Second and further
Tumor infiltrating lymphocytes enriched for Tumor Antigen Specificity (neoTIL) + Cyclophosphamide + Fludarabine + Low dose irradiation + IL2
To define the feasibility, safety and clinical efficacy of NeoTIL-ACT in combination with low dose irradiation in patients with advanced, recurrent or metastatic solid tumors, as categorized in two molecularly defined cohorts
Patients with advanced (not radically treatable), recurrent or metastatic solid tumors of any histology with the exception of primary central nervous system tumors, who have received, and then progressed or been intolerant to at least one standard therapy regimen in the advanced or metastatic setting if such a therapy exists, and have been considered for all other potentially efficacious therapies prior to enrollment.
Patients who have previously undergone tumor resection or biopsy and for whom pre-Rapid Expansion Protocol (REP) NeoTIL cultures are ongoing or completed.
At least one lesion accessible to biopsy for translational research (TR) at baseline and D30, without putting the patient at unusual risk.
Male or female age ≥ 18 to ≤ 70 years at the time of informed consent. Patients aged >70 will be evaluated by the investigator, and decision will be made according to patient's status, upon agreement with the PI.
Clinical performance status of Eastern Cooperative Oncology Group (ECOG) of 0 to 2.
Life expectancy of greater than 12 weeks.
Radiologically measurable disease (as per Response Evaluation Criteria in Solid Tumours [RECIST] v1.1).
a-Modified RECIST should be used for mesothelioma
b-Prostate Cancer Working Group 3 (PCWG3) criteria should be used for prostate cancer
Adequate serology defined by the following laboratory results:
a-Absolute neutrophil count ≥ 1.0 x 109 cell/L without the support of granulocyte colony stimulating factor (G-CSF).
b-Platelet count ≥ 100 x109 cell/L
c-Hemoglobin ≥ 80 g/L. Subjects may be transfused to reach this cut-off.
a. International normalization ratio (INR) ≤1.5 times the upper limit of normal (x ULN) unless the subject is receiving anticoagulant.
i) Exception: for patients with hepatocellular carcinoma (HCC), the INR may be up to 2.2, as long as the Child-Pugh score is A6 maximum.
b. Partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless the subject is receiving anticoagulant therapy.
a-Serum alanine transaminase (ALT) / aspartate aminotransferase (AST) ≤ to 3 x ULN i) Exception: ALT/AST considered related to liver metastasis ≤ to 5 x ULN ii) Exception: for patients with HCC serum ALT/AST ≤ to 5 x ULN
b-Total bilirubin ≤1.5 x ULN i) Exception: in patients with Gilbert's syndrome who must have a total bilirubin ≤2.5 x ULN ii) Exception: total bilirubin considered related to liver metastasis ≤3 x ULN iii) Exception: for patients with HCC total bilirubin ≤2.3 x ULN, as long as the Child-Pugh score is A6 maximum
c-Creatinine clearance by Cockcroft-Gault formula ≥ 40 ml/min
Adequate cardiovascular function, with documented left ventricular ejection fraction (LVEF) ≥ 45%. This parameter must be documented within 12 weeks before registration
Adequate respiratory function with forced expiratory volume in 1 second (FEV1) ≥ 50% predicted, forced vital capacity (FVC) ≥ than 50% predicted and diffusing capacity for carbon monoxide (DLCO) ≥ than 50% predicted corrected. Patients with lung cancer or mesothelioma and values slightly under these limits (but >30% of predicted) can be enrolled after discussion and approval by the PI. These parameters must be documented within 12 weeks before registration
At the time the patient receives the NMA chemotherapy regimen (D-7):
a-≥14 days or 5 half-lives must have elapsed from any chemotherapeutic cytotoxic drug, whichever is shorter.
b-≥28 days must have elapsed from bevacizumab, aflibercept and other anti-angiogenic antibodies
c-≥28 days or 5 half-lives (whichever is shorter) must have elapsed from a non-cytotoxic drug including but not limited to trastuzumab, pertuzumab, and other molecular targeted therapy (such as tyrosine kinase inhibitors, etc…) i) Note: In case of probable tumor flare upon stopping of the non-cytotoxic drug, the investigator may decide to shorten this delay, upon agreement of the Principal Investigator (PI), in a case-by-case approach.
d-≥21 days must have elapsed from the last antibody therapy that could affect an anti-cancer immune response, including but not limited to anti-Cytotoxic T-lymphocyte-associated protein 4 (CTLA4), anti-Programmed cell death protein 1 (PD-1), anti-Programmed death-ligand 1 (PD-L1), anti-Tumor Necrosis Factor Receptor Superfamily, member 4 (OX-40), or anti-Lymphocyte-activation gene 3 (LAG3) antibody therapy or their combination
e-Exceptions: denosumab and biphosphonates are permitted (and will be administered as standard of care [SOC]).
f-Exceptions: androgen-deprivation therapy (ADT) for prostate cancer and hormonal therapy for breast cancer are permitted (and will be administered as SOC).
Patients' toxicities from previous therapies must have recovered to at least grade 1 according to National Cancer Institute Common Terminology Criteria for Adverse v5.0 (NCI CTCAE v5.0), except for toxicities described below, as long as they do not put at risk the patient's condition and do not require systemic immunosuppressive steroids at immunosuppressive doses, including but not limited to:
Endocrinopathies requiring replacement treatment Note: For other medical conditions, or for any other toxicity with a higher grade but controlled by adequate treatment, prior discussion and agreement with the PI is mandatory.
Note: Patients may have undergone surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less.
For women of childbearing potential (WOCBP: sexually mature women who have not undergone a hysterectomy and/or bilateral oophorectomy, have not been naturally post-menopausal for at least 12 consecutive months or have a serum follicle-stimulating hormone (FSH) < 40 milli-International Unit [mIU]/ml):
Agreement to follow instructions for method(s) of contraception for the couple, from screening until month 6 post start of NMA chemotherapy of the study.
Negative pregnancy test (urine or serum) during screening
For men participating in the trial and their female partners: agreement to follow instructions for method(s) of contraception for the couple from screening until month 6 post start of NMA chemotherapy of the study.