study of cd19-directed allogeneic memory t-cell therapy for relapsed/refractory cd19+ leukemia

Conditions: Acute Lymphoblastic Leukemia, in Relapse; Acute Lymphoblastic Leukemia, Refractory; Pediatric ALL

Summary: this is a phase i clinical study evaluating the safety and maximum tolerated dose of a novel car t-cell product: allogeneic memory (cd45ra- negative) t-cells expressing a cd19-specific car 41bbz (cd19-car.cd45ra- negative t-cells) for the treatment of patients ≤ 21 years old with relapsed and/ or refractory cd19-positive leukemia. primary objective to determine the maximum tolerated dose (mtd) and characterize the safety profile and dose-limiting toxicities (dlts) of treatment with allogeneic cd19-car.cd45ra-negative t-cells in pediatric, adolescent and young adult patients ≤ 21 years of age, with relapsed and/or refractory cd19-positive leukemia. secondary objectives * to evaluate the anti-leukemic activity of allogeneic cd19-car.cd45ra-negative t-cells. * to determine rates and severity of graft-versus-host-disease (gvhd) after treatment with allogeneic cd19-car.cd45ra-negative t-cells. exploratory objectives * to study the expansion, persistence and phenotype of allogeneic cd19-car.cd45ra-negative t-cells. * to characterize the cytokine profile in the peripheral blood and csf after treatment with allogeneic cd19-car.cd45ra-negative t-cells. * to assess whether allogeneic cd19-car.cd45ra-negative t-cells acquire functional versus exhaustion-associated epigenetic programs. * to determine immune reconstitution post treatment, and the clonal structure and endogenous repertoire of allogeneic cd19-car.cd45ra-negative t-cells and relate inferred specificity to car response profiles. * to characterize incidence and mechanisms of relapse post-therapy with allogeneic cd19-car.cd45ra-negative t-cells.

this is a phase i dose escalation study using a 3+3 study design. two groups of patients will be evaluated in this study: group a - patients have received a prior stem cell transplant from their car t-cell donor; group b - patients have not received a prior stem cell transplant from their car t-cell donor. there will be up to 30 participants per group and a donor/ family member for each patient. .

Eligibility criteria:
inclusion criteria eligibility criteria for donors: apheresis and manufacturing * age ≥ 18 years old * at least single haplotype matched (≥ 3/6) family member * hiv negative * for females of child bearing age: not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment and not lactating with intent to breastfeed * completed the process of donor eligibility determination as outlined in 21 cfr 1271 and agency guidance for cohort a only, identified recipient with relapsed and/or refractory cd19-positive leukemia for cohort b only, iidentified recipient with relapsed and/or refractory cd19-positive leukemia who is not suitable to receive autologous cd19-car t-cell therapy as defined by the following: * relapsed and/or refractory disease despite prior treatment with autologous cd19- car t-cell therapy * history of prior autologous leukapheresis failure * history of prior autologous car t-cell manufacturing failure * unable to undergo autologous leukapheresis in the opinion of the study pi(s): examples may include - patient small size/low weight, inadequate t-cell counts, rapidly progressive leukemia, clinical status not amenable to apheresis eligibility criteria for patients: treatment * age ≤ 21 years old * relapsed and/or refractory cd19-positive leukemia\*: * refractory disease (defined as any of the following): * primary refractory disease despite at least 2 cycles of an intensive chemotherapy regimen designed to induce remission * refractory disease despite salvage therapy * relapsed disease (defined as any of the following): * 2nd or greater relapse * any relapse after allogeneic hematopoietic cell transplantation (hct) * 1st relapse if patient requires an allogeneic hct as part of standard of care relapse therapy, but is found to be ineligible and/or unsuitable for hct cd19-positivity confirmed within 2 months and after receipt of any cd19-directed therapy * patient cohorts: * cohort a: patient has previously received a hct from the selected car t-cell donor * cohort b - patient has not previously received a hct from the selected car t-cell donor. * for cohort b only, not suitable to receive autologous cd19-car t-cell therapy as defined above in criteria: eligibility criteria for donors: apheresis and manufacturing * detectable medullary cd19-positive leukemia * estimated life expectancy of ≥ 8 weeks * karnofsky or lansky performance score ≥ 50 * no cns-3 disease or any level of detectable leukemia in cns with associated neurologic symptoms * if history of allogeneic hct (regardless of donor type), prior to planned car t-cell infusion, must meet the following criteria: * ≥ 3 months from hct * have recovered from prior hct therapy * have no evidence of active gvhd within prior 2 months * have not received a donor lymphocyte infusion (dli) within the 28 days prior to planned car t-cell infusion * adequate cardiac function: left ventricular ejection fraction ≥ 40% or shortening fraction ≥ 25% (function may be supported by pharmacologic therapy) * ekg without evidence of clinically significant arrhythmia * adequate renal function: creatinine clearance or radioisotope gfr 50 ml/min/1.73m2 (gfr 40 ml/min/1.73m2 if \< 2 years of age) * adequate pulmonary function: forced vital capacity (fvc) ≥ 50% of predicted value; or pulse oximetry ≥ 92% on room air if patient is unable to perform pulmonary function testing * total bilirubin ≤ 3 times the upper limit of normal for age, except in subjects with gilbert's syndrome * alanine aminotransferase (alt) or aspartate aminotransferase (ast) ≤ 5 times the upper limit of normal for age * no history of hiv infection * no evidence of severe, uncontrolled bacterial, viral or fungal infection * has recovered from all nci ctae grade iii-iv, non-hematologic acute toxicities from prior therapy * for females of child bearing age: * not pregnant with negative serum or urine pregnancy test ≤ 7 days prior to enrollment and not lactating with intent to breastfeed * if sexually active, agreement to use birth control until 6 months after car t-cell infusion * no history of hypersensitivity reactions to murine protein-containing products * not receiving systemic steroids therapy exceeding the equivalent of 0.5 mg/kg/day of methylprednisolone ≤ 7 days prior to car t-cell infusion * not receiving systemic therapy ≤ 14 days prior to car t-cell infusion, which will interfere with the activity of the car t-cell product in vivo (in the opinion of the study pi(s)) * not receiving intrathecal chemotherapy ≤ 7 days prior to car t-cell infusion exclusion criteria: na