Genetically Modified Immune Cells (CART-38 Cells) for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Multiple Myeloma

Inclusion Criteria

• Male or female patients age >= 18 years
• Patients must have one of the following diagnoses: * Cohort A: Acute Myeloid Leukemia (AML) which meets one of the following criteria: ** Patients with second or greater relapse defined as flow cytometric confirmation of myeloid leukemia of at least 0.1% after second documented complete remission; OR ** Patients with detectable disease post-allogeneic transplant with flow cytometric confirmation (minimal residual disease [MRD]) of myeloid leukemia of at least 0.1%; OR ** Patients with refractory disease defined as persistent bone marrow involvement with > 5% blasts after two courses of standard chemotherapy for patients at initial presentation; OR ** Patients with relapsed disease (defined as > 5% bone marrow blasts after one course of standard chemotherapy) after previously achieving a complete remission. Note: Two cycles of combination therapy with a hypomethylating agent and venetoclax is considered one course of standard AML chemotherapy for the purpose of this criteria * Cohort B: Relapsed/refractory multiple myeloma (MM) according to International Myeloma Working Group (IMWG) 2016 criteria which meets both of the following conditions: ** Relapsed/refractory disease after receiving >= 3 lines of therapy, to ensure the patient has been exposed to >= 1 immunomodulatory imide drug (IMiD [registered trademark]), >= 1 proteasome inhibitor, and daratumumab; where refractory MM is defined as the achievement of less than a partial response (< PR after >= 2 cycles) and relapsed MM requires patients be =< 12 months from the last dose of their prior treatment regimen to confirmation of relapse); AND ** Patients must also have measurable disease as defined by one of the following: *** Serum M-protein >= 0.5 g/dL; *** Urine M-protein >= 200 mg/24 hours; *** Serum free light chain (FLC) assay; involved FLC level >= 100 mg/L provided the serum FLC ratio is abnormal; *** >= 30% clonal plasma cells in the bone marrow aspirate or biopsy sample; *** Measurable plasmacytomas > 2 cm in cross sectional diameter
• AML only: Documentation of CD38 expression on leukemic blasts by flow or by immunohistochemistry (IHC). Results must be confirmed after last documented relapse and after any CD38-directed therapy (if applicable)
• Confirmed availability of cells for a rescue transplant as a therapeutic back-up option as follows: * Cohort A (AML): Patients must have a suitable stem cell donor available who may donate cells in the event the subject needs to undergo an allogeneic hematopoietic stem cell transplantation (HSCT). Donor may be matched or mismatched and must be found to be suitable according to the institution’s standard criteria; donors must be fully cleared to proceed as the donor. * Cohort B (MM): Previously harvested autologous stem cells > 2 x 10^6/kg CD34+ cells
• Creatinine =< 2.5 mg/dl or creatinine clearance > 30ml/min
• Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 5x upper limit of normal range
• Direct bilirubin =< 2.0 mg/dl, unless the subject has Gilbert’s syndrome (=< 3.0 mg/dl)
• Must have a minimum level of pulmonary reserve defined as =< grade 1 dyspnea and pulse oxygen > 92% on room air
• Left Ventricle Ejection Fraction (LVEF) >= 40% confirmed by echocardiography (ECHO)/multigated acquisition (MUGA)
• Eastern Cooperative Oncology Group (ECOG) Performance Status that is either 0 or 1
• Signed informed consent form
• Subjects of reproductive potential must agree to use acceptable birth control methods
• ELIGIBILITY CRITERIA FOR RETREATMENT:
• Subjects may not have experienced a DLT during primary treatment (assessed by the investigator before retreatment with CART-38 cells [day 0-R])
• Subjects without a manufactured CART-38 product available which meets the minimum acceptable dose for infusion must obtain Sponsor approval for re-manufacturing (assessed by the investigator before retreatment with CART-38 cells [day 0-R])
• Confirmed availability of cells for a rescue transplant as a therapeutic back-up option
• Subjects must not have developed new disease complications, deterioration in performance status or overall clinical condition, new laboratory abnormalities, or new toxicities that would, in the opinion of the treating investigator, render it unsafe to proceed with retreatment. (assessed by the investigator before retreatment with CART-38 cells [day 0-R]). The following are specific conditions that warrant delaying CAR T cell infusion: * Pulmonary: New requirement for supplemental oxygen or presence of progressive radiographic abnormalities on chest x-ray (chest x-ray is not required at this juncture but should be evaluated if performed for clinical purposes) * Cardiac: New cardiac arrhythmia not controlled with medical management. Electrocardiogram (EKG) is not required to evaluate for arrhythmia in the absence of suggestive symptoms or exam findings * Hypotension requiring vasopressor support * Active Infection: Positive blood cultures for bacteria, fungus, or virus within 48 hours of study treatment
• Subject must have adhered to restrictions on pre-infusion therapy (assessed by the investigator before retreatment with CART-38 cells [day 0-R])
• Female subjects of child-bearing potential must not be pregnant as assessed by a negative serum beta human chorionic gonadotropin (HCG) test drawn within 14 days prior to retreatment infusion, and prior to the first day of lymphodepleting chemotherapy (as applicable) (assessed by the investigator before retreatment with CART-38 cells [day 0-R])
• Subjects must undergo a Respiratory Virus Panel (RVP; inclusive of SARS-CoV-2) within 14 days prior to the planned CAR T cell retreatment infusion and prior to administration of lymphodepleting chemotherapy. If the subject is positive for influenza, Tamiflu (registered trademark) or equivalent, should be administered per package insert. The subject must complete treatment prior to receiving lymphodepleting chemotherapy (as applicable) and CAR T cells. The RVP does not need to be repeated prior to the CAR T cell infusion; however, if influenza signs and symptoms are present, the CAR T cell retreatment infusion should be delayed until the subject is asymptomatic. If the subject is positive for another virus on the RVP, the lymphodepleting chemotherapy and CAR T cell retreatment infusion will be delayed for at least 7 days to be sure clinical symptoms of a viral infection do not develop; or longer if clinically appropriate for the respective viral pathogen. If clinical symptoms develop, the lymphodepleting chemotherapy and CAR T cell infusion will be delayed until resolution of these symptoms. (assessed by the investigator before retreatment with CART-38 cells [day 0-R])

