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A Study to Determine Dose and Tolerability of CC-220 Monotherapy, in Combination With Dexamethasone, and in Combination With Dexamethasone and Daratumumab or Bortezomib in Subjects With Relapsed and Refractory Multiple Myeloma (MM)

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ClinicalTrials.gov Identifier: NCT02773030
Recruitment Status : Recruiting
First Posted : May 16, 2016
Last Update Posted : August 21, 2019
Sponsor:
Information provided by (Responsible Party):
Celgene

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 MonoT, 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 MonoT and CC-220 in combination with DEX (DoubleT).

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: CC-220 Drug: Dexamethasone Drug: Daratumumab Drug: Bortezomib (BTZ) Drug: Carfilzomib Phase 1 Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 303 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Monotherapy and in Combination With Other Treatments in Subjects With Relapsed and Refractory Multiple Myeloma
Actual Study Start Date : October 14, 2016
Estimated Primary Completion Date : April 16, 2021
Estimated Study Completion Date : February 14, 2026

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Arm Intervention/treatment
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
Drug: CC-220
CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle.
Other Name: Iberdomide

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.
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

Experimental: Cohort C: CC-220 Monotherapy - Part 2
Oral CC-220 at Recommended Phase 2 dose (RP2D) from Day 1-21 of each 28-day cycle
Drug: CC-220
CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle.
Other Name: Iberdomide

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.
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

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 16 mg/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.
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
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

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.
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: 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

Experimental: Cohort G1 - CC-220 in combination with once weekly CFZ and DEX
  • 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 specified by cohort dose level thereafter on days 1, 8, 15 of each 28-day cycle
  • Oral DEX 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
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: Carfilzomib
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.
Other Name: Kyprolis

Experimental: Cohort G2 -CC-220 in combination with twice weekly CFZ and DEX
  • 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
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: Carfilzomib
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.
Other Name: Kyprolis




Primary Outcome Measures :
  1. 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)

  2. 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.

  3. Overall response rate (ORR) of CC-220 in combination with DEX 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 (Rajkumar, 2011) in CC-220 in combination with DEX


Secondary Outcome Measures :
  1. 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

  2. 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 (Rajkumar, 2011)

  3. 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).

  4. 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)

  5. 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

  6. Pharmacokinetics ‐Cmax [ Time Frame: Approximately 1 year ]
    Maximum plasma concentration of drug

  7. Pharmacokinetics ‐Tmax [ Time Frame: Approximately 1 year ]
    Time to Maximum plasma concentration of drug

  8. Pharmacokinetics ‐t1/2 [ Time Frame: Approximately 1 year ]
    Terminal-phase elimination half life

  9. Pharmacokinetics ‐CLss/F [ Time Frame: Approximately 1 year ]
    Apparent total plasma clearance when dosed daily

  10. Pharmacokinetics ‐Vss/F [ Time Frame: Approximately 1 year ]
    Apparent total volume of distribution at steady state when dosed orally

  11. 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

  12. Overall Survival (OS) in Part 2 [ Time Frame: Approximately 3 years ]
    Time from first dose of IP to death due to any cause



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Subjects must have a documented diagnosis of Multiple Myeloma and have measurable disease defined as:

    • M-protein (serum and/or urine protein electrophoresis (sPEP or uPEP)): sPEP ≥0.5 g/dL or uPEP ≥200 mg/24 hours and/or
    • 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 must have documented disease progression on or within 60 days from the last dose of their last myeloma therapy
  3. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2

Exclusion Criteria:

  1. Subject has nonsecretory or oligosecretory 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
    • 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 ([CrCl] <50 mL/min) or requiring dialysis would be excluded
  4. Subjects with peripheral neuropathy ≥Grade 2

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02773030


Contacts
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Contact: Associate Director Clinical Trial Disclosure 1-888-260-1599 clinicaltrialdisclosure@celgene.com

  Show 55 Study Locations
Sponsors and Collaborators
Celgene
Investigators
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Study Director: Amine Bensmaine, MD Celgene Corporation

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Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT02773030     History of Changes
Other Study ID Numbers: CC-220-MM-001
U1111-1182-9200 ( Registry Identifier: WHO )
2016-000860-40 ( EudraCT Number )
First Posted: May 16, 2016    Key Record Dates
Last Update Posted: August 21, 2019
Last Verified: July 2019

Keywords provided by Celgene:
Multiple Myeloma
Relapsed and refractory multiple myeloma
Relapsed
Refractory
Pharmacokinetics
Safety
Efficacy
CC-220
Dexamethasone
Daratumumab
Bortezomib

Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone
Dexamethasone acetate
Bortezomib
Daratumumab
BB 1101
Antibodies, Monoclonal
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal