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

• ClinicalTrials.gov Identifier: NCT02773030
• Recruitment Status: Active, not recruiting
• First Posted: May 16, 2016
• Last Update Posted: April 22, 2024
• Sponsor: Celgene
• Information provided by (Responsible Party): Celgene

Tracking Information

• First Submitted Date: May 12, 2016
• First Posted Date: May 16, 2016
• Last Update Posted Date: April 22, 2024
• Actual Study Start Date: October 14, 2016
• Estimated Primary Completion Date: April 30, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 5, 2023)

• Establish maximum tolerated doses (MTDs) of CC-220 as monotherapy and in combination with other treatment [ Time Frame: Approximately 3 years ]
  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 3 years ]
  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 Dexamethasone (DEX) in Cohort D [ Time Frame: Approximately 5 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 (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

Current Secondary Outcome Measures (submitted: October 5, 2023)

• Adverse Events (AEs) [ Time Frame: Approximately 5 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 5 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 5 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 5 years ]
  Is defined as Time from the first documentation of response (PR or greater) to the first documentation of Progressive disease (PD)
• Progression-free Survival (PFS) [ Time Frame: Approximately 5 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 relapsed and refractory multiple myeloma (RRMM) cohorts [ Time Frame: Approximately 5 years ]
  Time from first dose of IP to death due to any cause
• Pharmacokinetics - Area under the plasma concentration-time curve from time zero to tau, where tau is the dosing interval (AUC[TAU]) [ Time Frame: Approximately 1 year ]
• Pharmacokinetics - Maximum plasma concentration of drug (Cmax) [ Time Frame: Approximately 1 year ]
• Pharmacokinetics - Time to maximum plasma concentration of drug (Tmax) [ Time Frame: Approximately 1 year ]
• 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 (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 -AUC0-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: A Study to Determine Dose, Safety, Tolerability, Drug Levels, and Efficacy of CC-220 Monotherapy, and in Combination With Other Treatments in Participants With Multiple Myeloma
• Official Title: 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 monotherapy and CC-220 in combination with DEX for Relapsed Refractory Multiple Myeloma (RRMM), CC-220 in combination with DEX and BTZ, and CC-220 in combination with DEX and DARA for Newly Diagnosed Multiple Myeloma (NDMM).

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.

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 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 recommended phase 2 dose (RP2D) is established in Part 1 in either Cohort A, Cohort B, Cohort E or Cohort F. The cohorts 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: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Multiple Myeloma

Intervention

• Drug: CC-220
  Specified dose on specified days
  Other Name: Iberdomide
• Drug: Dexamethasone
  Specified dose on specified days
  Other Name: Decadron
• Drug: Daratumumab
  Specified dose on specified days
  Other Name: Darzalex
• Drug: Bortezomib
  Specified dose on specified days
  Other Name: Velcade
• Drug: Carfilzomib
  Specified dose on specified days
  Other Name: Kyprolis

Study Arms

• 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 (DEX) - 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

  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

  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 a dose of Subcutaneous DARA at 1800 mg over 3 to 5minutes on Days 1, 8, 15,and 22 at cycle 1-2 of a 28-day cycle, Days1, and 15 at cycle 3-6 of a 28-day cycle, and Day1 at cycle ≥7 of each 28-day cycle.

  Interventions:

  • Drug: CC-220
  • Drug: Dexamethasone
  • Drug: Daratumumab
• 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, and 8 at cycle ≥9 of each 21-day cycle.

  Interventions:

  • Drug: CC-220
  • Drug: Dexamethasone
  • Drug: Bortezomib
• 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, and 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 C1D2; 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, and 23 of each 28-day cycle. The DEX dose will be 20 mg.

  Interventions:

  • Drug: CC-220
  • Drug: Dexamethasone
  • Drug: Carfilzomib
• Experimental: Cohort I: CC-220 in combination with DEX in post BCMA RRMM - 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, 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: Cohort J1: CC-220 in combination with DEX and BTZ in NDMM - Part 2

  Oral CC-220 at 1.0mg, 1.3mg or 1.6mg administered at cycles 1 to 8 on Days 1 to 14 of each 21-day cycle and cycles ≥ 9 on Days 1 to 21 of each 28-day cycle.

  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
• Experimental: Cohort J2: 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
• Experimental: Cohort K: CC-220 with DEX and DARA in NDMM and not autologous stem cell transplant eligible - Part 2

  Oral CC-220 at 1.0mg, 1.3mg or 1.6mg from Days 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.

  Subcutaneous DARA at 1800 mg over 3 to 5minutes on Days 1, 8, 15, and 22 at cycle 1-2 of a 28-day cycle, Days1, and 15 at cycle 3-6 of a 28-day cycle, and Day1 at cycle ≥7 of each 28-day cycle.

  Interventions:

  • Drug: CC-220
  • Drug: Dexamethasone
  • Drug: Daratumumab
• Experimental: Cohort C: CC-220 Monotherapy in RRMM - Part 2
  CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle.
  Intervention: Drug: CC-220

• Publications *: Lonial S, Popat R, Hulin C, Jagannath S, Oriol A, Richardson PG, Facon T, Weisel K, Larsen JT, Minnema MC, Abdallah AO, Badros AZ, Knop S, Stadtmauer EA, Cheng Y, Amatangelo M, Chen M, Nguyen TV, Amin A, Peluso T, van de Donk NWCJ. Iberdomide plus dexamethasone in heavily pretreated late-line relapsed or refractory multiple myeloma (CC-220-MM-001): a multicentre, multicohort, open-label, phase 1/2 trial. Lancet Haematol. 2022 Nov;9(11):e822-e832. doi: 10.1016/S2352-3026(22)00290-3. Epub 2022 Oct 6.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: October 5, 2023): 532
• Original Estimated Enrollment (submitted: May 12, 2016): 106
• Estimated Study Completion Date: February 6, 2028
• Estimated Primary Completion Date: April 30, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2
• Relapsed and refractory multiple myeloma (RRMM) participants must have documented disease progression on or within 60 days from the last dose of their last myeloma therapy
• Newly diagnosed multiple myeloma (NDMM) participants must have documented diagnosis with previously untreated symptomatic multiple myeloma (MM)
• Participants in Cohorts J1 and K are those for whom autologous stem cell transplantation is not planned for initial therapy or are not considered by the investigator as eligible for high-dose chemotherapy and autologous stem cell transplantation

Exclusion Criteria:

• Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the participant from participating in the study
• Nonsecretory multiple myeloma
• Prior history of malignancies, other than MM and select non-invasive malignancies, unless the participant has been free of the disease for ≥ 5 years

Other protocol-defined inclusion/exclusion criteria apply

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: Australia, Canada, France, Germany, Israel, Italy, Japan, Netherlands, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT02773030
• Other Study ID Numbers: 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

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Celgene
• Original Responsible Party: Celgene Corporation
• Current Study Sponsor: Celgene
• Original Study Sponsor: Celgene Corporation
• Collaborators: Not Provided

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

• PRS Account: Celgene
• Verification Date: April 2024