A Single-Arm, Open-Label, Phase 1/2 Study Evaluating the Safety, Efficacy, and Cellular Kinetics/Pharmocodynamics of ALLO-501A, an Anti-CD19 Allogeneic Car T Cell Therapy in Subjects with Relapsed/Refractory Large B-Cell Lymphoma (LBCL)
The purpose of the ALPHA-2 study is to assess the safety, efficacy, and cell kinetics of ALLO-501A in adults with relapsed or refractory large B-cell lymphoma after a lymphodepletion regimen comprising fludarabine, cyclophosphamide, and ALLO-647.
Primary Objectives: Phase 1: To assess safety and tolerability at increasing dose levels of ALLO-501A in successive cohorts of subjects with relapsed/refractory (R/R) LBCL to estimate the maximum tolerated dose (MTD) of ALLO-501A administered following lymphodepletion with fludarabine/cyclophosphamide (Flu/Cy) and ALLO-647 and to select the recommended Phase 2 dose (RP2D) of ALLO-501A -To assess safety and tolerability of ALLO-647 in combination with Flu/Cy prior to ALLO-501A and to establish the RP2D of ALLO-647. Phase 2: -to assess clinical efficacy of ALLO-501A as measured by overall response rate (ORR) and assessed by Independent Radiology Review (IRR) in subjects with R/R/ LBCL. Secondary Objectives (Phase 1 and 2) -to evaluate the overall safety profile of ALLO-501A and ALLO-647 in combination with Flu/Cy -to evaluate anti-tumor activity of ALLO-501A (Phase 2 only) -To characterize cellular kinetics of ALLO-501A -to characterize the pharmacokinetics of ALLO-647 -to evaluate immunogenicity against ALLO-501A and ALLO-647 -to evaluate host immune cell depletion and reconstitution resulting from lymphodepletion with ALLO-647 in combination with Flu/Cy prior to ALLO-501A Exploratory Objectives (Phase 1 and 2) -to explore potential biomarker development based on assessment of blood cells and tumor cells for ALLO-501A and ALLO-647 -to explore changes in immunoregulatory transcripts (RNA profile) and T cell clonal diversity (TCR DNA sequencing) and its relationship to ALLO-501A expansion, persistence, and activity -to explore the impact of ALLO-501A on systemic soluble immune factors -to collect banked biospecimens for exploratory research, unless prohibited by local regulations or ethics committee decision -to assess MRD negativity -to explore the safety and efficacy of retreatment with ALLO-501A following lymphodepletion
ALLO-501A (); ALLO-647 (); Not Applicable (); cyclophosphamide (); cytoxan (cyclophosphamide); fludarabine (Fludarabine phosphate)
- Histologically confirmed relapsed/refractory large B-cell lymphoma with at least one measurable lesion
- At least 1 measurable lesion at time of enrollment according to revised IWG Response Criteria for Malignant Lymphoma
- Relapsed or refractory disease: At least 2 prior lines of chemotherapy including an anthracycline and an anti-CD20 monoclonal antibody.
- Prior CD19 therapy allowed with evidence of CD19 positive relapse following any prior CD19-directed therapy, including cell therapies
- Eastern Cooperative Oncology Group Performance Status of 0 or 1
- Absence significant of donor (product)-specific anti-HLA antibodies
- Adequate hematological, renal and liver function.
- LDH less than or equal to 2 x ULN
- Normal blood oxygen saturation level (SpO2) >92% on room air.
- Left ventricular ejection fraction (LVEF) ≥40% and no clinically significant cardiac related pericardial or pleural effusion at screen
- Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade 1 or less except for adverse events (AEs) not constituting a safety risk by investigator judgement.
- Negative for hepatitis B antigen; (Not eligible are subjects that are HBs Ag and/or Anti-HBc positive. If indeterminate results are obtained, viral DNA levels should be measured to confirm negative viral status).
- Seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then subjects must be tested for the presence of antigen by RT-PCR and subject must be HCV RNA negative.
- Urine or serum pregnancy test (for females of childbearing potential) negative at screening.
- Female participants of non-childbearing potential must meet at least 1 of the following criteria: (a) Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed with a serum follicle stimulating hormone level confirming the postmenopausal state; (b) Have undergone a documented hysterectomy and/or bilateral oophorectomy; (c) Have a medically confirmed ovarian failure. All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential. Fertile male participants and female participants of childbearing potential must be willing to use a highly effective method of contraception as outlined in Section 4.4 for at least 12 months (6 months for males) after the last documented use of cyclophosphamide.
- Other criteria may apply
- Active central nervous system (CNS) involvement by malignancy. Note: subjects with a history of CNS disease that has been effectively treated will be eligible
- Current thyroid disorder (including hyperthyroidism) with the exception of hypothyroidism controlled on stable dose of hormone replacement therapy
- Any other active malignancies that required systemic treatment within 3 years prior to enrollment (Note: cancers that can be adequately treated with local measures like surgical resection or local radiation with limited chance of recurrence or spread such as basal cell or squamous cell skin cancer, carcinoma in situ, or low Gleason score prostate cancers are acceptable)
- Radiation therapy within 2 weeks prior to ALLO-647
- Prior irradiation to more than 25% of the bone marrow
- Hypocellular bone marrow for age by institutional standard as determined from a bone marrow biopsy performed at time of screening.
- Donor lymphocyte infusion within 30 days prior to ALLO-647.
- Autologous hematopoietic stem cell transplant (HSCT) within last 6 months (24 weeks) or allogenic HCT within last 6 months (24 weeks) prior to ALLO-647
- Prior treatment with anti-CD19 targeted therapies (including CAR T cell therapy and bispecific antibodies, etc) will be excluded.
- Systemic anti-cancer therapy within 2 weeks prior to receiving ALLO-647. If the last immediate anti-cancer treatment contained an antibody-based agent(s) (approved or investigational), then an interval of 28 days or 5 half-lives (whichever is shorter) of the agent(s) prior to receiving ALLO-647. No bridging therapy (including corticosteroids for disease management) is permitted during the screening period before intitathing lymphodepletion.
- Active acute or chronic graft versus host disease (GVHD)
- Patients unwilling to participate in an extended safety monitoring period
- Other criteria apply
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