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A Study of CC-99712, a BCMA Antibody-Drug Conjugate, in Participants With Relapsed and Refractory Multiple Myeloma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04036461
Recruitment Status : Recruiting
First Posted : July 29, 2019
Last Update Posted : August 18, 2021
Sponsor:
Information provided by (Responsible Party):
Celgene

Study Description
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Brief Summary:
Study CC-99712-MM-001 is an open-label, Phase 1, dose escalation (Part A) and expansion (Part B), First-in-Human (FIH) clinical study of CC-99712 in monotherapy or combination in participants with relapsed and refractory multiple myeloma (MM). The dose escalation part (Part A) of the study will evaluate the safety and tolerability of escalating doses of CC-99712, administered intravenously (IV) in monotherapy (Arm 1) or combination (Arm 2), to determine the maximum tolerated dose (MTD) of CC-99712 guided by a Bayesian logistic regression model (BLRM). A modified accelerated titration design will also be used for Arm 1 and Arm 2. The MTD may be established separately for CC-99712 administered at Q3W and/ or Q4W schedules. The expansion part (Part B) will further evaluate the safety and efficacy of CC-99712 in monotherapy (Arm 1) or combination (Arm 2) administered at or below the MTD in selected expansion cohorts in order to determine the RP2D. One or more doses or dosing regimens may be selected for cohort expansion. All participants will be treated until confirmed disease progression per IMWG criteria, unacceptable toxicity, or participants//Investigator decision to withdraw.

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: CC-99712 Drug: BMS-986405 Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 160 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1, Multicenter, Open-label, Dose Finding Study of CC-99712, a BCMA Antibody-Drug Conjugate, in Subjects With Relapsed and Refractory Multiple Myeloma
Actual Study Start Date : August 26, 2019
Estimated Primary Completion Date : May 28, 2023
Estimated Study Completion Date : May 27, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm 1 (CC-99712 monotherapy)
CC-99712 will be administered via intravenous (IV) infusion once per 21-days on a Once every three weeks (Q3W) schedule, and once per 28-days on a Once every four weeks (Q4W) schedule
 Drug: CC-99712
CC-99712
Experimental: Arm 2 (CC-99712 and BMS-986405 combination)
CC-99712 will be administered as indicated above. BMS-986405 will be administered orally TIW every week during a 21-day cycle (eg, Day 1, Day 3, Day 5, Day 8, Day 10, Day 12, Day 15, Day 17, and Day 19), with 48 hours between each dose with a week
 Drug: CC-99712
CC-99712

Drug: BMS-986405
BMS-986405
Other Name: GSI (Gamma secretase inhibitor)


Outcome Measures
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Primary Outcome Measures :
  1. Adverse Events (AEs) [ Time Frame: From enrollment until at least 42 days after completion of study treatment ]
    Number of participants with adverse event

  2. Maximum Tolerated Dose (MTD) in participants with relapsed and refractory MM [ Time Frame: Up to 28 days ]
    Is defined as the highest dose that causes DLTs in no more than 33% of patient population during the first cycle of treatment.

  3. Dose Limiting Toxicity (DLT) in participants with relapsed and refractory MM [ Time Frame: Up to 28 days ]
    Is defined as any of the following toxicities occurring within the DLT assessment window


Secondary Outcome Measures :
  1. Overall Response Rate (ORR) [ Time Frame: Up to 3 years ]
    Is defined as the proportion of participants who achieve a partial response or better (eg, Partial response (PR), Very good partial response (VGPR), Complete response (CR) or sCR), according to IMWG response criteria.

  2. Time to Response [ Time Frame: Up to 3 years ]
    Is defined as the time from the first CC-99712 dose date to the date of first documented response (PR or better).

  3. Duration of Response [ Time Frame: Up to 3 years ]
    Is defined as the time from the earliest date of documented response (≥ PR) to the first documented disease progression or death, whichever occurs first.

  4. Progression-free Survival (PFS) [ Time Frame: Up to 3 years ]
    Is defined as the time from the first dose of CC-99712 to progressive disease (PD) or death from any cause, whichever occurs first.

  5. Overall Survival (OS) [ Time Frame: Up to 3 years ]
    Is defined as the time from the first dose of CC-99712 to death from any cause.

