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NCT02773030
Recruiting
May 16, 2016
May 7, 2021
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.
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.
| 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. |
| 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. 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. |
| 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. 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. |
| 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. |
Drug: CC-220 CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle. 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. 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. 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. |
| 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. 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. 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. |
| 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 |
Drug: CC-220 CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle. 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. 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. |
| 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 |
Drug: CC-220 CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle. 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. 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. |
| 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. |
Drug: CC-220 CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle. 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. |
| 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. |
Drug: CC-220 CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle. 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. 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. |
| 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. |
Drug: CC-220 CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle. 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. 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. |
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 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 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 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
Contact: Associate Director Clinical Trial Disclosure 1-888-260-1599 clinicaltrialdisclosure@celgene.com
United States, Arizona
Mayo Clinic
Scottsdale
United States, Arkansas
University of Arkansas for Medical Sciences
Little Rock
United States, Georgia
Winship Cancer Institute of Emory University
Atlanta
United States, Illinois
Robert H Lurie Comprehensive Cancer Center NW Univ
Chicago
United States, Kansas
University of Kansas Cancer Center
Fairway
United States, Maryland
University of Maryland School of Med
Baltimore
United States, Massachusetts
Beth Israel Deaconess Medical Center
Boston
United States, Massachusetts
Massachusetts General Hospital
Boston
United States, Massachusetts
Dana-Farber/Mass General Brigham Cancer Care, Inc
Boston
United States, Michigan
University of Michigan Comprehensive Cancer Center
Ann Arbor
United States, Michigan
Karmanos Cancer Institute
Detroit
United States, New Jersey
Hackensack University Medical Center
Hackensack
United States, New York
NYU Winthrop Hospital
Mineola
United States, New York
New York University School of Medicine
New York
United States, New York
Icahn School of Medicine at Mount Sinai Medical Center
New York
United States, New York
New York Presbyterian Hospital Weil Cornell Medical College
New York
United States, New York
University of Rochester Cancer Center
Rochester
United States, North Carolina
Levine Cancer Institute
Charlotte
United States, Ohio
Cleveland Clinic Foundation
Cleveland
United States, Ohio
The Ohio State University Comprehensive Cancer Center
Columbus
United States, Pennsylvania
University of Pennsylvania
Philadelphia
United States, South Carolina
Prisma Health Cancer Institute
Greenville
United States, Texas
University of Texas Southwestern Medical Center
Dallas
United States, Utah
Huntsman Cancer Institute at the University of Utah
Salt Lake City
Canada, Alberta
Tom Baker Cancer Centre
Calgary
Canada, British Columbia
Vancouver General Hospital
Vancouver
Canada, Nova Scotia
Queen Elizabeth II Health Sciences Centre
Halifax
Canada, Quebec
McGill University Health Center - Royal Victoria Hospital
Montreal
France
CHRU Hopital Claude Huriez
Lile Cedax
France
CHU Bordeaux
Pessac
France
Centre Hospitalier Lyon Sud
Pierre Benite cedex
France
CHU La Miletrie
Poitiers Cedex
Germany
Medizinische Kinik und Poliklinik I
Dresden
Germany
Universitaetsklinikum Duesseldorf
Dusseldorf
Germany
Universitaetsklinik Hamburg - Eppendorf
Hamburg
Germany
Universitaetsklinikum Heidelberg
Heidelberg
Germany
UKT Universitaetsklinikum Tuebingen
Tuebingen
Germany
Universitaets-klinikum Wuerzburg
Wuerzburg
Italy
I.R.C.C.S. Policlinico San Matteo - Universita di Pavia
Pavia
Italy
Azienda Ospedaliera di Reggio Emilia - Arcispedale Santa Maria Nuova
Reggio Emilia
Italy
Universita degli Studi di Roma La Sapienza - Umberto I Policlinico di Roma - Centro di Ematologia
Rome
Italy
Osp. S.Giovanni Battista Le Molinette
Torino
Japan
Aomori Prefectural Central Hospital
Aomori
Japan
Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital
Hiroshima City
Japan
Tokai University Hospital
Isehara City, Kanagawa
Japan
Kameda Medical Center
Kamogawa
Japan
University Hospital, Kyoto Prefectural University of Medicine
Kyoto-city
Japan
Matsuyama Red Cross Hospital
Matsuyama
Japan
Japanese Red Cross Nagasaki Genbaku Hospital
Nagasaki-shi
Japan
Aichi Cancer Center
Nagoya
Japan
Nagoya City University Hospital
Nagoya
Japan
Ogaki Municipal Hospital
Ogaki
Japan
Osaka City University Hospital
Osaka
Japan
Tohoku University Hospital
Sendai
Japan
NTT Medical Center Tokyo
Shinagawa-ku, Tokyo
Japan
Shizuoka Cancer Center
Sunto-gun
Japan
Toyohashi Municipal Hospital
Toyohashi
Netherlands
VU University Medical Center
Amsterdam
Netherlands
Maastricht University Medical Center
Maastrich
Netherlands
Erasmus Medical Center
Rotterdam
Netherlands
University Medical Center Utrecht
Utrecht
Spain
Hospital Universitari Germans Trias i Pujol Can Ruti
Badalona (Barcelona)
Spain
Hospital Val d'Hebron
Barcelona
Spain
Instituto Catalan de Oncologia-Hospital Duran i Reynals
Barcelona
Spain
Hospital Gregorio Maranon
Madrid
Spain
Hospital Universitario Ramon y Cajal
Madrid
Spain
Clinica Universidad de Navarra
Pamplona
Spain
Hospital Universitario Dr. Pesset
Valencia
United Kingdom
University Hospitals Birmingham NHS Foundation Trust - Queen Elizabeth Hospital
Birmingham
United Kingdom
Saint James University Hospital
Leeds
United Kingdom
Genesis Care
Oxford
United Kingdom
The Institut of Cancer Research
Sutton
United Kingdom
The Royal Marsden NHS Foundation Trust
Sutton
Celgene
Study Director: April Sorrell-Taylor, MD Celgene Corporation
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