Phase I study to establish safety and feasibility of intravenous or intrapleural administered lentiviral transduced huCART-meso cells with or without lymphodepletion. Intravenous administration of huCART-meso cells is planned with or without cyclophosphamide as lymphodepleting chemotherapy.
|First Received Date||February 9, 2017|
|Last Changed Date||May 8, 2017|
|Start Date||March 1, 2017|
|Anticipated Primary Completion Date||March 2021|
|Primary Outcome Measures||
Number of participants with treatment-related adverse events as assessed by CTCAE v4.03 [Time Frame: 2 years]
|Secondary Outcome Measures||
Clinical anti-tumor effect by standard criteria (RECIST) [Time Frame: Day 28, Month 3 and 6]
Clinical anti-tumor effect by standard criteria [modified RECIST for mesothelioma] [Time Frame: Day 28, Month 3 and 6]
Progression-free survival [Time Frame: Year 2]
Progression overall survival [Time Frame: Year 2]
|Study Arms / Comparison Groups||5 / 0|
This is a Phase I study evaluating the safety and feasibility of lentiviral transduced huCART-meso cells in 5 cohorts with and without cyclophosphamide in a 3+3 dose escalation design.
Cohort 1 subjects (N=3-6) will receive a single dose of 1-3x107 /m2 lentiviral transduced huCART-meso cells on day 0 without any conditioning chemotherapeutic regimen.
Cohort 2 subjects (N=3-6) will receive a single dose of 1-3x107 /m2 lentiviral transduced huCART-meso cells on day 0, following a flat dose of 1 grams/m2 of cyclophosphamide administered 2-4 days prior to huCART-meso cells (day - 4 to day -2).
Cohort 3 subjects (N=3-6) will receive a single dose of 1-3x108 /m2 lentiviral transduced huCART-meso cells on day 0 without any conditioning chemotherapeutic regimen.
Cohort 4 subjects (N=3-6) will receive a single dose of 1-3x108 /m2 lentiviral transduced huCART-meso cells on day 0, following a flat dose of 1 gram/m2 of cyclophosphamide administered 2-4 days prior to huCART-meso cells (day -4 to day -2).
Cohort 5 subjects (N=up to 6) will receive a single dose of 1-3x107 /m2 lentiviral transduced huCART-meso cells on day 0 by intrapleural infusion (IP) through an indwelling pleural catheter without any conditioning chemotherapeutic regimen. Subjects in this cohort will be enrolled after safety is demonstrated at this dose level by completion of Cohorts 1 and 2.
Subjects in Cohort 5 may be enrolled in parallel to Cohorts 3 and 4.
The Maximum Tolerated Dose (MTD) is defined as the dose at which 0-1 DLT occurs in 6 evaluable subjects tested within the dose range of this study. In order to gather additional data for the MTD dose level, the respective cohorts (both with and without lymphodepletion) may be expanded to treat up to 6 evaluable subjects.
Adverse events will be collected and evaluated during the protocol specified adverse event reporting period.
|Ages||18 Years - N/A|
|Accepts Healthy Volunteers||No|
Janos L Tanyi, MD, PhD
Histologically confirmed cancer (one of the following):
- Cohorts 1-4 patients:
- Metastatic or recurrent lung adenocarcinoma.
- Persistent or recurrent serous epithelial ovarian cancer or primary peritoneal carcinoma or fallopian tube carcinoma
- Malignant pleural and peritoneal mesothelioma (histologically confirmed epithelial)
- Cohort 5 patients:
- Metastatic or recurrent lung adenocarcinoma with documented pleural effusion
- Persistent or recurrent serous epithelial ovarian cancer or primary peritoneal carcinoma or fallopian tube carcinoma with documented pleural effusion
- Malignant pleural and peritoneal mesothelioma (histologically confirmed epithelial) with documented pleural effusion
- Confirmation of tumor mesothelin expression (≥50% of tumor cells)
- Failure of at least one prior standard of care chemotherapy for advanced stage disease. Prior therapies against PD-1 or PDL-1 are permissible if > 4 weeks from enrollment.
- Subjects must have measureable disease as defined by RECIST 1.1 criteria or modified RECIST criteria.
- Patients with asymptomatic CNS metastases that have been treated and are off steroids are allowed. They must meet the following at the time of enrollment:
- No concurrent treatment for the CNS disease
- No progression of CNS metastasis on MRI at screening scans
- No evidence of leptomeningeal disease or cord compression
- Patients > 18 years of age.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Satisfactory organ and bone marrow function as defined by the following:
- Absolute neutrophil count > 1,000/μl
- Platelets >75,000/μl
- Hemoglobin > 9 g/dL
- Bilirubin < 2.0x the institutional normal upper limit unless secondary to bile duct obstruction by tumor
- Creatinine < 1.5x the institutional normal upper limit
- Albumin ≥2
- Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 5x the institutional normal upper limit
- Cardiac ejection fraction of >40% as measured by resting echocardiogram, with no clinically significant pericardial effusion.
- Blood coagulation parameters: PT such that international normalized ratio (INR) is ≤ 1.5 and a PTT < 1.2 time the upper limit of normal unless the patient is therapeutically anti-coagulated for history of cancer-related thrombosis and has stable coagulation parameters.
- Provides written informed consent.
- Subjects of reproductive potential must agree to use acceptable birth control methods
- Sarcomatoid mesothelioma histology which is known in the literature to not express mesothelin; biphasic mesothelioma is also excluded.
- Known leptomeningeal carcinomatosis or spinal cord compression. Screening for this is not required unless suspicious symptoms.
- Patients with symptomatic CNS metastases are excluded.
- Participation in a therapeutic investigational study within 4 weeks prior to enrollment, or anticipated treatment with another investigational product while on study. This refers to non-commercially approved investigational drugs different than those used in this protocol.
- Active invasive cancer other than the one of the three cancers in this study. Patients with active non-invasive cancers (such as non-melanoma skin cancer, superficial cervical and bladder and prostate cancer with PSA level < 1.0) are not excluded.
- HIV infection
- Active hepatitis B or hepatitis C infection
- Active autoimmune disease (including but not limited to: systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, etc.) requiring immunosuppressive therapy within 4 weeks prior to enrollment visit, with the exception of thyroid replacement.
- Patients with ongoing or active infection.
- Planned concurrent treatment with systemic high dose corticosteroids. Patients may be on a stable low dose of steroids (<10mg equivalent of prednisone) for chronic respiratory conditions or adrenal insufficiency. Corticosteroids treatment as anti-emetic prophylaxis on the day of cyclophosphamide administration is allowed per institutional guidance.
- Patients requiring supplemental oxygen therapy.
- Prior therapy with lentiviral gene modified cells.
- History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40)
- Any clinically significant pericardial effusion, Class II-IV cardiovascular disability according to the New York Heard Association Classification (see Appendix 2) or other cardiovascular condition that would preclude assessment of mesothelin induced pericarditis or that may worsen as a result of toxicities expected for this study. This determination will be made by a cardiologist if cardiac issues are suspected.
- Any clinically significant pleural or peritoneal effusion that cannot be drained with standard approaches. An indwelling drainage device placed prior to enrollment is acceptable.
- Pregnant or breastfeeding women.
|Sponsor||University of Pennsylvania|
|Verification Date||May 2017|