A Trial to Determine The Safety and Efficacy of CC-92480 Alone and When Combined With Dexamethasone in People Who Have Myeloma That is Not Responsive After Treatment or Who Had Myeloma Which Has Returned After a Period of Treatment

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Celgene Corp.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

12 Apr 2018 → 23 Oct 2025

Decision date (initial)

2024-02-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2023-508727-12-00

EudraCT number

2017-001236-19

WHO UTN

U1111-1205-3650

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacogenomic, Dose response, Pharmacoeconomic, Efficacy, Pharmacodynamic, Pharmacokinetic

Part 1:
- To assess the pharmacokinetics (PK), safety/tolerability and define the maximally tolerated dose (MTD)/recommended Phase 2 dose (RP2D) of CC-92480 (also known as BMS-986348 and mezigdomide) in combination with dexamethasone in conjunction with a minimum of two CC-92480 dosing schedules.
- To assess the PK, safety/tolerability and define the MTD/RP2D of CC-92480 monotherapy on the QD 21/28 dosing schedule.
Part 2:
- To determine the efficacy of CC-92480 in combination with dexamethasone in subjects with RRMM in cohort expansion, as measured by overall response rate (ORR).

Secondary objectives 3

1. To assess the safety/tolerability of CC-92480 in combination with dexamethasone in subjects with RRMM in cohort expansion.
2. To evaluate additional efficacy parameters of CC-92480 in combination with dexamethasone in subjects with RRMM in cohort expansion including time-to-response (TTR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
3. To assess the preliminary efficacy of CC-92480 in combination with dexamethasone in subjects in Part 1.

Conditions and MedDRA coding

Relapsed and refractory multiple myeloma (RRMM)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).
2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
4. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2.
5. Subjects must have a documented diagnosis of MM and measurable disease at enrollment. Measurable disease is defined as: a. M-protein quantities ≥ 0.5 g/dL by sPEP or b. ≥ 200 mg/24 hour urine collection by uPEP or c. Serum FLC levels > 100 mg/L (milligrams/liter) involved light chain and an abnormal kappa/lambda (κ/λ) ratio in subjects without measurable serum or urine M-protein or d. for subjects with immunoglobulin class A (IgA) myeloma whose disease can only be reliably measured by quantitative immunoglobulin measurement, a serum IgA level ≥ 0.50 g/dL
6. All subjects must have: a. received at least 3 prior anti-myeloma regimens including at least 2 consecutive cycles of lenalidomide, pomalidomide, a proteasome inhibitor, a glucocorticoid and a CD38 antibody (note: induction with or without bone marrow transplant and with or without maintenance therapy is considered one regimen), b. documented disease progression on or within 60 days from the last dose of their last myeloma therapy, i. subjects who had CAR-T therapy as their last myeloma therapyare eligible as long as they have documented disease progression following CAR-T therapy, c. in addition to criteria above (a and b), subjects enrolled in Part 2, must have disease refractory to an immunomodulatory agent (lenalidomide and/or pomalidomide), a glucocorticoid, a proteasome inhibitor, and a CD38 antibody. Refractory is defined as disease that is nonresponsive on therapy (failure to achieve minimal response or development of progressive disease), or progresses within 60 days of last dose.
7. Subjects must have the following laboratory values: a. Absolute neutrophil count (ANC) ≥ 1.25 x 10 to the power 9 /L without growth factor support for ≥ 7 days (≥ 14 days for pegfilgrastim). ANC of ≥ 1.00 x 109/L is permitted for the dose expansion cohorts (Part 2). b. Hemoglobin (Hgb) ≥ 8 g/dL. c. Platelets (plt) ≥ 75 x 10 to the power 9 /L without transfusion for ≥ 7 days (≥ 50 x 10 to the power 9 /L for subjects with > 50% plasma cells in bone marrow). d. Corrected serum calcium ≤ 13.5 mg/dL (≤ 3.4 mmol/L). e. Creatinine clearance (CrCl) based on Cockcroft-Gault formula ≥ 45 mL/min. f. AST/SGOT and ALT/SGPT ≤ 3.0 x upper limit of normal (ULN). g. Serum bilirubin ≤ 1.5 x ULN or < 3.0 mg/dL for subjects with documented Gilbert's syndrome. h. Uric acid ≤ 7.5 mg/dL (446 μmol/L). i. PT/INR < 1.5 x ULN and partial thromboplastin time (PTT) < 1.5 x ULN, (for subjects not receiving therapeutic anticoagulation).
8. Females of childbearing potential (FCBP) must: a. Have two negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after discontinuation of CC- 92480. This applies even if the subject practices true abstinence from heterosexual contact. b. Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, two reliable forms of contraception as defined in the PPP (Appendix D) and provided to the subject at the time of informed consent, without interruption, 28 days prior to starting CC- 92480, during the study therapy (including during dose interruptions), and for 184 days after the last dose of CC-92480.
9. Male subjects must: Practice true abstinence* (which must be reviewed on a monthly basis) or agree to use of a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study (even during dose interruptions) and for at least 94 days following CC-92480 last dose in accordance with the PPP (Appendix D) provided to the subject at the time of informed consent, even if he has undergone a successful vasectomy. * True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and coitus interruptus (withdrawal) are not acceptable methods of contraception.
10. Males must agree to refrain from donating sperm while on CC-92480 for 94 days after the last dose of CC-92480. Females must agree to refrain from donating ova while on CC-92480 for 184 days after last dose.
11. All subjects must agree to refrain from donating blood while on CC- 92480 and for 28 days after its discontinuation.

