"Re-Stimulated" TILs And IL-2 Therapy for Platinum Resistant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Phase I Study Evaluating the Feasibility and Safety of Infusion of "Re-Stimulated" Autologous TILs Followed by Low-Dose IL-2 Therapy in Patients With Platinum Resistant High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

This is a phase I clinical study for patients with platinum-resistant high grade serous ovarian, fallopian tube, or primary peritoneal cancer, and the response to a combination of cyclophosphamide, autologous tumor-infiltrating lymphocytes (TILs), autologous dendritic cells (DCs), and OKT3 (anti-CD3 antibody), along with low-dose interleukin-2 (IL-2) therapy.

Study Overview

• Status: Active, not recruiting
• Conditions: Fallopian Tube Cancer; Primary Peritoneal Cancer; High Grade Serous Ovarian Cancer; Recurrent; Platinum-resistant
• Intervention / Treatment: Biological: Re-stimulated tumor-infiltrating lymphocytes (TILs); Biological: Interleukin-2; Drug: Cyclophosphamide

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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

Biological: Re-stimulated tumor-infiltrating lymphocytes (TILs); 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); Biological: Interleukin-2; 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; Other Names: Aldesleukin, Proleukin, Recombinant Human Interleukin 2; Drug: Cyclophosphamide; Intravenous infusion: 30 mg/kg/day for 2 days (Day -3 and -2 prior to infusion of TILs); Other Names: Procytox

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of occurrences and severity of side effects	Toxicities will be monitored on an ongoing basis by the investigators. Toxic effects will be categorized using the CTCAE v4.0 and will be reported using summary statistics. The highest toxicity for each patient in each category or subcategory will be described. Both events related and unrelated to treatment will be captured. The total number of episodes for each event reported, the severity and attribution to study therapy of each episode reported will also be displayed.	Starting at first dose of study treatment up to 10 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical response to treatment	Evaluation of the clinical response (clinical tumor regression), which will be monitored and reported according to RECIST v1.1 criteria and Immune-Related Response Criteria.	6 weeks after treatment
Number of patients with an immunity and no immunity to the study treatment	Immunological assessments of peripheral blood mononuclear cells, serum and tissue biopsies (if any) will be reported using units appropriate to each particular assay. Results from immunohistochemical evaluations of tissue biopsies will be reported descriptively. Descriptive statistics will be used to summarize immunological findings. Any correlation with clinical response rate will be reported descriptively.	From start of the study up to 11 years

Collaborators and Investigators

• Sponsor: University Health Network, Toronto
• Investigators: Principal Investigator: Marcus Butler, M.D., Princess Margaret Cancer Centre

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): June 1, 2024

Study Registration Dates

• First Submitted: June 11, 2013
• First Submitted That Met QC Criteria: June 18, 2013
• First Posted (Estimated): June 21, 2013

Study Record Updates

• Last Update Posted (Actual): March 22, 2024
• Last Update Submitted That Met QC Criteria: March 20, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Cyclophosphamide; Autologous dendritic cells; Tumor-Infiltrating Lymphocytes; Recurrent; Primary peritoneal cancer; Fallopian tube cancer; Platinum resistant; High grade serous ovarian cancer; Measurable; Low-Dose Interleukin-2; Anti-CD3 monoclonal antibody
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Peritoneal Diseases; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Digestive System Neoplasms; Endocrine Gland Neoplasms; Fallopian Tube Diseases; Abdominal Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Ovarian Neoplasms; Fallopian Tube Neoplasms; Peritoneal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Aldesleukin; Cyclophosphamide; Interleukin-2
• Other Study ID Numbers: TILs-001-DC