Exclusion Criteria

• Evidence of active hepatitis B or active hepatitis C. The following would not qualify as an active infection, thus would not exclude the subject from participating: * Positive Hepatitis B virus (HBV) serology with undetectable viral load and ongoing antiviral prophylaxis for potential HBV reactivation * Positive Hepatitis C virus (HCV) serology with quantitative polymerase chain reaction (PCR) for plasma HCV ribonucleic acid (RNA) below the lower limit of detection, with or without concurrent antiviral HCV treatment
• Any active, uncontrolled infection
• Severe, active co-morbidity that in the opinion of the physician-investigator would preclude participation in this study
• Class III/IV cardiovascular disability according to the New York Heart Association Classification
• Patients with known somatic JAK2 V617F mutation by PCR or next generation sequencing
• Patients < 3 months from prior autologous transplant or < 6 months from prior allogeneic stem cell transplant (alloASCT)
• Active acute or chronic graft-versus-host disease (GVHD) requiring systemic therapy
• Dependence on systemic steroids or immunosuppressant medications
• Active central nervous system (CNS) disease. Patients with a history of CNS involvement that was successfully treated are eligible. Additional CNS testing such as a lumbar puncture and/or brain imaging is only required for eligibility if a subject is experiencing signs/symptoms of CNS involvement
• Pregnant or nursing (lactating) women
• Patients with a known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the central nervous system, and unrelated to their cancer or previous cancer treatment
• Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to >= 10 mg of prednisone. Patients with autoimmune neurologic diseases (such as multiple sclerosis [MS]) will be excluded
• Known history of allergy or hypersensitivity to study product excipients (human serum albumin, dimethyl sulfoxide [DMSO], and Dextran 40)