Exclusion criteria 24

1. Subject has a significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
2. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
3. Subject has any condition that confounds the ability to interpret data from the study.
4. Subject has non-secretory multiple myeloma.
5. Subject has refractory primary multiple myeloma (ie, no history of at least a minor response to a prior treatment regimen).
6. Subject has plasma cell leukemia or active leptomeningeal myelomatosis.
7. Subject has documented, systemic light chain amyloidosis or Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin changes (POEMS) Syndrome.
8. Subject has immunoglobulin class M (IgM) myeloma.
9. Part 1: Subject has a history of allogeneic bone marrow transplantation. Part 2: Subject has a history of allogeneic bone marrow transplantation within 6 months prior to first dose. Subject should not have ongoing graft-versus-host disease (GVHD) requiring systemic immunosuppression.
10. Subject is undergoing dialysis.
11. Subjects with peripheral neuropathy ≥ Grade 2.
12. Subjects with gastrointestinal disease that may significantly alter the absorption of CC-92480.
13. Subject has impaired cardiac function or clinically significant cardiac disease, including any of the following: • LVEF < 45% as determined by ECHO or MUGA scan at Screening. • Complete left bundle branch, bifascicular block or other clinically significant abnormal electrocardiographic (ECG) finding at Screening. • A prolongation of QT interval on Screening ECG as defined by repeated demonstration of a QTc interval >480 milliseconds (ms) using Fridericia's QT correction formula; a history of or current risk factors for Torsades de Pointe (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). • Myocardial infarction ≤6 months prior to starting CC-92480. • Unstable or poorly controlled angina pectoris, including the Prinzmetal variant of angina pectoris.
14. Concurrent administration of strong CYP3A modulators; concurrent administration of proton-pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, pantoprazole) ≤ 2 weeks prior to starting CC-92480
15. Subject had prior systemic myeloma treatment with an investigational anti-myeloma agent (eg, anti-PD-1, anti-PD-L1) ≤ 5 halflives prior to starting CC-92480 (not applicable for subjects who had CAR-T as last prior regimen); Subject had prior systemic myeloma treatment with an investigational agent (eg. anti-PD-1, anti-PD-L1) ≤ 5 half-lives prior to starting CC-92480; or subject had prior exposure to approved myeloma therapies (including therapeutic monoclonal antibodies such as anti-CD38 or anti-SLAM-7) ≤5 half-lives or within 4 weeks prior to starting CC-92480 whichever is shorter.
16. Subject had major surgery ≤ 2 weeks prior to starting CC-92480. Note: Subjects must have recovered from any clinically significant effects of recent surgery.
17. Subject is a pregnant or nursing female, or intends to become pregnant or donate ova during participation in the study.
18. Subject has known human immunodeficiency virus (HIV) infection.
19. Subject has known active chronic hepatitis B or C virus (HBV/HCV) infection.
20. Subject has a history of concurrent second cancer requiring ongoing systemic treatment.
