Ensayos clínicos

Inclusion Criteria:

• Age ≥ 18 years at the time of consent.
• Signed informed consent form.
• Diagnosis of multiple myeloma (MM) with relapsed and/or refractory disease. Subjects must have received at least 3 prior anti-myeloma treatment regimens (note: induction with or without bone marrow transplant and with or without maintenance therapy is considered one regimen). Subjects must be refractory to the last anti-myeloma treatment regimen prior to entering the study. Refractory myeloma is defined as non-responsiveness (best response of ≤ stable disease) to last anti-myeloma treatment regimen or documented progressive disease during or within 60 days (measured from the last dose) of completing treatment with the last anti-myeloma treatment regimen before study entry. Subjects must have previously received all of the following therapies:
  • Autologous stem cell transplant;
  • 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 2 consecutive cycles 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. Subjects who have received prior allogeneic stem cell transplant or donor lymphocyte infusion (DLI) at least 100 days before enrollment with no signs of acute or chronic graft-versus-host disease (GVHD) will be considered eligible. Subjects who were not candidates to receive one or more of the above treatments (i.e., contraindicated) are eligible; the reason for not receiving treatment must be clearly documented in the case report form.
• Subjects must have measurable disease as determined by the central laboratory defined as meeting at least one of the criteria below:
  • Serum M-protein ≥ 1 g/dL;
  • Urine M-protein ≥ 200 mg/24 hour;
  • Involved serum free light chain (sFLC) level ≥ 10 mg/dL with abnormal κ/λ ratio (light chain disease is acceptable only for subjects without measurable disease in the serum or urine).
• Subject must be willing to provide a fresh bone marrow biopsy sample during Screening (and at Pre-treatment Screening, if required).
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Adequate organ function, defined as:
  • Adequate renal function, defined as calculated creatinine clearance (Cockcroft-Gault) ≥ 60 mL/min without the assistance of hydration.
    • Subjects must not have received IV rehydration within 3 days of renal function assessment.
  • Adequate bone marrow function, defined as absolute neutrophil count (ANC) ≥ 1000 cells/mm3 , hemoglobin (Hb) ≥ 8 g/dL, and platelet count ≥ 50,000/mm^3. Transfusions and growth factors must not be used to meet these requirements at initial Screening.
    • Subjects must not have received growth factors within 14 days of initial Screening;
    • Subjects must not have received red blood cell (RBC) transfusions within 21 days of initial Screening;
    • Subjects must not have received platelet transfusions within 7 days of initial Screening.
  • Adequate hepatic function, defined as:
    • Alanine aminotransferase (ALT) ≤ 3×ULN;
    • Aspartate aminotransferase (AST) ≤ 3×ULN;
    • Total bilirubin < 2.0 mg/dL (or < 3.0 mg/dL for subjects with documented Gilbert’s syndrome); 
    • International ratio (INR) or partial thromboplastin time (PTT) ≤ 1.5 × ULN.
  • Adequate pulmonary function, defined as 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 initial Screening.
• Subject either currently has central vascular access or is a candidate to receive central vascular access or peripheral vascular access for leukapheresis procedure.
• Subjects must be at least 100 days since autologous stem cell transplant (i.e., Day 0, receipt of hematopoietic stem cells) at the time of initial Screening, if performed.
• Recovery to ≤ Grade 1 or baseline of any non-hematological toxicities due to previous therapy, except alopecia and peripheral neuropathy.
• Females of reproductive potential (defined as all females physiologically capable of becoming pregnant) must agree to use one highly effective method of contraception from screening until at least 12 months following lymphodepleting chemotherapy. There are insufficient exposure data to provide any recommendation concerning the duration of contraception following treatment with JCARH125. Any decision regarding contraception after JCARH125 infusion should be discussed with the treating physician.
• Females of reproductive potential 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 within 7 days prior to the first dose of lymphodepleting chemotherapy). This applies even if the subject practices true abstinence* from heterosexual contact. *True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. In contrast, periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
• Males who have partners of childbearing potential must agree to use an effective barrier contraceptive method from initiation of lymphodepleting chemotherapy and for at least 12 months after and should not donate semen or sperm during the entire study period and for at least 12 months following lymphodepleting chemotherapy.
• Phase 2a prior BCMA-directed anti-myeloma therapy cohort only – Subjects with R/R MM who have been previously treated with prior BCMA-directed anti-myeloma therapy, achieved at least a partial response (PR) per IMWG response criteria and subsequently progressed on the following treatment:
  • Subjects who have received prior BCMA-directed CAR T-cell therapy. The last CAR T-cell therapy must have been received at least 6 months prior to JCARH125 study enrollment (screening);
  • Subjects who have received prior BCMA-directed TCE therapy;
  • Subjects who have received prior BCMA-directed ADC therapy. Subjects with prior BCMA-directed anti-myeloma therapy are not required to have received at least 3 prior anti-myeloma treatment regimens and do not have to be refractory to the last anti-myeloma regimen to be eligible for this trial.

