Clinical trial NCT03180736: 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.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Multiple Myeloma
Lead sponsor: European Myeloma Network B.V.
Sponsor class: NETWORK
Collaborators: name: Janssen Research & Development, LLC
First posted: 2017-06-08
Enrollment: 304
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Allocation: Randomized Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Comparison of Progression Free Survival Between Treatment Arms
timeFrame: Assessed monthly from randomization until disease progression (PD) or death whichever occurs first (approximately up to 3 years)]
Secondary outcomes:
measure: Overall Response Rate
timeFrame: Assessed monthly from Randomization until PD, (approximately up to 3 years)]
measure: Depth of Response
timeFrame: From randomization to disease progression or subsequent antimyeloma therapy, assessed up to approximately 3 years.
measure: Duration of Response
timeFrame: From informed consent until 30 days after last study treatment, assessed up to approximately 3 years.
measure: Time to Next Therapy
timeFrame: From randomization until the date to next anti-neoplastic therapy or death from any cause, whichever comes first (approximately up to 3 years)
measure: Overall Survival
timeFrame: From randomization until death from any cause (up to 5 years)
measure: Health-related Quality of Life-Time to Worsening in EORTC QLQ-C30 Scale Scores
timeFrame: Day 1 of each treatment cycle, at end of treatment, and every 4 weeks post treatment until PD (approximately up to 3 years)
measure: Health-related Quality of Life-Time to Worsening in EQ-5D-5L Utility Score
timeFrame: Day 1 of each treatment cycle, at end of treatment, and every 4 weeks post treatment until PD (approximately up to 3 years)
measure: Health-related Quality of Life-Time to Worsening in EQ-5D-5L Visual Analogue Scale
timeFrame: Day 1 of each treatment cycle, at end of treatment, and every 4 weeks post treatment until PD (approximately up to 3 years)
Other outcomes:
Locations:
city: Antwerpen
country: Belgium
facility: Antwerpen
city: Brussel
country: Belgium
facility: Brussel
city: Gent
country: Belgium
facility: UZ Gent
city: Yvoir
country: Belgium
facility: Yvoir
city: Brno
country: Czechia
facility: Brno
city: Ostrava
country: Czechia
facility: Ostrava
city: Praha
country: Czechia
facility: Praha 2
city: Odense
country: Denmark
facility: Odense
city: Vejle
country: Denmark
facility: Vejle
city: Freiburg
country: Germany
facility: Freiburg
city: Hamburg
country: Germany
facility: Hamburg
city: Heidelberg
country: Germany
facility: Heidelberg
city: Kiel
country: Germany
facility: Kiel
city: Schwerin
country: Germany
facility: Schwerin
city: Tübingen
country: Germany
facility: Tübingen
city: Würzburg
country: Germany
facility: Würzburg
city: Athens
country: Greece
facility: General Hospital of Athens "Evangelismos"
city: Athens
country: Greece
facility: University of Athens School of Medicine
city: Patra
country: Greece
facility: General University Hospital of Patras
city: Thessaloníki
country: Greece
facility: Anticancer Hospital of Thessaloniki "Theageneio"
city: Ancona
country: Italy
facility: Ancona
city: Bologna
country: Italy
facility: Bologna
city: Brescia
country: Italy
facility: Brescia
city: Milano
country: Italy
facility: Milano
city: Roma
country: Italy
facility: Roma
city: Torino
country: Italy
facility: Torino
city: Amsterdam
country: Netherlands
facility: VU MC
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Belgrade
country: Serbia
facility: Belgrade
city: Badalona
country: Spain
facility: Badalona
city: Barcelona
country: Spain
facility: Barcelona
city: Madrid
country: Spain
facility: Hospital Quirón Salud Madrid
city: Madrid
country: Spain
facility: Hospital Universitario de la Princesa
city: Salamanca
country: Spain
facility: Salamanca University Hospital
city: Valencia
country: Spain
facility: Doctor Peset University Hospital Medical Centre
city: Cebeci
country: Turkey
facility: Cebeci
city: Gaziantep
country: Turkey
facility: Gaziantep
city: İzmir
country: Turkey
facility: Izmir
city: Kayseri
country: Turkey
facility: Kayseri
city: Çapa
country: Turkey
facility: Capa
Study officials:
affiliation: Department of Clinical Therapeutics, University of Athens, School of Medicine, Athens, Greece
name: Evangelos Terpos, Prof
role: PRINCIPAL_INVESTIGATOR
References:
citation: He J, Berringer H, Heeg B, Ruan H, Kampfenkel T, Dwarakanathan HR, Johnston S, Mendes J, Lam A, Bathija S, Mackay EK. Indirect Treatment Comparison of Daratumumab, Pomalidomide, and Dexamethasone Versus Standard of Care in Patients with Difficult-to-Treat Relapsed/Refractory Multiple Myeloma. Adv Ther. 2022 Sep;39(9):4230-4249. doi: 10.1007/s12325-022-02226-x. Epub 2022 Jul 22.
citation: Dimopoulos MA, Terpos E, Boccadoro M, Delimpasi S, Beksac M, Katodritou E, Moreau P, Baldini L, Symeonidis A, Bila J, Oriol A, Mateos MV, Einsele H, Orfanidis I, Ahmadi T, Ukropec J, Kampfenkel T, Schecter JM, Qiu Y, Amin H, Vermeulen J, Carson R, Sonneveld P; APOLLO Trial Investigators. Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021 Jun;22(6):801-812. doi: 10.1016/S1470-2045(21)00128-5.