Clinical Trials /

Adoptive Transfer of Tumor Infiltrating Lymphocytes for Biliary Tract Cancers

NCT03801083

Description:

This is a Phase 2 study to evaluate the efficacy, using objective response rate, of a non-myeloablative lymphodepleting preparative regimen followed by infusion of autologous Tumor Infiltrating Lymphocytes (TIL) and high-dose aldesleukin in patients with locally advanced, recurrent, or metastatic biliary tract cancer. These are low-incidence cancers carry a poor prognosis. Participants will include patients with biliary tract cancers (BTC), including cholangiocarcinoma (both intrahepatic and extrahepatic) and gallbladder cancer, who are and are physically able to tolerate non-myeloablative chemotherapy and high-dose aldesleukin.

Related Conditions:
  • Biliary Tract Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Adoptive Transfer of Tumor Infiltrating Lymphocytes for Biliary Tract Cancers
  • Official Title: A Phase 2 Study to Evaluate the Efficacy and Safety of Adoptive Transfer of Autologous Tumor Infiltrating Lymphocytes in Patients With Locally Advanced, Recurrent, or Metastatic Biliary Tract Cancers

Clinical Trial IDs

  • ORG STUDY ID: 18-126
  • NCT ID: NCT03801083

Conditions

  • Biliary Tract Cancer
  • Cholangiocarcinoma
  • Biliary Tract Neoplasms

Interventions

DrugSynonymsArms
Tumor Infiltrating Lymphocytes (TIL)Tumor Infiltrating Lymphocytes (TIL)

Purpose

This is a Phase 2 study to evaluate the efficacy, using objective response rate, of a non-myeloablative lymphodepleting preparative regimen followed by infusion of autologous Tumor Infiltrating Lymphocytes (TIL) and high-dose aldesleukin in patients with locally advanced, recurrent, or metastatic biliary tract cancer. These are low-incidence cancers carry a poor prognosis. Participants will include patients with biliary tract cancers (BTC), including cholangiocarcinoma (both intrahepatic and extrahepatic) and gallbladder cancer, who are and are physically able to tolerate non-myeloablative chemotherapy and high-dose aldesleukin.

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 biliary tract cancers who
      have lesions that can be resected or biopsied with minimum morbidity will undergo resection
      or biopsy of tumor. Tumor Infiltrating Lymphocytes (TIL) will be obtained while enrolled on
      the companion protocol Cell Harvest and Preparation to Support Adoptive Cell Therapy Clinical
      Protocols and Pre-Clinical Studies. Separate tumor procurement(s) may be performed under the
      companion protocol to obtain TIL if initial tumor procurement(s) 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 2x1011 lymphocytes (minimum of 1x109 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 biliary tract cancers will receive the lymphocyte depleting preparative regimen consisting of fludarabine and cyclophosphamide, followed by infusion of up to 2x10^11 lymphocytes infused intravenously through a central vein catheter and 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)

Eligibility Criteria

        Inclusion Criteria:

          -  Measurable locally advanced, recurrent, or metastatic biliary tract carcinoma
             (including intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer, or
             ampullary carcinoma).

          -  Patients with locally advanced disease should be unresectable by conventional surgical
             approaches.

          -  Patients with distant metastatic spread must be refractory to approved standard
             systemic therapies (such as gemcitabine, cisplatin, or equivalents) 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, and 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), coagulation
             disorders or any other active major medical illnesses.

          -  History of clinically significant major organ autoimmune disease

          -  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:Up to 24 months
Safety Issue:
Description:Proportion of patients with response per Response Evaluation Criteria in Solid Tumors (RECIST v1.1): Complete Response (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. 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 at least 5 mm. The appearance ≥1 new lesion(s) is considered progression.. 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. ORR (proportion of patients) = # with CR + # with PR / # with CR + # with PR + # with SD + # with PD.

Secondary Outcome Measures

Measure:Complete response rate (CRR)
Time Frame:Up to 24 months
Safety Issue:
Description:Proportion of patients with complete response per Response Evaluation Criteria in Solid Tumors (RECIST v1.1): Complete Response (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. 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 at least 5 mm. The appearance ≥1 new lesion(s) is considered progression.. 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. CRR (proportion of patients) = # with CR / # with CR + # with PR + # with SD + # with PD.
Measure:Duration of Response (DOR)
Time Frame:Up to 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. DOR is measured as the time between the initial response to treatment per RECIST and subsequent disease progression.
Measure:Disease control rate (DCR)
Time Frame:Up to 24 months
Safety Issue:
Description:Proportion of patients with response or stable disease per Response Evaluation Criteria in Solid Tumors (RECIST v1.1):Complete Response (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. 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. 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. DCR (proportion of patients) = # with CR + # with PR + # with SD / # with CR + # with PR + # with SD + # with PD.
Measure:Progression-free survival (PFS)
Time Frame:Up to 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:Up to 24 months
Safety Issue:
Description:The length of time from the start of treatment that patients are still alive.
Measure:EORTC Quality of Life Questionnaire-Core 30 (QLQ-C30)
Time Frame:Prior to treatment and after treatment; Up to 24 months
Safety Issue:
Description:The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) v 3.0 is a multi-dimensional assessment of health-related quality of life (HRQoL). EORTC QLQ-C30 includes: five (5) multi-item functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, social functioning); three (3) multi-item symptom scales (fatigue, nausea, vomiting, pain); six (6) symptom single-item scales (dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties); (1) Global Health Status scale; (1) Global HRQoL scale. Each scale is measured from 0 to 100 after a linear transformation. Higher scores for functioning scales and for the Global Health Status or Global HRQoL indicate a higher level of functioning and a better HRQoL respectively, whereas higher scores in symptom scales represent a higher level of symptoms. Assessment of change is assessed across the 15 different domains.
Measure:EuroQol 5 dimensions 5 levels (EQ-5D-5L)
Time Frame:Prior to treatment and after treatment; Up to 24 months
Safety Issue:
Description:The EuroQol 5 dimensions 5 levels (EQ-5D-5L) provides a brief five-dimensional assessment of patient HRQoL on five levels along with a numeric rating of patient perceived overall health. The EQ-5D-5L contains the following content: (5) dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression); (5) levels within each dimension (no problems, slight problems, moderate problems, severe problems, extreme problems); visual analogue scale of overall health status (number from 0 to 100); Each dimension is expressed as a value from 1 to 5 depending on the level selected. The sum of the 5-dimensional values can be combined into a 5-digit number that describes the patient's health state. The visual analogue scale number is a quantitative measure of health outcomes that reflects the patient's own judgement. Higher scores are associated with a greater level of perceived health difficulty.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Udai Kammula

Trial Keywords

  • Biliary Tract Cancer
  • Cholangiocarcinoma

Last Updated

January 29, 2021