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 (EMN14)

• ClinicalTrials.gov Identifier: NCT03180736
• Recruitment Status: Active, not recruiting
• First Posted: June 8, 2017
• Last Update Posted: July 22, 2020
• Sponsor: European Myeloma Network
• Collaborator: Janssen Research & Development, LLC
• Information provided by (Responsible Party): European Myeloma Network

Tracking Information

• First Submitted Date: May 30, 2017
• First Posted Date: June 8, 2017
• Last Update Posted Date: July 22, 2020
• Actual Study Start Date: June 12, 2017
• Actual Primary Completion Date: July 21, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 7, 2017)

Comparison of Progression Free Survival between treatment arms [ Time Frame: Assessed monthly from randomization until disease progression (PD) or death whichever occurs first (approximately up to 3 years)] ]

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 6, 2017)

• Overall response rate [ Time Frame: Assessed monthly from Randomization until PD, (approximately up to 3 years)] ]
  Overall response rate is defined as the proportion of randomized subjects who achieve a best response of PR or better using modified IMWG criteria as their best overall response.
• VGPR or better rate [ Time Frame: Assessed monthly from Randomization until PD, (approximately up to 3 years)] ]
  Very good partial response (VGPR) or better rate is defined as the proportion of randomized subjects who achieve an objective response of VGPR or better using modified IMWG criteria.
• CR or better rate [ Time Frame: Assessed monthly from Randomization until PD, (approximately up to 3 years)] ]
  Complete response (CR) or better rate is defined as the proportion of randomized subjects who achieve an objective response of CR or better using modified IMWG criteria
• MRD negativity rate [ Time Frame: Frame: From Randomization until PD (approximately up to 3 years). Assessed at suspected CR and, 6, 12, 18, 24 months post CR/sCR and every 12 months thereafter in subjects with CR until PD ]
  Minimal residual disease (MRD) negativity rate is defined as the proportion of randomized subjects who achieve a negative result of MRD
• Time to response [ Time Frame: Assessed monthly from randomization up to first documented CR or PR (approximately up to 3 years) ]
  Time to response is defined for subjects who achieve a confirmed response as the time between the date of randomization and the first efficacy evaluation that the subject has met all criteria for PR or better
• Duration of response [ Time Frame: Assessed monthly from Randomization until PD, (approximately up to 3 years) ]
  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).
• Time to next therapy [ Time Frame: From randomization until the date to next anti-neoplastic therapy or death from any cause, whichever comes first (approximately up to 3 years) ]
  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.
• Overall survival [ Time Frame: From randomization until death from any cause (up to 5 years) ]
  Overall survival is defined as the time, in months, from randomization to the date of death from any cause.
• Safety (adverse events) [ Time Frame: Continuously throughout the study, starting from informed consent until 30 days after last study treatment (approximately up to 3 years) ]
  The incidence of Adverse Events will be assessed according to the common Terminology Criteria for Adverse Events
• • Scale and domain scores of the EORTC QLQ-C30 and EORTC QLQ-MY20 [ Time Frame: Day 1 of each treatment cycle, at end of treatment, and every 4 weeks post treatment until PD (approximately up to 3 years) ]
  The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Item is a cancer-specific PRO measure. It includes 30 items resulting in 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 Global Health Status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma Module is a MM PRO measure to be used in conjunction with the EORTC QLQ-C30 for assessing HRQoL in patients with MM. It includes 20 items resulting in 2 symptom scales (disease symptoms and side-effects of treatment), 1 function scale (future perspective), and a single item on body image.
• EQ-5D-5L health utility values [ Time Frame: Day 1 of each treatment cycle, at end of treatment, and every 4 weeks post treatment until PD (approximately up to 3 years) ]
  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"
• Immunomodulatory effects of daratumumab on T cells [ Time Frame: Day 1 of cycles 1 , 3, 6, 12 predose and at suspected CR and at PD (approximately up to 3 years) ]
  An evaluation of the immunomodulatory effects of daratumumab on T cells will be performed by molecular and phenotypic studies on bone marrow and whole blood samples.
• Daratumumab pharmacokinetic concentrations (Daratumumab IV and Dararatumumab SC) [ Time Frame: IV: Day 1 of cycles 1,3,7 predose and at the end of Infusion and at 4 and 8 weeks after the last dose. SC: Days 1,4 of cycles 1,3, Day 1 of cycles 5,7,12 and at 4 and 8 weeks after the last dose ]
  Blood samples to assess serum concentration (Cmin and Cmax) of daratumumab will be performed on all subjects in the experimental arm.
• Daratumumab immunogenicity, rHuPH20 immunogenicity in subjects who receive Daratumumab SC [ Time Frame: IV: Day 1 of first cycle predose, Day 1 of cycle 7 predose and at 4 and 8 weeks after the last dose (approx up to 3 years), SC and rHuPH20: Day 1 of cycle 1, 5, 7, 12 predose and at 4 and 8 weeks after the last dose ]
  Blood samples will be assessed for the generation of antibodies to daratumumab (immunogenicity) on all subjects in the experimental arm and to rHuPH20 on subjects who receive Daratumumab SC.