  6. Pharmacokinetics- Cmax [ Time Frame: Up to 3 years ]
    Maximum plasma concentration of drug

  7. Pharmacokinetics- Cmin [ Time Frame: Up to 3 years ]
    Minimum plasma concentration of drug

  8. Pharmacokinetics- AUC [ Time Frame: Up to 3 years ]
    Area under the curve

  9. Pharmacokinetics- tmax [ Time Frame: Up to 3 years ]
    Time to peak (maximum) serum concentration

  10. Pharmacokinetics- t1/2 [ Time Frame: Up to 3 years ]
    Half-life

  11. Pharmacokinetics- CL [ Time Frame: Up to 3 years ]
    Clearance

  12. Pharmacokinetics- Vss [ Time Frame: Up to 3 years ]
    Volume of Distribution

  13. Presence and frequency of ADA using a validated bridging immunoassay with electrochemiluminescence detection [ Time Frame: Up to 3 years ]
    Anti-CC-99712 antibodies


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

Participants must satisfy the following criteria to be enrolled in the study:

  1. Participant (male or female) is ≥ 18 years of age at the time of signing the informed consent form (ICF).

  2. Participant has a history of multiple myeloma (MM) with relapsed and refractory disease, and must:

    • Have disease that is nonresponsive while on their last antimyeloma therapy or documented disease progression on or within 60 days from the last dose of their last antimyeloma therapy; and,
    • Must have received at least 3 prior MM treatment regimens and,
    • Must have received a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody (eg, daratumumab); and,
    • Should have failed treatment with or are intolerant to all established therapies.

  3. Participants must have measurable disease, including at least one of the criteria below:

    • M-protein quantities ≥ 0.5 g/dL by sPEP or
    • ≥ 200 mg/24 hours 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 patients without detectable serum or urine M-protein or
    • For participants 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.
  4. Participant has an ECOG PS of 0-1.

  5. Participants must have the following laboratory values (determined by local laboratory):

    • Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L without growth factor support for 7 days (14 days if pegfilgrastim)
    • Platelets (plt) ≥ 75 x 10^9/L without transfusion for 7 days or plt ≥ 50 x 109/L when BM plasma cells ≥ 50%.
    • Potassium within normal limits or correctable with supplements.
    • Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 2.5 x upper limit of normal (ULN).
    • Serum bilirubin ≤ 1.5 x ULN (or ≤ 2.0 x ULN for participants with documented Gilbert's syndrome).
    • Estimated serum creatinine clearance of ≥ 60 mL/min
    • International normalized ratio (INR) < 1.5 x ULN and activated partial thromboplastin time (APTT) < 1.5 x ULN.

  6. Females of childbearing potential (FCBP) must:

    • 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, at least two effective contraceptive methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner), one of which must be barrier, from signing the ICF, throughout the study, during dose interruptions, and for up to 42 days following the last dose of CC-99712; and

    • Have two negative pregnancy tests as verified by the Investigator prior to starting CC-99712. Participant must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the participant practices true abstinence from heterosexual contact. The participant may not receive IP until the Investigator has verified that the result of the pregnancy test is negative.

      • a negative serum pregnancy test (sensitivity of at least 25 mIU/mL) at Screening
      • a negative serum or urine pregnancy test (Investigator's discretion) within 72 hours prior to Cycle 1 Day -1 of study treatment, and within 72 hours prior to Day -1 of every subsequent cycle (note that the Screening serum pregnancy test can be used as the test prior to Day -1 study treatment if it is performed within the prior 72 hours). A serum or urine pregnancy test (investigators discretion) must also be performed at the end of study for each FCBP.
    • Avoid conceiving for 42 days after the last dose of CC-99712.
    • Agree to ongoing pregnancy testing during the course of the study, and after the end of study treatment. This applies even if the participant practices true abstinence2 from heterosexual contact.
    • Males must practice true abstinence (which must be reviewed on a monthly basis) or agree to use a condom (a latex condom is recommended) during sexual contact with a pregnant female or a FCBP and will avoid conceiving from signing the ICF, while participating in the study, during dose interruptions, and for at least 42 days following CC-99712 discontinuation, even if he has undergone a successful vasectomy.
  7. Participant is willing and able to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria:

The presence of any of the following will exclude a participant from enrollment:

