Clinical trial NCT01946477: Pomalidomide in Combination With Low-dose Dexamethasone or Pomalidomide in Combination With Low-dose Dexamethasone and Daratumumab in Subjects With Relapsed or Refractory Multiple Myeloma Following Lenalidomide-based Therapy in the First or Second Line Setting
Official title: A Phase 2, Multicenter, Multi-cohort, Open-label Study of Pomalidomide in Combination With Low-dose Dexamethasone or Pomalidomide in Combination With Low-dose Dexamethasone and Daratumumab in Subjects With Relapsed or Refractory Multiple Myeloma Following Lenalidomide Based Therapy in the First or Second Line Setting.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: Multiple Myeloma, MM, cancer, oncology, hematology, plasma, neoplasm, plasmacytoma
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2013-09-19
Enrollment: 186
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This trial will evaluate the efficacy and safety of combination of pomalidomide (POM) and low-dose dexamethasone (LD-Dex) (Cohort A) or the combination of pomalidomide (POM) , daratumumab (DARA) and low-dose dexamethasone (LD-Dex) (Cohort B) in subjects with relapsed or refractory multiple myeloma who have received a first or second line treatment of lenalidomide-based therapy.

This trial will test the hypothesis for Cohort A that the proportion of patients will have an Overall Response Rate (ORR) of \> 30 % to reveal that Pomalidomide is efficacious in pretreated patients who are refractory to lenalidomide.

This trial will test the hypothesis for Cohort B that the proportion of patients will have an Overall Response Rate (ORR) of \> 70 % to reveal that POM+DARA+LD-Dex is efficacious in pretreated patients who are refractory to lenalidomide.

This trial will test the hypothesis for Cohort C that the proportion of patients will have an Overall Response Rate (ORR) of \>60% to reveal that POM+DARA+LD-Dex is efficacious in pretreated patients who are refractory to lenalidomide. This treatment will be in only Japanese patients.

Detailed description: A phase 2, multicenter, multi-cohort, open-label study of pomalidomide in combination with low-dose dexamethasone or pomalidomide in combination with low-dose dexamethasone and daratumumab in subjects with relapsed or refractory multiple myeloma following lenalidomide based therapy in the first or second line setting.

This trial will assess, Overall Response Rate (ORR), Overall Survival (OS), Progression-Free Survival (PFS), Duration of Response (DoR), Time to Response (TTR), Time to Progression(TTP) and safety.

Eligibility criteria: Inclusion Criteria:

* Subjects must satisfy the following criteria to be enrolled in the study:

  1. Adults (age ≥ 18 years at the time of signing the ICD) with documented diagnosis of MM and measurable disease (serum M-protein ≥ 0.5 g/dL or urine M-protein ≥ 200 mg/24 hours).
  2. Subjects enrolling in Cohort A (POM+LD-dex) must have received 2 prior treatment lines of anti-myeloma therapy. Subjects enrolling in Cohort B and Cohort C (POM+DARA+LD-dex) must have received 1 or 2 prior treatment lines of anti-myeloma therapy.
  3. All subjects must have received prior treatment with LEN or a LEN-containing regimen for at least 2 consecutive cycles as the most recent treatment regimen.
  4. All subjects must have documented disease progression during or after their last antimyeloma therapy.
  5. Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2.
  6. Subjects must understand and voluntarily sign an ICD prior to any study related assessments/procedures being conducted.
  7. Subjects must be able to adhere to the study visit schedule and other protocol requirements.
  8. All subjects must provide an adequate bone marrow sample at screening that definitively evaluates the presence or absence of myelodysplastic changes.
  9. Females with child-bearing potential (FCBP†) must agree to use 2 reliable forms of contraception\* simultaneously or practice complete abstinence from heterosexual contact for at least 28 days before starting study drug, while participating in the study (including during dose interruptions), and for at least 28 days after study treatment discontinuation and must agree to regular pregnancy testing during this timeframe. For subjects enrolled in Cohort B and Cohort C, pregnancy prevention and testing will continue until 3 months after last dose of daratumumab.
  10. Females must agree to abstain from breastfeeding during study participation and 28 days after study drug discontinuation. Female subjects enrolled in Cohort B and Cohort C must agree to abstain from breastfeeding and donating eggs during study participation and until 3 months after last dose of daratumumab.
  11. Males must agree to use a latex condom during any sexual contact with FCBP while participating in the study and for 28 days following discontinuation from this study, even if he has undergone a successful vasectomy. Male subjects enrolled in Cohort B and Cohort C must agree to use a latex condom during any sexual contact with FCBP while participating in the study and until 3 months after last dose of daratumumab.
  12. Males must also agree to refrain from donating semen or sperm during the treatment phase and for 28 days after discontinuation from this study treatment. Male subjects enrolled in Cohort B and Cohort C must also agree to refrain from donating semen or sperm during the treatment phase and until 3 months after last dose of daratumumab.
  13. All subjects must agree to refrain from donating blood while on study therapy and for 28 days after discontinuation from this study treatment.
  14. All subjects must agree not to share medication.

      Exclusion Criteria:

      The presence of any of the following will exclude a subject from study enrollment:

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  1. Any of the following laboratory abnormalities:

     • Absolute neutrophil count \< 1,000/μL

     • Platelet count \< 75,000/μL for subjects in whom \< 50% of bone marrow nucleated cells are plasma cells; or a platelet count \< 30,000/μL for subjects in whom ≥ 50% of bone marrow nucleated cells are plasma cells.

     • Severe renal impairment (Creatinine Clearance \[CrCl\] \< 30 mL/min) requiring dialysis.
     * Corrected serum calcium \> 11.5 mg/dL (\> 2.8 mmol/L)
     * Hemoglobin \< 8 g/dL (\< 4.9 mmol/L; prior red blood cell transfusion or recombinant human erythropoietin use is permitted)
     * Serum SGOT/AST or SGPT/ALT \> 3.0 x the upper limit of normal (ULN)
     * Serum total bilirubin \> 2.0 mg/dL (34.2 μmol/L); or \> 3.0 x ULN for subjects with hereditary benign hyperbilirubinemia
  2. Prior history of malignancies, other than MM, unless the subject has been free of the disease for more than 5 years. Allowed exceptions include the following:

     •Basal or squamous cell carcinoma of the skin

     •Carcinoma in situ of the cervix or breast

     • Incidental histological finding of prostate cancer (TNM \[tumor, nodes, metastasis\] stage of T1a or T1b)
  3. Previous therapy with pomalidomide or daratumumab
  4. Hypersensitivity to thalidomide, LEN, or dex (this includes ≥ Grade 3 rash during prior thalidomide or LEN therapy)
  5. Subjects who received an allogeneic bone marrow or allogeneic peripheral blood stem cell transplant less than 12 months prior to initiation of study treatment and who have not discontinued immunosuppressive treatment for at least 4 weeks prior to initiation of study treatment and are currently dependent on such treatment.
  6. Subjects with any one of the following:

     • Congestive heart failure (NY Heart Association Class III or IV)
     * Myocardial infarction within 12 months prior to starting study treatment
     * Unstable or poorly controlled angina pectoris, including Prinzmetal's variant angina pectoris
  7. Subjects who received any of the following within 14 days of initiation of study treatment:

     • Major surgery (kyphoplasty is not considered major surgery)

     • Use of any anti-myeloma drug therapy
  8. Use of any investigational agents including for the treatment of multiple myeloma within 28 days or 5 half-lives (whichever is longer) of treatment, unless approved by the sponsor.
  9. Incidence of gastrointestinal disease that may significantly alter the oral absorption of Pomalidomide.
  10. Subjects unable or unwilling to undergo antithrombotic prophylactic treatment
  11. Any serious medical condition, laboratory abnormality, or psychiatric illness, that would preclude participation in the study, or interfere with interpretation of the study results
  12. Pregnant or breastfeeding females
  13. Known human immunodeficiency virus (HIV) positivity; active infectious hepatitis A, B, or C; or chronic hepatitis B or C

