Clinical Trials /

T-Cell Infusion, Aldesleukin, and Utomilumab in Treating Patients With Recurrent Ovarian Cancer

NCT03318900

Description:

This phase I/Ib trial studies the side effects and best dose of utomilumab and how well it works with CD8-positive T-lymphocyte (T-cell infusion) and aldesleukin in treating patients with ovarian cancer that has come back. Aldesleukin may stimulate white blood cells to kill ovarian cancer cells. Giving white blood cells (T-cells) that have been activated by a vaccine with aldesleukin may kill more tumor cells. Immunotherapy with utomilumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving T-cell infusion with aldesleukin and utomilumab may work better in treating patients with ovarian cancer.

Related Conditions:
  • Ovarian Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: T Cell Immunotherapy for Advanced Ovarian Cancer
  • Official Title: Phase I/Ib Study of Adoptive Cellular Therapy Using Autologous IL-21-Primed CD8+ Tumor Antigen-Specific T Cells in Combination With Utomilumab (PF-05082566) in Patients With Platinum Resistant Ovarian Cancer

Clinical Trial IDs

  • ORG STUDY ID: 2016-0400
  • SECONDARY ID: NCI-2018-01034
  • NCT ID: NCT03318900

Conditions

  • Platinum Resistant Ovarian Cancer

Interventions

DrugSynonymsArms
Utomilumabanti-CD137, PF-05082566Leukapheresis + Utomilumab
CyclophosphamideCytoxan, NeosarLeukapheresis + Utomilumab
T Cell InfusionCD8+TLeukapheresis + Utomilumab
Interleukin-2IL-2, Aldesleukin, ProleukinLeukapheresis + Utomilumab

Purpose

The goal of this clinical research study is to find the highest tolerable dose of anti-CD137 (utomilumab) that can be given in combination with CD8+T cells, IL-2 (aldesleukin), and cyclophosphamide in patients with ovarian cancer. The effect of this combination treatment will also be studied. This study is divided into 2 parts: leukapheresis and treatment. In the leukapheresis part, blood cells will be collected from you to be made into modified CD8+T cells and then they will be given back to you in the treatment part.

Detailed Description

      Treatment Part 1, All cohorts have leukapheresis.

      Treatment Part 2, Cohort 1 Study Drug Administration:

      If found to be eligible to take part in this study, participants will receive
      cyclophosphamide by vein over about 30-60 minutes on Day -2 (2 days before they receive the
      CD8+ T cells). If the doctor thinks it is needed, they will be given standard drugs to help
      decrease the risk of side effects. They may ask the study staff for information about how the
      drug is given and its risks.

      On Day 0, they will receive the CD8+T cells by vein over about 30-60 minutes. They will stay
      in the hospital overnight after the dose to monitor their condition. Starting within 6 hours
      after the CD8+T cell infusion and then 2 times a day after that for 14 days, they will give
      aldesleukin as an injection into their skin around abdomen. They will be taught how to give
      themselves these injections. In order to reduce possible side effects they will take naproxen
      sodium twice daily beginning the day before their injections and continuing for the 14 days.

      All participants will receive the same dose level of cyclophosphamide, aldesleukin, and CD8+T
      cells. Participants in this cohort will not receive utomilumab.

      Study Visits:

      On Day -2:

        -  They will have a physical exam.

        -  Blood (about 1 tablespoon) will be drawn for routine tests. This routine blood draw will
           include a pregnancy test if they can become pregnant. To take part in this study, they
           must not be pregnant.

      On Day 0:

        -  They will have an EKG to check their heart function.

        -  They will a have physical exam before the infusion.

      On Days 1, 7, 14, 22, 28, 35, 43, 49, 57, 64, 70, 77, 85, 113, and 141:

        -  They will have a physical exam.

        -  Blood (about 5½ tablespoons) will be drawn for routine tests, immune system tests, and
           tests on how long the T-cells survive in their body.

        -  Between Day 35 and 42 and again between Day 77 and 84, they will have an MRI or CT scan
           to check the status of the disease.

      Treatment Part 2, Cohorts 2-3:

      Study Drug Administration:

      If found to be eligible to take part in this study, they will be assigned to a dose level of
      utomilumab based on when they join study. Up to 3 dose levels of utomilumab will be tested.
      The first group of participants will receive the lowest dose level. Each new group will
      receive a higher dose than the group before it, if no intolerable side effects were seen.
      This will continue until the highest tolerable dose of utomilumab is found.

      All participants will receive the same dose level of cyclophosphamide, aldesleukin, and CD8+T
      cells.

      Because they are enrolled in Cohorts 2 and 3, they will receive cyclophosphamide by vein over
      about 30-60 minutes on Day -2 (2 days before you receive the CD8+T cells).

