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A Study to Determine Dose, Safety, Tolerability and Efficacy of CC-220 Monotherapy, and in Combination With Other Treatments in Subjects With Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT02773030
Recruitment Status : Recruiting
First Posted : May 16, 2016
Last Update Posted : August 4, 2021
Sponsor:
Information provided by (Responsible Party):
Celgene

Tracking Information
First Submitted Date  ICMJE May 12, 2016
First Posted Date  ICMJE May 16, 2016
Last Update Posted Date August 4, 2021
Actual Study Start Date  ICMJE October 14, 2016
Estimated Primary Completion Date August 16, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 21, 2020)
  • Establish maximum tolerated doses (MTDs) of CC-220 as monotherapy and in combination with other treatment [ Time Frame: Approximately 1 year ]
    Establish the maximum tolerated doses (MTDs) of CC-220 monotherapy, in combination with DEX, and in combination with DEX and daratumumab (CC-220Dd), in combination with DEX and bortezomib (CC-220Vd), and in combination with DEX and carfilzomib (CC-220Kd)
  • Establish Recommended Phase 2 doses (RP2Ds) of CC-220 as monotherapy and in combination with other treatment [ Time Frame: Approximately 1 year ]
    RP2D is defined as the dose selected for phase 2 based on safety, pharmacokinetics and biomarker data from phase 1 of the study.
  • Overall response rate (ORR) of CC-220 in combination with DEX in Cohort D in Part 2 [ Time Frame: Approximately 3 years ]
    Tumor response, including progressive disease (PD) according to the International Myeloma Working Group (IMWG) Uniform Response Criteria (Kumar, 2011) in CC-220 in combination with DEX
Original Primary Outcome Measures  ICMJE
 (submitted: May 12, 2016)
  • Maximum Tolerated Dose (MTD) [ Time Frame: Approximately 1 year ]
    MTD is defined as the previous dose level where a Dose Limiting Toxicity (DLT) is observed in at least 2 subjects within the first cycle.
  • Dose Limiting Toxicity (DLT) [ Time Frame: Approximately 1 year ]
    Number of participants with a DLT
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 21, 2020)
  • Adverse Events (AEs) [ Time Frame: Approximately 3 years ]
    Type, frequency, seriousness and severity of adverse events (AEs) (and AEs of special interest) and relationship of AEs to investigational product
  • Overall response rate (ORR) [ Time Frame: Approximately 3 years ]
    Tumor response, including progressive disease (PD) according to the International Myeloma Working Group (IMWG) Uniform Response Criteria (Kumar, 2016) for subjects who achieved partial response (PR) or better
  • Time to Response (TTR) [ Time Frame: Approximately 3 years ]
    Is defined as the time from the first date of dosing of IP to the first date of documented response (partial response [PR] or greater).
  • Duration of Response (DOR) [ Time Frame: Approximately 3 years ]
    Is defined as Time from the first documentation of response (PR or greater) to the first documentation of Progressive disease (PD)
  • Pharmacokinetics -AUC 0-τ [ Time Frame: Approximately 1 year ]
    Area under the plasma concentration-time curve from time zero to tau, where tau is the dosing interval
  • Pharmacokinetics -Cmax [ Time Frame: Approximately 1 year ]
    Maximum plasma concentration of drug
  • Pharmacokinetics -Tmax [ Time Frame: Approximately 1 year ]
    Time to Maximum plasma concentration of drug
  • Pharmacokinetics -t1/2 [ Time Frame: Approximately 1 year ]
    Terminal-phase elimination half life
  • Pharmacokinetics -CLss/F [ Time Frame: Approximately 1 year ]
    Apparent total plasma clearance when dosed daily
  • Pharmacokinetics -Vss/F [ Time Frame: Approximately 1 year ]
    Apparent total volume of distribution at steady state when dosed orally
  • Progression-free Survival (PFS) [ Time Frame: Approximately 3 years ]
    Time from the first dose of investigational product (IP) to the first documentation of PD or death from any cause, whichever occurs first
  • Overall Survival (OS) in Part 2 RRMM cohorts [ Time Frame: Approximately 3 years ]
    Time from first dose of IP to death due to any cause
  • Very good partial response or better rate (VGPR) [ Time Frame: Approximately 4 years ]
    Tumor response, including progressive disease (PD) according to the International Myeloma Working Group (IMWG) Uniform Response Criteria (Kumar, 2016) for subjects who achieved VGPR or better
Original Secondary Outcome Measures  ICMJE
 (submitted: May 12, 2016)
  • Adverse Events (AEs) [ Time Frame: Approximately 2 years ]
    Number of participants with adverse events
  • Overall response rate (ORR) [ Time Frame: Approximately 2 years ]
    Will be calculated as the number of responders divided by the number of subjects in the Efficacy Evaluable (EE) Population.
  • Time to Response (TTR) [ Time Frame: Approximately 2 years ]
    Is defined as the time from the first date of dosing of IP to the first date of documented response (PR or better).
  • Duration of Response (DOR) [ Time Frame: Approximately 2 years ]
    Is defined as Time from the first documentation of response to the first documentation of Progressive disease (PD)
  • Pharmacokinetics -AUC 0-τ [ Time Frame: Approximately 1 year ]
    Area under the plasma concentration-time curve from time zero to tau, where tau is the dosing interval
  • Pharmacokinetics -Cmax [ Time Frame: Approximately 1 year ]
    Maximum plasma concentration of drug
  • Pharmacokinetics -Tmax [ Time Frame: Approximately 1 year ]
    Time to Maximum plasma concentration of drug
  • Pharmacokinetics -t1/2 [ Time Frame: Approximately 1 year ]
    Terminal-phase elimination half life
  • Pharmacokinetics -CLss/F [ Time Frame: Approximately 1 year ]
    Apparent total plasma clearance when dosed daily
  • Pharmacokinetics -Vss/F [ Time Frame: Approximately 1 year ]
    Apparent total volume of distribution at steady state when dosed orally
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Determine Dose, Safety, Tolerability and Efficacy of CC-220 Monotherapy, and in Combination With Other Treatments in Subjects With Multiple Myeloma
Official Title  ICMJE A Phase 1b/2a Multicenter, Open-label, Dose-escalation Study to Determine the Maximum Tolerated Dose, Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of CC-220 as Monotherapy and in Combination With Other Treatments in Subjects With Multiple Myeloma
Brief Summary This is a multicenter, multi-country, open-label, Phase 1b/2a dose-escalation study consisting of two parts: dose escalation (Part 1) for CC-220 monotherapy, CC-220 in combination with DEX, CC-220 in combination with DEX and DARA, CC-220 in combination with DEX and BTZ and CC-220 in combination with DEX and CFZ; and the expansion of the RP2D (Part 2) for CC-220 in combination with DEX for Relapsed Refractory Multiple Myeloma and CC-220 in combination with DEX and BTZ for Newly Diagnosed Multiple Myeloma.
Detailed Description

Subjects assigned to CC-220 monotherapy, who develop progressive disease (PD) will have the option to receive DEX in addition to CC-220 after consultation with the Medical Monitor. The dose of CC-220 will not be higher than the dose of CC-220 used in combination with dexamethasone in Cohort B that has been determined to be safe. Progressive disease must be confirmed in accordance with international myeloma working group (IMWG) criteria.

The starting dose of DEX will be 40 mg for subjects who are ≤75 years of age and 20 mg for subjects who are >75 years of age, given once weekly. This treatment will continue until PD, unacceptable toxicity or the subject withdraws consent.

For Cohorts A and B, the starting dose level of CC-220, dose level 1, is 0.3 mg. A dose level -1, of 0.15 mg, may also be evaluated if the starting dose level of 0.3 mg for 21 days of a 28-day cycle is not tolerated. For Cohorts E and F, the starting dose level of CC-220, dose level 1, is one dose level below the maximum dose for Cohort B that has been determined to be safe by the dose escalation committee (DEC) at the start of enrollment for both cohorts. For Cohort E in addition to CC-220 and DEX, daratumumab will be administered intravenously (IV) at a 16mg/kg dose. For Cohort F in addition to CC-220 and DEX, bortezomib will be administered subcutaneous (SC) at a 1.3mg/m2 dose.

All subjects with a minimal response (MR) or better who discontinue study treatment in Part 1 or Part 2 of the study for a reason other than PD or withdrawal of consent from the study will be followed for response assessment every 28 days (every 21 days for Cohort F) until PD.

The study will be conducted in compliance with the International Council for Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements.

