OBJECTIVES:

I. Evaluate safety and tolerability of MDM2 inhibitor AMG-232 (AMG-232) in combination with carfilzomib, lenalidomide, and dexamethasone (KRd).

II. Determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of AMG-232 in combination with carfilzomib, lenalidomide, and dexamethasone (KRd).

SECONDARY OBJECTIVES:

I. Evaluate progressive disease (PD) effects of AMG-232 through serum MIC-1 levels.

II. To assess AMG-232 exposure-response relationships (PD, toxicity, and efficacy).

TERTIARY OBJECTIVES:

I. To observe and record anti-tumor activity of AMG-232 in combination with carfilzomib, lenalidomide, and dexamethasone (KRd) in relapsed/refractory myeloma by International Myeloma Working Group (IMWG) criteria.

II. Evaluate ribonucleic acid (RNA) expression levels of relevant genes in the TP53 pathway that may predict response to therapy using pre- and post-treatment bone marrow biopsies.

OUTLINE: This is a dose-escalation study of MDM2 inhibitor AMG-232.

Patients receive MDM2 inhibitor AMG-232 orally (PO) once daily (QD) on days 1-7, carfilzomib intravenously (IV) over 10-30 minutes on days 1-2, 8-9, and 15-16 of courses 1-12 and on days 1-2 and 15-16 of courses 13-18, lenalidomide PO on days 1-21, and dexamethasone PO or IV on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unexpected toxicity.

After c
Sponsor: National Cancer Institute (NCI)

Current Primary Outcome:

  • Change in laboratory test results (hematology and blood chemistry) [ Time Frame: Baseline up to 30 days after last dose ]
    Abnormal laboratory results will be graded according to NCI-CTCAE, version 4, if applicable. A shift table, presenting the 2-way frequency tabulation for baseline and the worst post-treatment value according to the NCI-CTCAE grade, will be provided for selected clinical laboratory tests. Abnormal clinical laboratory test results that are deemed of clinical significance or of grade 3 or 4 will be listed.
  • Change in vital sign [ Time Frame: Baseline up to 30 days after last dose ]
    Descriptive statistics will be provided for the vital signs measurements and changes from baseline by scheduled time of evaluation, including the end-of-treatment visit and the maximum and minimum post-treatment values.
  • Incidence of treatment-emergent adverse event (TEAE) assessed by NCI CTCAE version 4 [ Time Frame: Up to 30 days after last dose ]
    A TEAE is defined as an adverse event that emerges during the treatment period (from first dose date till 30 [+/- 5] days after the last dosing date), having been absent at pre-treatment; or reemerges during treatment, having been present at baseline but stopped prior to treatment; or worsens in severity after starting treatment relative to the pre-treatment state, when the adverse event is continuous. The number and percentage of subjects reporting TEAEs will be tabulated by the worst NCI-CTCAE grade, system organ class, and preferred term. Similarly, the number and percentage of subjects rep
  • Safety parameters assessed by National Cancer Institute (

    Original Primary Outcome: Same as current

    Current Secondary Outcome:

    • Complete response assessed by flow cytometry or DNA sequencing per IMWG criteria [ Time Frame: Up to 30 days after last dose ]
      A two-sided 95% exact binominal CI will be calculated.
    • Minor response per Group for Blood and Marrow Transplantation criteria [ Time Frame: Up to 30 days after last dose ]
      A two-sided 95% exact binominal CI will be calculated.
    • Myeloma response rate [ Time Frame: Up to 30 days after last dose ]
      The myeloma response rate (responses >= partial response) will also be tabulated by dose cohort and overall.
    • Overall survival [ Time Frame: Time from the initial administration of MDM2 inhibitor AMG-232 + KRd to death form any cause, assessed up to 30 days after last dose ]
      Time to response will be summarized by descriptive statistics by dose cohorts. Kaplan-Meier methods will be used to estimate the OS function. Subjects who do not die will be censored at the date that the subject was last known to be alive.
    • Partial response per IMWG criteria [ Time Frame: Up to 30 days after last dose ]
      A two-sided 95% exact binominal CI will be calculated.
    • Pharmacokinetic profile of MDM2 inhibitor AMG-232 assessed by liquid chromatography/tandem mass spectrometric method [ Time Frame: Up to 30 days after last dose ]
      Descriptive statistics will be provided for selected pharmacokinetics, and pharmacodynamics data by dose and time as appropriate. Descriptive statistics on continuous data will include means, medians, standard deviations, and ranges, while categorical data will be summarized using frequency counts and percentages. Graphical summaries of the data may be presented. For MDM2 inhibitor AMG-232 , the individual pharmacokinetic parameters from a single dose will be estimated for concentration maximum (Cmax), area under the curve (AUC), T1/2, apparent Cl/F, and apparent V/F using non-compartmental or
    • Progression-free survival (PFS) [ Time Frame: Time from the time of enrollment until documented disease progression, as determined by the Investigator using IMWG uniform response criteria, or death from any cause, whichever occurs first, assessed up to 30 days after last dose ]
      Time to response will be summarized by descriptive statistics by dose cohorts. Kaplan-Meier methods will be used to estimate PFS over time and the median duration of PFS. Subjects with no PFS event will be censored at the date of their last myeloma disease assessment.
    • Serum MIC-1 levels [ Time Frame: Up to 30 days after last dose ]
      Each individual level will be normalized to the baseline level for that subject. changes in MIC-1 will be tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) calculated for each dose level. MIC-1 changes will be compared across dose level using nonparametric statistical testing techniques.
    • Stable disease per IMWG Uniform Response criteria [ Time Frame: Up to 30 days after last dose ]
      A two-sided 95% exact binominal CI will be calculated.
    • Stringent complete response assessed by immunohistochemistry or 2- to 4-color flow cytometry per Clinical Relapse of Multiple Myeloma or Plasma Cell Leukemia (IMWG) criteria [ Time Frame: Up to 30 days after last dose ]
      A two-sided 95% exact binominal CI will be calculated.
    • Time to response [ Time Frame: Up to 30 days after last dose ]
      Time-to-event analyses will be done using Kaplan-Meier analyses.
    • Very good partial response assessed by immunofixation and electrophoresis per IMWG criteria [ Time Frame: Up to 30 days after last dose ]
      A two-sided 95% exact binominal CI will be calculated.


    Original Secondary Outcome: Same as current

    Information By: National Cancer Institute (NCI)

    Dates:
    Date Received: January 25, 2017
    Date Started: October 17, 2017
    Date Completion: July 31, 2018
    Last Updated: April 23, 2017
    Last Verified: April 2017