21. Subjects has a history of prior malignancy other than MM, except if the subject has been free of disease for ≥3 years OR the subject had one of the following noninvasive malignancies treated with curative intent without known recurrence: • Basal or squamous cell carcinoma of the skin. • Carcinoma in situ of the cervix or breast. • Stage 1 bladder cancer. • Incidental histological findings of localized prostate cancer such as tumor stage 1a or 1b (T1a or T1b) using the Tumor/Node/Metastasis (TNM) classification of malignant tumors OR prostate cancer that has been treated with curative intent.
22. Subject has a history of anaphylaxis to thalidomide, lenalidomide, pomalidomide or dexamethasone.
23. Subject has known or suspected hypersensitivity to the excipients (excipients include silica dimethyl silylate, anhydrous colloidal silicon dioxide, mannitol, fumaric acid and stearic acid) contained in the formulation of CC-92480 or dexamethasone.
24. Subject has undergone either of the following within 14 days of initiating CC-92480: • Plasmapheresis. • Radiation therapy other than local therapy for symptomatic relief of MM associated bone lesions.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Safety: Type, frequency, seriousness, severity and relationship of AEs to CC- 92480 and dexamethasone; changes from baseline in clinically-relevant physical findings, vital signs, selected laboratory analytes, ECGs and ECHO/MUGA scans.
2. PK parameters: Area under the plasma concentration-time curve (AUC), maximal plasma concentration (Cmax), time to Cmax(Tmax), terminal-phase elimination half-life (t1/2),apparent total clearance of the drug from plasma after oral administration (CL/F) and apparent volume of distribution during terminal phase after non-intravenous administration (Vz/F) for CC- 92480 monotherapy and in combination with dexamethasone and the Renantiomer (CC0982796) of CC-92480 (if data allow).
3. Recommended Phase 2 Dose: Establish the MTD/RP2D for CC-92480 monotherapy and in combination with dexamethasone at each dosing schedule.
4. Overall Response Rate (ORR) Best response ≥ partial response (PR), according to the IMWG Uniform Response Criteria.

Secondary endpoints 6

1. Overall response rate (ORR): Best response ≥ PR, according to the IMWG Uniform Response Criteria.
2. Safety: Type, frequency, seriousness, severity and relationship of AEs to CC- 92480 and dexamethasone; changes from baseline in clinically-relevant physical findings, vital signs, selected laboratory analytes, ECGs and ECHO/MUGA scans.
3. Time to response (TTR): Time from 1st dose of CC-92480 to the first documentation of response ≥ PR.
4. Duration of response (DOR): Time from the first documentation of response ( ≥ PR) to the first documentation of PD or death.
5. Progression free survival: Time from 1st dose of CC-92480 to the first occurrence of disease progression or death from any cause.
6. Overall survival (OS): Time from first dose of CC-92480 to death due to any cause

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 11

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Celgene Corp.

Sponsor organisation

Celgene Corp.

Address

Route 206 And Province Line Road

City

Princeton

Postcode

08543-4000

Country

United States

Scientific contact point

Organisation

Celgene Corp.

Contact name

GSM-CT

Public contact point

Organisation

Celgene Corp.

Contact name

GSM-CT

Third parties 4

Locations

2 EU/EEA countries · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 27 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications