Phase I study to establish safety and feasibility of both intravenous administration and
local delivery of lentiviral transduced huCART-meso cells with or without lymphodepletion.
This is a Phase I study evaluating the safety and feasibility of lentiviral transduced
huCART-meso cells with and without cyclophosphamide and via different routes of
administration.
- Cohort 1 (N=3-6): will receive a single dose of 1-3x10^7 /m^2 lentiviral transduced
huCART-meso cells on day 0 without any conditioning chemotherapeutic regimen.
- Cohort 2 (N=3-6): will receive a single dose of 1-3x10^7 /m^2 lentiviral transduced
huCART-meso cells on day 0, following a flat dose of 1 gram/m2 of cyclophosphamide
administered 2-4 days prior to huCARTmeso cells (day -4 to day -2).
- Cohort 3 (N=3-6): will receive a single dose of 1-3x10^8 /m^2 lentiviral transduced
huCART-meso cells on day 0 without any conditioning chemotherapeutic regimen. **Cohort 3
permanently closed**
- Cohort 4 subjects (N=3-6) will receive a single dose of 1-3x10^8 /m^2 lentiviral
transduced huCART-meso cells on day 0, following a flat dose of 1 gram/m^2 of
cyclophosphamide administered 2-4 days prior to huCART-meso cells (day -4 to day -2).
**Cohort 4 permanently closed**
- Cohort 5 (N=up to 6): will receive a single dose of 1-3x10^7 /m^2 lentiviral transduced
huCART-meso cells on day 0 by intrapleural infusion (IP) through an indwelling pleural
catheter without any conditioning chemotherapeutic regimen. The safety of this dose
level has been established by Cohorts 1 and 2.
- Cohort 6 (N=up to 6): will receive lentiviral transduced huCART-meso cells at a dose of
1-3x10^7 via IV infusion on Day 0, following a flat dose of 1 gram/m^2 of
cyclophosphamide administered 2-4 days prior to huCART-meso cells (~Day -4 to -2). This
initial infusion may be followed by up to two additional IV infusions of huCART-meso
cells at the same dose level, given between 21-42 days apart, if the subject meets
eligibility to receive additional infusions. Cyclophosphamide will not be repeated prior
to subsequent doses of huCART-meso cells. Enrollment into Cohort 6 will occur in
parallel with Cohort 5.
- Cohort 7 (N = up to 6): will receive a single dose of 1-3x107 huCART-meso cells/m2 via
intraperitoneal (i.p.) administration, following lymphodepleting chemotherapy with
cyclophosphamide 300 mg/m2/day and fludarabine 30 mg/m2/day given over 3 days by
intravenous infusion. Lymphodepleting chemotherapy will be scheduled such that the last
day of chemotherapy is 3 days (+/- 1 day) prior to the 1st infusion of huCART-meso
cells. This initial i.p. infusion may be followed by up to two additional infusions of
huCART-meso cells via intravenous (IV) administration at the same dose level, given
between 21-42 days apart. The subject must meet eligibility to receive additional
infusions . Lymphodepleting chemotherapy will not be repeated prior to additional
infusions of huCART-meso cells.
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. The maximum tolerated dose has
been established as 1-3x10^7/m^2 lentiviral transduced huCART-meso cells.
Adverse events will be collected and evaluated during the protocol specified adverse event
reporting period
Inclusion Criteria
1. Histologically confirmed cancer (one of the following):
1. Cohorts 1-4 and Cohort 6 participants:
**Note: Cohorts 3 and 4 permanently closed**
**Note: As of 1-Feb-2021 lung adenocarcinoma patients are no longer being
enrolled in this trial**
- 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)
2. Cohort 5 participants: **Note: As of 1-Feb-2021 lung adenocarcinoma patients are
no longer being enrolled in this trial**
- 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
3. Cohort 7 patients:
- Persistent or recurrent serous epithelial ovarian cancer or primary
peritoneal carcinoma or fallopian tube carcinoma with evidence of ascites
- Malignant peritoneal mesothelioma (histologically confirmed epithelial) with
evidence of ascites **Note: Ascites does not need to be confirmed malignant
by cytology.
