A Phase I, Multicenter Study of CD4- Directed Chimeric Antigen Receptor Engineered T-cells (CD4CAR) in Patients with Relapsed or Refractory CD4+ Hematological Malignancies

Description

This study is designed as a single arm open label Phase I, 3x3, multicenter study of CD4-directed chimeric antigen receptor engineered T-cells (CD4CAR) in patients with relapsed or refractory T-cell leukemia and lymphoma. Specifically, the study will evaluate the safety and feasibility of CD4CAR T-cells. Funding Source - FDA OOPDThe study will be performed as a dose-escalation protocol. Due to the relatively low incidence and prevalence of cluster of differentiation 4-positive (CD4+) hematological malignancies and the associated aggressive nature of these diseases and the sequel of treatment failure, the investigators expect to recruit 20 subjects at Stony Brook, Indiana University, and other identified sites with an expected dropout rate of 25% primarily due to rapid progression or death and screen and or manufacturing failure. Taking this into account, the investigators expect to treat 15 patients. The study will utilize autologous CD4CAR T-cells that are engineered to express a chim

Trial Eligibility

Inclusion Criteria In order to be eligible to participate in this study, an individual will be enrolled if they meet the following criteria: 1. Patients must voluntarily sign and date informed consent forms that state his or her willingness to comply with all study procedures and availability for the duration of the study. 2. Age 12 years old or older 3. Subjects with any documented CD4+ T cell hematologic malignancies. Male and female subjects with CD4+ T-cell hematologic malignancies with either relapsed or refractory disease (including those patients who have undergone a prior transplant (if allogeneic, subjects are eligible if there are no remaining donor cells) and patients with an inadequate response after 4-6 cycles of standard chemotherapy) are eligible. Response criteria for each disease subset will be evaluated based on Standard of Care Guidelines. 4. Creatinine clearance of \> 60 ml/min (or otherwise non clinically-significant, per study investigator) 5. ALT/AST \< 3 x ULN 6. Bilirubin \< 2 x ULN 7. Pulmonary Function Test (PFT) with a DLCO of ≥ 60%. 8. Adequate echocardiogram with EF of ≥50% 9. Adequate venous access for apheresis and no other contraindications for leukapheresis Exclusion Criteria 1. Pregnant or lactating women. The safety of this therapy on unborn children is not known. Female study participants of reproductive potential (see definition below) must have a negative serum or urine pregnancy test prior to initiation of conditioning chemotherapy, per research sites' clinical policy. 2. Uncontrolled active infection necessitating systemic therapy. 3. Active hepatitis B or hepatitis C infection. Active hepatitis C is defined as the hepatitis C antibody is positive while quantitative HCV RNA results exceed the lower detection limit. Note the following subjects will be eligible: * Subjects with a history of hepatitis B but have received antiviral therapy and have non-detectable viral DNA for 6 months prior to enrollment are eligible * Subjects seropositive for HBS antibodies due to hepatitis B virus vaccine with no signs or active infection (Negative HBs Ag, HBc and HBe Ags) are eligible * Subjects who had hepatitis C but have received antiviral therapy and show no detectable hepatitis C virus (HCV) viral RNA for 6 months are eligible * If hepatitis C antibody test is positive, then patients must be tested for the presence of antigen by reverse transcription-polymerase chain reaction (RT-PCR) and be hepatitis C virus ribonucleic acid (HCV RNA) negative. 4. Concurrent use of systemic glucocorticoids in greater than replacement doses (unless as a part of a standard of care salvage therapy or conditioning protocol), or steroid dependency defined in rheumatological and pulmonary diseases as uninterrupted corticosteroid intake for more than a year at a dosage of 0.3 mg/kg/day or greater, and where the underlying disease worsens on temporary stoppage of steroid therapy, with symptoms of steroids withdrawal (eg, lethargy, headache, weakness, pseudorheumatism, emotional disturbances, etc) precipitated by the temporary stoppage. Subjects who receive daily corticosteroids in replacement doses can be included in the study. The replacement doses are defined as following: 1. Hydrocortisone 25mg/day or less 2. Prednisone 10mg/day or less 3. Dexamethasone 4mg or less Note: Recent or current use of inhaled glucocorticoids is not exclusionary, as this route pertains extremely minimal systemic penetration. 5. Any previous treatment with any gene therapy products. 6. Any uncontrolled active medical disorder that would preclude participation as outlined in the opinion of the treating investigator and/or study chair 7. HIV infection. 8. Patients declining to consent for treatment 9. Subjects who have received or will receive live vaccines within 30 days before the first experimental cell treatment. Inactivated seasonal flu vaccination is allowed. 10. Subjects with active autoimmune diseases who need systematic treatments (such as disease modifying agents, corticosteroids and immunosuppressive drugs) in the last 2 years. Note: Replacement therapy (thyroxine, insulin or physiological corticosteroid replacement therapy (up to10 mg of oral daily prednisone or equivalent in hydrocortisone and dexamethasone) to treat adrenal dysfunction or pituitary dysfunction) is not considered as systematic therapy. Subjects who need inhalation corticosteroid therapy can be included in this trial. Subjects with vitiligo or in long-term remission of pediatric asthma or allergic diseases can be included in this trial. 11. Subjects with a history of mental disorders or drug abuse that may influence treatment compliance. 12. Active malignancy not related to a T-cell malignancy that has required therapy in the last 3 years or is not in complete remission. Exceptions to this criterion include successfully treated non-metastatic basal cell or squamous cell skin carcinoma, or prostate cancer that does not require therapy. Other similar malignant conditions may be discussed with and permitted by the Principal Investigator. Eligibility for Conditioning Chemotherapy 1. Specific organ function criteria for cardiac, renal, and liver function must be similar to initial inclusion values. 2. Review of co-morbidities to confirm no major changes in health status (examples of major changes include heart attack, stroke, and any major trauma) 3. Planned infusion dose was successfully manufactured and met release criteria. Screen Failure Subjects who fail to cytoreduce with conditioning chemotherapy with persistence of high disease burden will be considered a screenfail according to the guidelines below: 1. CD4+ Leukemias ( Liquid Blood and marrow disease): 1. Subjects at study entry with bone marrow malignant replacement estimated at \> 80% of total cellularity and accompanied by significant peripheral pancytopenia, ANC \<500, platelet count \< 50,000 will need to have roughly 50% or greater reduction on the marrow malignant component to be considered eligible after cytoreductive chemotherapy and for CD4CAR infusion. This will be determined and approved by PI, treating physician and study team as applicable. 2. Subjects at study entry with bone marrow malignant replacement estimated at less than 80% of total cellularity will need to have stable disease or disease that is less than 80% in the marrow as determined and approved by the PI, treating physician and study team as applicable. Note: Bone marrow sampling is not an accurate reflection of disease burden because only a small biopsy is obtained to represent a patchy disease distributed all over the marrow. Hence these numbers and in the absence of severe cytopenias that are attributed to documented marrow replacement with malignant cells should not be formidable as is and borderline cases should be discussed and approved by the PI and the study team as applicable before moving forward. 2. Solid Mass Forming CD4+ lymphomas: (in lymph nodes or extra nodal sites) 1. Stage IV disease: Subjects with Stage IV disease that is deemed bulky by the standard definition of the presence of at least one site with a mass that is \> 7.5 cm in largest diameter who have a 50% estimated reduction of total disease burden by imagining as read by radiology after conditioning chemotherapy are eligible to continue on study. In borderline cases, where they don't meet this criteria but are thought to have bulky disease by the treating investigator, clinical judgment will be required to determine eligibility of subjects who experience for example mixed responses; improved sites and progressed sites. In these cases, the PI, treating physician, and study team as applicable should agree and document that total disease burden has been reduced by about 50% when taking all sites involved into account as there is no objective method to make this estimated reduction if some areas improve and others don't, or even new sites arise. 2. Stage I-III disease: Subjects with stage I-III ( No extra nodal disease) who continue to have stable disease or better after conditioning chemotherapy are eligible to continue on study. 3. Skin Disease a. There will be no response or non-response criteria assessed that will be specific to skin disease since disease burden is almost never expected to be high without skin barrier violation and often involve infections that would make subjects ineligible at the time Eligibility for CD4CAR infusion: Inclusion 1. Afebrile and not receiving antipyretics, and no evidence of active infection 2. Specific organ function criteria for cardiac, renal, and liver function must be similar to initial inclusion values. The following tests do not need repeated: an echocardiogram if within 6 weeks of initial assessment, and the PFT if completed within 6 months from Day 0. 3. Negative pregnancy testing (if applicable) 4. If previous history of corticosteroid chemotherapy, subject must be off all but adrenal replacement doses 3 days before the CD4CAR infusion.

Study Info

Interventions

Locations Recruiting

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