Ixazomib, ONC201, and Dexamethasone in Relapsed/Refractory Multiple Myeloma

NCT03492138 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: GCO 17-2680
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

ONC201 is a novel dopamine receptor D2 antagonist that is able to activate the integrated stress response pathway. It is active against multiple myeloma cells in vitro, both as a single agent and in combination with corticosteroids and proteasome inhibitors. In order to document superiority over the combination compared to the individual agents of ixazomib and ONC201 in a single arm study, there will initially be a run-in period of weekly ONC201 625 mg with dexamethasone 40 mg such that if there is progression of disease (25% increase) after 4 weeks or less than a minimal response (25% reduction) after 8 weeks then ixazomib will be added. Dexamethasone is dose-reduced to 20 mg at the same schedule for subjects ≥ 75 years old. If patients do achieve single-agent responses with ONC201 (minimal response or better), they will continue with weekly ONC201 and dexamethasone until progression, with response assessments after each 28-day cycle. Patients who have previously been treated on another clinical trial with weekly ONC201 625mg with dexamethasone with progression while receiving treatment do not need to complete the run-in phase of the study. At the time of progression, they will proceed to the 3 drug combination phase of the study. It is at the point of 3 drug initiation, that below phase I DLT principles or phase II disease control rate considerations apply.

Conditions

Multiple Myeloma

Keywords

Multiple Myeloma; Relapsed and Refractory

Outcome Measures

Primary Outcomes (1)

• Recommended phase II dose (RPTD)

  of triplet therapy (ixazomib + ONC201+ dexamethasone) following a 3+3 escalation design

  9 Months

Secondary Outcomes (4)

• Disease control rate

  2 months

• Progression free survival (PFS)

  6 months

• Duration of response (DOR)

  6 months

• Clinical benefit rate (CBR)

  6 months

Study Arms (1)

Participants with relapsed/refractory multiple myeloma

EXPERIMENTAL

ONC201, ixazomib, and dexamethasone in relapsed/refractory multiple myeloma. Run-in phase of ONC201 and dexamethasone weekly until progression at 4 weeks, lack of response at 8 weeks, or progression followed by the addition of weekly ixazomib.

Drug: ONC201; Drug: Ixazomib; Drug: Dexamethasone

Interventions

ONC201 DRUG

625mg

Participants with relapsed/refractory multiple myeloma

Ixazomib DRUG

Dose to be determined in Phase 1 of study

Participants with relapsed/refractory multiple myeloma

Dexamethasone DRUG

40mg

Participants with relapsed/refractory multiple myeloma

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed Written Informed Consent: Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care
• Target Population
• Symptomatic MM having progressed on 2 prior therapies including proteasome inhibitor (i.e. bortezomib, carfilzomib ixazomib), immunomodulatory drug (i.e., thalidomide, lenalidomide, pomalidomide), and daratumumab or other CD38 targeting monoclonal antibody. Proteasome inhibitor refractory patients are eligible. Subjects must not be candidates for treatment regimens known to provide clinical benefit to be eligible for this study.
• Male or female patients 18 years or older
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Patients must have measurable disease defined by at least 1 of the following 3 measurements:
• i. Serum M-protein \> 0.5 g/dL ii. Urine M-protein \> 200 mg/24 hours iii. Serum free light chain assay: involved free light chain level \>10 mg/dL (\> 100 mg/L) provided the serum free light chain ratio is abnormal

You may not qualify if:

• Medical History and Concurrent Diseases
• Peripheral neuropathy \> Grade 2 or \>Grade 1 with pain on clinical examination during the Screening period.
• Significant cardiac disease as determined by the investigator including:
• i. Known or suspected cardiac amyloidosis ii. Congestive heart failure of Class III or IV of the NYHA classification iii. Uncontrolled angina, hypertension or arrhythmia iv. Myocardial infarction in the past 6 months v. Any uncontrolled or severe cardiovascular disease vi. QTc \> 470 milliseconds (msec) on a 12-lead ECG obtained during the Screening period. If a machine reading is above this value, the ECG should be reviewed by a qualified reader and confirmed on a subsequent ECG.
• c. Known active hepatitis B (defined as most recent serum PCR or hepatitis B surface antigen positive) or active hepatitis C (note, hepatitis C in sustained virologic response defined as negative RNA PCR at least 12 weeks after any therapy is permitted).
• d. Any medical conditions that, in the investigator's opinion, would impose excessive risk to the subject, e.g., any uncontrolled disease, such as pulmonary disease, infection, seizure disorder, uncontrolled hyperglycemia.
• e. Any altered mental status or any psychiatric condition that would interfere with the understanding of the informed consent or limit compliance with study requirements.
• f. Prior or concurrent malignancy, except for the following: i. Adequately treated basal cell or squamous cell skin cancer ii. Cervical carcinoma in situ iii. Adequately treated Stage I or II cancer from which the subject is currently in complete remission.
• iv. Or any other cancer from which the subject has been disease-free for ≥ 3 years g. Diarrhea \> Grade 1, based on the NCI CTCAE grading, in the absence of antidiarrheals.
• h. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of study drug, including difficulty swallowing.
• i. Males or females of childbearing potential who do not agree to practice 2 effective methods of contraception, at the same time through 90 days after the last dose of study drug j. Females who are pregnant or breastfeeding. k. Diagnosis of Waldenstrom's macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell leukemia, myeloproliferative syndrome, or primary amyloidosis (with the exception of patients whose amyloidosis has been documented as a complication of MM, who will be evaluated on a case-by-case basis for trial participation).
• l. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study drug administration.
• m. Parkinson's disease 4) Physical and Laboratory Test Findings
• a. Corrected serum calcium ≥ 14 mg/dl within 2 weeks of enrollment (despite appropriate measure such a short course of steroids, bisphosphonates, hydration, and calcitonin).
• b. Absolute neutrophil count \< 1000 cells/mm3. No growth factors allowed within 1 week of enrollment.

Sponsors & Collaborators

• Ajai Chari: lead

Study Sites (1)

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

MeSH Terms

Conditions

Multiple Myeloma; Recurrence

Interventions

TIC10 compound; ixazomib; Dexamethasone

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Officials

• Ajai Chari, MD

  Icahn School of Medicine at Mount Sinai

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor

Model Details: Single arm, open-label, standard 3+3 phase 1 with a Simon 2-stage design followed by stage 2

Study Record Dates

• First Submitted: March 22, 2018
• First Posted: April 10, 2018
• Study Start: March 26, 2018
• Primary Completion: January 14, 2020
• Study Completion: January 14, 2020
• Last Updated: May 29, 2020

Record last verified: 2020-05

Locations

US (1)