A Study to Evaluate CC-98633 to Treat Subjects with Relapsed and/or Refractory Multiple Myeloma

Overview

About this study

The purpose of this Phase 1 first-in human study is to evaluate the safety and preliminary efficacy of CC-98633 in adult subjects with relapsed and/or refractory MM. A challenge in CAR T-cell development is to generate a product that consistently expands, persists, and mediates durable antitumor responses after infusion. Multiple preclinical and translational studies have suggested that the differentiation state of adoptively transferred T cells can influence the ability of these cells to persist and promote durable antitumor immunity. Less differentiated T cells have shown an increased ability to proliferate, persist, and mediate responses in mouse tumor models compared to more differentiated effector memory cell subsets in certain studies.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria:

  • Age ≥ 18 years at the time of informed consent.
  • Subjects must understand and voluntarily sign written informed consent obtained prior to any study procedure/assessment being conducted.
  • Willing and able to adhere to the study visit schedule and other protocol requirements.
  • Diagnosis of relapsed and/or refractory multiple myeloma (MM):
    • Subjects must have received at least 3 prior antimyeloma treatment regimens (note: induction with or without bone marrow transplant and with or without maintenance therapy is considered one regimen). Subject must have documented progressive disease during or within 12 months (measured from the last dose) of completing treatment with the last anti-myeloma treatment regimen before study entry. Also, subjects with documented evidence of progressive disease within the previous 6 months and who are refractory or non-responsive to their most recent anti-myeloma treatment regimen afterwards will be also eligible;
  • Subjects must have received at least 3 prior antimyeloma treatment regimens (note: induction with or without bone marrow transplant and with or without maintenance therapy is considered one regimen). Subjects must have previously received all of the following therapies:
    • Autologous stem cell transplant (ASCT). Subjects who were not candidates to receive ASCT treatment (due to age or other factors) are eligible; the reason for not receiving ASCT must be documented in the electronic case report form (eCRF);
    • A regimen that included an immunomodulatory agent (e.g., thalidomide, lenalidomide, pomalidomide) and a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib), either alone or in combination. Subjects must have undergone at least 1 complete cycle of treatment for each regimen unless progressive disease was the best response to the regimen;
    • Anti-CD38 (e.g., daratumumab) as part of a combination regimen or as a monotherapy.
  • Measurable disease as determined by the central laboratory based on one or more of the following findings:
    • Serum M-protein ≥ 0.5 g/dL by serum protein electrophoresis (SPEP);
    • Urine M-protein ≥ 200 mg/24-hour by urine protein electrophoresis (UPEP);
    • Involved serum free light chain (SFLC) level ≥ 10 mg/dL with abnormal kappa/lambda ratio (light chain disease is acceptable only for subjects without measurable disease in the serum or urine).
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 7. Adequate organ function as determined by site’s local laboratory defined as:
    • Peripheral blood absolute neutrophil count (ANC) ≥ 1.0 × 10^9 /L without growth factor support within 7 days (14 days if pegfilgrastim), hemoglobin ≥ 8 g/dL without red blood cell (RBC) transfusions within 21 days, and platelet count ≥ 50 × 10^9 /L without platelet transfusion support within 7 days of screening;
    • Creatinine clearance (CrCl) ≥ 60 mL/min, measured in 24-hours urine collection or calculated from serum creatinine using the Cockcroft-Gault equation, without the support of hydration within 3 days of renal assessment;
    • Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) ≤ 3.0 × upper limit of normal (ULN) and total bilirubin < 1.5 × ULN (or direct bilirubin < 1.5 × ULN with documented Gilbert’s syndrome);
    • Prothrombin time (PT) or international ratio (INR) and partial thromboplastin time (PTT) ≤ 1.5 × ULN;
    • Adequate pulmonary function, defined as ≤ CTCAE Grade 1 dyspnea and saturated oxygen (SaO2 ≥ 92%) on room air;
    • Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥ 40% as assessed by echocardiogram (ECHO) or multiple uptake gated acquisition (MUGA) scan performed within 8 weeks prior to screening.
  • Adequate vascular access for leukapheresis.
  • Willing to undergo serial bone marrow aspirations and/or biopsies or tumor biopsies during study.
  • Recovery to ≤ Grade 1 or baseline of any non-hematological toxicities due to previous therapy, except alopecia and peripheral neuropathy.
  • Agree to refrain from tissue donation including egg donation, sperm donation, or any other tissue/blood/organ donations for at least 1 year following LD chemotherapy. There are no exposure data to provide any recommendation concerning the duration of refraining from tissue donation following treatment with CC-98633. Any decision regarding tissue donation after CC-98633 infusion should be discussed with the treating physician.
  • Females of childbearing potential (FCBP* ) must:
    • Have 2 negative pregnancy tests as verified by the Investigator (one negative serum beta human chorionic gonadotropin (ß-hCG) pregnancy test result at screening and one negative serum pregnancy test within 48 hours prior to the first dose of LD chemotherapy). She must agree to ongoing pregnancy testing after receiving study therapy. 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, highly effective contraception without interruption from screening through at least 1 year following the LD chemotherapy. There are no exposure data to provide any recommendation concerning the duration of contraception following treatment with CC-98633. Any decision regarding contraception after CC-98633 infusion should be discussed with the treating physician.
    • Note: Highly effective methods are defined as those that result in a low failure rate (ie, less than 1% per year) when used consistently and correctly. The following are examples of highly effective methods of contraception:
      • Intrauterine device (IUD);
      • Hormonal (birth control pill, injections, implants);
      • Bilateral tubal ligation;
      • Successful vasectomy.
    • Agree to abstain from breastfeeding during study participation and for at least 1 year following LD chemotherapy. There are no exposure data to provide any recommendation concerning the duration of abstaining from breastfeeding following treatment with CC-98633. Any decision regarding breastfeeding after CC-98633 infusion should be discussed with the treating physician.
  • Male subjects must practice true abstinence** (which must be reviewed on a monthly basis and source documented) or agree to use a condom during sexual contact with a pregnant female or a FCBP while participating in the study and until at least 1 year following the LD chemotherapy even if he has undergone a successful vasectomy. There are no exposure data to provide any recommendation concerning the duration of contraception following treatment with CC-98633. Any decision regarding contraception after CC-98633 infusion should be discussed with the treating physician.

