IRB Study Number 20-209
Status Recruiting
Phase Phase 2
Institute Taussig Cancer Institute
Description
Primary Objective
To evaluate the efficacy of JCAR017 in subjects with r/r follicular lymphoma and marginal zone lymphoma.
Secondary Objective(s)
To evaluate other measures of efficacy
To evaluate the safety of JCAR017
To characterize the pharmacokinetic (PK) profile of JCAR017
To evaluate the Health-Related-Quality of Life (HRQoL) using preselected primary domains of interest in the EORTC QLQ-C30 (global health/QoL, physical functioning, fatigue, pain) and FACT-LymS (lymphoma specific symptoms)
Inclusion Criteria
- Subject has FL (Grade 1, 2, or 3a) or MZL histologically confirmed within 6 months of screening, as assessed by local pathology. Availability of adequate archival tumor biopsy tissue from the last relapse, with corresponding pathology report for retrospective central pathology confirmation of diagnosis is required. If archival sample is before the last relapse or there is no tissue or insufficient tissue available, a new tumor biopsy is required. Tissue from fine needle aspirate is not permitted.
- Subject must have relapsed or refractory disease, as assessed by the investigator.
a. Relapsed lymphoma is defined as relapse after an initial response of CR or PR to the prior therapy
b. Refractory lymphoma is defined as a best response of SD or PD after prior therapy
- Subject must have measurable disease as follows:
a. For FL subjects (Cohorts 1, 2, and 3), PET-positive disease with at least one PETpositive lesion and at least one measurable nodal or extranodal lesion according to the ‘Celgene interpretation of the Lugano Classification’ (refer to Appendix F) in two perpendicular dimensions. Nodal lesions greater than 1.5 cm in the long axis regardless of the short axis and extranodal lesions > 1.0 cm in the long and short axis on cross section imaging by CT are considered measurable.
b. MZL subjects (Cohort 4) with PET non-avid disease should have at least one measurable nodal lesion greater than 2.0 cm in the long axis (PET-positive disease is not required for MZL) according to the ‘Celgene interpretation of the Lugano Classification’ (refer to Appendix F). In cases where the subject has no measurable nodal lesions greater than 2.0 cm in the long axis at baseline, then the subject must have at least one measurable extranodal lesion.
- Subject must have received the following, depending on cohort assignment:
a. Cohort 1 (4L+ r/r FL): received at least 3 prior lines of systemic therapy. At least one of these lines must be a combination which included an anti-CD20 antibody (eg, rituximab, obinutuzumab) and an alkylating agent. Prior HSCT is permitted as a prior line of therapy. A group of 4L+ double-refractory subjects will be enrolled in this cohort. In addition to these requirements, double-refractory subjects must also meet one of the following criteria:
i. Are refractory to a systemic line of therapy which included an anti-CD20 antibody and an alkylating agent
ii. Have relapsed within 6 months after completion of a prior line of systemic therapy, which included an anti-CD20 antibody and an alkylating agent
iii. Have relapsed during anti-CD20 antibody maintenance following 2 or more lines of therapy or within 6 months after maintenance completion
b. Cohort 2 (3L r/r FL): received 2 prior lines of systemic therapy. At least one of these lines must be a combination which included an anti-CD20 antibody (eg, rituximab, obinutuzumab) and an alkylating agent. In addition to this requirement, subjects must meet one of the following high-risk criteria:
i. Have relapsed or refractory disease within 12 months of completion of a prior line of therapy and have received prior combination therapies. Monotherapy with a PI3Ki is an accepted line of therapy
ii. Relapsed after HSCT
iii. Meet the definition of double refractory. Double refractory subjects must meet one of the following criteria:
- Are refractory to a systemic line of therapy which included an anti-CD20 antibody and an alkylating agent
- Have relapsed within 6 months after completion of a prior line of systemic therapy, which included an anti-CD20 antibody and an alkylating agent
- Have relapsed during anti-CD20 antibody maintenance following 2 or more lines of therapy or within 6 months after maintenance completion
c. Cohort 3 (2L r/r FL): received 1 prior line of combination systemic therapy, which included an anti-CD20 antibody (eg, rituximab, obinutuzumab) and an alkylating agent. A group of POD24 subjects, defined as having progressive disease within 24 months of diagnosis and have received treatment within 6 months of the original FL diagnosis, will be enrolled to this cohort. The 2L subjects that do not meet this POD24 definition must instead meet one of the modified GELF criteria (NCCN, 2019), as outlined in inclusion criterion 5.
