The protocol was amended to modify the dose range. Pre-medication language was added to manage the site effects following T cell infusion. The packaging of the cells was re-designed to allow for the split dosing. Safety and adverse events section was updated with the DLT definition.

Number of subjects was revised from 10 to 20; intra-patient dose escalation was modified as an additional safety feature; duration of administration drug is expected to persist at detectable levels in circulation for 2 weeks to 6 weeks was revised to weeks to months; pre-entry Evaluations section has been modified to add the following language: If a prior pheresis product from a CHP-784 collection and consent is used, an aliquot of this product should be used for this purpose, and not a peripheral blood specimen; enrollment and baseline assessment has been clarified that viral serologies will be based on Miller-Keystone Autologous Panel.

Primary endpoints were amended with an addition of the Q-PCR testing for CART-19 vector sequences after each infusion. Study inclusion criteria was added to allow enrollment of the other high-grade NHL. Exclusion criteria was modified to exclude concurrent use of systemic steroids at the time of the cell infusion or cell collection. Treatment regimen and preparation and administration of the study drug was revised with additional guidelines for the split dosing. The tumor response assessments, safety, statistical plan were modified accordingly.

Number of subjects updated from 20 to 34-40; clarified that CAR constructs would be manufactured at CHOP; Clinical data to date was updated with summary of CART19 infusions to date and GVDH risk language was added; Primary study objectives were revised as follows: Determine the safety and feasibility of administration of chimeric antigen receptor T cells transduced with the anti-CD19 lentiviral vector (referred to as “CART-19” cells), in patients who either: a) did not received a prior allogeneic SCT or had 0% residual donor engraftment (“no allo” cohort), or b) had relapsed after prior allogeneic SCT with any degree of residual donor engraftment (“allo” cohort); Study Design was updated with the revised number of patients treated; Also, it was clarified that in the first cohort 28 subjects would be included: 14 evaluable patients in the “no allo” cohort and 14 in the “allo” cohort”; Primary Study Endpoints were added; capillary leak, hypotension, GVDH (in the allo cohort only); Inclusion Criteria 1a was modified as follows: ALL without curative options for therapy, including those not eligible for allogeneic SCT because of age, comorbid disease or other contraindications to TBI-based conditioning (required for ALL SCT), lack of suitable donor or prior SCT. i) Patient could be in any complete response, or ii) Patient could have active disease but responding or stable after most recent therapy; The intent was not to enroll patients with no degree of disease control, or rapidly increasing disease burden between enrollment and cell infusion; Inclusion criteria 2 was modified as follows: Age 1 to 24 years. Patients ages 22-24 could only be enrolled if they were being treated at CHOP. Inclusion criteria 8a (have reverted to recipient hematopoiesis (no evidence of donor cells by STR analysis on 2 occasions separated by at least 1 month) was deleted

Treatment Regimen added the following language: the toxicities that would preclude the next dose of T cells were DLTs of GDHD attributable to the cell infusion, and not toxicities attributable to the prior chemotherapy, such as cytopenias. A DLT prevented the infusion of the next dose, even if fully resolved by that time; CART-19 Infusion # 1 with intra-patient dosing escalation; Day 14 was modified to state that 30% of the dose could be given if no evidence for grade 3 toxicity, or higher, prolonged fever, or T cell expansion as suggested by appearance of large granual lymphocytes on the peripheral smear. Day 28 was modified to state that 60% of the dose could be given if no evidence for grade 3 toxicity, or higher, prolonged fever, or T cell expansion as suggested by appearance of large granual lymphocytes on the peripheral smear. Language to permit subsequent infusions to initiate, consolidate or extend a response was added; Day 28 evaluation; it has been clarified that the day 28 evaluation will occur regardless of whether the second dose was given or not. The day 28 evaluation was repeated 28 days after the third (60%) infusion if the patient received the infusion; Quarterly evaluations for up 2 years post infusion: RCL test (i.e. HIV-gag or VSV-G) performed at 3 and 6 months post CART-19 infusion was removed.

Day 28 evaluation section was clarified that the day 28 evaluation may be repeated 28 days after the third (60%) infusion if the patient received this infusion; Tumor Response Assessments: Day 56 evaluation was removed; Accrual was deleted, as accrual had stated that accrual was anticipated to take approximately 12 months; Independent Data and Safety Monitoring Board: the number of individuals on the board was revised from four to six.

Inclusion Criteria 1a was added as follows: ALL without curative options for therapy, including those not eligible for allogenic SCT because patient declined SCT (in CR3) as a therapeutic option after documented discussion about the role of SCT with a BMT physician not part of the study team; Treatment Regimen ; Day 14 regimen was replaced with Day 1 (30% of total dose). Day 28 was replaced with day 14 (60% to total dose); Packaging was revised due to the treatment regimen changes.

Study title update as follows: CHP 959 – A Phase I/IIA Study of Redirected Autologous T Cells Engineered to Contain Anti-CD19 Attached to TCRzeta and 4-1BB Signaling Domains in Patients with Chemotherapy Resistant Or Refractory CD19+ Leukemia and Lymphoma

CART-19 Infusion #1 with intra-patient dose escalation; blood sample for determination of baseline CART-19 levels obtained 20 minutes after post infusion was removed; Stopping rules related to CNS3 cohort Stopping was updated with the toxicity attribution rules; Management of toxicity section was updated with the following language: Events of Cytokine Release Syndrome (CRS) was reported and graded based on the below criteria for all patients that experienced CRS moving forward. Events prior to this amendment was reviewed and retrospectively graded and reported by the primary investigator per source documentation. The Penn Grading Scale for Cytokine Release Syndrome (PGS-CRS) was used for grading of CRS. The start date of CRS is a retrospective assessment of the date of onset of persistent fevers and/or myalgia consistent with CRS and not explained by other events (i.e. sepsis). The stop date of CRS was defined as the date when the patient had been afebrile for 24 hours and off vasopressors for 24 hours; High Dose Vasopressor Use was updated as per the new CRS criteria.

Study design was updated to reflect secondary follow-up post end of study to allow for survival information and relapse free survival (as applicable); Patient withdrawal section was updated to remove patient non-compliance as a reason for premature study discontinuation. Given the nature of this investigational therapy, subjects were followed on study as long as possible for safety reasons; Data collection and follow-up section was updated to further clarify study follow-up requirements; Prior and concomitant section was updated to align with the Schedule of Study Procedures; anti-neoplastic therapies clarified requirements related to the collection of antineoplastic therapy pre- and post-CART19 infusion; Secondary Follow-up Phase was added to allow for the collection of secondary follow-up data (survival and PFS as applicable) under this protocol.

Study design updated to reflect the target number of subjects to be enrolled and the maximum number of subjects to be infused under this protocol across all cohorts; Exclusion criteria #5 and #6 retired and replaced with Exclusion Criteria #13, which now aligns with the criteria in other CAR T-cell protocols; Treatment regimen Updated to reflect the maximum number of subjects to be infused under this protocol across all cohorts; Exclusion criterion #5 regarding Grade 2-4 acute or chronic GVHD was retired with protocol version 14. Consequently, the definition for Grade 2-4 GVHD provided in this section is not needed; All GVHD requiring systemic therapy was exclusionary; Topical GVHD therapy was permitted.