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

Multiple Myeloma Clinical Trial

Official title: A Phase I/II Study of the Addition of Ixazomib to ONC201 and Dexamethasone in Relapsed and/or Refractory Multiple Myeloma

Status Terminated

Clinical Trial 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.

Clinical Trial Description

Phase I Study Design

• Phase I will follow a 3+3 dose escalation design to determine the RPTD of ixazomib in combination with ONC201 and Dexamethasone.

The dose escalation rules for the phase I portion of the study are as follows, escalating in cohorts of 3 patients per dose level including a de-escalation option in case of early toxicity. Dose limiting toxicity (DLT) is defined as any grade 3 or higher toxicity seen during the first 28 day cycle of the triplet regimen (ONC201, ixazomib, and dexamethasone). Of note, grade 3 and higher absolute lymphopenia and hematologic toxicities without clinical sequelae (eg. neutropenia without fever/infection, anemia without symptoms, thrombocytopenia without bleeding) and also responsive to growth factors/transfusions will not be considered DLTs. AST or ALT values of ≥ 3x ULN AND with serum total bilirubin level of > 2x ULN or international normalized ratio (INR) > 1.5 without signs of cholestasis and with no other clear alternative reason to explain the observed liver-related laboratory abnormalities is also considered a DLT. Three patients will be treated at the current dose level. If at least 2 patients are observed to have a DLT, the prior dose level is defined as the RPTD unless only 3 patients have been treated at that level, in which case it is the tentative RPTD. If 0 of the 3 patients are observed to have DLT, the dose level is escalated one dose level for the next cohort of 3 patients, and the process continues as above. If exactly 1 of the 3 patients treated show DLT, 3 additional patients are treated at the current dose level. If none of these additional 3 patients show DLT, the dose level is escalated for the next cohort of 3 patients, and the process continues as above; otherwise, the prior dose level is defined as the RPTD (unless only 3 patients have been treated at that level, in which case it is the tentative RPTD). A tentative RPTD becomes final when a total of 6 patients are treated with less than 2 showing DLT.

If, unexpectedly, at least 2 patients are observed to have DLT at the initial dose level 0, then the next dose level evaluated will be the lowest dose level, -2, and further dose escalations to dose level -1 will proceed as outlined above from that dose level. If there is no RPTD declared, there will be no expansion to the phase II portion of the study. The phase I portion of the study will include between 9 and 12 patients depending upon the number of dose levels evaluated.

Phase II Study Design Phase II will follow a Simon's Optimal two-stage design to indicate proof of concept regarding the PFS rate of ixazomib in combination with ONC201 and Dexamethasone at the RPTD established in phase I. Once the RPTD for combination therapy has been established, an additional 24 patients will be enrolled for a total of 30 evaluable patients (24 + 6 from phase I at RPTD).

In considering a Simon's Optimal two-stage design, the plan is to look at each patient at 2 months after initiating study treatment (3 drug combination) and classify each patient as responder or non-responder at the 2 month time point. A responder is a patient who has stable disease or better (not progressed) since initiating study treatment; a non-responder is someone whose disease has progressed according to IMWG criteria. The population of relapsed and refractory MM patients in this study will likely all have progressed on standard therapy; therefore the null hypothesis being tested is that the disease control rate at 2 months is 5%. As per IMWG criteria, if patients show progression after 1 cycle of triplet therapy, they will continue on therapy and a repeat assessment will be performed after cycle 2 in order to confirm progression of disease.

Stage 1:

• Enroll 9 patients including the 6 patients being evaluated from the phase I portion of the study

• Evaluate patients at 2 months post initiation of treatment

• If 0 have responded (progression-free), i.e. if all 9 have progressed, then stop trial for futility and conclude that the proportion who will be progression-free at 2 months is less than 5%.

• If 1 or more have responded (progression-free) at 2 months, then proceed to Stage 2.

Stage 2:

• Enroll an additional 21 patients

• Evaluate patients at 2 months post initiation of treatment If 4 or more of the 30 patients have responded (progression-free) at 2 months then the null hypothesis is rejected and further investigation of this treatment combination is warranted. ;

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

• NCT number: NCT03492138
• Study type: Interventional
• Source: Icahn School of Medicine at Mount Sinai
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: March 26, 2018
• Completion date: January 14, 2020