This is an open-label, multicenter, Phase 1/2 study to determine the maximum tolerated dose
(MTD) / recommended phase 2 dose (RP2D), and to evaluate the safety and preliminary efficacy
of CC-92480 in combination with standard treatments.
Inclusion Criteria:
Key Inclusion criteria
- Subject is ≥ to 18 years of age the time of signing the informed consent form (ICF).
- Subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of
0, 1 or 2.
For subjects in Cohorts A, B, C, D, E, F, H, I, J, and K the following inclusions will also
apply:
- Subject has documented diagnosis of MM and measurable disease, defined as: M-protein
quantities ≥ 0.5 g/dL by serum protein electrophoresis (sPEP) or ≥ 200 mg/24-hour
urine collection by urine protein electrophoresis (uPEP) and/or Serum free light chain
(FLC) levels > 100 mg/L (10 mg/dL) involved light chain and an abnormal kappa/lambda
(κ/λ) ratio in subjects without measurable disease in the serum or urine
- Subject has received 2 to 4 (for Cohorts A, B, C, H, and I) or 1 to 3 (Cohorts D, E,
and F) or ≥ 2 (Cohorts J and K) prior anti-myeloma regimens.
- Subject has received prior treatment with a lenalidomide-containing regimen for at
least 2 consecutive cycles.
- Subject achieved a response (minimal response [MR] or better) to at least 1 prior
treatment regimen.
- Subject must have documented disease progression during or after their last
anti-myeloma regimen.
For Cohorts J and K:
- Subject has also received prior treatment with a proteasome inhibitor (bortezomib,
carfilzomib, or ixazomib) given alone or in combination for at least 2 consecutive
cycles AND
- Subject has failed therapy with lenalidomide and a proteasome inhibitor, given alone
or in combination, defined as progression on or within 60 days of treatment, or
disease progression within 6 months after achieving at least a partial response.
Subject is refractory (progressed on or within 60 days of treatment) to their last
treatment.
- Cohort F: Prior therapy with a proteasome inhibitor (PI), excluding carfilzomib, is
allowed as long as the subject had at least a PR to prior PI therapy, was not removed
from PI therapy due to toxicity, and will have at least a 6-month PI treatment-free
interval from last dose received until first study treatment (Subjects may receive
maintenance therapy with drugs that are not in PI class during this 6-month treatment
free interval).
- For subjects in Cohort G, the following inclusions will also apply:
Considered by the investigator to be eligible for high-dose chemotherapy and autologous
stem cell transplantation (ASCT) 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.
Subject must have documented diagnosis with previously untreated symptomatic MM AND have
measurable disease, as assessed by central laboratory.
Exclusion Criteria:
Key Exclusion criteria
- Subject has any of the following laboratory abnormalities:
1. Absolute neutrophil count (ANC) < 1,000/µL (for Phase 1 without growth factor
support for ≥ 7 days [≥ 14 days for pegfilgrastim])
2. Platelet count: < 75,000/µL (it is not permissible to transfuse a subject to
reach this level)
3. Hemoglobin < 8 g/dL (< 4.9 mmol/L)
4. Creatinine clearance (CrCl) < 45 mL/min (< 30 mL/min for Cohort G)
5. Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L)
6. Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x
ULN
7. Serum total bilirubin > 1.5 x ULN or > 3.0 mg/dL for subjects with documented
Gilbert's syndrome
8. Prothrombin time (PT)/international normalized ratio (INR) 1.5 x ULN or partial
thromboplastin time (PTT) 1.5 x ULN, (for subjects not receiving therapeutic
anticoagulation).
- Subject has peripheral neuropathy ≥ Grade 2
- Subject with gastrointestinal disease that may significantly alter the absorption of
CC-92480.
- Subject has prior history of malignancies, other than MM, unless the subject has been
free of the disease for ≥ 5 years with the exception of the following non-invasive
malignancies: Basal cell carcinoma of the skin, Squamous cell carcinoma of the skin,
Carcinoma in situ of the cervix, Carcinoma in situ of the breast, Incidental
histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes,
metastasis] clinical staging system) or prostate cancer that is curative.
- Subject has plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome
(polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
or clinically significant amyloidosis.
- Subject with known central nervous system (CNS) involvement with myeloma.
- Subject has received immunosuppressive medication within the last 14 days of
initiating study treatment. The following are exceptions to this criterion:
Intranasal, inhaled, topical or local corticosteroid injections (eg, intra-articular
injection).
- Systemic corticosteroids at doses that do not exceed 10 mg/day of prednisone or the
equivalent.
- Steroids as premedication for hypersensitivity reactions (eg, computed tomography [CT]
scan premedication).
- Subject has impaired cardiac function or clinically significant cardiac disease,
including any of the following:
1. Left ventricular ejection fraction (LVEF) < 45% as determined by echocardiogram
(ECHO) or multigated acquisition (MUGA) scan at Screening.
