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"Re-Stimulated" Tumor-Infiltrating Lymphocytes And Low-Dose Interleukin-2 Therapy in Patients With Platinum Resistant High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Primary Purpose

Recurrent, Platinum Resistant High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Status
Active
Phase
Phase 1
Locations
Canada
Study Type
Interventional
Intervention
Re-stimulated tumor-infiltrating lymphocytes (TILs)
Interleukin-2
Cyclophosphamide
Sponsored by
University Health Network, Toronto
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Recurrent, Platinum Resistant High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer focused on measuring Measurable, Recurrent, Platinum resistant, Tumor-Infiltrating Lymphocytes, Low-Dose Interleukin-2, Autologous dendritic cells, Anti-CD3 monoclonal antibody, High grade serous ovarian, fallopian tube, or primary peritoneal cancer, Cyclophosphamide

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria (Eligibility for TIL Evaluation):

  1. Platinum resistant high grade serous ovarian, fallopian tube, or primary peritoneal cancer.
  2. Tumor is suitable for harvest (i.e., lesion to be harvested for TIL evaluation has a total volume of ≥1cm3) or patient has previously undergone tumor harvest under other REB approved studies involving clinical evaluation of TILs.
  3. If tumor harvest is required, subject must be a suitable surgical candidate in the opinion of the operating surgeon.
  4. Patient age: ≥ 18 years.
  5. Clinical performance status of ECOG 0 or 1.
  6. Life expectancy > 5 months from the date of consent for TIL evaluation.
  7. Ability to understand and has signed the Pre-Screening Consent Form.
  8. Patients are willing to be tested for transmissible diseases (active Hepatitis B (HBV) or Hepatitis C (HCV), human immunodeficiency virus (HIV), Human T-Cell Lymphotropic Virus (HTLV), Herpes Simplex Virus (HSV), Cytomegalovirus (CMV), Syphilis (with West Nile Virus only tested between May 1st and November 30th)
  9. Confirmation that the Translational Immunotherapy Lab is able to process the specimen
  10. If there is a history of allergy to penicillin, gentamycin, streptomycin, or anti-fungals, the ability to generate TILs should first be confirmed with the cell manufacturing lab (i.e., Translational Immunotherapy Laboratory).

Inclusion Criteria (Eligibility for Treatment):

  1. Prior to the performance of any study-specific procedure, the subject has signed and dated the informed consent form, approved by a Research Ethics Board (REB), after the nature of the study has been explained and the subject has had the opportunity to ask questions.
  2. Recurrent platinum resistant high grade serous ovarian, fallopian tube, or primary peritoneal cancer, with evidence of disease progression from previous line of treatment.
  3. Measurable disease by RECIST 1.1.
  4. Subjects should have no brain metastases. Note if brain metastases are present, these lesions must undergo definitive treatment with surgery and/or radiation at least 30 days prior to the first dose of lymphodepleting chemotherapy. If in the opinion of the PI or his designee the lesion(s) no longer represents active disease, the subject will be considered eligible.
  5. Clinical performance status of ECOG 0 or 1.
  6. Life expectancy > 3 months from the date of consent for TIL treatment.
  7. Laboratory analyses of tumor-infiltrating lymphocytes (TILs) from the subject must demonstrate that the TILs are suitable for use in protocol treatment (performed by the Translational Immunotherapy Laboratory, Princess Margaret Cancer Centre)
  8. More than 30 days has elapsed since any prior systemic therapy at the time of the cell infusion. All subjects' toxicities must have recovered to a CTCAE grade 1 or less; however, patients with residual CTCAE grade 2 neuropathy from previous carboplatin/taxol treatment will not be excluded. Subjects may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to CTCAE grade 1 or less or as specified in the inclusion criteria listed above.
  9. Adequate organ function as defined by the following criteria:

