huCART-meso + VCN-01 in Pancreatic and Ovarian Cancer

This is a Phase I study evaluating the safety and feasibility of lentiviral transduced huCARTmeso cells when given in combination with VCN-01.

Dose Finding Phase:

This study was initiated using a 3+3 dose (de)escalation design in order to explore the initial safety of these drugs when given in combination, as well as to establish the recommended expansion dose of VCN-01 in this setting.

Expansion Phase:

The trial was expanded to include two parallel treatment arms further exploring the dosing sequence and schedule of these two investigational products when given in combination.

Inclusion criteria

• Patients with one of the following diagnoses:

• Histologically confirmed unresectable or metastatic pancreatic adenocarcinoma; OR
• Persistent or recurrent serous epithelial ovarian cancer
• Progression or intolerance to at least one prior standard of care chemotherapy for advanced stage disease.
• Subjects must have measurable disease as defined by RECIST 1.1 criteria.
• Patients ≥ 18 years of age.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Adequate organ and bone marrow function defined as:

• Hemoglobin ≥ 9 g/dL
• Platelets ≥ 75,000/µl
• PT/INR and PTT ≤ 1.5 x ULN
• Bilirubin ≤ 2.0 x ULN
• Creatinine ≤ 1.5 x ULN
• ALT/AST ≤ 5 x ULN (subjects with liver metastases) or ALT/AST ≤ 2.5 x ULN (subjects without liver metastases)
• Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen > 92% on room air
• Left Ventricle Ejection Fraction (LVEF) ≥ 40% confirmed by ECHO/MUGA
• Provides written informed consent.
• Subjects of reproductive potential must agree to use acceptable birth control methods, as described in the protocol

Exclusion criteria

• Patients with known CNS metastases
• Active invasive cancer other than the one of the two cancers targeted by 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.
• Active hepatitis B or hepatitis C infection.
• Chronic hepatitis C with a FibroScan score equivalent to fibrosis stage 2 (F2) or greater.
• Patients with known cirrhosis.
• Patients with ongoing or active infection.
• Patients with a known history of Li Fraumeni syndrome or retinoblastoma protein pathway germinal deficiency.
• Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10 mg of prednisone. Patients with autoimmune neurologic diseases (such as MS) will be excluded.
• Planned concurrent treatment with systemic high dose corticosteroids. Patients may be on a stable low dose of steroids (≤ 10mg equivalent of prednisone). Use of inhaled steroids is allowable.
• Patients requiring supplemental oxygen therapy.
• 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 Heart Association Classification 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.
• Pregnant or breastfeeding women.
• RETIRED WITH PROTOCOL VERSION 5.
• Patients with significant lung disease as follows:

• 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.
• Patients with radiographic and/or clinical evidence of active radiation pneumonitis.
• 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.)
• Patients with prior/ongoing treatment that will not accommodate washout requirements for immune checkpoint inhibitors