*  A female subjects of childbearing potential (FCBP) is a female who:

  • has achieved menarche at some point;
  • has not undergone a hysterectomy or bilateral oophorectomy; or
  • 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).

**True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. In contrast, periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

Exclusion Criteria:

  • Uncontrolled medical, psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol, as judged by the Investigator; or unwillingness or inability to follow the procedures required in the protocol.
  • Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
  • Any condition that confounds the ability to interpret data from the study.
  • Known active or history of central nervous system (CNS) involvement of MM.
  • Active or history of plasma cell leukemia, Waldenstrom’s macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome, or clinically significant amyloidosis.
  • Any prior CAR T-cell or another genetically modified T-cell therapy.
  • Subject has received prior investigational therapy directed at BCMA including, but not limited to, bispecific T cell-engaging antibodies or molecules, antibody-drug conjugates (BCMA-ADC), or BCMA-directed T- cell therapy (e.g., BCMA chimeric antigen receptor (CAR) T cells).
  • Treatment with the following therapies or procedure within the specified period:
    • Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 14 days before leukapheresis. Physiologic replacement, topical, intranasal, and inhaled steroids are permitted;
    • Anti-MM antibody within 14 days before leukapheresis;
    • Alkylating agents, with the exception of bendamustine, within 4 weeks before leukapheresis;
    • Bendamustine within 6 months before leukapheresis;
    • Any other systemic therapy approved for the treatment of MM within 14 days before leukapheresis;
    • Any experimental agents within 28 days or 5 half-lives before leukapheresis, whichever is shorter (minimum 14 days);
    • Immunosuppressive therapies within 4 weeks of leukapheresis (e.g., calcineurin inhibitors, methotrexate or other chemotherapeutics, mycophenolate, rapamycin, immunosuppressive antibodies such as anti-TNF, anti-IL6, or anti-IL6R) or in need of such therapies;
    • Donor lymphocyte infusions within 6 weeks before leukapheresis;
    • Radiation to a single lesion or a large bone marrow field such as the pelvis or sternum within 14 days before leukapheresis;
    • Plasmapheresis within 14 days before leukapheresis;
    • Autologous stem cell transplant (i.e., Day 0 receipt of hematopoietic stem cells) within 9 months of leukapheresis;
    • Washout of prior therapy (e.g., bridging therapy for disease control) as defined in Table 6 at pre-treatment evaluation.
  • Active autoimmune disease requiring immunosuppressive therapy.
  • Allogenic stem-cell transplant (i.e., Day 0 receipt of hematopoietic stem cells) within 12 months of leukapheresis or presence of ongoing symptoms or treatment for chronic graftversus-host disease (GVHD).
  • Hypersensitivity to fludarabine and/or cyclophosphamide.
  • Prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 2 years except for the following non-invasive malignancies:
    • Basal or squamous cell carcinoma of the skin;
    • Carcinoma in situ of the cervix or 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;
    • Other completely resected stage 1 solid tumor with low risk for recurrence.
  • Active hepatitis B, hepatitis C, or any evidence of human immunodeficiency virus (HIV) infection at the time of Screening.
  • Uncontrolled or active systemic fungal, bacterial, viral or other infection despite appropriate anti-infective treatment at the time of leukapheresis, or within 72 hours before LD chemotherapy, or 5 days before CC-98633 administration.
  • History of any one of the following cardiovascular conditions within the 6 months prior to screening: Class III or IV heart failure as defined by the New York Heart Association, myocardial infarction, unstable angina, angioplasty or stenting, or other clinically significant cardiac disease.
  • History or presence of clinically significant CNS pathology such as seizure disorder, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, or cerebellar disease. Presence of clinically active psychosis.
  • History of Grade ≥ 2 hemorrhage within 30 days of screening.
  • Use of any live vaccines against infectious disease within 8 weeks before CC-98633 administration. 
  • Pregnant or nursing (lactating) women.
  • Previous SARS-CoV-2 infection within 10 days for mild or asymptomatic infections or 20 days for severe/critical illness prior to leukapheresis or initiation of LD chemotherapy:
    • Acute symptoms must have resolved and, based on Investigator assessment in consultation with the Sponsor Medical Monitor, there are no sequelae that would place the participant at a higher risk of receiving study treatment.
  • Previous SARS-CoV-2 vaccine within 14 days prior to leukapheresis or initiation of LD chemotherapy.

 

 

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Rochester, Minn.

Mayo Clinic principal investigator

Shaji Kumar, M.D.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

Scottsdale/Phoenix, Ariz.

Mayo Clinic principal investigator

Peter Bergsagel, M.D.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

More information

Publications

Publications are currently not available
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CLS-20493136

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