A Phase 2 Study to Evaluate the Efficacy and Safety of Adoptive Transfer of Autologous Tumor Infiltrating Lymphocytes in Patients With Advanced Solid Cancers
Overview
- Phase
- Phase 2
- Intervention
- Tumor Infiltrating Lymphocytes (TIL)
- Conditions
- Gastric Cancer
- Sponsor
- Udai Kammula
- Enrollment
- 240
- Locations
- 1
- Primary Endpoint
- Objective Response Rate (ORR)
- Status
- Recruiting
- Last Updated
- 9 months ago
Overview
Brief Summary
This is a Phase 2 study to evaluate the efficacy of a non-myeloablative lymphodepleting preparative regimen followed by infusion of autologous TIL and high-dose aldesleukin in patients with locally advanced, recurrent, or metastatic cancer associated with one of the following cancer types: 1.) gastric/esophagogastric, 2.) colorectal, 3.) pancreatic, 4.) sarcoma, 5.) mesothelioma, 6.) neuroendocrine, 7.) squamous cell cancer, 8.) Merkle cell, 9.) mismatch repair deficient and/or microsatellite unstable cancers, and 10.) patients who have exhausted conventional systemic therapy options by using the objective response rate (ORR).
Detailed Description
This Phase 2 study will be conducted in conjunction with companion protocol (Cell Harvest and Preparation to Support Adoptive Cell Therapy Clinical Protocols and Pre-Clinical Studies) as described below: Cell Preparation: Patients with evaluable locally advanced, recurrent, or metastatic gastric/esophagogastric, colorectal, pancreatic, sarcoma, mesothelioma, neuroendocrine, cutaneous/anal squamous cell, Merkel cell, cancers refractory to systemic therapy, and those with deficient mismatch repair and/or microsatellite instability cancers who have lesions that can be resected or biopsied with minimum morbidity will undergo resection or biopsy of tumor. TIL will be obtained while enrolled on the companion protocol HCC 17-220 (Cell Harvest and Preparation to Support Adoptive Cell Therapy Clinical Protocols and Pre-Clinical Studies). Separate tumor procurements may be performed under HCC 17-220 protocol to obtain TIL if initial tumor procurements could not successfully generate TIL. The TIL will be grown and expanded for this trial according to standard operating procedures submitted in the IND. The TIL will be assessed for potency by interferon-gamma release. Treatment Phase: Once cells exceed the potency requirement and are projected to exceed the minimum number specified in the COA, the patient will be registered on this study and receive the lymphocyte depleting preparative regimen consisting of fludarabine and cyclophosphamide, followed by infusion of up to 2x10\^11 lymphocytes (minimum of 1x10\^9 cells) and administration of high-dose intravenous aldesleukin. It is anticipated that TIL that meet the COA will not be achievable in approximately 20% of patients who undergo resection. These patients may undergo a second resection to grow TIL, if another suitable lesion exists. Approximately 6 weeks (+/- 2 weeks) after TIL administration, patients will undergo a complete tumor evaluation and evaluation of toxicity and immunologic parameters. Patients will receive one course of treatment. The start date of the course will be the start date of the chemotherapy; the end date will be the day of the first post-treatment evaluation. Patients may undergo a second treatment. Patients will receive no other experimental agents while on this protocol.
Investigators
Udai Kammula
Director, Solid Tumor Cell Therapy Program
University of Pittsburgh
Eligibility Criteria
Inclusion Criteria
- •Measurable locally advanced, recurrent, or metastatic cancer associated with one of the following cancer types: 1.) gastric/esophagogastric, 2.) colorectal, 3.) pancreatic, 4.) sarcoma, 5.) mesothelioma, 6.) neuroendocrine, 7.) squamous cell cancer, 8.) Merkle cell, 9.) mismatch repair deficient and/or microsatellite unstable cancers, and 10.) patients who have exhausted conventional systemic therapy options
- •Patients with locally advanced disease should be unresectable by conventional surgical approaches.
- •Patients with distant metastatic spread must have previously received approved first-line systemic therapies if they are eligible to receive these treatments.
- •Patients must be co-enrolled on the companion protocol HCC 17-220 (Cell Harvest and Preparation to Support Adoptive Cell Therapy Clinical Protocols and Pre-Clinical Studies) and have available TIL cultures for therapy.
- •Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible.
- •Greater than or equal to 18 years of age and less than or equal to age 75
- •Able to understand and sign the Informed Consent Document
- •Clinical performance status of ECOG 0 or 1
- •Life expectancy of greater than three months
- •Patients of both genders who are of child-bearing potential must be willing to practice birth control from the time of enrollment on this study and for up to four months after receiving the treatment.
Exclusion Criteria
- •Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
- •Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
- •Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities).
- •Active systemic infections (e.g.: requiring anti-infective treatment),
- •Clinically significant coagulation disorder
- •Active major medical illnesses deemed clinically significant by the treating physician
- •History of clinically significant major organ autoimmune disease
- •Patients with a history of hypothyroidism are eligible
- •Concurrent systemic steroid therapy.
- •History of severe immediate hypersensitivity reaction to any of the agents used in this study.
Arms & Interventions
Tumor Infiltrating Lymphocytes (TIL)
Patients with locally advanced, recurrent, or metastatic gastric/esophagogastric, colorectal, pancreatic, sarcoma, mesothelioma, neuroendocrine, cutaneous/anal squamous cell, Merkel cell, cancers refractory to systemic therapy, and those with deficient mismatch repair and/or microsatellite instability cancers will receive the lymphocyte depleting preparative regimen consisting of fludarabine and cyclophosphamide, followed by infusion of up to 2x10\^11 lymphocytes infused through a central vein catheter and administered at a dose of 600,000 IU/kg (based on total body weight) as an intravenous bolus over a 15-minute period approximately every 8 hours beginning within 24 hours of cell infusion and continuing for up to a maximum of 6 doses.
Intervention: Tumor Infiltrating Lymphocytes (TIL)
Tumor Infiltrating Lymphocytes (TIL)
Patients with locally advanced, recurrent, or metastatic gastric/esophagogastric, colorectal, pancreatic, sarcoma, mesothelioma, neuroendocrine, cutaneous/anal squamous cell, Merkel cell, cancers refractory to systemic therapy, and those with deficient mismatch repair and/or microsatellite instability cancers will receive the lymphocyte depleting preparative regimen consisting of fludarabine and cyclophosphamide, followed by infusion of up to 2x10\^11 lymphocytes infused through a central vein catheter and administered at a dose of 600,000 IU/kg (based on total body weight) as an intravenous bolus over a 15-minute period approximately every 8 hours beginning within 24 hours of cell infusion and continuing for up to a maximum of 6 doses.
Intervention: Fludarabine + Cyclophosphamide combination
Outcomes
Primary Outcomes
Objective Response Rate (ORR)
Time Frame: 24 months
Number of patients with Complete Response (CR) + Number of patients with Partial Response (PR) / total number of patients (# with CR + # with PR + # with SD + # with PD), per RECIST v1.1: CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: ≥ 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. Progressive Disease (PD): ≥ 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance ≥1 new lesion(s) is considered progression.
Secondary Outcomes
- Disease control rate (DCR)(24 months)
- Overall survival (OS)(24 months)
- Complete Response Rate (CRR)(24 months)
- Duration of response (DOR)(24 months)
- Progression-free survival (PFS)(24 months)