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A Safety, PK and Efficacy Study of CC-92480 Monotherapy and in Combination With Dexamethasone in Subjects With Relapsed and Refractory Multiple Myeloma (RRMM)

  • Clinicaltrials.gov identifier

    NCT03374085

  • Recruitment Status

    Recruiting

  • First Posted

    December 15, 2017

  • Last update posted

    July 14, 2021

Study Description

Brief summary:

This is an open-label, multi-center, international, Phase 1/2 study to assess the safety, PK and efficacy of CC-92480 monotherapy and in combination with dexamethasone in subjects with relapsed and refractory multiple myeloma (RRMM). RRMM patient previously treated with at least 3 prior regimens including lenalidomide or pomalidomide, a proteasome inhibitor and a CD38 antibody will be eligible.

  • Condition or Disease:Multiple Myeloma
  • Intervention/Treatment: Drug: CC-92480
    Drug: Dexamethasone
  • Phase: Phase 1/Phase 2

Detailed Description

N/A

Study Design

  • Study Type: Interventional
  • Estimated Enrollment: 201 participants
  • Allocation: Non-Randomized
  • Intervention Model: Parallel Assignment
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • Official Title: A Phase 1/2 Multicenter, Open-label Study to Assess the Safety, Pharmacokinetics and Efficacy of CC-92480 Monotherapy and in Combination With Dexamethasone in Subjects With Relapsed and Refractory Multiple Myeloma
  • Actual Study Start Date: February 2018
  • Estimated Primary Completion Date: April 2022
  • Estimated Study Completion Date: May 2022

Arms and interventions

Arm Intervention/treatment
Experimental: Administration of CC-92480 in combination with dexamethasone
Escalating doses of CC-92480 and in combination with a fixed dose of dexamethasone administered according to different dosing schedules
Drug: CC-92480
CC-92480

Drug: Dexamethasone
Dexamethasone
Experimental: Administration of CC-92480 monotherapy
Escalating doses of CC-92480 Monotherapy administered according to different dosing schedules
Drug: CC-92480
CC-92480

Outcome Measures

  • Primary Outcome Measures: 1. Adverse Events (AEs) [ Time Frame: From enrollment until at least 28 days after completion of study treatment ]
    Number of participants with AEs to CC-92480 and/or dexamethasone (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).
  • 2. Pharmacokinetics- AUC [ Time Frame: Up to approximately 28 days ]
    Area under the plasma concentration-time curve
  • 3. Pharmacokinetics- Cmax [ Time Frame: Up to approximately 28 days ]
    Maximal plasma concentration
  • 4. Pharmacokinetics- Tmax [ Time Frame: Up to approximately 28 days ]
    Time to Cmax
  • 5. Pharmacokinetics- t1/2 [ Time Frame: Up to approximately 28 days ]
    Terminal-phase elimination half-life
  • 6. Pharmacokinetics- CL/F [ Time Frame: Up to approximately 28 days ]
    Apparent total clearance of the drug from plasma after oral administration
  • 7. Pharmacokinetics- Vz/F [ Time Frame: Up to approximately 28 days ]
    Apparent volume of distribution during terminal phase after non-intravenous administration
  • 8. Maximum tolerated dose (MTD) [ Time Frame: Up to approximately 28 days ]
    The highest dose of CC-92480 in combination with dexamethasone associated acceptable safety and tolerability.
  • 9. Overall Response Rate (ORR) [ Time Frame: Up to approximately 3 years ]
    Overall response rate (ORR) of CC-92480 in combination with dexamethasone in Part 2
  • Secondary Outcome Measures: 1. Overall response rate (ORR) [ Time Frame: Up to approximately 3 years ]
    Best response ≥ partial response (PR), according to the IMWG Uniform Response Criteria
  • 2. Time to response (TTR) [ Time Frame: Up to approximately 3 years ]
    Time from 1st dose of CC-92480 to the first documentation of response ≥ PR.
  • 3. Duration of response (DOR) [ Time Frame: Up to approximately 3 years ]
    Time from the first documentation of response (≥ PR) to the first documentation of PD or death.
  • 4. Progression free survival [ Time Frame: Up to approximately 3 years ]
    Time from 1st dose of CC-92480 to the first occurrence of disease progression or death from any cause.
  • 5. Overall survival (OS) [ Time Frame: Up to approximately 3 years ]
    Time from first dose of CC-92480 to death due to any cause
  • 6. Adverse Events (AEs) [ Time Frame: Time from first dose of CC-92480 to death due to any cause ]
    Number of participants with AEs to CC-92480 and/or dexamethasone (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).

Eligibility Criteria

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

Criteria

Inclusion Criteria: 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: - M-protein quantities ≥ 0.5 g/dL by sPEP or - ≥ 200 mg/24 hour urine collection by uPEP or - 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 - 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: - 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). - 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 are eligible as long as they have documented disease progression following CAR-T therapy. - 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: - Absolute neutrophil count (ANC) ≥ 1.25 x 109/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). - Hemoglobin (Hgb) ≥ 8 g/dL. - Platelets (plt) ≥ 75 x 109/L without transfusion for ≥ 7 days. - Corrected serum calcium ≤ 13.5 mg/dL (≤ 3.4 mmol/L). - Creatinine clearance (CrCl) based on Cockcroft-Gault formula ≥ 45 mL/min. - AST/SGOT and ALT/SGPT ≤ 3.0 x upper limit of normal (ULN). - Serum bilirubin ≤ 1.5 x ULN or < 3.0 mg/dL for subjects with documented Gilbert's syndrome. - Uric acid ≤ 7.5 mg/dL (446 µmol/L). - 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: - 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. - 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 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 28 days after discontinuation of study therapy. Note: A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point and, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months). 1. 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 3 months following CC-92480 discontinuation in accordance with the PPP 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. 2. Males must agree to refrain from donating sperm while on CC-92480 for 90 days after its discontinuation. Females must agree to refrain from donating ova while on CC-92480 for 28 days after its discontinuation. 3. All subjects must agree to refrain from donating blood while on CC-92480 and for 28 days after its discontinuation. Exclusion Criteria: 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 half-lives prior to starting CC-92480 (not applicable for subjects who had CAR-T as last prior regimen); 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. 25. Subject has received immunosuppressive medication within 14 days prior to the first dose of CC-92480. 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). 26. Subject is unable or unwilling to undergo protocol required venous thromboembolism (VTE) prophylaxis.

Contacts and Locations

Contacts

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

Locations

United States, California
City of Hope Cancer Center
Duarte

United States, Colorado
Colorado Blood Cancer Institute
Denver

United States, Georgia
Emory Clinic
Atlanta

United States, Massachusetts
Dana Farber Cancer Institute
Boston

United States, New York
Roswell Park Cancer Center
Buffalo

United States, New York
Memorial Sloan Kettering Cancer Center
New York

United States, South Carolina
Gibbs Cancer Center & Research
Spartanburg

United States, Tennessee
Sarah Cannon Cancer Center
Nashville

United States, Texas
MD Anderson Cancer Center The University of Texas
Houston

United States, Virginia
University of Virginia Cancer
Charlottesville

United States, Washington
University of WA School of Medicine
Seattle

Australia, New South Wales
Royal Prince Albert Hospital
Camperdown

Australia, South Australia
Royal Adelaide Hospital
Adelaide

Australia, Victoria
Monash Medical Centre
Clayton

Australia, Victoria
St.Vincent's Hospital Melbourne
Fitzroy

Australia, Victoria
The Alfred Hospital
Melbourne

Belgium, Namur
CHU Mont-Godinne
Yvoir

Belgium, Oost-Vlaanderen
UZ Gent
Gent

Belgium, Wallon
UZ Leuven
Leuven

Belgium
UZ Leuven
Antwerpen

Canada, Alberta
Tom Baker Cancer Center
Calgary

Canada, Ontario
London Health Sciences Centre
London

Canada, Ontario
Ottawa General Hospital
Ottawa

Canada, Ontario
Princess Margaret Cancer Centre
Toronto

Canada, Quebec
McGill
Montreal

Canada
CHUQ
Quebec

Denmark, Syddanmark
Odense University Hospital
Odense

Denmark
Rigshospitalet University Hospital
Copenhagen

Finland
Helsinki University Hospital
Helsinki

Japan, Hyogo
Kobe City Medical Center
Kobe

Japan
Kyushu Medical Center
Fukuoka

Japan
Okayama Medical Center
Okayama

Korea, Republic of, Gyeonggido
Seoul National University Hospital
Seoul

Korea, Republic of, Gyeonggido
Severance Hospital
Seoul

Spain, Cantabria
Hospital Universitario Marques
Santander

Spain, Comunidad De Madrid
Hospital Quironsalud Madrid
Madrid

Spain
Hospital Universitari Germans Trias i Pujol Can Ruti
Badalona (Barcelona)

Spain
Hospital San Pau
Barcelona

Spain
Hospital San Pedro de Alcantara
Caceres

Spain
Hospital 12 de Octobre
Madrid

Spain
Clínica Universidad de Navarra
Pamplona

Spain
Hospital Universitario de Salamanca
Salamanca

Spain
Hospital Universitario La Fe
Valencia

United Kingdom, Wales
University Hospital of Wales
Cardiff

United Kingdom
University College London Hospitals Cancer Clinical Trials Unitist FloorCentral wing
London

United Kingdom
Oxford University Hospitals NHS Trust- Churchill Hospital-Oxford Centre for Respiratory Medicine
Oxford

United Kingdom
The Royal Marsden NHS Foundation Trust
Sutton

Sponsors and Collaborators

Celgene

Investigators

Study Director: David Yao, MD, PhD Bristol-Myers Squibb

More Information

  • Responsible Party: Celgene
  • ClinicalTrials.gov Identifier: NCT03374085 History of Changes
  • Other Study ID Numbers: CC-92480-MM-001, U1111-1205-3650, 2017-001236-19
  • First Posted: December 15, 2017 Key Record Dates
  • Last Update Posted: July 14, 2021
  • Last Verified: July 2021
  • Studies a U.S. FDA-regulated Drug Product: Yes
  • Studies a U.S. FDA-regulated Device Product: No
  • Keywords provided by Celgene: Refractory
    Relapsed
    CC-92480
    Efficacy
    Safety
    Multiple Myeloma
  • Additional relevant MeSH terms: Neoplasms, Plasma Cell Multiple Myeloma