2. CRITERIA HAS BEEN RETIRED
3. Failure of at least one prior standard of care chemotherapy for advanced stage
disease. ALLOWANCE FOR PRIOR PD-1 or PDL-1 THERAPIES REMOVED.
4. Subjects must have measureable disease as defined by RECIST 1.1 criteria or modified
RECIST criteria (mesothelioma only).
5. Subjects with asymptomatic CNS metastases that have been treated (and are off steroids
for the treatment of CNS disease) are allowed. They must meet the following at the
time of enrollment:
1. No concurrent treatment for the CNS disease
2. No progression of CNS metastasis on MRI at screening scans
3. No evidence of leptomeningeal disease or cord compression
6. Subjects ≥ 18 years of age.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. Satisfactory organ and bone marrow function as defined by the following:
- Absolute neutrophil count ≥ 1,000/μl
- Platelets ≥75,000/μl
- Hemoglobin ≥ 8 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 viii.
- Cardiac ejection fraction of ≥40% as measured by resting echocardiogram, with no
clinically significant pericardial effusion.
9. 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.
10. Provide written informed consent.
11. Subjects of reproductive potential must agree to use acceptable birth control methods.
Exclusion Criteria
1. Sarcomatoid mesothelioma histology which is known in the literature to not express
mesothelin; biphasic mesothelioma is also excluded.
2. Known leptomeningeal carcinomatosis or spinal cord compression. Screening for this is
not required unless suspicious symptoms.
3. Subjects with symptomatic CNS metastases are excluded.
4. EXCLUSION CRITERIA HAS BEEN RETIRED
5. Active invasive cancer other than the one of the three cancers in this study. Subjects
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.
6. HIV infection
7. Active hepatitis B or hepatitis C infection
8. 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 four (4) weeks prior
to eligibility confirmation by physician-investigator, with the exception of thyroid
replacement.
9. Patients with ongoing or active infection.
10. Planned concurrent treatment with systemic high dose corticosteroids. Subjects 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.
11. Patients requiring supplemental oxygen therapy.
12. Prior therapy with lentiviral gene modified cells.
13. History of allergy or hypersensitivity to study product excipients (human serum
albumin, DMSO, and Dextran 40)
14. Any clinically significant pericardial effusion, Class II-IV cardiovascular disability
according to the New York Heard Association Classification or other cardiovascular
condition that would preclude assessment of mesothelin induced pericarditis, or which
may worsen as a result of expected toxicities in this study. This determination will
be made by a cardiologist if cardiac issues are suspected.
15. Any clinically significant pleural or peritoneal effusion that cannot be drained with
standard approaches. An indwelling drainage device placed prior to eligibility
confirmation by physician / investigator is acceptable.
16. Pregnant or breastfeeding women.
17. EXCLUSION HAS BEEN RETIRED
18. Treatment with a PD-1 or PD-L1 inhibitor, including but not limited to nivolumab,
pembrolizumab, atezolizumab, and/or durvalumab, within two (2) months prior to
eligibility confirmation by investigator.
19. Subjects with significant lung disease as follows:
- Subjects with radiographic evidence of greater than lobar lymphangitic pulmonary
involvement, greater than lobar bronchial wall thickening suggestive of
peribronchial lymphatic disease extension, and/or evidence of extensive bilateral
parenchymal metastatic burden.
- Subjects with radiographic and/or clinical evidence of active radiation
pneumonitis.
- Subjects with radiographic evidence of underlying interstitial lung disease,
including evidence of unresolved drug toxicity from any agent (e.g. chemotherapy,
targeted agents, amiodarone, nitrofurantoin, etc.)
**No exceptions to eligibility will be granted.**