    1. Serum ALT ≤ 2.5 x upper limit of normal (ULN) (for patients with liver metastases, serum ALT ≤ 3 x ULN;
    2. Serum AST ≤ 2.5 x upper limit of normal (ULN) (for patients with liver metastases, serum AST ≤ 3 x ULN;
    3. Total serum bilirubin ≤ 2xULN (patients with Gilbert's Syndrome - direct serum bilirubin ≤ 2 x ULN);
    4. Absolute neutrophil count (ANC) ≥ 1.5x109/L;
    5. Platelets ≥100x109/L;
    6. Hemoglobin ≥ 90 g/L for female;
    7. Alkaline phosphatase ≤ 2 x ULN;
    8. Serum creatinine within normal institutional limits OR serum creatinine clearance ≥ 60 mL/min/1.73m2 for patients with creatinine levels above institutional normal;
    9. Serum lipase≤ 1.5 x ULN;
    10. Serum amylase ≤ 1.5 x ULN
  10. Women of child-bearing potential must have a negative pregnancy test. Acceptable birth control failure rate of less than or equal to 1% when used consistently and correctly such as implants, injectables, combined oral contraceptives, double barrier, some intrauterine devices (IUDs), sexual abstinence or vasectomized partner. Subjects are considered to be not of child bearing potential if they are considered to be post-menopausal or surgically sterilized (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy. Women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, ovarian suppression or any other reversible reason.

Exclusion Criteria:

  1. Subjects with ongoing or prior use systemic steroid therapy within 4 weeks before the TILs infusion will be excluded. Use of topical, intranasal and inhaled corticosteroids, or systemic corticosteroids at physiologic doses are allowed. Oral steroid use as premedication to prevent allergic reactions to radiologic contrast is allowed.
  2. Subjects cannot be HIV positive.
  3. Subjects cannot have active hepatitis B or hepatitis C, syphilis, or Human T-Cell Lymphotropic Virus (HTLV).
  4. The number of prior lines of chemotherapy is not limited. However, if the subject has had ≥3 lines of prior chemotherapy for platinum refractory or platinum resistant disease, documentation of a response to one of these lines is required. Response can be defined by RECIST 1.1 or CA125 as defined by the modified GCIG criteria (See Section 11).
  5. The subject cannot have any active systemic infections, coagulation disorders or other active major medical illnesses of the cardiovascular, respiratory or immune system, uncontrolled psychiatric disorders, or other conditions that may affect compliance with the trial.
  6. The subject must have no active underlying cardiac illnesses defined by positive stress test, LVEF<40% or ongoing life-threatening arrhythmias (i.e., for patients older than 60 years of age or otherwise clinically indicated).
  7. Subjects who have a prolonged history of cigarette smoking or symptoms of respiratory dysfunction will be excluded if they have an abnormal pulmonary function test as evidenced by a FEV1 < 60% predicted.

Sites / Locations

  • Princess Margaret Cancer Centre

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Re-Stimulated Tumor-Infiltrating Lymphocytes and interleukin-2

Arm Description

Cyclophosphamide will be given prior to Re-Stimulated Tumor-Infiltrating Lymphocytes, and interleukin-2.

Outcomes

Primary Outcome Measures

Number occurrences and severity of side effects

Secondary Outcome Measures

Clinical response to treatment
Number of patients with an immunity and no immunity to the study treatment

Full Information

First Posted
June 11, 2013
Last Updated
June 1, 2022
Sponsor
University Health Network, Toronto
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1. Study Identification

Unique Protocol Identification Number
NCT01883297
Brief Title
"Re-Stimulated" Tumor-Infiltrating Lymphocytes And Low-Dose Interleukin-2 Therapy in Patients With Platinum Resistant High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Official Title
A Phase I Study Evaluating the Feasibility and Safety of Infusion of "Re-Stimulated" Autologous Tumor-Infiltrating Lymphocytes (TILs) Followed by Low-Dose Interleukin-2 Therapy in Patients With Platinum Resistant High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
June 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
January 2015 (undefined)
Primary Completion Date
June 2023 (Anticipated)
Study Completion Date
December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Health Network, Toronto

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a phase I clinical study for patients with platinum resistant (does not respond to platinum-based chemotherapy) high grade serous ovarian, fallopian tube, or primary peritoneal cancer. Prior to the main treatment, patients will receive cyclophosphamide by vein. Patients will then receive an infusion (given by vein) of autologous tumor-infiltrating lymphocytes (TILs) which will first be taken from the patient, then be stimulated with certain substances called autologous dendritic cells (DCs) and OKT3 (anti-CD3 antibody), and then given back to the patient as an infusion. This is believed to make the TILs work better. TILs are a type of white blood cells that recognizes tumor cells and enter them which causes the tumor cells to break down. After infusion of TILs, low-dose interleukin-2 (IL-2) therapy will be given.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Recurrent, Platinum Resistant High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Keywords
Measurable, Recurrent, Platinum resistant, Tumor-Infiltrating Lymphocytes, Low-Dose Interleukin-2, Autologous dendritic cells, Anti-CD3 monoclonal antibody, High grade serous ovarian, fallopian tube, or primary peritoneal cancer, Cyclophosphamide

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
3 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Re-Stimulated Tumor-Infiltrating Lymphocytes and interleukin-2
Arm Type
Experimental
Arm Description
Cyclophosphamide will be given prior to Re-Stimulated Tumor-Infiltrating Lymphocytes, and interleukin-2.
Intervention Type
Biological
Intervention Name(s)
Re-stimulated tumor-infiltrating lymphocytes (TILs)
Intervention Description
Intravenous infusions: Dose level 1 (3 patients): 3x10^7 TILs (with maximum 3x10^6 autologous dendritic cells); Dose level 2 (3 patients): 1x10^8 TILs (with maximum 1x10^7 autologous dendritic cells); Dose level 3 (3 patients): 3x10^8 TILs (with maximum 3x10^8 autologous dendritic cells)
Intervention Type
Biological
Intervention Name(s)
Interleukin-2
Other Intervention Name(s)
Aldesleukin, Proleukin, Recombinant Human Interleukin 2
Intervention Description
Subcutaneous injections of IL-2 x 4 days during the first week and x 5 days the second week with 2 days of rest in between each week of dosing
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Procytox
Intervention Description
Intravenous infusion: 30 mg/kg/day for 2 days (Day -3 and -2 prior to infusion of TILs)
Primary Outcome Measure Information:
Title
Number occurrences and severity of side effects
Time Frame
Starting at first dose of study treatment up to 10 years
Secondary Outcome Measure Information:
Title
Clinical response to treatment
Time Frame
6 weeks after treatment
Title
Number of patients with an immunity and no immunity to the study treatment
Time Frame
From start of the study up to 11 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria (Eligibility for TIL Evaluation): Platinum resistant high grade serous ovarian, fallopian tube, or primary peritoneal cancer. Tumor is suitable for harvest (i.e., lesion to be harvested for TIL evaluation has a total volume of ≥1cm3) or patient has previously undergone tumor harvest under other REB approved studies involving clinical evaluation of TILs. If tumor harvest is required, subject must be a suitable surgical candidate in the opinion of the operating surgeon. Patient age: ≥ 18 years. Clinical performance status of ECOG 0 or 1. Life expectancy > 5 months from the date of consent for TIL evaluation. Ability to understand and has signed the Pre-Screening Consent Form. Patients are willing to be tested for transmissible diseases (active Hepatitis B (HBV) or Hepatitis C (HCV), human immunodeficiency virus (HIV), Human T-Cell Lymphotropic Virus (HTLV), Herpes Simplex Virus (HSV), Cytomegalovirus (CMV), Syphilis (with West Nile Virus only tested between May 1st and November 30th) Confirmation that the Translational Immunotherapy Lab is able to process the specimen If there is a history of allergy to penicillin, gentamycin, streptomycin, or anti-fungals, the ability to generate TILs should first be confirmed with the cell manufacturing lab (i.e., Translational Immunotherapy Laboratory). Inclusion Criteria (Eligibility for Treatment): Prior to the performance of any study-specific procedure, the subject has signed and dated the informed consent form, approved by a Research Ethics Board (REB), after the nature of the study has been explained and the subject has had the opportunity to ask questions. Recurrent platinum resistant high grade serous ovarian, fallopian tube, or primary peritoneal cancer, with evidence of disease progression from