Comparison of Pomalidomide and Dexamethasone With or Without Daratumumab in Subjects With Relapsed or Refractory Multiple Myeloma Previously Treated With Lenalidomide and a Proteasome InhibitorDaratumumab/Pomalidomide/Dexamethasone vs Pomalidomide/Dexamethasone

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effects of the addition of daratumumab to pomalidomide and dexamethasone in terms of progression-free survival in subjects with relapsed or refractory Multiple Myeloma.

Detailed Description
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This is a multicenter, Phase 3, randomized, open-label study comparing daratumumab, pomalidomide and low-dose dexamethasone (DaraPomDex) with pomalidomide and low-dose dexamethasone (PomDex) in subjects with relapsed or refractory Multiple Myeloma who have received at least 1 prior treatment regimen with both lenalidomide and a proteasome inhibitor and have demonstrated disease progression. Subjects will be randomized in a 1:1 ratio to receive either DaraPomDex or PomDex. The original design of this study was to treat subjects with daratumumab for intravenous (IV) infusion (Dara IV); however, as of Amendment 1, all new subjects will be dosed subcutaneously with daratumumab co-formulated with recombinant human hyaluronidase rHuPH20 (hereafter referred to as Dara SC). Subjects who already began treatment with Dara IV (ie, prior to Amendment 1) will have the option to switch to Dara SC on Day 1 of any cycle starting with Cycle 3 or later for the remainder of their participation in the study, and they will be counted toward the total of 302 subjects. Subjects will receive treatment until disease progression or unacceptable toxicity. Drug administration and follow-up visits will occur more frequently for early cycles (e.g., weekly or bi-weekly). Disease evaluations will occur every cycle and consist mainly of measurements of myeloma proteins. Subject safety will be assessed throughout the study. The primary endpoint will be progression-free survival (PFS). Study end is anticipated at approximately 5 years after the last subject is randomized.

Official Title
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A Phase 3 Study Comparing Pomalidomide and Dexamethasone With or Without Daratumumab in Subjects With Relapsed or Refractory Multiple Myeloma Who Have Received at Least One Prior Line of Therapy With Both Lenalidomide and a Proteasome Inhibitor.

