B-Cell Non-Hodgkin Lymphoma (NHL), Hodgkin Lymphoma, Richter's Transformation, T-Cell Non-Hodgkin Lymphoma
Conditions
Brief summary
This is a phase 1, open-label, dose-finding study to assess the safety, feasibility, pharmacokinetics and preliminary efficacy of autologous base edited anti-CD45 CAR T cells (referred to as "CART-45 cells") following an autologous transplant of CD45 base edited hematopoietic stem and progenitor cells (referred to as "CD45BE-HSPC") in patients with relapsed or refractory hematologic malignancies.
Interventions
BIOLOGICALCART-45 cells
Autologous base edited anti-CD45 CAR T cells
BIOLOGICALCD45BE-HSPC
CD45 base edited hematopoietic stem and progenitor cells
Sponsors
University of Pennsylvania
Kite, A Gilead Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1\. Signed informed consent form 2. Male or females age ≥ 18 years 3. Disease-Specific Criteria a. B-cell Non-Hodgkin Lymphoma (B-cell NHL)- including the following sub-types: i. Patients with any of the following large B-cell lymphoma diagnoses who meet the prior treatment criteria outlined below: Diffuse Large B-cell Lymphoma not otherwise specified (DLBCL NOS); Primary Cutaneous DLBCL; Primary Mediastinal (thymic) Large B-cell Lymphoma; ALK+ Anaplastic Large B-cell Lymphoma; High-Grade B-cell Lymphoma with MYC and BCL2 and/or BCL6 rearrangements (i.e., "Double or Triple Hit"); High-grade B-cell Lymphoma, NOS; T-cell Rich B-cell Lymphoma; Transformed Follicular Lymphoma; or any aggressive B-cell lymphoma arising from indolent lymphoma. 1\. Patients must have either failed/relapsed after, or be ineligible for, prior commercial CAR T cell therapy; AND 2. Relapsed/refractory disease after at least 2 prior lines of appropriate therapy. ii. Follicular Lymphoma 1. Patients must have either failed/relapsed after, or be ineligible for, prior commercial CAR T cell therapy; AND 2. Relapsed/refractory disease after at least 2 prior lines of systemic therapy (not including a single agent monoclonal antibody therapy). iii. Mantle Cell Lymphoma 1. Patients must have either failed/relapsed after, or be ineligible for, prior commercial CAR T cell therapy; AND 2. Relapsed/refractory disease after at least 2 prior lines of systemic therapy, including a Bruton tyrosine kinase (TKI) inhibitor. Single-agent monoclonal antibody therapy does not count towards prior lines of therapy. iv. Marginal Zone Lymphoma- relapsed/refractory disease after at least 2 prior lines of appropriate therapy, including a Bruton tyrosine kinase (TKI) inhibitor. Note: Single-agent monoclonal antibody therapy does not count towards prior lines of therapy. b. T-cell Non-Hodgkin Lymphoma (T-cell NHL) i. Histologically or cytologically confirmed relapsed or refractory (r/r) mature aggressive T- and NK-cell neoplasms as defined in the 5th edition of the WHO Classification of Hematolymphoid tumors, which includes any of the following diagnoses: • Peripheral T-cell Lymphoma, NOS (PTCL-NOS); • Nodal T-cell Lymphomas with T Follicular Helper \[TFH\] Phenotype, including Follicular T cell Lymphoma, Angioimmunoblastic Lymphoma, or Anaplastic Large Cell Lymphoma (ALCL); • ALK+ or ALK-, Enteropathy-Associated T-cell Lymphoma (EATL); • Monomorphic Epitheliotropic Intestinal T-cell Lymphoma (MEITL); • Extranodal NK/T-cell Lymphoma; • Primary Cutaneous T-cell Lymphoma (CTCL); • Transformed Mycosis Fungoides (tMF) without blood involvement; • Primary Cutaneous Aggressive Epidermotropic CD8+ Cytotoxic T-Cell Lymphoma; • Subcutaneous Panniculitis-like T-cell Lymphoma. ii. Must have received at least one prior line of systemic therapy for their lymphoma. Additional prior treatment provisions required for the following indications: 1\. Participants with Anaplastic Large Cell Lymphoma (ALCL) must have received prior Brentuximab vedotin, unless contraindicated. 2\. Participants with Subcutaneous Panniculitis-like T-cell Lymphoma or Transformed Mycosis Fungoides (tMF) must have received at least 2 prior lines of systemic therapy. c. Hodgkin Lymphoma (HL) i. Patients with histologically proven classical Hodgkin Lymphoma that is CD45 positive by IHC or flow cytometry by a CLIA certified laboratory; AND ii. Relapsed/refractory disease after at least 2 prior lines of therapy which must include the following: 1. Brentuximab vedotin and immune checkpoint inhibitors (unless contraindicated); AND 2. Autologous stem cell transplant (unless patient has chemorefractory disease to salvage treatment) d. Large Cell Transformation of CLL (Richter's Transformation) i. Patients must be primary refractory or received at least 1 prior line of treatment for Richter's Transformation. 4\. Patients are appropriate candidates for autologous HSCT as per physician-investigator clinical discretion 5\. Patients with relapsed disease after prior allogeneic SCT must meet the following criteria: a. Have no active GVHD and require no immunosuppression b. Are more than 6 months from transplant at the time of physician-investigator confirmation of eligibility 6\. Adequate organ function defined as: 1. Serum creatinine ≤ 1.5x ULN or estimated creatinine clearance ≥ 35 mL/min and not on dialysis 2. ALT/AST ≤ 3 x ULN 3. Direct bilirubin ≤ 2.0 mg/dl; for patients with Gilbert's syndrome direct bilirubin must be ≤ 3.0 mg/dl 4. Left Ventricular Ejection Fraction (LVEF) ≥ 40% confirmed by ECHO/MUGA 5. DLCO \> 45% predicted value; adjusted for level of hemoglobin 6. Must have minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen \> 92% on room air 7. ECOG Performance Status 0-1
