Clinical Trials /

Adoptive Transfer of Tumor Infiltrating Lymphocytes for Advanced Solid Cancers

NCT03935893

Description:

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).

Related Conditions:
  • Colorectal Carcinoma
  • Esophagogastric Carcinoma
  • Gastric Carcinoma
  • Malignant Solid Tumor
  • Merkel Cell Carcinoma
  • Mesothelioma
  • Neuroendocrine Carcinoma
  • Pancreatic Carcinoma
  • Sarcoma
  • Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Adoptive Transfer of Tumor Infiltrating Lymphocytes for Advanced Solid Cancers
  • Official Title: A Phase 2 Study to Evaluate the Efficacy and Safety of Adoptive Transfer of Autologous Tumor Infiltrating Lymphocytes in Patients With Advanced Solid Cancers

Clinical Trial IDs

  • ORG STUDY ID: 19-004
  • NCT ID: NCT03935893

Conditions

  • Gastric Cancer
  • Colorectal Cancer
  • Pancreatic Cancer
  • Sarcoma
  • Mesothelioma
  • Neuroendocrine Tumors
  • Squamous Cell Cancer
  • Merkel Cell Carcinoma
  • Mismatch Repair Deficiency
  • Microsatellite Instability

Interventions

DrugSynonymsArms
Tumor Infiltrating Lymphocytes (TIL)Tumor Infiltrating Lymphocytes (TIL)
Fludarabine + Cyclophosphamide combinationFludara; CytoxanTumor Infiltrating Lymphocytes (TIL)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Tumor Infiltrating Lymphocytes (TIL)ExperimentalPatients 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.
  • Tumor Infiltrating Lymphocytes (TIL)
  • Fludarabine + Cyclophosphamide combination

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.

        Serology:

          -  Seronegative for HIV antibody. (The experimental treatment being evaluated in this
             protocol depends on an intact immune system. Patients who are HIV seropositive can
             have decreased immune-competence and thus be less responsive to the experimental
             treatment and more susceptible to its toxicities.)

          -  Seronegative for hepatitis B antigen

          -  Seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then
             patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.

        Women of child-bearing potential must have a negative pregnancy test because of the
        potentially dangerous effects of the treatment on the fetus.

        Hematology

          -  Absolute neutrophil count greater than 1000/mm3 without the support of filgrastim

          -  WBC ≥ 3000/mm3

          -  Platelet count ≥ 100,000/mm3

          -  Hemoglobin > 8.0 g/dl

        Chemistry

          -  Serum ALT/AST ≤ to 3.5 times the upper limit of normal Serum creatinine ≤ to 1.6 mg/dl

          -  Total bilirubin ≤ to 2.0 mg/dl, except in patients with Gilbert's Syndrome who must
             have a total bilirubin less than 3.0 mg/dl.

        More than four weeks must have elapsed since any prior systemic therapy at the time the
        patient receives the preparative regimen, and patients' toxicities must have recovered to a
        clinically manageable level (except for toxicities such as alopecia or vitiligo). (Note:
        Patients may have undergone minor surgical procedures within the past 3 weeks, as long as
        all toxicities have recovered to grade 1 or less)

        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.

        History of active coronary or ischemic symptoms.

        Documented LVEF of less than or equal to 45%; note: testing is required in patients with:

          -  Age > 65 years' old

          -  Clinically significant atrial and or ventricular arrhythmias including but not limited
             to: atrial fibrillation, ventricular tachycardia, second- or third-degree heart block
             or have a history of ischemic heart disease, chest pain.

        Documented FEV1 less than or equal to 60% predicted tested in patients with:

          -  A prolonged history of cigarette smoking (20 pk/year of smoking within the past 2
             years).

          -  Symptoms of respiratory dysfunction

        Patients who are receiving any other investigational agents.
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate (ORR)
Time Frame:24 months
Safety Issue:
Description: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 Outcome Measures

Measure:Complete Response Rate (CRR)
Time Frame:24 months
Safety Issue:
Description: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.
Measure:Duration of response (DOR)
Time Frame:24 months
Safety Issue:
Description: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.
Measure:Disease control rate (DCR)
Time Frame:24 months
Safety Issue:
Description: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.
Measure:Progression-free survival (PFS)
Time Frame:24 months
Safety Issue:
Description: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.
Measure:Overall survival (OS)
Time Frame:24 months
Safety Issue:
Description:The length of time from the start of treatment that patients are still alive.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Udai Kammula

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