P-CD19CD20-ALLO1 Allogeneic CAR-T Cells in the Treatment of Subjects With B Cell Malignancies

Study Overview
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Brief Summary
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Phase 1 study comprised of open-label, dose escalation and expansion cohort study of P-CD19CD20-ALLO1 allogeneic T stem cell memory (Tscm) CAR-T cells in subjects with relapsed/refractory B cell malignancies

Detailed Description
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Phase 1 study consisting of two parts. Part 1 is a weight-based dose escalation following a 3+3 design of dose-escalating cohorts to determine a Recommended Phase 2 Dose (RP2D). Part 2 includes administration at a fixed dose. After enrollment, subjects may receive a lymphodepletion therapy regimen before administration of allogeneic CAR-T cells, administered as a single dose. Treated subjects will undergo serial measurements of safety, tolerability and response. Rimiducid may be administered as indicated.

Official Title
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Open-Label, Multicenter, Phase 1 Study to Assess the Safety of P-CD19CD20-ALLO1 in Subjects With Selected Relapsed/Refractory B Cell Malignancies

Conditions
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Diffuse Large B Cell Lymphoma, Follicular Lymphoma, Mantle Cell Lymphoma, Marginal Zone Lymphoma, Primary Mediastinal Large B-cell Lymphoma (PMBCL), Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Biological: P-CD19CD20-ALLO1
* Drug: Rimiducid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have signed written, informed consent. Males or females ≥ 18 years of age. Must have prior biopsy proven confirmed diagnosis of DLBCL, FL, MCL, MZL, PMBCL, or CLL. Diagnosis of one of the following: DLBCL, FL, MCL, MZL, or PMBCL by World Health Organization (WHO) 2016 (Swerdlow, 2016) criteria CLL that meets published diagnostic criteria (Hallek, 2018): i. Monoclonal B cells (either kappa or lambda light chain restricted) that are clonally co-expressing ≥ 1 B cell marker (CD19, CD20, or CD23) and CD5. ii. Prolymphocytes comprising ≤ 55% of blood lymphocytes. iii. Presence of ≥ 5 × 109 B lymphocytes/L (5000/µL) in the peripheral blood (at any point since initial diagnosis). CLL must be documented as CD20-positive. CLL must be documented as active disease meeting ≥ 1 of the following iwCLL 2018 criteria (Hallek, 2018) for requiring treatment: Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin < 10 g/dL) and/or thrombocytopenia (platelets < 100,000/μL) Massive (i.e., ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly. Massive nodes (i.e., ≥ 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy. Progressive lymphocytosis with an increase of > 50% over a 2 month period or a lymphocyte doubling time (LDT) of < 6 months. LDT may be obtained by linear regression extrapolation of absolute lymphocyte count (ALC) obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In subjects with initial blood lymphocyte counts of < 30 × 109/L (30,000/μL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (e.g., infections) should be excluded. Constitutional symptoms documented in the subject's chart with supportive objective measures, as appropriate, defined as ≥ 1 of the following disease-related symptoms or signs: i. Unintentional weight loss ≥ 10% within the previous 6 months before Screening. ii. Significant fatigue (ECOG performance score 2; inability to work or perform usual activities). iii. Fevers higher than 100.5°F or 38.0°C for ≥ 2 weeks before Screening without evidence of infection. iv. Night sweats for > 1 month before Screening without evidence of infection. DLBCL, FL, MCL, MZL, or PMBCL must have measurable disease as defined by Lugano 2016 criteria (Cheson, 2016). Must have relapsed/refractory disease as defined by the following: DLBCL, FL, MCL, or PMBCL: received 2 lines of therapy that must include rituximab, cyclophosphamide, doxorubicin hydrochloride (i.e., hydroxydaunomycin), vincristine sulfate (i.e., oncovin), and prednisone (R-CHOP) or equivalent regimen and either autologous stem cell transplant (ASCT) or autologous CD19 targeting CAR-T therapy, or not a candidate for ASCT or autologous CD19 targeting CAR-T. OR MZL: received 2 lines of therapy that must include a CD20 monoclonal antibody (mAb) and a Bruton tyrosine kinase inhibitor (BTKi) OR CLL: received 2 lines of therapy that must include a CD20 mAb and a BTKi Must be willing to practice birth control from the time of Screening and throughout the first year of the study after P-CD19CD20-ALLO1 administration (both males and females of childbearing potential). Must have a negative serum pregnancy test at Screening and a negative urine pregnancy test within 3 days prior to initiating the lymphodepletion chemotherapy regimen (females of childbearing potential). Must be at least 90 days since ASCT, if performed. Must be at least 4 weeks since autologous CAR-T therapy if such therapy was administered (medical monitor must approve prior CAR T therapy or other prior T cell targeted therapy). Must have adequate vital organ function, defined as follows (or medical monitor approval): Serum creatinine ≤ 1.5 mg/dL or estimated creatinine clearance ≥ 30 mL/min as calculated using the Cockcroft Gault formula and not dialysis-dependent. Adequate hematologic function, including: i. Absolute neutrophil count (ANC) ≥ 1000/μL in the absence of growth factor support (granulocyte-colony stimulating factor [G-CSF] within 7 days or peg-G-CSF within 14 days) ii. Platelet count ≥ 50,000/μL in the absence of transfusion support (platelet transfusion within 7 days) iii. Hemoglobin ≥ 8 g/dL in the absence of transfusion support (red blood cell count or whole blood within 7 days) c. Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 3 × the upper limit of normal (ULN), and total bilirubin ≤ 2.0 mg/dL (unless there is a history of Gilbert's Syndrome in which case bilirubin levels ≤ 3 mg/dL). d. Left ventricular ejection fraction (LVEF) ≥ 45%. LVEF assessment must have been performed within 4 weeks of enrollment. Must have recovered from toxicities due to prior therapies to Grade ≤ 2 according to the NCI CTCAE v5.0 criteria or to the subject's prior baseline. Must have an ECOG performance status of 0 to 2. Exclusion Criteria: Is pregnant or lactating. Has inadequate venous access. Has active hemolytic anemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), disseminated intravascular coagulation, leukostasis, or amyloidosis. Has an active second malignancy (not disease-free for at least 5 years) in addition to non-Hodgkin lymphoma or CLL, excluding low-risk neoplasms such as non-metastatic basal cell or squamous cell skin carcinoma. Has active autoimmune disease, such as psoriasis, multiple sclerosis, lupus, rheumatoid arthritis, etc. (the medical monitor will determine if a disease is active and autoimmune). Has a history of significant central nervous system (CNS) disease, such as stroke, epilepsy, primary CNS lymphoma, etc. (the medical monitor will determine if significant). Has an active systemic infection (e.g., causing fevers or requiring antimicrobial treatment). Has a history of hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), or human T-lymphotropic virus (HTLV) infection, or any immunodeficiency syndrome. Subjects with a history of treated hepatitis C can be enrolled if negative by hepatitis C polymerase chain reaction (PCR) on multiple occasions and with medical monitor approval. Is positive for human herpes virus (HHV)-6 or HHV-7 infection by polymerase chain reaction (PCR) at the Screening Visit (subjects may be included in the study if they are HHV-6 or HHV-7 antibody-positive but PCR-negative). Has New York Heart Association (NYHA) Class III or IV heart failure, unstable angina, or a history of myocardial infarction or significant arrhythmia (e.g., atrial fibrillation, sustained [> 30 seconds] ventricular tachyarrhythmias, etc.). Has any psychiatric or medical disorder (e.g., cardiovascular, endocrine, renal, gastrointestinal, genitourinary, immunodeficiency or pulmonary disorder not otherwise specified) that would, in the opinion of the Investigator or medical monitor, preclude safe participation in and/or adherence to the protocol (including medical conditions or laboratory findings that indicate a significant probability of not qualifying for or being unable to undergo, conditioning chemotherapy and/or CAR-T cell administration). Has received non-mAb anti-cancer medications within 2 weeks of the time of initiating conditioning chemotherapy. Has received mAb therapy within 4 weeks of initiating conditioning chemotherapy. Has received immunosuppressive medications within 2 weeks of the time of administration of P-CD19CD20-ALLO1, and/or expected to require them while on study (the medical monitor will determine if a medication is considered immunosuppressive). Has received systemic corticosteroid therapy ≥ 5 mg/day of prednisone or equivalent dose of another corticosteroid within 1 week or 5 half-lives (whichever is shorter) of the administration of P-CD19CD20-ALLO1 or is expected to require it during the course of the study. (Topical and inhaled steroids are permitted. Systemic corticosteroids are contraindicated after receiving P-CD19CD20-ALLO1 cells outside of study-specific guidance). Has CNS metastases or symptomatic CNS involvement (including leptomeningeal carcinomatosis, cranial neuropathies or mass lesions and spinal cord compression). Has a history of severe immediate hypersensitivity reaction to any of the agents used in this study. Has a history of having undergone allogeneic or xenogeneic transplant, or has undergone autologous transplantation within 90 days. Has received prior allogeneic cellular therapy. History or Grade ≥ 3 HLH/MAS or neurotoxicity with prior therapies (all symptoms of HLH/MAS, neurotoxicity, or CRS from prior therapies must be resolved at the time of enrollment).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: P-CD19CD20-ALLO1 CAR-T Cells<br>After 2 rest days following the lymphodepletion chemotherapy regimen, subjects will be treated with P-CD19CD20-ALLO1 administered IV on Day 0 (single administration). | Biological: P-CD19CD20-ALLO1<br>* Allogeneic chimeric antigen receptor T cells (CAR-T) targeting both CD19 and CD20<br>Drug: Rimiducid<br>* Safety switch activator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the safety and MTD of P-CD19CD20-ALLO1 based on dose limiting toxicities (DLT) | Number of subjects with DLT at each dose level to define an MTD | Baseline through 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The safety of P-CD19CD20-ALLO1 (AEs) | Incidence and severity of adverse events (AEs) | Baseline through 36 months | 
| The safety of P-CD19CD20-ALLO1 (CRS) | o Cytokine release syndrome (CRS) graded using American Society for Transplantation and Cellular Therapy (ASTCT) criteria | Baseline through 36 months | 
| The anti-B cell malignancy effect of P-CD19CD20-ALLO1 (ORR) | Overall Response Rate (ORR) - Percentage of patients with complete response (CR), very good partial response (VGPR), or partial response (PR) | Baseline through 15 years | 
| The anti-B cell malignancy effect of P-CD19CD20-ALLO1 (DOR) | Duration of Response - Time from complete response (CR), very good partial response (VGPR), or partial response (PR) to progressive disease | Baseline through 15 years | 
| The anti-B cell malignancy effect of P-CD19CD20-ALLO1 (PFS) | Progression Free Survival (PFS) - Time from P-CD19CD20-ALLO1 treatment to progressive disease | Baseline through 15 years | 
| The anti-B cell malignancy effect of P-CD19CD20-ALLO1 (OS) | Overall Survival (OS) - Duration of survival from time of treatment with P-CD19CD20-ALLO1 | Baseline through 15 years |