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

  • STATUS
    Recruiting
  • End date
    Oct 31, 2027
  • participants needed
    464
  • sponsor
    Celgene
Updated on 13 August 2021
cancer
calcium
anemia
measurable disease
cell transplantation
bone marrow procedure
dexamethasone
chemotherapy regimen
bone lesion
bortezomib
serum calcium
immunoglobulins
electrophoresis
carfilzomib
daratumumab
high dose chemotherapy
refractory multiple myeloma
bone marrow plasma cells

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.

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.

Details
Condition Multiple Myeloma, Lymphoproliferative Disorder, Lymphoproliferative disorders, multiple myeloma (mm)
Treatment Dexamethasone, Daratumumab, Carfilzomib, CC-220, Bortezomib (BTZ), Daratumumab - 16mg/kg, Daratumumab- 1800mg
Clinical Study IdentifierNCT02773030
SponsorCelgene
Last Modified on13 August 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

All subjects in RRMM cohorts 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 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
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 mol/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 (/) 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

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/L
Platelet count < 75,000/L for Part 1. For Part 2; platelet count < 75,000/L
for subjects in whom < 50% of bone marrow nucleated cells are plasma cells
otherwise platelet count < 50,000/L (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
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