The initiation of Part 2 will begin when the RP2D is established in Part 1 in either Cohort A or Cohort B. Either cohort may begin once the RP2D is determined for each cohort independently during Part 1. All expansion decisions will be determined by the DEC after review of all safety, PK, biomarker and preliminary efficacy data, as applicable. During Part 2, the Independent Expert Reviewer will review safety data and any other data deemed relevant so that subject safety is ensured.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Multiple Myeloma
Intervention  ICMJE
  • Drug: CC-220
    CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle.
    Other Name: Iberdomide
  • Drug: Dexamethasone
    Oral DEX 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects >75 years old, oral DEX will be administered at 20 mg on Days 1, 8, 15, and 22 of each 28-day cycle.
    Other Name: Decadron
  • Drug: Daratumumab - 16mg/kg
    Daratumumab (DARA) 16mg/kg by intravenous infusion on Days 1, 8, 15, and 22 at cycle 1-2, Days 1, 15 at cycle 3-6, and Day 1 at cycle ≥7 of each 28-day cycle.
    Other Name: Darzalex
  • Drug: Bortezomib (BTZ)
    Bortezomib 1.3 mg/m^2 on Days 1, 4, 8 and 11 at cycle 1-8, and Days 1, 8 at cycle ≥9 of each 21-day cycle.
    Other Name: Velcade
  • Drug: Carfilzomib
    Intravenous (IV) CFZ administered at a starting dose of 20 mg/m2 on C1D1 and C1D2; and at a dose level specified by cohort dose level thereafter Days 1, 2, 8, 9, 15, 16 of each 28-day cycle.
    Other Name: Kyprolis
  • Drug: Daratumumab- 1800mg
    Daratumumab (DARA) 1800 mg by subcutaneous injection on Days 1, 8, 15, and 22 at cycle 1-2, Days 1, 15 at cycle 3-6, and Day 1 at cycle ≥7 of each 28-day cycle.
    Other Name: Darzalex Faspro
Study Arms  ICMJE
  • Experimental: Cohort A: CC-220 Monotherapy - Part 1
    Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle
    Intervention: Drug: CC-220
  • Experimental: Cohort B: CC-220 in combination with Dexamethasone - Part 1
    • Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle.
    • For subjects ≤ 75 years old, oral DEX 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects >75 years old, DEX will be administered at 20 mg on Days 1, 8,15, and 22 of each 28-day cycle. Subjects who surpass the age of 75 years while on treatment may be switched to the 20 mg QD dosage based on the investigator's best judgment.
    Interventions:
    • Drug: CC-220
    • Drug: Dexamethasone
  • Experimental: Cohort D: CC-220 in combination with Dexamethasone - Part 2
    • Oral CC-220 at Recommended Phase 2 dose (RP2D) from Day 1-21 of each 28-day cycle
    • Oral DEX 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects >75 years old, DEX will be administered at 20 mg on Days 1, 8, 15, and 22 of each 28-day cycle.
    Interventions:
    • Drug: CC-220
    • Drug: Dexamethasone
  • Experimental: Cohort E: CC-220 with DEX and daratumumab (DARA) - Part 1
    • Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle.
    • Oral DEX for subjects ≤ 75 years old at 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects >75 years old, oral DEX at 20 mg on Days 1, 8, 15, and 22 of each 28-day cycle.
    • Intravenous DARA at dose 16mg/kg on Days 1, 8, 15, and 22 at cycle 1-2, Days 1, 15 at cycle 3-6, and Day 1 at cycle ≥7 of each 28-day cycle.

    Once the MTD and/or RP2D is determined in Cohort E (CC-220Dd), subjects will be enrolled at this dose level using SC DARA.

    • Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle.
    • Oral DEX for subjects ≤ 75 years old at 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects >75 years old, oral DEX at 20 mg on Days 1, 8, 15, and 22 of each 28-day cycle.
    • Subcutaneous DARA at dose 1800 mg over 3 to 5 minutes on Days 1, 8, 15, and 22 at cycle 1-2, Days 1, 15 at cycle 3-6, and Day 1 at cycle ≥7 of each 28-day cycle.
    Interventions:
    • Drug: CC-220
    • Drug: Dexamethasone
    • Drug: Daratumumab - 16mg/kg
    • Drug: Daratumumab- 1800mg
  • Experimental: Cohort F: CC-220 with DEX and bortezomib - Part 1
    • Oral CC-220 at dose specified by cohort dose level from Day 1-14 of each 21-day cycle.
    • Oral DEX for subjects ≤ 75 years old at 40 mg on Days 1, 8, and 15 of each 21-day cycle. For subjects >75 years old, oral DEX at 20 mg on Days 1, 8, and 15 of each 21-day cycle.
    • Subcutaneous BTZ at dose 1.3 mg/m^2 on Days 1, 4, 8 and 11 at cycle 1-8, and Days 1, 8 at cycle ≥9 of each 21-day cycle.
    Interventions:
    • Drug: CC-220
    • Drug: Dexamethasone
    • Drug: Bortezomib (BTZ)
  • Experimental: Cohort G1-CC-220 in combination with CFZ and DEX -Part 1
    • Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle
    • Intravenous (IV) CFZ (Carfilzomib)administered at a starting dose of 20 mg/m2 on C1D1; and at a dose specified by cohort dose level thereafter on days 1, 8, 15 of each 28-day cycle
    • Oral DEX (Dexamethasone) on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects ≤ 75 years old, the DEX dose will be 40 mg. For subjects > 75 years old, the DEX dose will be 20 mg
    Interventions:
    • Drug: CC-220
    • Drug: Dexamethasone
    • Drug: Carfilzomib
  • Experimental: Cohort G2 - CC-220 in combination with CFZ and DEX - Part 1
    • Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle
    • Intravenous (IV) CFZ administered at a starting dose of 20 mg/m2 on C1D1; and at a dose level specified by cohort dose level thereafter Days 1, 2, 8, 9, 15, 16 of each 28-day cycle
    • Oral DEX on Days 1, 2, 8, 9, 15, 16, 22, 23 of each 28-day cycle. The DEX dose will be 20 mg
    Interventions:
    • Drug: CC-220
    • Drug: Dexamethasone
    • Drug: Carfilzomib
  • Experimental: CohortI-CC-220 in combination with DEX in post BCMA RRMM-Part2
    • Oral CC-220 at Recommended Phase 2 dose (RP2D) from Day 1-21 of each 28-day cycle
    • Oral DEX 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects >75 years old, oral DEX will be administered at 20 mg on Days 1, 8, 15, and 22 of each 28-day cycle.
    Interventions:
    • Drug: CC-220
    • Drug: Dexamethasone
  • Experimental: CohortJ1:CC-220 in combination with DEX and BTZ in NDMM-Part 2
    • Oral CC-220 at Recommended Phase 2 Dose from Day 1-14 of each 21-day cycle (Cycle 1 to 8) and from Day 1-21 of each 28-day cycle (Cycle 9 and above).
    • Oral DEX at Cycles 1 to 8, 20 mg (≤ 75 years old) or 10 mg (> 75 years old) on Days 1, 2, 4, 5, 8, 9, 11 and 12 of each 21-day cycle and Cycles ≥ 9, 40 mg (≤ 75 years old) or 20 mg (> 75 years old) on Days 1, 8, 15, and 22 of each 28-day cycle.
    • Subcutaneous BTZ at dose 1.3 mg/m2 on Days 1, 4, 8 and 11 at Cycle 1-8 of each 21-day cycle.
    Interventions:
    • Drug: CC-220
    • Drug: Dexamethasone
    • Drug: Bortezomib (BTZ)
  • Experimental: CohortJ2:CC-220 in combination with DEX and BTZ in NDMM-Part 2
    • Oral CC-220 at Recommended Phase 2 Dose from Day 1-14 of each 21-day cycle.
    • Oral DEX at 20 mg/day (≤ 75 years old) or 10 mg/day (> 75 years old) for Cycles 1 to 6 on Days 1, 2, 4, 5, 8, 9, 11 and 12 of a 21-day cycle.
    • Subcutaneous BTZ at dose 1.3 mg/m2 on Days 1, 4, 8 and 11 at Cycle 1-6 of each 21-day cycle.
    Interventions:
    • Drug: CC-220
    • Drug: Dexamethasone
    • Drug: Bortezomib (BTZ)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 14, 2020)
464
Original Estimated Enrollment  ICMJE
 (submitted: May 12, 2016)
106
Estimated Study Completion Date  ICMJE October 31, 2027
Estimated Primary Completion Date August 16, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

1. All subjects in RRMM cohorts must have a documented diagnosis of Multiple Myeloma and have measurable disease defined as:

  1. M-protein (serum and/or urine protein electrophoresis (sPEP or uPEP)): sPEP ≥0.5 g/dL or uPEP ≥200 mg/24 hours and/or
  2. Light chain Multiple Myeloma without measurable disease in the serum or urine: serum immunoglobulin free light chain ≥ 10 mg/dL (100 mg/L) and abnormal serum immunoglobulin kappa lambda free light chain ratio 2. All subjects in RRMM cohorts must have documented disease progression on or within 60 days from the last dose of their last myeloma therapy. Subjects who had CAR T therapy as their last myeloma therapy must have documented disease progression.