      On Day 0, they will receive the CD8+T cells by vein over about 30-60 minutes. They will stay
      in the hospital overnight after the dose to monitor your condition. Starting within 6 hours
      after the CD8+T cell infusion and then 2 times a day after that for 14 days, they will give
      aldesleukin as an injection into their skin around their abdomen. They will be taught how to
      give themselves these injections.

      On Days 1, 29, 57, 85, 113, and 141, they will receive utomilumab by vein over about 90
      minutes. Study Visits

      On Day -2:

        -  They will have a physical exam.

        -  Blood (about 1 tablespoon) will be drawn for routine tests. This routine blood draw will
           include a pregnancy test if they can become pregnant. To take part in this study, they
           must not be pregnant.

      On Day 0:

        -  They will have an EKG to check their heart function.

        -  They will have a physical exam before the infusion.

      On Days 1, 7, 14, 22, 28, 35, 43, 49, 57, 64, 70, 77, 85, 113, and 141:

        -  They will have a physical exam.

        -  Blood (about 5½ tablespoons) will be drawn for routine tests, immune system tests, and
           tests on how long the T-cells survive in their body.

        -  Between Day 35 and 42 and again between Day 77 and 84, they will have an MRI or CT scan
           to check the status of the disease.

      On Day 3, blood (about 5½ tablespoons) will be drawn for routine tests, immune system tests,
      and tests on how long the T-cells survive in their body.
    

Trial Arms

NameTypeDescriptionInterventions
Leukapheresis + UtomilumabExperimentalPart 1 Leukapheresis then Part 2 Treatment, Dose escalation of Utomilumab given in combination with CD8+T cells, IL-2 and Cyclophosphamide. Utomilumab begins with dose level 2.
  • Utomilumab
  • Cyclophosphamide
  • Interleukin-2

Eligibility Criteria

        Inclusion Criteria:

          1. Histopathologic documentation (must be performed or reviewed at MD Anderson) of
             recurrent high grade epithelial ovarian cancer.

          2. At least one prior line of platinum-based chemotherapy (subjects are eligible for
             enrollment and leukopheresis while still platinum-sensitive, however, they must have
             developed platinum resistant disease for treatment (turnstile 2)).

          3. 18 to 75 years of age

          4. Tumor expressing PRAME and/or COL6A3

          5. Expression of HLA-A*0201

          6. ECOG performance status of 0-1 and an expected survival of greater than 16 weeks.

          7. Willing and able to give informed consent

          8. Adequate normal organ and marrow function as defined below: Hemoglobin >/= 9.0 g/dL;
             Absolute neutrophil count (ANC) >/= 1.0 x 10^9/L (> /=1000 per mm^3); Platelet count
             >/= 75 x 10^9/L (>/=100,000 per mm^3); Serum bilirubin </= 1.5 x institutional upper
             limit of normal (ULN) unless diagnosed with Gilbert's syndrome; AST and ALT </= 2.5 x
             ULN unless liver metastases are present, in which case it must be </= 5x ULN; Serum
             creatinine CL >40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection
             for determination of creatinine clearance: Creatinine CL (mL/min) = [Weight (kg) x
             (140 - Age) x 0.85]/[72 x serum creatinine (mg/dL)].

          9. Subjects must either be of non-reproductive potential (ie, post-menopausal by history:
             >/=50 years old and no menses for >/=1 year without an alternative medical cause; OR
             history of hysterectomy, OR history of bilateral tubal ligation, OR history of
             bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.

         10. Women of childbearing potential (WOCBP) must be using an adequate method of
             contraception to avoid pregnancy throughout the study in such a manner that the risk
             of pregnancy is minimized. Suggested precautions should be used to minimize the risk
             or pregnancy for at least 1 month before start of therapy, and while women are on
             study for up to 3 months after T cell infusion, and at least 8 weeks after the study
             drug is stopped

         11. {Turnstile 2} Subjects must have platinum resistant disease (progression on a
             platinum-containing regimen or recurrence within 180 days of last dose of
             platinum-containing chemotherapy). Subjects that are not platinum resistant but are
             deemed not to be candidates for platinum-based chemotherapy due to prior significant
             allergic reaction may participate with PI approval.

         12. {Turnstile 2} Bi-dimensionally measurable disease by radiographic imaging (MRI or CT
             scan).

         13. {Turnstile 2} At least 4 Weeks must have elapsed since the last chemotherapy,
             immunotherapy, radiotherapy or major surgery. At least 6 Weeks for bevacizumab.

         14. {Turnstile 2} Toxicity related to prior therapy must either have returned to </= grade
             1, baseline, or been deemed irreversible.

