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Cyclophosphamide

Fludarabine

Fludarabine phosphate

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Alkylating Agents

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.

TIL are to be infused intravenously through a central vein catheter over 20-30 minutes followed by Aldesleukin, 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.

Tumor Infiltrating Lymphocytes (TIL)

Preparative lymphocyte depleting (immunosuppressive) combination regimen consisting of fludarabine and cyclophosphamide administered prior to TIL infusion.

Fludarabine + Cyclophosphamide combination

Josh Tobin

Allyson Welsch

Josh Tobin, RN

Allyson L Welsch, RN

Udai S Kammula, MD

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).

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.

This study will follow the Bayesian basket design proposed by Simon et al (2016). Treatment will be considered active in a specific histology cohort if the response rate is over 20% (phi = 0.2) and not active if the response rate is less than 5% (plo = 0.05).

Adoptive Transfer of Tumor Infiltrating Lymphocytes for Advanced Solid Cancers

A Phase 2 Study to Evaluate the Efficacy and Safety of Adoptive Transfer of Autologous Tumor Infiltrating Lymphocytes in Patients With Advanced Solid Cancers

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.

Proportion of patients with complete response per Response Evaluation Criteria in Solid Tumors (RECIST v1.1): Number of patients with Complete Response (CR) / total number of patients (# with CR + # with PR + # with SD + # with PD). CR: disappearance of all target lesions. Any pathological lymph nodes (target or non-target) with reduction in short axis to \<10 mm. 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 (this 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.

Time between the initial response to treatment per Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) and subsequent disease progression among patients achieving Complete Response (CR) or Partial Response (PR). Per RECIST v1.1, Complete Response (CR): disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Number of patients with Complete Response (CR) + Number of patients with Partial Response (PR) + Number of patients with Stable Disease (SD) / 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 (target or non-target) with reduction in short axis to \<10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD):Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease (PD):≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.

The length of time after TIL infusion treatment that a patient lives with disease that does not progress per RECIST v1.1. Per RECIST, Progressive Disease (PD): ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.

The length of time from the start of treatment that patients are still alive.

Udai Kammula

Director, Solid Tumor Cell Therapy Program

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