Condition or disease | Intervention/treatment | Phase |
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Gastric Cancer Colorectal Cancer Pancreatic Cancer Sarcoma Mesothelioma Neuroendocrine Tumors Squamous Cell Cancer Merkel Cell Carcinoma Mismatch Repair Deficiency Microsatellite Instability | Biological: Tumor Infiltrating Lymphocytes (TIL) Drug: Fludarabine + Cyclophosphamide combination | Phase 2 |
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.
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 10 participants |
Allocation: | N/A |
Intervention Model: | Single Group Assignment |
Intervention Model Description: | 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). |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
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 |
Actual Study Start Date : | December 3, 2019 |
Estimated Primary Completion Date : | June 1, 2029 |
Estimated Study Completion Date : | June 1, 2030 |
Arm | Intervention/treatment |
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Experimental: 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.
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Biological: Tumor Infiltrating Lymphocytes (TIL)
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.
Drug: Fludarabine + Cyclophosphamide combination Preparative lymphocyte depleting (immunosuppressive) combination regimen consisting of fludarabine and cyclophosphamide administered prior to TIL infusion.
Other Name: Fludara; Cytoxan
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Ages Eligible for Study: | 18 Years to 75 Years (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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:
Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.
Hematology
Chemistry
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:
Documented FEV1 less than or equal to 60% predicted tested in patients with:
Patients who are receiving any other investigational agents.
Contact: Samantha Devine, PA-C | 412-623-5960 | perkinssj@upmc.edu | |
Contact: Catherine (Grace) Davis, BSN | 4126233077 | davisc20@umc.edu |
United States, Pennsylvania | |
UPMC Hillman Cancer Center | Recruiting |
Pittsburgh, Pennsylvania, United States, 15232 | |
Contact: Samantha Devine, PA-C 412-623-5960 perkinssj@upmc.edu | |
Contact: Catherine (Grace) L Davis, BSN 412-623-3077 davisc20@upmc.edu | |
Principal Investigator: Udai S Kammula, MD |
Principal Investigator: | Udai S Kammula, MD | UPMC Hillman Cancer Center |
Tracking Information | |||||||||
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First Submitted Date ICMJE | April 26, 2019 | ||||||||
First Posted Date ICMJE | May 2, 2019 | ||||||||
Last Update Posted Date | March 30, 2021 | ||||||||
Actual Study Start Date ICMJE | December 3, 2019 | ||||||||
Estimated Primary Completion Date | June 1, 2029 (Final data collection date for primary outcome measure) | ||||||||
Current Primary Outcome Measures ICMJE |
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.
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Original Primary Outcome Measures ICMJE | Same as current | ||||||||
Change History | |||||||||
Current Secondary Outcome Measures ICMJE |
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Original Secondary Outcome Measures ICMJE | Same as current | ||||||||
Current Other Pre-specified Outcome Measures | Not Provided | ||||||||
Original Other Pre-specified Outcome Measures | Not Provided | ||||||||
Descriptive Information | |||||||||
Brief Title ICMJE | Adoptive Transfer of Tumor Infiltrating Lymphocytes for Advanced Solid Cancers | ||||||||
Official Title ICMJE | A Phase 2 Study to Evaluate the Efficacy and Safety of Adoptive Transfer of Autologous Tumor Infiltrating Lymphocytes in Patients With Advanced Solid Cancers | ||||||||
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. |
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Study Type ICMJE | Interventional | ||||||||
Study Phase ICMJE | Phase 2 | ||||||||
Study Design ICMJE | Allocation: N/A Intervention Model: Single Group Assignment Intervention Model Description: 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). Masking: None (Open Label)Primary Purpose: Treatment |
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Condition ICMJE |
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Intervention ICMJE |
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Study Arms ICMJE | Experimental: 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.
Interventions:
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Publications * | Not Provided | ||||||||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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Recruitment Information | |||||||||
Recruitment Status ICMJE | Recruiting | ||||||||
Estimated Enrollment ICMJE |
10 | ||||||||
Original Estimated Enrollment ICMJE |
240 | ||||||||
Estimated Study Completion Date ICMJE | June 1, 2030 | ||||||||
Estimated Primary Completion Date | June 1, 2029 (Final data collection date for primary outcome measure) | ||||||||
Eligibility Criteria ICMJE |
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:
Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus. Hematology
Chemistry
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:
Documented FEV1 less than or equal to 60% predicted tested in patients with:
Patients who are receiving any other investigational agents. |
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Sex/Gender ICMJE |
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Ages ICMJE | 18 Years to 75 Years (Adult, Older Adult) | ||||||||
Accepts Healthy Volunteers ICMJE | No | ||||||||
Contacts ICMJE |
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Listed Location Countries ICMJE | United States | ||||||||
Removed Location Countries | |||||||||
Administrative Information | |||||||||
NCT Number ICMJE | NCT03935893 | ||||||||
Other Study ID Numbers ICMJE | 19-004 | ||||||||
Has Data Monitoring Committee | Yes | ||||||||
U.S. FDA-regulated Product |
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IPD Sharing Statement ICMJE |
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Responsible Party | Udai Kammula, University of Pittsburgh | ||||||||
Study Sponsor ICMJE | Udai Kammula | ||||||||
Collaborators ICMJE | Not Provided | ||||||||
Investigators ICMJE |
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PRS Account | University of Pittsburgh | ||||||||
Verification Date | March 2021 | ||||||||
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |