A FIH, Phase I/IIa, Trial Assessing Feasibility of Administrations of TIL-based Immunotherapy in Patients With Metastatic CRC and PC

Inclusion criteria

• Patient (female or male) has signed informed consent according to ICH/GCP and national/local regulations prior to any trial-specific procedure.
• Patient is 18 years or older at the time of signing the informed consent form.
• Patient must live in an area where a hospital for care can be reached within a maximum of 50 km.
• Patient has histological or cytological confirmation of:
• colorectal cancer, which is stage IV (any T / any N / M1), not amenable to curative surgery, OR
• prostate cancer, which is stage III locally advanced, not amenable to curative surgery (T3-4 / N0 / M0 or any T / N1 / M0), or stage IV metastatic (any T / any N / M1)
• Patient has received all lines of therapy that
• are considered SOC for the patient's indication according to applicable European/national professional society medical guidelines and local medical practice at time of enrollment
• are available via the national health insurance system and the patient is considered eligible for but led to insufficient response or were medically not justified or refused by the patient.
• Patient has confirmed disease progression by radiologic imaging from the previous line of therapy.
• Patient has sufficient amount of previously not irradiated tumor tissue in adequate quality for TIL harvest and expansion, i.e., either:
• Primary or metastatic lesion has been selected for surgery (e.g., to reduce tumor burden, pain relief), Or
• Patient has consented to surgery for the purpose of tissue harvesting for TIL expansion and is considered suitable to undergo surgery for this purpose. Note: Patients with a non-justifiable anesthesiologic and/or surgical risk, as determined by the investigator, should be excluded
• Patient has a least one measurable or assessable lesion according to RECIST 1.1 remaining after tumor resection for CC-38 manufacturing has been performed.
• Patient has ECOG performance status of 0 or 1.
• Patient has a minimum life expectancy of 6 months in the opinion of the investigator from the time of consent date.
• Patient has adequate bone marrow, hepatic and renal function in the opinion of the investigator:
• Hemoglobin ≥ 9.0 g/dL,
• Absolute neutrophil count (ANC) ≥ 1.0 x 109 /L,
• Platelets ≥ 80 x 109 /L,
• Calculated creatinine clearance ≥ 50 mL/min (Cockcroft-Gault formula),
• Serum bilirubin ≤ 1.5 x ULN (or ≤ 2.5 x ULN in the presence of documented Gilbert's Syndrome \[unconjugated hyperbilirubinemia\] or liver metastases),
• AST/ ALT and alkaline phosphatase ≤ 2.5 x ULN (or ≤5 times ULN in the presence of bone and/or liver metastases), ALP ≤ 2.5 x ULN,
• International normalized ration (INR) ≤ 1.5 or prothrombin time (PT) ≤ ULN + 4 seconds.
• Female patients must be post-menopausal or use contraceptive methods with a failure rate of \< 1% 6 months after last administration of CC-38, whatever is later, to prevent pregnancy. Male patients with fertile female partners must be willing to use condoms with spermicide, and the fertile partner must use contraceptive methods with a failure rate of \< 1% for the same time period. Male patients must also refrain from donating sperm for the same time period.
• Successful tumor tissue sampling by surgery, including presence of TILs in the tumor tissue in the pathological evaluation.
• Successful TIL expansion defined as obtaining the final CC-38 drug product

Exclusion criteria

• Patient as any of the following condition:
• Congestive heart failure NYHA class III or IV,
• myocardial infarction or coronary artery bypass graft within 6 months prior to enrollment,
• history of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration,
• history of severe non-ischemic cardiomyopathy,
• uncontrolled blood pressure as defined as systolic \> 160 mmHg, diastolic \> 100 mmHg within 3 months prior to enrollment,
• left ventricular ejection fraction (LVEF) \< 45% as assessed by echocardiogram or multiple-gated acquisition (MUGA) scan,
• any other clinically significant cardiovascular events such as unstable angina, angioplasty, stroke, or transient ischemic attack (TIA) within less than 6 months before enrolment,
• other conditions that the treating physicians believe may endanger the health of the patients by their participation in this clinical trial.
• Patient has any of the following pulmonary conditions:
• Forced expiratory volume in 1 second (FEV1)\<60%,
• Active obstructive chronic pulmonary disease,
• oxygen dependence as defined by a blood oxygen saturation that can only be maintained above 92% by oxygen inhalation (finger oxygen detection method),
• other pulmonary conditions that increase the anesthesiologic risk.
• Patient has a current or history of central nervous system (CNS) metastatic disease, leptomeningeal disease, or cord compression,
• Patient has ulcers in the upper GI tract, untreated or incompletely treated esophageal varices with high risk of bleeding in the investigator's discretion.
• Patient requiring therapeutic anticoagulant therapy or having other increased risk of bleeding events.
• Patient has any severe acute or chronic medical condition that places the patient at increased risk or interferes with the interpretation of trial results in the opinion of the investigator.
• Patient has any form of primary immunodeficiency (such as severe combined immunodeficiency disease \[SCID\] and acquired immune deficiency syndrome \[AIDS\]).
• Patient has active or history of autoimmune or inflammatory disorders. Note: Patients may be eligible if they have been assessed in discussion between Principal Investigator, Chief Medical Officer and Senior Medical Consultant as not posing an increased risk to the patient.
• Patient receiving immunosuppressive concomitant medications (≥ 10 mg prednisone daily or other equivalent). Steroid medications are allowed if they are used as substitution or are administrated topically or as inhalations.
• Patient has received an organ and/or allogenic stem cell transplant.
• Patient has known acute or chronic infection with hepatitis B or C virus.
• Patient has known HIV infection (seropositive for HIV antibody).
• Patient has known infection with syphilis.
• Patient has known bone-marrow aplasia.
• Patient has known (chronical) urinary tract infection and/ or acute urothelial toxicity from previous cytotoxic chemotherapy or radiation therapy or urinary flow obstructions.
• Female patient, who is pregnant or breast-feeding, or plan to become pregnant within 12 months after cyclophosphamide or 6 months after last dose of CC-38, whichever last. Women of childbearing potential must have a negative pregnancy test at screening and before every CC-38 application.
• Patient is unable to comply with trial procedures, restrictions, or requirements.
• Patient received last previous systemic cancer treatment (including anti-testosterone treatment) within less than 4 weeks prior enrollment.
• Note: Bridging therapies (specified in trial design \[section 2 - subsection: screening and TIL harvesting\]) after TIL harvesting and before CC-38 administration are permitted after consultation between Principal Investigator, Chief Medical Officer and Senior Medical Consultant.
• Patient received last palliative radiotherapy within less than 4 weeks prior enrollment - where RECIST 1.1 evaluable metastases are within the radiation area.
• Patient received minor surgery (as judged by the investigator, i.e., port implantation) within less than 3 weeks prior enrollment.
• Patient with AEs from previous treatment that have not recovered to CTCAE v5.0 ≤ grade 1 Note: Clinically insignificant grade 2 AEs that may be allowable if discussed between and approved by Principal Investigator, Chief Medical Officer and Senior Medical Consultant.
• Patient participates in any other interventional clinical trial or has been treated with any investigational research products within 4 weeks prior to the initiation of screening.
• Patient has bone metastasis only.
• Patient has known hypersensitivity to any component of the trial regimen.
• For colorectal cancer: Patient has been diagnosed with histologically or cytologically proven BRAF-V600 positive CRC.
• Patient has any further contraindication to the IMP pembrolizumab or any of the auxiliary medicinal products (i.e., IL-2, cyclophosphamide, uromitexan) as per current EU SmPCs to the respective product.