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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

NCT02773030

Description:

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.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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: 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

Clinical Trial IDs

  • ORG STUDY ID: CC-220-MM-001
  • SECONDARY ID: U1111-1182-9200
  • SECONDARY ID: 2016-000860-40
  • NCT ID: NCT02773030

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
CC-220IberdomideCohort A: CC-220 Monotherapy - Part 1
DexamethasoneDecadronCohort B: CC-220 in combination with Dexamethasone - Part 1
Daratumumab - 16mg/kgDarzalexCohort E: CC-220 with DEX and daratumumab (DARA) - Part 1
Bortezomib (BTZ)VelcadeCohort F: CC-220 with DEX and bortezomib - Part 1
CarfilzomibKyprolisCohort G1-CC-220 in combination with CFZ and DEX -Part 1
Daratumumab- 1800mgDarzalex FasproCohort E: CC-220 with DEX and daratumumab (DARA) - Part 1

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort A: CC-220 Monotherapy - Part 1ExperimentalOral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle
  • CC-220
Cohort B: CC-220 in combination with Dexamethasone - Part 1ExperimentalOral 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.
  • CC-220
  • Dexamethasone
Cohort D: CC-220 in combination with Dexamethasone - Part 2ExperimentalOral 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.
  • CC-220
  • Dexamethasone
Cohort E: CC-220 with DEX and daratumumab (DARA) - Part 1ExperimentalOral 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.
  • CC-220
  • Dexamethasone
  • Daratumumab - 16mg/kg
  • Daratumumab- 1800mg
Cohort F: CC-220 with DEX and bortezomib - Part 1ExperimentalOral 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.
  • CC-220
  • Dexamethasone
  • Bortezomib (BTZ)
Cohort G1-CC-220 in combination with CFZ and DEX -Part 1ExperimentalOral 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
  • CC-220
  • Dexamethasone
  • Carfilzomib
Cohort G2 - CC-220 in combination with CFZ and DEX - Part 1ExperimentalOral 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
  • CC-220
  • Dexamethasone
  • Carfilzomib
CohortI-CC-220 in combination with DEX in post BCMA RRMM-Part2ExperimentalOral 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.
  • CC-220
  • Dexamethasone
CohortJ1:CC-220 in combination with DEX and BTZ in NDMM-Part 2ExperimentalOral 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.
  • CC-220
  • Dexamethasone
  • Bortezomib (BTZ)
CohortJ2:CC-220 in combination with DEX and BTZ in NDMM-Part 2ExperimentalOral 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.
  • CC-220
  • Dexamethasone
  • Bortezomib (BTZ)

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Establish maximum tolerated doses (MTDs) of CC-220 as monotherapy and in combination with other treatment
Time Frame:Approximately 1 year
Safety Issue:
Description: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)

Secondary Outcome Measures

Measure:Adverse Events (AEs)
Time Frame:Approximately 3 years
Safety Issue:
Description:Type, frequency, seriousness and severity of adverse events (AEs) (and AEs of special interest) and relationship of AEs to investigational product
Measure:Overall response rate (ORR)
Time Frame:Approximately 3 years
Safety Issue:
Description: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
Measure:Time to Response (TTR)
Time Frame:Approximately 3 years
Safety Issue:
Description: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).
Measure:Duration of Response (DOR)
Time Frame:Approximately 3 years
Safety Issue:
Description:Is defined as Time from the first documentation of response (PR or greater) to the first documentation of Progressive disease (PD)
Measure:Pharmacokinetics -AUC 0-τ
Time Frame:Approximately 1 year
Safety Issue:
Description:Area under the plasma concentration-time curve from time zero to tau, where tau is the dosing interval
Measure:Pharmacokinetics -Cmax
Time Frame:Approximately 1 year
Safety Issue:
Description:Maximum plasma concentration of drug
Measure:Pharmacokinetics -Tmax
Time Frame:Approximately 1 year
Safety Issue:
Description:Time to Maximum plasma concentration of drug
Measure:Pharmacokinetics -t1/2
Time Frame:Approximately 1 year
Safety Issue:
Description:Terminal-phase elimination half life
Measure:Pharmacokinetics -CLss/F
Time Frame:Approximately 1 year
Safety Issue:
Description:Apparent total plasma clearance when dosed daily
Measure:Pharmacokinetics -Vss/F
Time Frame:Approximately 1 year
Safety Issue:
Description:Apparent total volume of distribution at steady state when dosed orally
Measure:Progression-free Survival (PFS)
Time Frame:Approximately 3 years
Safety Issue:
Description:Time from the first dose of investigational product (IP) to the first documentation of PD or death from any cause, whichever occurs first
Measure:Overall Survival (OS) in Part 2 RRMM cohorts
Time Frame:Approximately 3 years
Safety Issue:
Description:Time from first dose of IP to death due to any cause
Measure:Very good partial response or better rate (VGPR)
Time Frame:Approximately 4 years
Safety Issue:
Description: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

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Celgene

Trial Keywords

  • Multiple Myeloma
  • Relapsed
  • Refractory
  • Pharmacokinetics
  • Safety
  • Efficacy
  • CC-220
  • Relapsed and refractory multiple myeloma
  • Dexamethasone
  • Daratumumab
  • Bortezomib

Last Updated

October 19, 2020