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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03492138
Recruitment Status : Terminated (Low enrollment)
First Posted : April 10, 2018
Last Update Posted : May 29, 2020
Information provided by (Responsible Party):
Ajai Chari, Icahn School of Medicine at Mount Sinai

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.

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: ONC201 Drug: Ixazomib Drug: Dexamethasone Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Single arm, open-label, standard 3+3 phase 1 with a Simon 2-stage design followed by stage 2
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of the Addition of Ixazomib to ONC201 and Dexamethasone in Relapsed and/or Refractory Multiple Myeloma
Actual Study Start Date : March 26, 2018
Actual Primary Completion Date : January 14, 2020
Actual Study Completion Date : January 14, 2020

Arm Intervention/treatment
Experimental: Participants with relapsed/refractory multiple myeloma
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
Dose to be determined in Phase 1 of study

Drug: Dexamethasone

Primary Outcome Measures :
  1. Recommended phase II dose (RPTD) [ Time Frame: 9 Months ]
    of triplet therapy (ixazomib + ONC201+ dexamethasone) following a 3+3 escalation design

Secondary Outcome Measures :
  1. Disease control rate [ Time Frame: 2 months ]
    2 month disease control rate defined as the proportion of patients that have stable or better disease after two months of treatment initiation according to IMWG criteria: Stable disease, partial remission, or complete remission

  2. Progression free survival (PFS) [ Time Frame: 6 months ]
    Median Progression free survival for the phase I and II patients treated at the recommended phase II dose. PFS is defined as the duration of time from start of treatment to the first occurrence of disease progression or death on study from any cause, whichever occurs earlier.

  3. Duration of response (DOR) [ Time Frame: 6 months ]
    Median duration of response for the phase I and II patients treated at the recommended phase II dose. DOR is defined as the time from first evidence of PR or better to confirmation of disease progression.

  4. Clinical benefit rate (CBR) [ Time Frame: 6 months ]
    Clinical benefit rate for the phase I and II patients treated at the recommended phase II dose level. CBR is the combination of the ORR and minimal response (MR) i.e. this includes sCR, CR, VGPR, PR, and MR.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • 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

    1. 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.
    2. Male or female patients 18 years or older
    3. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
    4. 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

Exclusion Criteria:

  • Medical History and Concurrent Diseases

    1. Peripheral neuropathy > Grade 2 or >Grade 1 with pain on clinical examination during the Screening period.
    2. 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.

c. Platelets < 75,000 cell/mm3 (75 x 109/L). Qualifying laboratory value must occur at most recent measurement before enrollment and must be no more than 14 days before enrollment. No transfusions are allowed within 72 hours prior to study drug administration.

d. Hemoglobin < 8 g/dL. Qualifying laboratory value must occur at most recent measurement before enrollment and must be no more than 14 days before enrollment. No transfusions are allowed within 72 hours before qualifying laboratory value e. Serum bilirubin ≥ 1.5 x ULN, patients with Gilbert's syndrome and a total bilirubin of < 3 times ULN are permitted) f. AST or ALT ≥ 3 x ULN. g. CrCl < 30 ml/min/1.73m2. Creatinine clearance is estimated by the CKD-EPI formula. (Calculator available at

  • Prior Therapy or Surgery

    1. Major surgery or radiation therapy within 14 days before study drug administration.
    2. Kyphoplasty or vertebroplasty within 1 week of enrollment.
    3. Administration of chemotherapy, biological, immunotherapy, or investigational agent (therapeutic or diagnostic) within 3 weeks before enrollment (14 days for non-myelosuppressive therapy). Subjects should be 6 weeks from last dose of nitrosourea, nitrogen mustards or monoclonal antibody, 12 weeks from autologous SCT, and 16 weeks from allogeneic SCT.
    4. Corticosteroids use exceeding a cumulative dose of 160 mg of dexamethasone during screening.
    5. If prior allogeneic stem cell transplant, history of moderate to severe chronic graft versus host disease (GVHD).
    6. Treatment with plasmapheresis within 4 weeks before enrollment.
    7. NSAIDs, IV contrast, aminoglycosides, or other potentially nephrotoxic drugs within 2 weeks of enrollment.
    8. Current use of a non-standard dialysis membrane.
    9. Systemic treatment with strong inhibitors or inducers of CYP450 system should not be used on study including but not limited to fluvoxamine, enoxacin, ciprofloxacin, clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole, rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital, buproprion, fluoxetine, paroxetine, ticlopidine, or St. John's wort within 14 days before the first dose of study treatment. Ixazomib has significant drug-drug interactions with strong CYP3A inducers. No drug-drug interactions with the CYP450 screen have been found with ONC201, but the analysis of these studies is not complete, so during the study use of inhibitors or inducers of CYP450 system is excluded.
    10. Failure to have fully recovered (i.e., Grade 1 toxicity or less, with the exception of alopecia) from clinically significant effects of prior chemotherapy regardless of interval since last treatment.
  • Allergies and Adverse Drug Reaction Known hypersensitivity to bortezomib, ixazomib, dexamethasone, ONC201

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03492138

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United States, New York
Icahn School of Medicine at Mount Sinai
New York, New York, United States, 10029
Sponsors and Collaborators
Ajai Chari
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Principal Investigator: Ajai Chari, MD Icahn School of Medicine at Mount Sinai
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Responsible Party: Ajai Chari, Associate Professor, Icahn School of Medicine at Mount Sinai Identifier: NCT03492138    
Other Study ID Numbers: GCO 17-2680
First Posted: April 10, 2018    Key Record Dates
Last Update Posted: May 29, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Data and safety will be monitored using an internal Data and Safety Monitoring Plan (DSMP) led by the PI. Other members involved with the review will include sub-Investigators, the myeloma research program manager, and clinical research coordinators. All of these individuals have experience in the routine clinical care as well clinical research and monitoring of subjects with multiple myeloma. A statistician will also be involved with the review.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ajai Chari, Icahn School of Medicine at Mount Sinai:
Multiple Myeloma
Relapsed and Refractory
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Anti-Inflammatory Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action