Phase 1a/b Study of GPRC5D CART Therapy in Relapsed/Refractory Multiple Myeloma and Light-chain Amyloidosis

Prior treatment

• Ongoing treatment with chronic immunosuppressant or systemic steroids (physiological replacement doses of steroids are allowed up to 12 mg/m2/d hydrocortisone or equivalent)

Other illness

• Known bulky central nervous system disease.
• Significant co-morbid condition or disease which in the judgment of the Investigator would place the subject at undue risk or interfere with the study; examples include, but are not limited to, cirrhotic liver disease, sepsis, recent significant traumatic injury, and other conditions.
• Known human immunodeficiency virus (HIV) positive status.
• Active Hepatitis B or Hepatitis C infections.
• Active CMV infection.
• Have suffered from a stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control and is not expected to resolve or stabilize within 3 months.
• Chronic atrial fibrillation with uncontrolled heart rate.
• Second primary malignancy that has required therapy in the last 2 years or is not in complete remission. This exclusion criterion does not exclude the following subjects: successfully treated non- metastatic basal cell or squamous cell skin carcinoma, or prostate cancer under control with hormonal therapy
• Subjects who have had a venous thromboembolic event (e.g., pulmonary embolism or deep vein thrombosis) requiring anticoagulation and who meet any of the following criteria:
  • Have been on a stable dose of anticoagulation for \< 1 month (except for acute line insertion induced thrombosis).
  • Have had a Grade 2, 3, or 4 hemorrhage in the last 30 days
  • Are experiencing continued symptoms from their venous thromboembolic event (e.g. continued dyspnea or oxygen requirement).

Lab values

• Inadequate hepatic function defined by aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \> 2.5 x upper limit of normal (ULN) and direct bilirubin \> 4x ULN.
• Inadequate renal function defined by serum creatinine clearance/estimated clearance of \<20 (ml/min).
• International ratio (INR) or partial thromboplastin time (PTT) \> 2 x ULN, unless on a stable dose of anticoagulant for a thromboembolic event (provided this event is not an exclusion criteria).
• Inadequate bone marrow function defined by absolute neutrophil count (ANC) \< 1000 cells/mm3, platelet count \< 30,000 mm3, or hemoglobin \< 8 g/dL.
• Echocardiogram with left ventricular ejection fraction \< 40%.
• Subjects with Absolute Lymphocyte Count (ALC) ≤0.3 × 109/L or \< 300 cells/mm3 (due to potential challenges with producing CART cells), per investigator judgement

Other

• Pregnant or lactating women.
• Contraindication to a study treatment/procedure or is anticipated to receive treatment/procedure that may preclude performance of study procedures.

• ≥18 years of age at the time of signing informed consent.
• Voluntarily signed informed consent form.
• Diagnosis of relapsed/refractory multiple myeloma or AL amyloidosis, with measurable disease at screening visit as follows:
  • Multiple Myeloma (at least one of the criteria below):
  • Serum M-protein greater or equal to 0.5 g/dL.
  • Positive test for urine M-protein.
  • Serum free light chain (FLC) assay: involved FLC level greater or equal to 3 mg/dL (30 mg/L) provided serum FLC ratio is abnormal.
  • A biopsy- or PET-CT- proven evaluable plasmacytoma\*.
  • Bone marrow plasma cells \> 10% of total bone marrow cells\*.
  • Non secretory patient will be allowed provided they have measurable disease by PET-CT or MRI or bone marrow aspiration, as designated\*.
  • Results pre-dating the Screening visit by up to 28 days may be used to establish eligibility AL Amyloidosis Serum free light chain (FLC) assay: involved FLC level greater or equal to 3 mg/dL (30 mg/L) provided serum FLC ratio is abnormal.
• Prior Exposure:
  • Multiple Myeloma: Subject must have been exposed to at least 3 prior lines of therapy including the following agents:
  • proteasome inhibitor
  • immunomodulatory (IMiDs) drug
  • anti-CD38 antibody
  • AL Amyloidosis: Subject have been exposed to 2 prior lines of therapy which include/s the following agents:
  • proteasome inhibitor
  • anti-CD38 antibody
• Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2.
• Women of child-bearing potential (WCBP), defined as a sexually mature woman who has not undergone a hysterectomy or tubal ligation or who has not been naturally postmenopausal for at least 24 consecutive months, must have a negative serum pregnancy test prior to treatment. All sexually active WCBP and all sexually active male subjects must agree to use effective methods of birth control throughout the study.
• Recovery to ≤ Grade 2 or baseline of any non-hematologic toxicities due to prior treatments, excluding alopecia and Grade 3 neuropathy.
• Ability and willingness to adhere to the study visit schedule and all protocol requirements.
• Subjects who have previously undergone allogenic stem cell transplantation are without evidence of graft versus host disease after cessation of any immunosuppressive therapy for at least one month before recruitment to the study.
• Subjects with Absolute Lymphocyte Count (ALC) \> 0.3 × 109/L