Exclusion Criteria:

• Subjects with known active or history of central nervous system (CNS) involvement by malignancy.
• Subjects with solitary plasmacytoma; active or history of plasma cell leukemia (PCL); Waldenstrom's macroglobulinemia; POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasmaproliferative disorder, Skin changes); or symptomatic amyloidosis.
• Subjects who are considered eligible to receive and have refused an autologous stem cell transplant.
• History of another primary malignancy that has not been in remission for at least 3 years. The following are exempt from the 3-year limit: non-melanoma skin cancer, curatively treated localized prostate cancer, cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Pap smear, and in situ breast cancer that has been completely resected.
• Require systemic immunosuppressive therapies (eg, calcineurin inhibitors, methotrexate, mycophenolate, rapamycin, thalidomide, immunosuppressive antibodies such as anti-interleukin 6 [IL-6] or anti-interleukin 6 receptor [IL-6R]).
• Prior CAR T-cell or other genetically-modified T-cell therapy (not applicable to Phase 2a cohorts).
• Prior treatment with a BCMA-directed therapy (not applicable to Phase 2a cohorts).
• Human immunodeficiency virus (HIV) infection positive subjects.
• Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection as indicated by positive serology or nucleic acid testing. Subjects who are solely hepatitis B surface antibody (HBsAb)-positive are eligible.
• Untreated or active infection at the time of initial Screening, at the time of leukapheresis, within 72 hours before lymphodepletion, or 5 days before JCARH125 infusion. Subjects with ongoing use of prophylactic antibiotics, antifungals, or antivirals are eligible if no evidence of active infection.
• History of any one of the following cardiovascular conditions within the 6 months prior to initial Screening:
  • Class III or IV heart failure as defined by the New York Heart Association (NYHA), myocardial infarction, unstable angina, uncontrolled or symptomatic atrial arrhythmias, any ventricular arrhythmias, or other clinically significant cardiac disease.
• History or presence of clinically relevant CNS pathology such as epilepsy, seizure, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis.
• History of ≥ Grade 2 hemorrhage within 30 days or requirement for ongoing treatment with chronic, therapeutic doses of anticoagulants (e.g., warfarin, low molecular weight heparin, or Factor Xa inhibitors).
• Pregnant or nursing (lactating) women.
• Treatment with the following therapies within the specified time period:
  • Monoclonal antibodies (anti-CD38 and anti-SLAMF7 antibody) within 4 weeks prior to leukapheresis;
  • Any other systemic therapy approved for the treatment of MM within 14 days before leukapheresis or within 14 days before lymphodepleting chemotherapy;
  • Any experimental therapy within 8 weeks (for biologics) or 5 half-lives (for small molecules) before leukapheresis;
  • Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 14 days before leukapheresis. Physiologic replacement, topical, and inhaled steroids are permitted;
  • Radiation to a single lesion within 14 days before leukapheresis;
  • Radiation that includes a large bone marrow field such as the pelvis or sternum within 6 weeks before leukapheresis.
• Plasmapheresis within 14 days before leukapheresis.
• Any medical, psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol, as judged by the Investigator; medical or psychiatric conditions or laboratory abnormalities that could jeopardize subject safety, as judged by the Investigator or Sponsor Medical Monitor; or unwillingness or inability to follow the procedures required in the protocol.
• Use of any live vaccines against infectious diseases within 8 weeks before JCARH125 infusion.
• Subjects with known hypersensitivity to Escherichia coli (E. coli)-derived proteins (only applicable for subjects getting prophylactic anakinra).
• History of severe immediate hypersensitivity reaction to any of the protocol-mandated and recommended agents used in this study.