A Phase 1-2 Dose Escalation Study Evaluating Safety and Feasibility of BPX-501 T Cells after Partially Mismatched, Related, T Cell-Depleted HSCT

Summary

This is a Phase1/2 dose escalation study evaluating the safety and feasibility of BPX-501 infused after partially mismatched, related (haploidentical), T cell-depleted HSCT. The purpose of this clinical trial is to determine whether BPX-501 infusion can facilitate engraftment, enhance immune reconstitution and potentially improve the graft versus leukemia (GVL) effect, with the potential for reducing the severity and duration of severe acute graft versus host disease (GvHD). The trial will evaluate the treatment of GvHD by the infusion of dimerizer drug (aP1903) in those subjects who present with severe GvHD (Grades iii and iV) as well as those subjects with Grade i and ii who progress on corticosteroid therapy or do not respond within 3 days.

The initial proposed dose of 2x10e5/kg has been shown to be safe in haploidentical stem cell transplant with non-transduced T cells in the absence of GvHD prophylaxis (1) and the highest proposed dose (5X10e6/kg) represents half the dose shown to be safe and capable of inducing immune reconstitution as a dose limiting incidence (DLi) postxhaplotransplantation. The hypothesis is that 5X10e6/kg will have a higher probability of containing precursor cells reactive to known tumor-antigen-derived peptides. a continual reassessment method based on a logistic dose-response curve with cohorts of size 2 will be empllyed to determine the maximal tolerated dose. Cohorts of size 2 will be accrued beginning at dose level 1 and the dose-response curve is estimated after toxicity.

Two patients may be treated at a given dose level, however, no further patients may be treated at that dose level or at the next dose level, until the 2nd patient is at least 40-days post-transplant.

Dose Level 1: 2 x 10e5 BPX 501 T cells/Kg

Dose Level 2: 5 x 10e5 BPX 501 T cells/Kg

Dose Level 3: 1 x 10e6 BPX 501 T cells/Kg

Dose Level 4: 5 x 10e6 BPX 501 T cells/Kg

Participant Eligibility

1. Signed informed Consent
2. Males or females
3. Age >= 18 years and <= 65 years
4. Deemed eligible for allogeneic stem cell transplantation
5. Lack of suitable conventional donor (i.e. 7/8 or 8/8 related or 7/8 or 8/8 unrelated donor) or presence of rapidly progressive disease not permitting time to identify an unrelated donor
6. HLA typing will be performed at high resolution (allele level) for the HLA-A, -B, Cw, and DRBl, and loci.
a. A minimum genotypic identical match of 4/8 is required.
b. The donor and recipient must be identical, as determined by high resolution typing, at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, and HLADRB1.
7. Subjects with adequate physical function as measured by:
a. Cardiac: Left ventricular ejection fraction at rest must be >=45%.
b. Hepatic: Bilirubin <= 2.5 mg/dL ALT, AST, and Alkaline Phosphatase < 5 x ULN.
c. Renal: Serum creatinine within normal range for age, or creatinine clearance or GFR >= 40 mL/min/1.73m2.
d. Pulmonary: FEV 1, FVC, DLCO (diffusion capacity) >= 50% predicted (corrected for hemoglobin); or 02 saturation >= 92% on room air.
8. Clinical Diagnosis of one of the following:
a. Acute Leukemia (includes T lymphoblastic lymphoma) in 2nd or subsequent CR
b. Acute Lymphoblastic Leukemia in high risk CR1 (including features such as those listed in i-iii)
i. Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), MLL rearrangements
ii. Subjects over 30 years of age
iii. Time to Complete Remission was greater than 4 weeks
c. Acute Myelogenous Leukemia high risk (including features such as those listed in I-iv)
i. Greater than 1 cycle of induction therapy require to achieve remission
ii. Preceding myelodysplastic syndrome (MDS)
iii. Presence of Flt3 abnormalities
iv. FAB M6 or M7leukemia or
v. Adverse cytogenetics for overall survival such as those associated with MDS
vi. Complex karyotype (>3 abnormalities)
vii. Any of the following: inv(3) or t(3;3), t(6;9), 5(6;11), +8 [alone or with other abnormalities except for t(8;21), t(9;11), inv(16) or t(16;16)], t(l1;19)(q23;p13.1)
d. High risk Myelodysplastic Syndrome
e. Non-Hodkin[Single Quote]s Lymphoma in relapse after autologous transplantation
f. Non-Hodgkin[Single Quote]s Lymphoma with insufficient autologous hematopoietic stem cells to undergo autologous transplantation.
9. Subjects must have received cytotoxic chemotherapy within 3 months of consent date (measured from the start date of chemotherapy).
10. Performance status: Karnofsky/Lansky score >= 60%.

Donor Inclusion Criteria:
Eligible donors include biological parents, siblings, or children, or half-siblings, etc. Matching will be determined by class I and class II DNA typing.
1. Donor age must be > 18 and < 70 years.
2. The donor should be sufficiently healthy not to be at increased risk from the mobilization procedure.
3. Should more than one
* equally
* MHC compatible donor be identified, other selection criteria will include age and size of donor, CMV status and sex. The physician treating the subject will make the final decision.
4. Donors must meet the selection criteria as defined by the Foundation for the Accreditation of Cell Therapy (FACT) and will be screened per the FDA and American Association of Blood Banks (AABB) guidelines.
5. The donor must have been informed of the investigational nature of the BPX 501 process and have signed an informed consent form that they will undergo a second pheresis procedure.
6. Donor must have adequate peripheral venous catheter access for leukapheresis or must agree to placement of a central catheter.