d. Cohort 4 (3L+ MZL): received at least 2 prior systemic therapies, including at least one line of combination systemic therapy, therapy with an anti-CD20 antibody (eg, rituximab, obinutuzumab) and an alkylating agent, or relapsed after HSCT. Splenectomy for Splenic MZL (SMZL) is considered as a line of therapy. Antibiotics for extranodal MZL (ENMZL) are not considered as a prior line of therapy.
- Cohort 3 (2L r/r FL) subjects must meets at least one criterion in the modified GELF criteria (NCCN, 2019) if they do not meet criteria of POD24 (having progression of disease within 24 months from diagnosis and must have received treatment for FL within 6 months of diagnosis):
a. symptoms attributable to FL (not limited to B symptoms)
b. threatened end-organ function; OR cytopenia secondary to lymphoma; OR bulky disease (single mass > 7 cm or 3 or more masses > 3 cm)
c. splenomegaly
d. steady progression over at least 6 months
- Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).
- Subjects who have received previous CD19-targeted therapy must have CD19-positive lymphoma confirmed on a biopsy since completing the prior CD19-targeted therapy
- Subject has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (refer to Appendix B)
- Subject has adequate organ function, defined as:
a. Adequate bone marrow function to receive lymphodepleting chemotherapy, as assessed by the investigator
b. Serum creatinine ≤ 1.5 × age-adjusted upper limit of normal (ULN) OR calculated creatinine clearance (Cockcroft and Gault; refer to Appendix C) > 30 mL/min
c. Alanine aminotransferase (ALT) ≤ 5 x ULN and total bilirubin < 2.0 mg/dL (or < 3.0 mg/dL for subjects with Gilbert's syndrome or lymphomatous infiltration of the liver)
d. Adequate pulmonary function, defined as ≤ Grade 1 dyspnea according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 and oxygen saturation (SaO2) ≥ 92% on room air
e. Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥ 40% as assessed by echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) performed within 4 weeks of determination of eligibility
- Subject has adequate vascular access for leukapheresis procedure.
- Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
- Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
- Subjects must agree to not donate blood, organs, sperm or semen, and egg cells for usage in other individuals for at least 1 year following lymphodepleting chemotherapy. There are insufficient exposure data to provide any recommendation concerning the duration of refraining from tissue donation following treatment with JCAR017. Therefore, subjects treated with JCAR017 should not donate blood, organs, tissues and cells for transplantation.
- Females of childbearing potential (FCBP) subjects must:
a. Have 2 negative pregnancy tests as verified by the Investigator (one negative serum beta-human chorionic gonadotropin [ß-hCG] pregnancy test result at screening, and within 7 days prior to the first dose of lymphodepleting chemotherapy). This applies even if the subject practices true abstinence from heterosexual contact.
b. Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, effective contraception without interruption. Contraception methods must include 1 highly effective method from screening until at least 12 months after the lymphodepleting chemotherapy.
c. Agree to abstain from breastfeeding during study participation and for at least 12 months following lymphodepleting chemotherapy.
d. There are insufficient exposure data to provide any recommendation concerning the duration of contraception and the abstaining from breastfeeding following treatment with JCAR017. Any decision regarding contraception and breastfeeding after JCAR017 infusion should be discussed with the treating physician. Note: Highly effective methods are defined as those that result in a low failure rate (ie, less than 1% per year) when used consistently and correctly. The following are examples of highly effective and additional effective methods of contraception:
Intrauterine device (IUD)
Hormonal (birth control pill, injections, implants)
Tubal ligation
Partner’s vasectomy
- Male subjects must:
a. Practice true abstinence2 (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential for 12 months after lymphodepleting chemotherapy even if he has undergone a successful vasectomy.
b. There are insufficient exposure data to provide any recommendation concerning the duration of contraception following treatment with JCAR017. Any decision regarding contraception after JCAR017 infusion should be discussed with the treating physician.