      All subjects will be tested for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (antiHBs), and hepatitis B core antibody (antiHBc). Subjects with the following serological testing are considered not eligible:
      * HBsAg positive
      * HBsAg negative, anti-HBs positive and/or anti-HBc positive and detectable viral DNA

      Note:
      * Subjects who are HBsAg negative, anti-HBs positive, and/or anti-HBc positive, viral DNA negative are eligible. For these subjects, DNA monitoring and prophylactic medication for HBV reactivation are recommended per local practice.
      * Subjects who are seropositive because of hepatitis B virus vaccination are eligible (anti-HBs positive, anti-HBc negative, and HBsAg negative).

      All subjects will be tested for hepatitis C antibody. Subjects are not eligible if known seropositive for hepatitis C virus.

      Note:

      • Subjects who are hepatitis C antibody positive but show no detectable viral RNA for 6 months prior to initiation of study treatment are eligible.
  14. For subjects enrolling in Cohort B and Cohort C - Subject has known allergies, hypersensitivity to mannitol, corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to the Daratumumab IB), or known sensitivity to mammalian-derived products.

Primary outcomes:
measure: Overall response rate (ORR)
timeFrame: Approximately 2 years
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: Up to 7 years
measure: Progression-free survival (PFS)
timeFrame: Up to 7 years
measure: Duration of Response (DoR)
timeFrame: Up to 7 years
measure: Time to Response (TTR)
timeFrame: Up to 2 years
measure: Time to progression (TTP)
timeFrame: 6 months after 100% enrollment and 5 years from Last Patient First Visit
measure: Adverse Events
timeFrame: Up to 7 years
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Local Institution - 126
state: Arizona
city: Greenbrae
country: United States
facility: Local Institution - 137
state: California
city: Los Angeles
country: United States
facility: Local Institution - 109
state: California
city: Pleasant Hill
country: United States
facility: Local Institution - 104
state: California
city: Whittier
country: United States
facility: Local Institution - 108
state: California
city: Denver
country: United States
facility: Local Institution - 138
state: Colorado
city: Stamford
country: United States
facility: Local Institution - 120
state: Connecticut
city: Jacksonville
country: United States
facility: Local Institution - 145
state: Florida
city: Orlando
country: United States
facility: Local Institution - 127
state: Florida
city: Pembroke Pines
country: United States
facility: Local Institution - 133
state: Florida
city: Saint Petersburg
country: United States
facility: Local Institution - 136
state: Florida
city: Fairway
country: United States
facility: Local Institution - 134
state: Kansas
city: Topeka
country: United States
facility: Local Institution - 142
state: Kansas
city: Louisville
country: United States
facility: Local Institution - 124
state: Kentucky
city: Westminster
country: United States
facility: Local Institution - 103
state: Maryland
city: Gross Pointe
country: United States
facility: Local Institution - 146
state: Michigan
city: Kansas City
country: United States
facility: Local Institution - 102
state: Missouri
city: Saint Louis
country: United States
facility: Local Institution - 110
state: Missouri
city: East Orange
country: United States
facility: Local Institution - 118
state: New Jersey
city: Hackensack
country: United States
facility: Local Institution - 101
state: New Jersey
city: Bronx
country: United States
facility: Local Institution - 149
state: New York
city: Glens Falls
country: United States
facility: Local Institution - 129
state: New York
city: Durham
country: United States
facility: Local Institution - 130