Exclusion criteria
1. Active hepatitis B or hepatitis C infection 2. Any active, uncontrolled infection. 3. Class III/IV cardiovascular disability according to the New York Heart Association Classification. 4. Clinically apparent arrhythmia or arrhythmias that are not stable on medical management within two weeks of physician-investigator confirmation of eligibility. 5. Severe, active co-morbidity that, in the opinion of the physician-investigator, would preclude participation in this study. 6. Prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen. 7. Active acute or chronic GVHD requiring systemic therapy. 8. Dependence on systemic steroids or immunosuppressant medications. For additional details regarding use of steroid and immunosuppressant medications. 9. Active CNS involvement. Patients with a history of CNS involvement that was successfully treated are eligible. A CNS evaluation is only required for eligibility if a subject is experiencing signs/symptoms of CNS involvement. 10. Patients with evidence of a circulating T-cell malignancy as measured by flow cytometry. 11. History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40). 12. Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10mg of prednisone. Patients with autoimmune neurologic diseases (such as MS) will be excluded. 13. Pregnant or nursing (lactating) patients. Participants of reproductive potential must agree to use acceptable birth control methods.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events as assessed by CTCAE v6.0 | Up to 15 years post infusion | Type, frequency and severity of adverse events as assessed by CTCAE V6.0. Each disease-specific cohort will be analyzed separately. |
| Occurrence of dose-limiting toxicities (DLTs) | 28 days post-CART-45 infusion | Unacceptable toxicity as defined by the protocol. DLTs will be evaluated separately by each disease-specific cohort. |
| Identification of the maximum tolerated dose (MTD) | 28 days post-CART-45 infusion | Selected based on an isotonic regression model. The MTD will be established separately by disease-specific cohort |
| Identification of a recommended dose for expansion (RDE) | 3 months post-CART-45 infusion | Evaluated by Cohort/dose level using a multi-criteria decision analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of CD45BE-HSPC products that fail to meet the product release criteria | 3 months | Calculated based on the proportion of subjects with CD45BE-HSPC products that fail to meet the product release criteria, out of the number of subjects in whom manufacturing was attempted. |
| Proportion of CART-45 products that fail to meet the product release criteria | 3 months | Calculated based on the proportion of subjects with CART-45 products that fail to meet the product release criteria, out of the number of subjects in whom manufacturing was attempted. |
| Proportion of CD45BE-HSPC products that fail to meet the protocol-defined dose | 3 months | Calculated based on the proportion of subjects with CD45BE-HSPC products that fail to meet the assigned dose, out of the number of subjects in whom manufacturing was attempted. |
| Proportion of CART-45 products that fail to meet the assigned dose. | 3 months | Calculated based on the proportion of subjects with CART-45 products that fail to meet the assigned dose, out of the number of subjects in whom manufacturing was attempted. |
| Evaluate study feasibility | 3 months | Proportion of eligible patients who receive both investigational products as planned; by individual disease-specific cohort and in aggregate. |
| Engraftment of CD45BE-HSPC | 28 days after treatment | Number of subjects with engraftment of CD45BE-HSPC. |
| Overall survival (OS) | Up to 15 years after last CART-45 Cells administration | Duration of time from CD45BE-HSPC infusion (Day 0) to the date of death, for any reason |
| Overall Response/Remission Rate (ORR) | Up to 12 months following CART-45 administration | Proportion of subjects with CR or PR at Month 3 as compared to baseline. |
| Best Overall Response (BOR) | Up to 12 months following CART-45 administration | Proportion of subjects with a best objective disease response of CR or PR recorded between Month 3 and the end of primary follow-up (Month 12); or start of new anticancer therapy, whichever comes first. |
| Duration of Response (DOR) | Up to 12 months following CART-45 administration | Time from the date when the response criteria of CR or PR is first met (at or following Month 3), to the date of confirmed disease progression, death, or other censoring event as described below. |
| Progression-Free Survival (PFS) | Up to 15 years after product administration | The duration of time from the CD45BE-HSPC transplant (Day 0) to the date of confirmed disease progression or death, whichever occurs first. Otherwise, PFS will be censored at the date of the last response assessment, date of new anti-cancer treatment is initiated (including CART-45 retreatment) or the data cut-off date; whichever occurs first. |
Countries
United States
Contacts
CONTACTAbramson Cancer Center Clinical Trials Service
PRINCIPAL_INVESTIGATORNoelle Frey, MD
University of Pennsylvania
Outcome results
None listed