Original Secondary Outcome Measures (submitted: June 7, 2017)

Overall response rate [ Time Frame: Assessed monthly from Randomization until PD, (approximately up to 3 years)] ]

Overall response rate is defined as the proportion of randomized subjects who achieve a best response of PR or better using modified IMWG criteria as their best overall response.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Official Title: 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.
• Brief Summary: 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: 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.
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

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

Masking: Single (Participant)
Masking Description:

Masking: Open Label

Primary Purpose: Treatment

• Condition: Multiple Myeloma

Intervention

• Drug: Daratumumab
  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.
• Drug: Pomalidomide
  Pomalidomide will be administered at full dose of 4 mg orally (PO) on Days 1 through 21 of each 28-day cycle.
• Drug: Dexamethasone
  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.

Study Arms

• Experimental: Daratumumab+Pomalidomide+Dexamethasone
  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
  Interventions:

  • Drug: Daratumumab
  • Drug: Pomalidomide
  • Drug: Dexamethasone
• Active Comparator: Pomalidomide + Dexamethasone
  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
  Interventions:

  • Drug: Pomalidomide
  • Drug: Dexamethasone

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: July 16, 2019): 304
• Original Estimated Enrollment (submitted: June 7, 2017): 302
• Estimated Study Completion Date: April 30, 2024
• Actual Primary Completion Date: July 21, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Males and females at least 18 years of age.
2. Voluntary written informed consent before performance of any study-related procedure.

3. 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.
4. 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.
5. 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.
6. 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).
7. Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2.
8. Willingness and ability to participate in study procedures.
9. For subjects experiencing toxicities resulting from previous therapy, the toxicities must be resolved or stabilized to ≤Grade 1.

10. Any of the following laboratory test results during Screening:

    1. Absolute neutrophil count ≥1.0 × 109/L;
    2. Hemoglobin level ≥7.5 g/dL (≥4.65 mmol/L); (transfusions are not permitted to reach this level);
    3. 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;
    4. Alanine aminotransferase (ALT) level ≤2.5 times the upper limit of normal (ULN);
    5. Aspartate aminotransferase (AST) level ≤2.5 x ULN;
    6. Total bilirubin level ≤1.5 x ULN, (except for Gilbert Syndrome: direct bilirubin ≤1.5 × ULN);
    7. Creatinine clearance ≥30 mL/min
    8. 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).

11. Reproductive Status

    1. 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.
    2. Women must not be breastfeeding.
    3. 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.
    4. 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.
    5. Male subjects must not donate sperm for up to 90 days post-treatment completion.
    6. Female subject must not donate eggs for up to 90 days post-treatment completion.
    7. 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:

1. Previous therapy with any anti-CD38 monoclonal antibody.
2. Previous exposure to pomalidomide.
3. 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).
4. Previous allogenic stem cell transplant; or autologous stem cell transplantation (ASCT) within 12 weeks before C1D1.
5. 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).
6. Clinical signs of meningeal involvement of MM.
7. 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.

8. Clinically significant cardiac disease, including:

   1. 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).
   2. Cardiac arrhythmia (Common Terminology Criteria for Adverse Events [CTCAE] Grade 3 or higher) or clinically significant electrocardiogram (ECG) abnormalities.
   3. Electrocardiogram showing a baseline QT interval as corrected QTc >470 msec.
9. Known active hepatitis A, B, or C.
10. Known HIV infection.
11. Gastrointestinal disease that may significantly alter the absorption of pomalidomide.
12. 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.
13. 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.
14. Ongoing ≥ Grade 2 peripheral neuropathy.
15. Subject had ≥Grade 3 rash during prior therapy.
16. 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.
17. Pregnant or nursing women.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Czechia, Denmark, Germany, Greece, Italy, Netherlands, Serbia, Spain, Turkey
• Removed Location Countries: Romania

Administrative Information

• NCT Number: NCT03180736
• Other Study ID Numbers: EMN14/54767414MMY3013
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: European Myeloma Network
• Study Sponsor: European Myeloma Network
• Collaborators: Janssen Research & Development, LLC

Investigators

• Principal Investigator: Evangelos Terpos, Prof; Department of Clinical Therapeutics, University of Athens, School of Medicine, Athens, Greece

• PRS Account: European Myeloma Network
• Verification Date: July 2020