A Study of Venetoclax in Combination With Pomalidomide and Dexamethasone in Participants With Relapsed or Refractory Multiple Myeloma

Study Overview
=================
Brief Summary
-----------------
This was an open-label, multicenter study designed to evaluate the safety and preliminary efficacy of venetoclax combined with pomalidomide and dexamethasone in participants with relapsed or refractory (R/R) multiple myeloma (MM) who received at least 1 prior line of therapy with documented evidence of progression during or after the participant's last treatment regimen. The study was designed to consist of 2 parts: Part 1 (dose escalation) and Part 2 (dose expansion). For Part 2 the participants were to be divided into 2 cohorts, participants positive for t(11;14) translocation and participants negative for t(11;14) translocation.

Detailed Description
-----------------
Following communication of the results of the primary progression-free survival (PFS) analysis from the Phase 3 BELLINI study (Study M14-031; NCT02755597), the company-sponsored MM studies were placed on partial clinical hold (PCH) in March 2019 by the United States (US) Food and Drug Administration and enrollment was halted. The sponsor did not pursue release of the PCH for this study; therefore, enrollment was not re-opened. In accordance with the terms of the PCH, participants who were deriving clinical benefit were allowed to continue to receive treatment. One participant was still active in Part 1 of the study when the sponsor decided not to pursue release of the PCH (in January 2020) and, therefore, continued to receive treatment and have regular assessments until disease progression. The study was discontinued when the last participant completed study treatment. No participants were enrolled in Part 2 of the study.

Official Title
-----------------
A Phase 2, Open-Label, Multicenter, Dose-Escalation and Expansion Study of Venetoclax in Combination With Pomalidomide and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma

Conditions
-----------------
Multiple Myeloma

Intervention / Treatment
-----------------
* Drug: Venetoclax
* Drug: Pomalidomide
* Drug: Dexamethasone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Relapsed or refractory (R/R) multiple myeloma (MM) with documented evidence of progression during or after the participant's last treatment regimen Measurable disease as described in the protocol Received at least 1 prior line of therapy as described in the protocol Must meet prior antimyeloma treatment parameters, as described in the protocol, and includes: Received at least 2 consecutive cycles of lenalidomide or a lenalidomide-containing regimen Refractory to lenalidomide Exposed to a proteasome inhibitor (PI) alone or in combination with another agent Had a response of partial response (PR) or better to prior therapy based on the investigator's determination of response as defined by International Myeloma Working Group (IMWG) criteria Has t(11;14) status as described in the protocol and meets the following criteria: For Part 1: MM participants independent of cytogenetic profile For Part 2, Arm A: participant must be t(11;14) positive For Part 2, Arm B: participant must be t(11;14) negative An Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Adequate kidney, liver and hematologic laboratory values Exclusion Criteria: Previous treatment with venetoclax or other BCL-2 inhibitors, or previous treatment with pomalidomide Known sensitivity to any IMiDs Allogenic or syngeneic stem cell transplant within 6 months before the first dose of study drug or active ongoing graft versus host disease Autologous stem cell transplant within 12 weeks before the first dose of study drug Known meningeal involvement of MM

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Dose Escalation<br>Venetoclax (400 mg oral [PO], once daily [QD]) administered with pomalidomide (4 mg PO, QD) and dexamethasone (40 mg once weekly [qw]) in 28-day cycles until documented disease progression, documented unacceptable toxicity, withdrawal of consent, or the participant met other criteria for discontinuation per study protocol | Drug: Venetoclax<br>* Tablet; oral<br>* Other names: Venclexta;Drug: Pomalidomide<br>* Capsule; oral<br>* Other names: Pomalyst;Drug: Dexamethasone<br>* Administered orally; for participants over 75 years of age, dexamethasone could have been administered at a 20 mg dose [qw]<br>|
| Experimental: Part 2: Dose Expansion, t(11;14) positive<br>Participants positive for t(11;14) translocation were to receive the venetoclax dose determined to be safe in Part 1 as well as pomalidomide (4 mg oral [PO], once daily [QD]) and dexamethasone (40 mg once weekly [qw]) | Drug: Venetoclax<br>* Tablet; oral<br>* Other names: Venclexta;Drug: Pomalidomide<br>* Capsule; oral<br>* Other names: Pomalyst;Drug: Dexamethasone<br>* Administered orally; for participants over 75 years of age, dexamethasone could have been administered at a 20 mg dose [qw]<br>|
| Experimental: Part 2: Dose Expansion, t(11;14) negative<br>Participants negative for t(11;14) translocation were to receive the venetoclax dose determined to be safe in Part 1 as well as pomalidomide (4 mg oral [PO], once daily [QD]) and dexamethasone (40 mg once weekly [qw]) | Drug: Venetoclax<br>* Tablet; oral<br>* Other names: Venclexta;Drug: Pomalidomide<br>* Capsule; oral<br>* Other names: Pomalyst;Drug: Dexamethasone<br>* Administered orally; for participants over 75 years of age, dexamethasone could have been administered at a 20 mg dose [qw]<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The investigator assessed the relationship of each event to the use of study drug as either reasonable possibility or no reasonable possibility. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent events (TEAEs/TESAEs) are defined as any event that began or worsened in severity after the first dose of study drug. For more details on adverse events please see the Adverse Event section. | From first dose of study drug until 30 days following last dose of study drug (up to 70 weeks) | 
| Overall Response Rate (ORR) | ORR is defined as the percentage of participants experiencing a stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) using the International Myeloma Working Group (IMWG) 2016 criteria for disease response and progression. CR= negative immunofixation of serum and urine and disappearance of any soft tissue plasmacytomas, and < 5% plasma cells in bone marrow; sCR= CR + normal serum free light chain (FLC) ratio and absence of clonal cells in bone marrow; VGPR= serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M-protein level + urine M-protein level < 100 mg per 24 hours; PR= ≥ 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥ 90% or to < 200 mg per 24 hours. | Approximately 15 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS is defined as the number of days from the date of first dose of any study drug to the date of disease progression or death, whichever occurs first. All disease progression was to be included regardless of whether the event occurred during or after the participant was taking any study drug. | Approximately 20 months | 
| Duration of Response (DOR) | DOR for a given participant is defined as the number of days from the date of that participant's first documented response (Partial Response [PR] or better) to the date of first documented disease progression (PD) or death due to multiple myeloma (MM), whichever occurs first. If the participant with a documented response did not have an event of PD and the participant had not died due to MM, the participant's data was to be censored. | Approximately 15 months | 
| Time-to-progression (TTP) | TTP for a given participant is defined as the number of days from the date of first dose to the date of first documented disease progression (PD) or death due to multiple myeloma (MM), whichever occurs first. If the participant did not have an event of PD and the participant had not died due to MM, the participant's data was to be censored. | Approximately 15 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cancer, Multiple Myeloma (MM), Relapsed or Refractory (R/R), Venetoclax, Pomalidomide, Dexamethasone