state: North Carolina
city: Cleveland
country: United States
facility: Local Institution - 123
state: Ohio
city: Cleveland
country: United States
facility: Local Institution - 121
state: Ohio
city: Cleveland
country: United States
facility: Local Institution - 115
state: Ohio
city: Mayfield Heights
country: United States
facility: Local Institution - 122
state: Ohio
city: Hershey
country: United States
facility: Local Institution - 107
state: Pennsylvania
city: Chattanooga
country: United States
facility: Local Institution - 135
state: Tennessee
city: Nashville
country: United States
facility: Local Institution - 131
state: Tennessee
city: Lubbock
country: United States
facility: Local Institution - 128
state: Texas
city: Plano
country: United States
facility: Local Institution - 143
state: Texas
city: Spokane
country: United States
facility: Local Institution - 106
state: Washington
city: Calgary
country: Canada
facility: Local Institution - 113
state: Alberta
city: Surrey
country: Canada
facility: Local Institution - 144
state: British Columbia
city: Vancouver
country: Canada
facility: Local Institution - 114
state: British Columbia
city: Moncton
country: Canada
facility: Local Institution - 139
state: New Brunswick
city: St John's
country: Canada
facility: Local Institution - 140
state: Newfoundland and Labrador
city: Toronto
country: Canada
facility: Local Institution - 112
state: Ontario
city: Toronto
country: Canada
facility: Local Institution - 148
state: Ontario
city: Montreal
country: Canada
facility: Local Institution - 117
state: Quebec
city: Fukuoka
country: Japan
facility: Local Institution - 205
city: Kamogawa
country: Japan
facility: Local Institution - 208
city: Kyoto-city
country: Japan
facility: Local Institution - 204
city: Nagoya
country: Japan
facility: Local Institution - 202
city: Okayama
country: Japan
facility: Local Institution - 203
city: Shibukawa-shi, Gunma-ken
country: Japan
facility: Local Institution - 206
city: Toyohashi
country: Japan
facility: Local Institution - 207
city: San Juan
country: Puerto Rico
facility: Local Institution - 119
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: Pelligra CG, Parikh K, Guo S, Chandler C, Mouro J, Abouzaid S, Ailawadhi S. Cost-effectiveness of Pomalidomide, Carfilzomib, and Daratumumab for the Treatment of Patients with Heavily Pretreated Relapsed-refractory Multiple Myeloma in the United States. Clin Ther. 2017 Oct;39(10):1986-2005.e5. doi: 10.1016/j.clinthera.2017.08.010. Epub 2017 Sep 28.
citation: Bahlis NJ, Siegel DS, Schiller GJ, Samaras C, Sebag M, Berdeja J, Ganguly S, Matous J, Song K, Seet CS, Acosta-Rivera M, Bar M, Quick D, Anz B, Fonseca G, Chung W, Lee K, Mouro J, Agarwal A, Reece D. Pomalidomide, dexamethasone, and daratumumab immediately after lenalidomide-based treatment in patients with multiple myeloma: updated efficacy, safety, and health-related quality of life results from the phase 2 MM-014 trial. Leuk Lymphoma. 2022 Jun;63(6):1407-1417. doi: 10.1080/10428194.2022.2030477. Epub 2022 Feb 8.
citation: Pierceall WE, Amatangelo MD, Bahlis NJ, Siegel DS, Rahman A, Van Oekelen O, Neri P, Young M, Chung W, Serbina N, Parekh S, Agarwal A, Thakurta A. Immunomodulation in Pomalidomide, Dexamethasone, and Daratumumab-Treated Patients with Relapsed/Refractory Multiple Myeloma. Clin Cancer Res. 2020 Nov 15;26(22):5895-5902. doi: 10.1158/1078-0432.CCR-20-1781. Epub 2020 Sep 14.
citation: Siegel DS, Schiller GJ, Song KW, Agajanian R, Stockerl-Goldstein K, Kaya H, Sebag M, Samaras C, Malek E, Talamo G, Seet CS, Mouro J, Pierceall WE, Zafar F, Chung W, Srinivasan S, Agarwal A, Bahlis NJ. Pomalidomide plus low-dose dexamethasone in relapsed refractory multiple myeloma after lenalidomide treatment failure. Br J Haematol. 2020 Feb;188(4):501-510. doi: 10.1111/bjh.16213. Epub 2019 Oct 6.