Exclusion Criteria
Evidence of composite DLBCL and FL, or of transformed FL. Subjects with World Health Organization (WHO) sub-classification of duodenal-type FL
Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study based on investigator’s judgement.
Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study based on investigator’s judgement.
Any condition that confounds the ability to interpret data from the study based on investigator’s judgement.
Central nervous system (CNS)-only involvement by malignancy (note: subjects with secondary CNS involvement are allowed on study).
History of another primary malignancy that has not been in remission for at least 2 years, with the exception of the following non-invasive malignancies:
Basal cell carcinoma of the skin
Squamous cell carcinoma of the skin
Carcinoma in situ of the cervix
Carcinoma in situ of the breast
Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) or prostate cancer that is curative
Other completely resected stage 1 solid tumor with low risk for recurrence
Previous treatment with alemtuzumab within 6 months of leukapheresis, or treatment with fludarabine or cladribine within 3 months of leukapheresis.
Prior CAR T-cell or other genetically-modified T-cell therapy.
History of or active human immunodeficiency virus (HIV).
Active hepatitis B or active hepatitis C. Subjects with a negative PCR assay for viral load for hepatitis B or C are permitted. Subjects positive for hepatitis B surface antigen and/or anti-hepatitis B core antibody with negative viral load are eligible and should be considered for prophylactic antiviral therapy.
Uncontrolled systemic fungal, bacterial, viral or other infection (including tuberculosis) despite appropriate antibiotics or other treatment.
Active autoimmune disease requiring immunosuppressive therapy.
Presence of acute or chronic graft-versus-host disease (GVHD).
History of any of the following cardiovascular conditions within the past 6 months prior to signing the ICF: Class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease.
History or presence of clinically relevant central nervous system (CNS) pathology not related to disease under study such as epilepsy, seizure, aphasia, stroke, cerebral edema, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, or psychosis.
Subject is a pregnant or nursing (lactating) woman.
Subject has an intolerance to dimethyl sulfoxide (DMSO) and/or dextran
Progressive vascular tumor invasion, thrombosis, or embolism
Venous thrombosis or embolism not managed on a stable regimen of anticoagulation
Subject has received or undergone the following:
a. Therapeutic doses of corticosteroids (defined as >20 mg/day prednisone or equivalent) within 7 days prior to unstimulated leukapheresis. Physiologic replacement, topical, and inhaled steroids are permitted.
b. Cytotoxic chemotherapeutic agents that are not considered lymphotoxic (see below) and intrathecal (IT) chemotherapy must be stopped ≥ 7 days prior to unstimulated leukapheresis.
c. Lymphotoxic chemotherapeutic agents (eg, cyclophosphamide > 300 mg/m2, ifosfamide, bendamustine) 2 weeks prior to unstimulated leukapheresis.
d. Experimental agents within 4 weeks prior to signing the ICF unless no response or PD is documented on the experimental therapy and at least 3 half-lives have elapsed prior to unstimulated leukapheresis.
e. Ibrutinib, lenalidomide and PI3Ki within 3 half-lives prior to unstimulated leukapheresis
f. Immunosuppressive therapies within 4 weeks prior to leukapheresis and JCAR017 infusion (eg, calcineurin inhibitors, methotrexate or other chemotherapeutics, mycophenolate, rapamycin, thalidomide, immunosuppressive antibodies such as anti-tumor necrosis factor [TNF], anti-IL6, or anti-IL6R)
g. Donor lymphocyte infusion (DLI) within 6 weeks prior to JCAR017 infusion
h. Radiation within 6 weeks of leukapheresis. Subject must have progressive disease in irradiated lesions or have additional non-irradiated, PET-positive lesions to be eligible. Radiation to a single lesion, if additional non-irradiated PET-positive lesions are present, is allowed up to 2 weeks prior to unstimulated leukapheresis.
i. Systemic immunostimulatory agents (including but not limited to interferon and IL-2) within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to JCAR017 infusion.