Complete left bundle branch, bifascicular block or other clinically significant
abnormal electrocardiogram (ECG) finding at Screening
2. A prolongation of QT interval on Screening ECG as defined by repeated
demonstration of a QTc interval > 470 milliseconds (msec) using Fridericia's QT
correction formula; a history of or current risk factors for torsades de pointes
(eg, heart failure, hypokalemia, or a family history of Long QT Syndrome); and
concurrent administration of medications that prolong the QT/QTc interval
Congestive heart failure (New York Heart Association Class III or IV).
3. Myocardial infarction within 12 months prior to starting study treatment.
Unstable or poorly controlled angina pectoris, including the Prinzmetal variant
of angina pectoris
4. History of severe coronary artery disease, severe uncontrolled ventricular
arrhythmias, sick sinus syndrome, pericardial disease or electrocardiographic
evidence of acute ischemia or Grade 3 conduction system abnormalities unless
subject has a pacemaker
5. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to
enrollment.
6. Concurrent administration of strong CYP3A modulators; concurrent administration
of proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole,
pantoprazole) ≤ 2 weeks prior to starting CC-92480.
- Subject is a female who is pregnant, nursing or breastfeeding, or who intends to
become pregnant during the participation in the study.
Subject is positive for human immunodeficiency virus (HIV), chronic or active hepatitis B,
or active hepatitis A or C.
- Subject has a history of anaphylaxis or hypersensitivity to thalidomide, lenalidomide,
pomalidomide, BTZ (for Cohorts A, D and G), DARA (for Cohorts B and E), CFZ (for
Cohorts C and F), ELO (for Cohorts H and J), ISA (for Cohorts I and K), or
dexamethasone.
- Subject has known or suspected hypersensitivity to the excipients contained in the
formulation of CC-92480, BTZ (for Cohorts A, D and G), DARA (for Cohorts B and E), CFZ
(for Cohorts C and F), ELO (for Cohorts H and J), ISA (for Cohorts I and K), or
dexamethasone.
- Contraindications to the standard treatment regimens, per local prescribing
information.
- Subject is unable or unwilling to undergo protocol required thromboembolism
prophylaxis.
For subjects in Cohorts A, B, C, D, E, F, H, I, J, and K, the following exclusions will
also apply:
- Subject received any of the following within the last 14 days of initiating study
treatment:
1. Plasmapheresis
2. Major surgery (as defined by the Investigator)
3. Radiation therapy other than local therapy for myeloma associated bone lesions
4. Use of any systemic anti-myeloma drug therapy
5. Cohorts A and D: Subjects who had progression during treatment or within 60 days
of the last dose of BTZ or discontinued BTZ due to toxicity.
6. Cohorts B and I: Subjects who had progression during treatment or within 60 days
of the last dose of DARA/ISA or discontinued DARA/ISA due to toxicity.
7. Cohort C: Subjects who had progression during treatment or within 60 days of the
last dose of CFZ or discontinued CFZ due to toxicity.
8. Cohorts D, E, F, J, and K: Previous treatment with pomalidomide (POM).
9. Cohorts E and K: Previous treatment with DARA or ISA.
10. Cohort F: Previous treatment with CFZ.
11. Subject used any investigational agents within 28 days or 5 half-lives (whichever
is longer) of initiating study treatment.
12. Subject has received previous allogeneic stem cell transplantation or received
autologous stem cell transplantation within 12 weeks prior to starting study
treatment.
13. Cohorts B, E, I, and K: Subject has known chronic obstructive pulmonary disease
(COPD) with a forced expiratory volume in 1 second (FEV1) 50% of predicted
normal. Note that forced expiratory testing (FEV1) is required for subjects
suspected of having COPD and subjects must be excluded if FEV1 is < 50% of
predicted normal.
14. Cohorts B, E, I, and K: Subject has known moderate or severe persistent asthma,
or currently has uncontrolled asthma of any classification.
15. Cohorts C and F: Subject has mild hepatic impairment defined as elevated
bilirubin 1.0 but < 1.5 x ULN or normal bilirubin with any elevation of AST.
16. Cohort H: Subjects who had progression during treatment or within 60 days of the
last dose of ELO or discontinued ELO due to toxicity
17. Cohort J: Previous treatment with ELO
For subjects in Cohort G, the following exclusion criteria will also apply:
- Previous treatment with anti-myeloma therapy (does not include radiotherapy,
bisphosphonates, or a single short course of steroid [ie, less than or equal to the
equivalent of dexamethasone 40 mg/day for 4 days; such a short course of steroid
treatment must not have been given within 14 days of initiating study treatment]).
For subjects in all cohorts:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection within 14 days
for mild or asymptomatic infections or within 28 days for severe/critical illness
prior to enrollment.
- Acute symptoms must have resolved and there must be no sequelae that would place the
subject at a higher risk of clinically significant complications from receiving study
treatment, based on the Investigator's assessment in consultation with the Sponsor
Medical Monitor.
