A Study Designed to Evaluate the Safety and Efficacy of Venetoclax Plus Dexamethasone (VenDex) Compared With Pomalidomide Plus Dexamethasone (PomDex) in Participants With t(11;14)-Positive Relapsed or Refractory Multiple Myeloma.

Study Overview
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Brief Summary
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A study designed tocompare progression-free survival (PFS) in participants with t(11;14)-positive MM treated with venetoclax in combination with dexamethasone versus pomalidomide in combination with dexamethasone.

Official Title
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A Phase 3, Multicenter, Randomized, Open Label Study of Venetoclax and Dexamethasone Compared With Pomalidomide and Dexamethasone in Subjects With t(11;14)-Positive Relapsed or Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented diagnosis of multiple myeloma (MM) based on standard International Myeloma Working Group (IMWG) criteria. Measurable disease at screening as defined per protocol. Has received at least 2 prior lines of therapy as described in the protocol. Has had documented disease progression on or within 60 days after completion of the last therapy. Has received at least 2 consecutive cycles of lenalidomide and be relapsed/refractory to lenalidomide, as defined per protocol. Has received at least 2 consecutive cycles of a proteasome inhibitor (PI). Has t(11;14)-positive status determined by an analytically validated fluorescent in situ hybridization (FISH) assay per centralized laboratory testing. An Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2. Laboratory values (liver, kidney and hematology laboratory values) that meet criteria as described per protocol. Exclusion Criteria: History of treatment with venetoclax or another B-Cell Lymphoma (BCL)-2 inhibitor or pomalidomide. History of other active malignancies, including myelodysplastic syndromes (MDS), within the past 3 years (exceptions described in the protocol). Evidence of ongoing graft-versus-host disease (GvHD) if prior stem cell transplant (SCT). Prior treatment with any of the following: allogeneic or syngeneic SCT within 16 weeks prior to randomization; or autologous SCT within 12 weeks prior to randomization. Known central nervous system involvement of MM. Concurrent conditions as listed in the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 VenDex<br>Venetoclax administered orally once daily (QD) plus dexamethasone administered orally once every week (Q1W) for each 28-day cycle. | Drug: Dexamethasone<br>* oral, locally available form<br>Drug: Venetoclax<br>* tablet; oral<br>* Other names: GDC-0199;|
| Active Comparator: Arm 2 PomDex<br>Pomalidomide administered orally once daily (QD) on Days 1 - 21 for each 28-day cycle plus dexamethasone administered orally once every week (Q1W) for each 28-day cycle. | Drug: Pomalidomide<br>* capsule, oral<br>* Other names: Pomalyst;Drug: Dexamethasone<br>* oral, locally available form<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS is defined as the time in days from subject randomization to the date of the first documented progressive disease (PD) or death due to any cause, whichever occurs first. | Up to approximately 43 months from first randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR is defined as the percentage of participants with documented best response (sCR, CR, VGPR or partial response [PR]) prior to first documented PD. | Up to approximately 43 months from first randomization | 
| Very Good Partial Response or Better Response Rate (VGPR) | VGPR or better response rate is defined as the proportion of participants with documented stringent complete response (sCR), complete response (CR), or VGPR. | Up to approximately 43 months from first randomization | 
| Overall survival (OS) | OS is defined as the number of days from the date that the participant was randomized to the date of the participant's death. | Up to approximately 51 months from first randomization | 
| Minimal Residual Disease (MRD) Negativity Rate | MRD defined as the percentage of participants with MRD negativity status. MRD negativity will be defined at 10^-5 threshold as measured by centralized testing of bone marrow aspirate samples by next generation sequencing (NGS). | Up to approximately 43 months from first randomization | 
| Time to Deterioration in Disease Symptoms | Time to deterioration in disease symptoms is measured by the disease symptom domain of the European Organization for Research and Treatment of Cancer Quality of Life Multiple Myeloma Module 20 (EORTC QLQ-MY20). | Up to approximately 51 months from first randomization | 
| Time to Deterioration in Physical Functioning | Time to deterioration in physical functioning is measured by the physical functioning domain of European Organization for Research and Treatment of Cancer Quality of Life Core 30 Question Questionnaire (EORTC-QLQ-C30). | Up to approximately 51 months from first randomization | 
| Change from Baseline in PROMIS Fatigue Score | Change from baseline in the Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 7a score. | Up to approximately 51 months from first randomization | 
| Change from Baseline in BPI-SF Worst Pain Score | Change from baseline in the Brief Pain Inventory - Short Form (BPI-SF) worst pain score. | Up to approximately 51 months from first randomization | 
| Change from Baseline in EuroQoL 5 Dimension 5 Level (EQ-5D-5L) | EQ-5D-5L consists of 2 components: the EQ-5D descriptive system and the EQ visual analog scale (VAS). The EQ-5D descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The EQ VAS records the participant's self-rated health on a vertical VAS where the endpoints are labelled The best health you can imagine and The worst health you can imagine. | Up to approximately 51 months from first randomization | 
| Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) | EORTC QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including 5 functional scales (physical, role, emotional, social, and cognitive), 3 symptom scales (fatigue, nausea and vomiting, and pain), a global health status/quality of life scale, and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). | Up to approximately 51 months from first randomization | 
| Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Multiple Myeloma Module 20 (EORTC QLQ-MY20) | EORTC QLQ-MY20 includes scales for disease symptoms, side effects of treatment, future perspective, and body image. Values for each scale range from 0 to 100. | Up to approximately 51 months from first randomization | 
| Duration of response (DOR) | DOR for a participant is defined as the number of days from the date of first documented response (PR or better) to the date of first documented PD or death due to multiple myeloma, whichever occurs first. | Up to approximately 43 months from first randomization | 
| Time to Disease Progression (TTP) | TTP for a participant is defined as the number of days from the date of randomization to the date of first documented PD or death due to multiple myeloma, whichever occurs first. | Up to approximately 43 months from first randomization | 
| Time to Response (TTR) | TTR for a participant is defined as the number of days from the date of randomization to the date of first documented response (PR or better). | Up to approximately 43 months from first randomization | 
| Cmax of Venetoclax | Maximum plasma concentration (Cmax) of venetoclax | Up to approximately 225 days from initial dose | 
| Trough Concentration (Ctrough) of Venetoclax | Observed plasma concentration at trough (Ctrough) of venetoclax. | Up to approximately 225 days from initial dose | 
| Number of Participants With Adverse Events (AEs) | An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study. | Up to approximately 51 months from first randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer, Multiple Myeloma (MM), Relapsed or Refractory Multiple Myeloma (R/R MM), pharmacokinetics, CANOVA