Détails de l'étude

Étude ouverte de phase 1 multicentrique visant à déterminer la posologie du CC-99712, un conjugué anticorps-médicament anti-BCMA, chez des sujets atteints d’un myélome multiple récidivant et réfractaire

Phase I

Type de maladie :
Traitement :
Population :
Rechute, Réfractaire
Anti-body drug conjugate

1. Subject must understand and voluntarily sign an informed consent form (ICF) prior to any study-related assessments/procedures being conducted.
2. Subject (male or female) is ≥ 18 years of age at the time of signing the ICF.
3. Subject has a history of MM with relapsed and refractory disease, and must:
• Have disease that is nonresponsive while on their last antimyeloma therapy (failure to obtain a MR or better) or documented disease progression on or within 60 days from the last dose of their last antimyeloma therapy (subjects with documented disease progression who received chimeric antigen receptor [CAR] T cells as their last myeloma therapy are permitted to enroll with disease that is nonresponsive (failure to obtain a MR or better) or documented disease progression beyond 60 days from CAR T infusion) and;
• Have received at least 3 prior MM treatment regimens. Note: induction with or without hematopoietic stem cell transplant and with or without maintenance therapy is considered a single regimen. Subjects must have previously received each of the following therapies:
o A regimen that included an immunomodulatory agent (eg, lenalidomide, pomalidomide) and a proteasome inhibitor (eg, bortezomib, carfilzomib, ixazomib), alone or in combination. Subjects must have undergone at least 2 complete cycles of treatment unless progressive disease was the best response to the regimen.
o A regimen that included anti-CD38 (eg, daratumumab) monotherapy or as part of a combination regimen.
o Autologous stem cell transplant, unless the subject was ineligible. The reason for not receiving stem cell transplant should be documented in the electronic case report form (eCRF).
4. Subjects must have measurable disease (as determined by the central laboratory), 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 subjects with immunoglobulin class A (IgA) myeloma whose disease can only be reliably measured by quantitative immunoglobulin measurement, a serum monoclonal IgA level ≥ 0.50 g/dL.
5. Subject consents to serial bone marrow aspirations and/or biopsies which will be taken
during Screening, study treatment, and at the end of treatment.
6. Subject has an ECOG PS of 0-1.
7. Subjects must have the following laboratory values (determined by local laboratory):
• Absolute neutrophil count (ANC) ≥ 1.0 x 109/L without growth factor support for 7 days (14 days if pegfilgrastim).
• Platelets (plt) ≥ 75 x 109/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 subjects with documented Gilbert’s syndrome).
• Estimated serum creatinine clearance of ≥ 60 mL/min using the Cockcroft-Gault equation or directly calculated from the 24-hour urine collection method.
• International normalized ratio (INR) < 1.5 x ULN and activated partial thromboplastin time (APTT) < 1.5 x ULN.
8. Females of childbearing potential (FCBP)1 must:
• Either commit to true abstinence2 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, and for up to 220 days following the last dose of CC-99712 and, in Arm 2, for 220 days after the last dose of BMS-986405; and
• Have two negative pregnancy tests as verified by the Investigator prior to starting CC-99712. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence from heterosexual contact. The subject 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 220 days after the last dose of CC-99712 and, in Arm 2, for 220 days after the last dose of BMS-986405.
• Agree to ongoing pregnancy testing during the course of the study, and after the end of study treatment. This applies even if the subject practices true abstinence from heterosexual contact.
9. 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 130 days following CC-99712 discontinuation and, in Arm 2, for 130 days after the last dose of
BMS-986405, even if he has undergone a successful vasectomy.
10. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.

  1. Subject 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. Subject has symptomatic central nervous system involvement of MM.
  3. Subject has nonsecretory MM, MM with IgM subtype, plasma cell leukemia, Waldenstrom’s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or amyloidosis.
  4. Subjects 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. Subject had a prior autologous stem cell transplant ≤ 3 months prior to starting CC-99712.
  6. Subject 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. Subject had a prior chimeric antigen receptor T (CAR T) cell product ≤ 4 weeks prior to starting CC-99712.
  8. Subject had a prior systemic cancer-directed treatments or investigational modalities within 5 pharmacokinetic half-lives or 4 weeks prior to starting CC-99712, whichever is shorter. Subject received prior cytotoxic chemotherapy, the washout window is within 2 weeks. The only exception is emergency use of a short course of corticosteroids (eg, equivalent of dexamethasone 40 mg/day for a maximum 4 days) before treatment.
  9. Subject had major surgery ≤ 2 weeks prior to starting CC-99712. Subjects must have recovered from any clinically significant effects of recent surgery.
  10. Subject is a pregnant or lactating female.
  11. Subject has known human immunodeficiency virus (HIV) infection.
  12. Subject has active hepatitis B or C (HBV/HCV) infection.
    a. Subject with no active hepatitis B infection (eg, HBsAg negative, anti-HBc positive) who are under adequate prophylaxis against HBV re-activation are eligible.
    b. Subject who had HCV but have received a curative antiviral treatment and show no
    evidence of active HCV infection are eligible.
  13. Subject requires ongoing treatment with chronic, therapeutic dosing of anti-coagulants (eg, warfarin, low molecular weight heparin, Factor Xa inhibitors).
  14. Subject has a history of concurrent second cancers requiring active, ongoing systemic treatment.
  15. Subject has known history of cirrhosis or has clinically significant liver or biliary disease. Subjects 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. Subject has a history of clinically significant corneal disease requiring therapy or ongoing
    active corneal disease.
  17. Subject has active peripheral neuropathy or neuropathic pain at Grade 2 or higher, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v5.0).
  18. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
  19. Subject has any condition including the presence of laboratory abnormalities, such as active or uncontrolled infection, which places the subject at unacceptable risk if he/she were to participate in the study.
  20. Subject has any condition that confounds the ability to interpret data from the study.
  21. Subject has confirmed extramedullary plasmacytoma in pulmonary, cardiac, or hepatic
  22. Subject has documented malabsorptive syndromes including enteropathies, gastroenteritis (acute or chronic) or diarrhea (acute or chronic) with active treatment.
  23. Subject has previous SARS-CoV-2 infection within 10 days for mild or asymptomatic infections or 20 days for severe/critical illness prior to C1D1.
  24. Subject 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 subject at risk.
  25. Subject received live virus vaccines within at least 4 weeks prior to starting study drug.

Hopital Maisonneuve-Rosemont ( CIUSSS de l’Est-de-l’Ile-de-Montréal)