  1. In Part A only, participant has received prior therapy directed at BCMA including, but not limited to, antibody-drug conjugates (BCMA-ADC), bispecific T cell-engaging antibodies or molecules, or BCMA-directed T cell therapy (eg, BCMA chimeric antigen receptor [CAR] T cells).
  2. Participant has symptomatic central nervous system involvement of MM.
  3. Participant has nonsecretory MM, plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or amyloidosis.
  4. Participants with a history of class III or IV congestive heart failure (CHF) or severe non-ischemic cardiomyopathy, unstable angina, myocardial infarction, or ventricular arrhythmia within the previous 6 months prior to signing ICF.
  5. Participant had a prior autologous stem cell transplant ≤ 3 months prior to starting CC-99712.
  6. Participant had a prior allogeneic stem cell transplant with either standard or reduced intensity conditioning ≤ 6 months prior to starting CC-99712 or is on systemic immunosuppression for graft-versus host disease.
  7. Participant had a prior chimeric antigen receptor T (CAR T) cell product ≤ 4 weeks prior to starting CC-99712.
  8. Participant had a prior systemic cancer-directed treatments or investigational modalities within 5 pharmacokinetic half-lives or 2 weeks prior to starting CC-99712, whichever is longer. The only exception is emergency use of a short course of corticosteroids (equivalent of dexamethasone 40 mg/day for a maximum 4 days) before treatment.
  9. Participant had major surgery ≤ 2 weeks prior to starting CC-99712. Participants must have recovered from any clinically significant effects of recent surgery.
  10. Participant is a pregnant or lactating female.
  11. Participant has known human immunodeficiency virus (HIV) infection.
  12. Participant has known history of chronic, active hepatitis B or C virus (HBV/HCV) infection.
  13. Participant requires ongoing treatment with chronic, therapeutic dosing of anti-coagulants (eg, warfarin, low molecular weight heparin, Factor Xa inhibitors).
  14. Participant has a history of concurrent second cancers requiring active, ongoing systemic treatment.
  15. Participant has known history of cirrhosis or has clinically significant liver or biliary disease. Participants with stable chronic liver or biliary disease (such as Gilbert's syndrome, asymptomatic gallstones, or hepatobiliary involvement of malignancy) may participate in the study, however, sponsor medical monitor must be contacted for a discussion before enrollment.
  16. Participant has a history of clinically significant corneal disease requiring therapy or ongoing active corneal disease.
  17. Participant has active peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v5.0).
  18. Participant has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the participant from participating in the study.
  19. Participant has any condition including the presence of laboratory abnormalities, such as active or uncontrolled infection, which places the participant at unacceptable risk if he/she were to participate in the study.
  20. Participant has any condition that confounds the ability to interpret data from the study.
  21. Participant has confirmed extramedullary plasmacytoma in pulmonary, cardiac, or hepatic systems.
  22. Participant has documented malabsorptive syndromes including enteropathies, gastroenteritis (acute or chronic) or diarrhea (acute or chronic) with active treatment.

  23. Participant has previous SARS-CoV-2 infection within 10 days for mild or asymptomatic infections or 20 days for severe/critical illness prior to C1D1.

    • Acute symptoms must have resolved and based on investigator assessment in consultation with the medical monitor, there are no sequelae that would place the participant at a higher risk of receiving study treatment.

  24. Participant has previous SARS-CoV-2 vaccine within 14 days of C1D1. For vaccines requiring more than one dose, the full series (eg, both doses of a two-dose series) should be completed at least 14 days prior to C1D1 when feasible and when a delay in C1D1 would not put the study participant at risk.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04036461


Contacts
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Contact: Recruiting sites have contact information. Please contact the sites directly. If there is no contact information, please email: Clinical.Trials@bms.com
Contact: First line of the email MUST contain NCT # and Site #.

Locations
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Sponsors and Collaborators
Celgene
Investigators
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Study Director: Eric Kim, MD Celgene
More Information
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Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT04036461    
Other Study ID Numbers: CC-99712-MM-001
U1111-1231-9404 ( Other Identifier: WHO )
2020-004514-35 ( EudraCT Number )
First Posted: July 29, 2019    Key Record Dates
Last Update Posted: August 18, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Information relating to our policy on data sharing and the process for requesting data can be found at the following link:

https://www.celgene.com/research-development/clinical-trials/clinical-trials-data-sharing/
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: See Plan Description
Access Criteria: See Plan Description
URL: https://www.celgene.com/research-development/clinical-trials/clinical-trials-data-sharing/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Celgene:
Multiple Myeloma
Relapsed and refractory
CC-99712
 BCMA
Antibody drug conjugate
BMS-986405
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
 Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases