Phase I study to establish the safety and feasibility of both intravenous administration and
local delivery of lentiviral transduced huCART-meso cells in patients with histologically
confirmed unresectable or metastatic pancreatic adenocarcinoma
This is a Phase I study evaluating the safety and feasibility of lentiviral transduced
huCART-meso cells in up to 4 cohorts. Lymphodepleting chemotherapy will not be utilized as
part of the planned dosing strategy.
• Cohort 1 (N=3-6): will receive a single dose of 1-3x107/m2 lentiviral transduced
huCART-meso cells on day 0 via intravenous infusion.
- Enrollment into Cohort 1 will be paused after the 3rd subject is infused to allow for a
formal DLT assessment (performed by the Clinical PI and Medical Director) and DSMB
review. If 1 DLT/3 subjects occurs in Cohort 1, the Sponsor (with guidance from the
DSMB), will determine whether the study will enroll an additional 3 subjects at this
dose level to further establish safety via intravenous infusion, or advance to Cohorts 2
and 3 to explore local delivery of huCART-meso cells at the same dose level. If 0 DLT/3
subjects or 1 DLT/6 subjects occurs at any time, the study may advance to Cohorts 2 and
3.
- If 2 DLTs occur at this dose level at any time, enrollment in Cohort 1 will be stopped
and the dose will be de-escalated by 10-fold to 1-3x106 cells/m2 (Cohort -1).
- The infusions in Cohort 1 will be staggered by at least 28 days to allow for the
assessment of DLTs for cohort progression, expansion, or dose de-escalation.
In the event that 2 DLTs occur among subjects enrolled in Cohort 1, then enrollment in Cohort
1 will be stopped and the dose will be de-escalated by 10-fold to 1-3x106 cells/m2. This
de-escalated cohort will be designated Cohort -1.
• Cohort -1 (N=3-6): will receive a single dose of 1-3x106 cells/m2 lentiviral transduced
huCART-meso cells on day 0. Up to 6 subjects will be infused in Cohort -1 if ≤ 1 DLT occurs.
If 0 DLT/3 subjects or 1 DLT/6 subjects occurs in Cohort 1, the study may advance to Cohorts
2 and 3. Enrollment into Cohort 2 and Cohort 3 may occur in parallel.
- Cohort 2 (N= up to 6): will receive a single dose of 1-3x107/m2 lentiviral transduced
huCART-meso cells on day 0 via intraperitoneal (i.p.) administration. The 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.
o Infusion #1 for the first three subjects in Cohort 2 will be staggered by at least 21
days to allow for the assessment of DLTs. A DLT assessment will be performed after the
2nd subject reaches the Day 21 safety follow-up visit. If no DLTs are identified in the
1st two subjects, subsequent infusions may occur consecutively, however no more than two
new subjects may be infused concurrently.
- Cohort 3 (N= up to 6): will receive a single dose of 1-3x107/m2 lentiviral transduced
huCART-meso cells on day 0 via intrahepatic delivery (Hepatic Arterial Infusion). The
initial intrahepatic 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.
- Infusion #1 for the first three subjects in Cohort 3 will be staggered by at least
21 days to allow for the assessment of DLTs. A DLT assessment will be performed
after the 2nd subject reaches the Day 21 safety follow-up visit. If no DLTs are
identified in the 1st two subjects, subsequent infusions may occur consecutively,
however no more than two new subjects may be infused concurrently.
Adverse events will be collected and evaluated during the protocol specified adverse event
reporting period. Subjects will be continually evaluated for dose-limiting toxicities (DLT).
In the event of 2 DLTs in a specific cohort, additional enrollment and treatment activity
will be paused to allow for further investigation.
- Inclusion Criteria
1. Patients with the following diagnoses:
1. Cohorts 1 and -1: Histologically confirmed unresectable or metastatic
pancreatic adenocarcinoma
2. Cohort 2: Histologically confirmed unresectable or metastatic pancreatic
adenocarcinoma; and either cytologically-proven ascites or known peritoneal
disease on radiologic imaging.
3. Cohort 3: Histologically confirmed unresectable or metastatic pancreatic
adenocarcinoma with liver metastases as confirmed by pathology or
radiographic imaging.
2. INCLUSION CRITERIA HAS BEEN RETIRED
3. Failure of at least one prior standard of care chemotherapy for advanced stage
disease.
4. Subjects must have measurable disease as defined by RECIST 1.1 criteria.
5. Patients ≥ 18 years of age.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
7. Satisfactory organ and bone marrow function as defined by the following:
i. Absolute neutrophil count ≥ 1,000/μl ii. Platelets ≥75,000/μl iii. Hemoglobin
≥ 8 g/dL iv. Bilirubin ≤ 2.0x the institutional normal upper limit v. Creatinine
≤ 1.5x the institutional normal upper limit vi. Albumin ≥ 2 vii. 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.
8. 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.
9. Provides written informed consent.
10. Subjects of reproductive potential must agree to use acceptable birth control
methods
- Exclusion Criteria:
1. EXCLUSION CRITERIA HAS BEEN RETIRED
2. Active invasive cancer other than pancreatic adenocarcinoma. Patients with active
non-invasive cancers (such as non-melanoma skin cancer, superficial cervical and
bladder cancer, or prostate cancer with PSA level < 1.0) are not excluded.
3. HIV infection
4. Active hepatitis B or hepatitis C infection
5. 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 eligibility confirmation by physician-investigator, with
the exception of thyroid replacement.
6. Patients with ongoing or active infection.
7. 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.
8. Patients requiring supplemental oxygen therapy.
9. Prior therapy with lentiviral gene modified cells.
10. History of allergy or hypersensitivity to study product excipients (human serum
albumin, DMSO, and Dextran 40)
11. Any clinically significant pericardial effusion, Class II-IV cardiovascular
disability according to the New York Heart Association Classification (see
Appendix 3) 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.
12. 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.
13. Pregnant or breastfeeding women.
14. EXCLUSION CRITERIA HAS BEEN RETIRED
15. Treatment with a PD-1 or PD-L1 inhibitor, including but not limited to nivolumab,
pembrolizumab, atezolizumab, and/or durvalumab, within 2 months prior to
eligibility confirmation by investigator.
16. Patients with significant lung disease as follows:
1. Patients 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.
2. Patients with radiographic and/or clinical evidence of active radiation
pneumonitis.
3. Patients 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) 17. Cohort 3 Subjects Only:
Patients with a contraindication to IV contrast.