        Exclusion Criteria:

          1. Clinically significant pulmonary dysfunction, as determined by medical history and
             physical exam. Patients so identified will undergo pulmonary functions testing and
             those with FEV1 < 60% of normal or DLco (corr for Hgb) < 55% will be excluded.

          2. Significant cardiovascular abnormalities including any one of the following:
             Congestive heart failure, Clinically significant hypotension, Symptoms of coronary
             artery disease, Presence of cardiac arrhythmias on EKG requiring drug therapy; or
             Patients with a history of cardiovascular disease. (Patients with the above will
             undergo a cardiac evaluation which can include a stress test and/or echocardiography.
             Results of this evaluation will be considered before excluding patients on the basis
             of cardiovascular abnormalities). Subjects with evidence of stress-induced cardiac
             ischemia or ejection fraction less than 55% will be excluded.

          3. History of central nervous system (CNS) metastasis.

          4. Autoimmune disease: Patients with a history of Inflammatory Bowel Disease are excluded
             from this study, as are patients with a history of autoimmune disease (e.g. Systemic
             Lupus Erythematosus, vasculitis, infiltrating lung disease) whose possible progression
             during treatment would be considered by the Investigator to be unacceptable.

          5. {Turnstile 2} Participation in another clinical study with an investigational product
             administered during the last 28 days.

          6. {Turnstile 2} Receipt of the last dose of previous chemotherapy, hormonal, or biologic
             treatment for ovarian, fallopian tube, or primary peritoneal cancer in the last 28
             days (in the last 6 weeks for bevacizumab).

          7. {Turnstile 2} Current or prior use of immunosuppressive medication within 28 days
             before enrollment, with the exceptions of intranasal and inhaled corticosteroids or
             systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of
             prednisone, or an equivalent corticosteroid.

          8. {Turnstile 2} Any prior Grade >/=3 immune-related adverse event (irAE) while receiving
             any previous immunotherapy agent, or any unresolved irAE >Grade 1.

          9. History of allogeneic organ transplant.

         10. Unresolved partial or complete small or large bowel obstruction.

         11. {Turnstile 2} Receipt of live attenuated vaccination within 30 days prior to
             enrollment or within 30 days of planned lymphodepletion.

         12. Any underlying medical or psychiatric condition, which in the opinion of the
             Investigator, will make the administration of study drug hazardous or obscure the
             interpretation of adverse events.

         13. Active viral hepatitis

         14. Confirmed HIV infection
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Limiting Toxicity Summary associated with Utomilumab Dose Escalation
Time Frame:Up to 6-8 weeks
Safety Issue:
Description:Safety and toxicity of adoptively transferred central memory-type CTL targeting ovarian cancer antigens administered alone, and in combination with, an Utomilumab, an agonistic anti-CD137 antibody, in patients with platinum resistant ovarian cancer reported at each dose level. Safety and toxicity will be assessed using the latest version of Common Terminology Criteria for Adverse Events (CTCAE).

Secondary Outcome Measures

Measure:Best overall response rate (BORR)
Time Frame:12 weeks up to 1 year
Safety Issue:
Description:BORR is defined as the total number of participants who's BOR is complete response (CR) or partial response (PR), divided by the total number of participants. Radiographic imaging and clinical assessment of residual disease will be compared with pre-infusion baseline assessment according to modified RECIST 1.1 for response: complete response (CR) defined as total regression of all tumor, a partial response (PR) as 30% or greater decrease in sum of longest diameter of target lesions and progressive disease (PD) as 20% increase in sum of longest diameter of target lesions (modified world health organization criteria or mWHO). Assessment at 6 and 12 weeks following T cell infusion and then every 8 weeks (+/- 1 week) until disease progression or intervening therapy. The overall response rate (OR) will be after 1 cycle (12) weeks.
Measure:Progression free survival (PFS)
Time Frame:6 months after the T cell infusion
Safety Issue:
Description:PFS is defined as the time between T cell infusion date and the date of progression or death. A participant who dies without reported prior progression will be considered to have progressed on the date of death. For those who remain alive and have not progressed, PFS will be censored on the date of last tumor assessment. For participants who have PD prior to Week 12 and a subsequent assessment of SD, PR or CR, the date of PD following response (where available) will be used in the analysis of PFS; otherwise these participants will be censored on the date of their last tumor assessment. PFS is estimated for each arm using the Kaplan-Meier product limit method.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • adoptively transferred central memory-type CTL targeting ovarian cancer antigens
  • in vivo persistence
  • Adoptive Cellular Therapy
  • IL-21-Primed CD8+ Tumor Antigen-Specific T Cells
  • epithelial ovarian cancer

Last Updated