Conditions
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Multiple Myeloma

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females at least 18 years of age. Voluntary written informed consent before performance of any study-related procedure. Subject must have measurable disease of MM as defined by the criteria below: IgG multiple myeloma: Serum M protein level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours, or IgA, IgD, IgE, IgM multiple myeloma: Serum M-protein level ≥0.5 g/dL or urine M-protein level ≥200 mg/24 hours; or Light chain multiple myeloma, for subjects without measurable disease in the serum or urine: Serum immunoglobulin free light chain (FLC) ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio. Subjects must have received prior antimyeloma treatment. The prior treatment must have included both a PI- and lenalidomide-containing regimens. The subject must have had a response (ie, PR or better based on the investigator's determination of response as defined by the modified IMWG criteria) to prior therapy. Subjects must have documented evidence of PD based on the investigator's determination of response as defined by the modified IMWG criteria on or after the last regimen. Subjects who received only 1 line of prior treatment must have demonstrated PD on or within 60 days of completion of the lenalidomide containing regimen (ie, lenalidomide refractory). Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2. Willingness and ability to participate in study procedures. For subjects experiencing toxicities resulting from previous therapy, the toxicities must be resolved or stabilized to ≤Grade 1. Any of the following laboratory test results during Screening: Absolute neutrophil count ≥1.0 × 109/L; Hemoglobin level ≥7.5 g/dL (≥4.65 mmol/L); (transfusions are not permitted to reach this level); Platelet count ≥75 × 109/L in subjects in whom <50% of bone marrow nucleated cells are plasma cells and platelet count ≥50 x 109/L in subjects in whom ≥50% of bone marrow nucleated cells are plasma cells; Alanine aminotransferase (ALT) level ≤2.5 times the upper limit of normal (ULN); Aspartate aminotransferase (AST) level ≤2.5 x ULN; Total bilirubin level ≤1.5 x ULN, (except for Gilbert Syndrome: direct bilirubin ≤1.5 × ULN); Creatinine clearance ≥30 mL/min Serum calcium corrected for albumin ≤14.0 mg/dL (≤3.5 mmol/L), or free ionized calcium ≤ 6.5 mg/dL (≤1.6 mmol/L). Reproductive Status Women of childbearing potential (WOCBP) must have 2 negative serum or urine pregnancy tests, one 10-14 days prior to start of study treatment and one 24 hours prior to the start of study treatment. Females are not of reproductive potential if they have been in natural menopause for at least 24 consecutive months, or have had a hysterectomy and/or bilateral oophorectomy. Women must not be breastfeeding. WOCBP must agree to follow instructions for methods of contraception for 4 weeks before the start of study treatment, for the duration of study treatment, and for 3 months after cessation of daratumumab or 4 weeks after cessation of pomalidomide, whichever is longer. Males who are sexually active must always use a latex or synthetic condom during any sexual contact with females of reproductive potential, even if they have undergone a successful vasectomy. They must also agree to follow instructions for methods of contraception for 4 weeks before the start of study treatment, for the duration of study treatment, and for a total of 3 months post-treatment completion. Male subjects must not donate sperm for up to 90 days post-treatment completion. Female subject must not donate eggs for up to 90 days post-treatment completion. Azoospermic males and WOCBP who are not heterosexually active are exempt from contraceptive requirements. However, WOCBP will still undergo pregnancy testing as described in this section. Highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly. Subjects must agree to the use of 2 methods of contraception, with 1 method being highly effective and the other method being additionally effective. Because of the embryo-fetal risk of pomalidomide, all subjects must adhere to the pomalidomide pregnancy prevention program applicable in their region. Investigators should comply with the local label for pomalidomide for specific details of the program. Exclusion Criteria: Previous therapy with any anti-CD38 monoclonal antibody. Previous exposure to pomalidomide. Subject has received antimyeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of the treatment, whichever is longer, before the date of randomization. The only exception is emergency use of a short course of corticosteroids (equivalent of dexamethasone 40 mg/day for a maximum of 4 days) for palliative treatment before Cycle 1, Day 1 (C1D1). Previous allogenic stem cell transplant; or autologous stem cell transplantation (ASCT) within 12 weeks before C1D1. History of malignancy (other than MM) within 3 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 3 years). Clinical signs of meningeal involvement of MM. Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal. Clinically significant cardiac disease, including: Myocardial infarction within 6 months, before C1D1 or unstable or uncontrolled condition (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV). Cardiac arrhythmia (Common Terminology Criteria for Adverse Events [CTCAE] Grade 3 or higher) or clinically significant electrocardiogram (ECG) abnormalities. Electrocardiogram showing a baseline QT interval as corrected QTc >470 msec. Known active hepatitis A, B, or C. Known HIV infection. Gastrointestinal disease that may significantly alter the absorption of pomalidomide. Subject has plasma cell leukemia (>2.0 × 109/L circulating plasma cells by standard differential) or Waldenström's macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) or amyloidosis. Any concurrent medical or psychiatric condition or disease (eg, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results or that, in the opinion of the investigator, would constitute a hazard for participating in this study. Ongoing ≥ Grade 2 peripheral neuropathy. Subject had ≥Grade 3 rash during prior therapy. Subject has had major surgery within 2 weeks before randomization, or has not fully recovered from an earlier surgery, or has surgery planned during the time the subject is expected to participate in the study or within 2 weeks after the last dose of study drug administration. Note: subjects with planned surgical procedures to be conducted under local anesthesia may participate. Kyphoplasty or vertebroplasty are not considered major surgery. Pregnant or nursing women.

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
Interventional Model Description: Allocation: Randomized Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Daratumumab+Pomalidomide+Dexamethasone<br>Daratumumab at a dose of 16 mg/kg administered as an IV infusion (Dara IV) or 1800 mg subcutaneously (Dara SC) at weekly intervals (QW) for 8 weeks, then every 2 weeks (Q2W) for an additional 16 weeks, then every 4 weeks (Q4W) thereafter. Pomalidomide 4 mg orally (PO) on Days 1 through 21 of each 28-day cycle Dexamethasone 40 mg (20 mg for patients ≥75 years of age) orally, once daily on Days 1, 8, 15, and 22 of each 28-day treatment cycle | Drug: Daratumumab<br>* Daratumumab will be given at a dose of 16 mg/kg administered as an IV infusion (Dara IV) or 1800 mg subcutaneously (Dara SC) at weekly intervals (QW) for 8 weeks, then every 2 weeks (Q2W) for an additional 16 weeks, then every 4 weeks (Q4W) thereafter. Subjects will receive pre-infusion medications before infusions to mitigate potential IRRs.<br>Drug: Pomalidomide<br>* Pomalidomide will be administered at full dose of 4 mg orally (PO) on Days 1 through 21 of each 28-day cycle.<br>Drug: Dexamethasone<br>* Dexamethasone will be administered at a dose of 40 mg (20 mg for patients ≥75 years of age) orally, once daily on Days 1, 8, 15, and 22 of each 28-day treatment cycle.<br>|
| Active Comparator: Pomalidomide + Dexamethasone<br>Pomalidomide 4 mg orally (PO) on Days 1 through 21 of each 28-day cycle Dexamethasone 40 mg (20 mg for patients ≥75 years of age) orally, once daily on Days 1, 8, 15, and 22 of each 28-day treatment cycle | Drug: Pomalidomide<br>* Pomalidomide will be administered at full dose of 4 mg orally (PO) on Days 1 through 21 of each 28-day cycle.<br>Drug: Dexamethasone<br>* Dexamethasone will be administered at a dose of 40 mg (20 mg for patients ≥75 years of age) orally, once daily on Days 1, 8, 15, and 22 of each 28-day treatment cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of Progression Free Survival Between Treatment Arms | Comparison of Progression Free Survival between treatment arms (Daratumumab /Pomalidomide /Dexamethasone vs Pomalidomide / Dexamethasone)[ Time Frame: Assessed monthly from randomization until disease progression (PD) or death whichever occurs first (approximately up to 3 years)] Progression free survival is defined as the time, in months, from randomization to the date of the first documented PD or death due to any cause, whichever comes first. PD will be assessed by the investigator based on the analysis of serum and urine protein electrophoresis (sPEP and uPEP), serum and urine immunofixation (sIFE and uIFE), serum free light chain protein (sFLC),corrected serum calcium assessment, imaging and bone marrow assessments as per modified IMWG guidelines. | Assessed monthly from randomization until disease progression (PD) or death whichever occurs first (approximately up to 3 years)] | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Overall response rate is defined as the percentage of randomized subjects who achieve a best response of PR or better using modified IMWG criteria as their best overall response | Assessed monthly from Randomization until PD, (approximately up to 3 years)] | 
| Depth of Response | To assess the depth of response by analyzing the percentage of patients with Minimal Residual Disease (MRD) negativity (<10-5), considering the patients who have achieved CR or better, and patients with suspected CR/sCR. | From randomization to disease progression or subsequent antimyeloma therapy, assessed up to approximately 3 years. | 
| Duration of Response | Duration of response will be restricted to the randomized subjects who achieve a best objective response of PR or better. It is measured from the time, in months, that the criteria for objective response are first met until the date of a progression event (according to the primary definition of PFS). | From informed consent until 30 days after last study treatment, assessed up to approximately 3 years. | 
| Time to Next Therapy | Time to next therapy will be defined as the time, in months, from randomization to the date to next anti-neoplastic therapy or death from any cause, whichever comes first. | From randomization until the date to next anti-neoplastic therapy or death from any cause, whichever comes first (approximately up to 3 years) | 
| Overall Survival | Overall survival is defined as the time, in months, from randomization to the date of death from any cause. | From randomization until death from any cause (up to 5 years) | 
| Health-related Quality of Life-Time to Worsening in EORTC QLQ-C30 Scale Scores | Worsening is defined as a decrease in score that is at least half of standard deviation from baseline values, where standard deviation is calculated from the scores at baseline combining both treatment groups. | Day 1 of each treatment cycle, at end of treatment, and every 4 weeks post treatment until PD (approximately up to 3 years) | 
| Health-related Quality of Life-Time to Worsening in EQ-5D-5L Utility Score | Worsening is defined as a decrease in score that is at least half of standard deviation from baseline values, where standard deviation is calculated from the scores at baseline combining both treatment groups. The EQ-5D-5L is a 5 item questionnaire that assesses 5 domains including mobility, self care, usual activities, pain/discomfort, and anxiety/depression plus a visual analog scale rating health today | Day 1 of each treatment cycle, at end of treatment, and every 4 weeks post treatment until PD (approximately up to 3 years) | 
| Health-related Quality of Life-Time to Worsening in EQ-5D-5L Visual Analogue Scale | Worsening is defined as a decrease in score that is at least half of standard deviation from baseline values, where standard deviation is calculated from the scores at baseline combining both treatment groups. The EQ-5D-5L is a 5 item questionnaire that assesses 5 domains including mobility, self care, usual activities, pain/discomfort, and anxiety/depression plus a visual analog scale rating health today | Day 1 of each treatment cycle, at end of treatment, and every 4 weeks post treatment until PD (approximately up to 3 years) |