    3. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2 3. Subject must have documented diagnosis with previously untreated symptomatic MM as defined by the criteria below (Rajkumar, 2016): MM diagnostic criteria;

    - Clonal bone marrow plasma cells ≥ 10% or biopsy-proven bony or extramedullary plasmacytoma

    - Any one or more of the following myeloma defining events:

    • One or more of the following myeloma-related organ dysfunction (at least one of the following);

      • [C] Calcium elevation (serum calcium > 0.25 mmol/L [> 1 mg/dL] higher than the upper limit of laboratory normal or > 2.75 mmol/L [> 11 mg/dL])

      • [R] Renal insufficiency (serum creatinine > 2 mg/dl [> 177 μmol/L] or creatinine clearance < 40 ml/min)

      • [A] Anemia (hemoglobin < 10 g/dl or > 2 g/dL below the lower limit of laboratory normal)
      • [B] Bone lesions (lytic or osteopenic) one or more bone lesions on skeletal radiography, computed tomography (CT), or positron emission tomography (PET)/CT
    • One or more of the following biomarkers of malignancy:

      • Clonal bone marrow plasma cell percentage* ≥ 60%
      • Abnormal serum free light-chain (FLC) ratio ≥ 100 (involved kappa) or <0.01 (involved lambda) and involved FLC level must be ≥ 100 mg/L
      • >1 focal lesion detected by magnetic resonance imaging (MRI) (at least 5 mm in size)

    AND have measurable disease, as assessed by central laboratory, defined by any of the following:

    - Immunoglobulin (Ig)G myeloma: serum M-protein level ≥ 1.0 g/dL or urine M-protein level ≥ 200 mg/24 hours; or

    - IgA, IgM, IgD, or IgE multiple myeloma: serum M-protein level ≥ 0.5 g/dL or urine M-protein level ≥ 200 mg/24 hours; or

    - Light chain multiple myeloma without measurable disease in serum or urine: serum FLC ≥ 100 mg/L and abnormal kappa lambda (κ/λ) ratio 4. Subjects in Cohort J1 are not considered by the investigator as eligible for high-dose chemotherapy and autologous stem cell transplantation due to:

    - Age ≥65 years, OR

    - In subjects <65 years: presence of important comorbid condition(s) likely to have a negative impact on tolerability of high-dose chemotherapy with autologous stem cell transplantation.

    5. Subjects in Cohort J2 are considered by the investigator as eligible for high-dose chemotherapy and autologous stem cell transplantation according to the institution's criteria based on age, medical history, cardiac and pulmonary status, overall health and condition, co-morbid condition(s), physical examination, and laboratory data.

    Exclusion Criteria:

    1. Subject has nonsecretory multiple myeloma 2. Subjects with Plasma Cell leukemia or amyloidosis 3. Any of the following laboratory abnormalities

    • Absolute neutrophil count (ANC) <1,000/μL

    • Platelet count < 75,000/μL for Part 1. For Part 2; platelet count < 75,000/μL for subjects in whom < 50% of bone marrow nucleated cells are plasma cells; otherwise platelet count < 50,000/μL (transfusions are not permitted to achieve minimum platelet counts

    • Corrected serum calcium >13.5 mg/dL (>3.4 mmol/L)

    • Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST) or serum glutamic pyruvic transaminase (SGPT)/alanine aminotransferase (ALT)≥2.0 x upper limit of normal (ULN)
    • Serum total bilirubin and alkaline phosphatase >1.5 x ULN
    • Subjects with serious renal impairment creatinine clearance ([CrCl] <45 mL/min) or requiring dialysis would be excluded 4. Subjects with peripheral neuropathy ≥Grade 2
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Associate Director Clinical Trial Disclosure 1-888-260-1599 clinicaltrialdisclosure@celgene.com
Listed Location Countries  ICMJE Canada,   France,   Germany,   Italy,   Japan,   Netherlands,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02773030
Other Study ID Numbers  ICMJE CC-220-MM-001
U1111-1182-9200 ( Registry Identifier: WHO )
2016-000860-40 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Celgene
Study Sponsor  ICMJE Celgene
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: April Sorrell-Taylor, MD Celgene Corporation
PRS Account Celgene
Verification Date August 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP