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Patients receive MDM2 Inhibitor KRT-232 PO QD on days 1-7, carfilzomib IV over 10-30 minutes on days 1-2, 8-9, and 15-16 of cycles 1-12 and on days 1-2 and 15-16 of cycles 13-18, lenalidomide PO on days 1-21, and dexamethasone PO or dexamethasone sodium phosphate IV on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unexpected toxicity. Patients undergo echocardiography during screening and bone marrow biopsy and aspiration, and blood sample collection throughout the study.

Biospecimen Collection

Undergo bone marrow aspiration and biopsy

Bone Marrow Aspiration and Biopsy

Carfilzomib

Dexamethasone Sodium Phosphate

Echocardiography

Navtemadlin

Site Public Contact

Aaron Rosenberg

Jorge Monge Urrea

William H. Matsui

Hans C. Lee

Brian L. McClune

Hans C Lee

This phase I trial studies the side effects and best dose of MDM2 Inhibitor KRT-232 when given together with carfilzomib, lenalidomide, and dexamethasone in treating patient with multiple myeloma that has come back (relapsed) or has not responded to previous treatment (refractory). KRT-232 (AMG 232) may stop the growth of cancer cells by blocking a protein called MDM2 that is needed for cell growth. Lenalidomide help shrink or slow the growth of multiple myeloma. Drugs used in chemotherapy, such as carfilzomib 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. Giving MDM2 Inhibitor KRT-232, lenalidomide, carfilzomib, and dexamethasone together may work better in treating patients with multiple myeloma.

PRIMARY OBJECTIVES:

I. Evaluate safety and tolerability of MDM2 Inhibitor KRT-232 (KRT-232 \[AMG 232\]) in combination with carfilzomib, lenalidomide, and dexamethasone (KRd). (Part A) II. Determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of KRT-232 (AMG 232) in combination with carfilzomib, lenalidomide, and dexamethasone (KRd). (Part A) III. Confirm the safety and tolerability of KRT-232 (AMG 232) in combination with carfilzomib, lenalidomide, and dexamethasone (KRd) at MTD/tentative RP2D in a goal of 10 subjects with relapsed and/or refractory myeloma. (Part B)

SECONDARY OBJECTIVES:

I. Evaluate progressive disease (PD) effects of KRT-232 (AMG 232) through serum MIC-1 levels. (Part A) II. Assess KRT-232 (AMG 232) exposure-response relationships (PD, toxicity, and efficacy). (Part A) III. Evaluate the overall response rate of KRT-232 (AMG 232) in combination with carfilzomib, lenalidomide, and dexamethasone (KRd) in relapsed/refractory myeloma by International Myeloma Working Group (IMWG) criteria. (Part B) IV. Evaluate PD effects of KRT-232 (AMG 232) through serum MIC-1 levels. (Part B) V. Assess KRT-232 (AMG 232) exposure-response relationships (PD, toxicity, and efficacy). (Part B)

EXPLORATORY OBJECTIVES:

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

OUTLINE: This is a dose-escalation study of MDM2 Inhibitor KRT-232.

Patients receive MDM2 Inhibitor KRT-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 cycles 1-12 and on days 1-2 and 15-16 of cycles 13-18, lenalidomide PO on days 1-21, and dexamethasone PO or dexamethasone sodium phosphate IV on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unexpected toxicity. Patients undergo echocardiography during screening and bone marrow biopsy and aspiration, and blood sample collection throughout the study.

After completion of study treatment, patients are followed up for 30 days.

Testing the Addition of KRT-232 (AMG 232) to Usual Chemotherapy for Relapsed Multiple Myeloma

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

Assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Safety parameters will include severe adverse events, treatment-emergent adverse events, physical examination findings (including Eastern Cooperative Oncology Group performance status), vital sign measurements, and standard clinical laboratory parameters (serum chemistry, hematology, urinalysis). In the Dose Escalation part, the incidence of dose limiting toxicities will also be evaluated.

Assessed by NCI CTCAE version 5.0. 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 reporting treatment-emergent severe adverse event (SAE)s will be tabulated, as well as TEAEs/SAEs considered related to treatment.

Abnormal laboratory results will be graded according to NCI-CTCAE, version 5.0, 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.

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.

Assessed by liquid chromatography/tandem mass spectrometric method. 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 compartmental pharmacokinetic methods with the software WinNonlin.

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.

Assessed by immunohistochemistry or 2- to 4-color flow cytometry per Clinical Relapse of Multiple Myeloma or Plasma Cell Leukemia (IMWG) criteria. A two-sided 95% exact binominal confidence interval (CI) will be calculated.

Assessed by flow cytometry or deoxyribonucleic acid sequencing per IMWG criteria. A two-sided 95% exact binominal CI will be calculated.

Assessed by immunofixation and electrophoresis per IMWG criteria. A two-sided 95% exact binominal CI will be calculated.

Assessed per IMWG criteria. A two-sided 95% exact binominal CI will be calculated.

Assessed per IMWG Uniform Response criteria. A two-sided 95% exact binominal CI will be calculated.

Assessed per Group for Blood and Marrow Transplantation criteria. A two-sided 95% exact binominal CI will be calculated.

The myeloma response rate (responses \>= partial response) will also be tabulated by dose cohort and overall.

Time-to-event analyses will be done using Kaplan-Meier analyses.

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.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Testing the Addition of KRT-232 (AMG 232) to Usual Chemotherapy for Relapsed Multiple Myeloma	NCT03031730	Plasmacytoma Recurrent Multi... Refractory Mult...	Biospecimen Col... Bone Marrow Asp... Carfilzomib Dexamethasone Dexamethasone S... Echocardiograph... Lenalidomide Navtemadlin	18 Years -	National Cancer Institute (NCI)
Testing the Addition of KRT-232 (AMG 232) to Usual Chemotherapy for Relapsed Multiple Myeloma	NCT03031730	Plasmacytoma Recurrent Multi... Refractory Mult...	Biospecimen Col... Bone Marrow Asp... Carfilzomib Dexamethasone Dexamethasone S... Echocardiograph... Lenalidomide Navtemadlin	18 Years -	National Cancer Institute (NCI)

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