previous line of treatment. Measurable disease by RECIST 1.1. Subjects should have no brain metastases. Note if brain metastases are present, these lesions must undergo definitive treatment with surgery and/or radiation at least 30 days prior to the first dose of lymphodepleting chemotherapy. If in the opinion of the PI or his designee the lesion(s) no longer represents active disease, the subject will be considered eligible. Clinical performance status of ECOG 0 or 1. Life expectancy > 3 months from the date of consent for TIL treatment. Laboratory analyses of tumor-infiltrating lymphocytes (TILs) from the subject must demonstrate that the TILs are suitable for use in protocol treatment (performed by the Translational Immunotherapy Laboratory, Princess Margaret Cancer Centre) More than 30 days has elapsed since any prior systemic therapy at the time of the cell infusion. All subjects' toxicities must have recovered to a CTCAE grade 1 or less; however, patients with residual CTCAE grade 2 neuropathy from previous carboplatin/taxol treatment will not be excluded. Subjects may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to CTCAE grade 1 or less or as specified in the inclusion criteria listed above. Adequate organ function as defined by the following criteria: Serum ALT ≤ 2.5 x upper limit of normal (ULN) (for patients with liver metastases, serum ALT ≤ 3 x ULN; Serum AST ≤ 2.5 x upper limit of normal (ULN) (for patients with liver metastases, serum AST ≤ 3 x ULN; Total serum bilirubin ≤ 2xULN (patients with Gilbert's Syndrome - direct serum bilirubin ≤ 2 x ULN); Absolute neutrophil count (ANC) ≥ 1.5x109/L; Platelets ≥100x109/L; Hemoglobin ≥ 90 g/L for female; Alkaline phosphatase ≤ 2 x ULN; Serum creatinine within normal institutional limits OR serum creatinine clearance ≥ 60 mL/min/1.73m2 for patients with creatinine levels above institutional normal; Serum lipase≤ 1.5 x ULN; Serum amylase ≤ 1.5 x ULN Women of child-bearing potential must have a negative pregnancy test. Acceptable birth control failure rate of less than or equal to 1% when used consistently and correctly such as implants, injectables, combined oral contraceptives, double barrier, some intrauterine devices (IUDs), sexual abstinence or vasectomized partner. Subjects are considered to be not of child bearing potential if they are considered to be post-menopausal or surgically sterilized (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy. Women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, ovarian suppression or any other reversible reason. Exclusion Criteria: Subjects with ongoing or prior use systemic steroid therapy within 4 weeks before the TILs infusion will be excluded. Use of topical, intranasal and inhaled corticosteroids, or systemic corticosteroids at physiologic doses are allowed. Oral steroid use as premedication to prevent allergic reactions to radiologic contrast is allowed. Subjects cannot be HIV positive. Subjects cannot have active hepatitis B or hepatitis C, syphilis, or Human T-Cell Lymphotropic Virus (HTLV). The number of prior lines of chemotherapy is not limited. However, if the subject has had ≥3 lines of prior chemotherapy for platinum refractory or platinum resistant disease, documentation of a response to one of these lines is required. Response can be defined by RECIST 1.1 or CA125 as defined by the modified GCIG criteria (See Section 11). The subject cannot have any active systemic infections, coagulation disorders or other active major medical illnesses of the cardiovascular, respiratory or immune system, uncontrolled psychiatric disorders, or other conditions that may affect compliance with the trial. The subject must have no active underlying cardiac illnesses defined by positive stress test, LVEF<40% or ongoing life-threatening arrhythmias (i.e., for patients older than 60 years of age or otherwise clinically indicated). Subjects who have a prolonged history of cigarette smoking or symptoms of respiratory dysfunction will be excluded if they have an abnormal pulmonary function test as evidenced by a FEV1 < 60% predicted.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marcus Butler, M.D.
Organizational Affiliation
Princess Margaret Cancer Centre
Official's Role
Principal Investigator
Facility Information:
Facility Name
Princess Margaret Cancer Centre
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada

12. IPD Sharing Statement

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"Re-Stimulated" Tumor-Infiltrating Lymphocytes And Low-Dose Interleukin-2 Therapy in Patients With Platinum Resistant High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

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