Clinical Trials /

Systemic Immune Checkpoint Blockade and Intraperitoneal Chemo-Immunotherapy in Recurrent Ovarian Cancer

NCT03734692

Description:

This is a phase II single arm efficacy/safety trial that will evaluate the effectiveness of combining intensive locoregional intraperitoneal (IP) chemoimmunotherapy of cisplatin with IP rintatolimod (TLR-3 agonist) and IV infusion of the checkpoint inhibitor pembrolizumab (IVP) for patients with recurrent platinum-sensitive ovarian cancer (OC).

Related Conditions:
  • Fallopian Tube Adenocarcinoma
  • Fallopian Tube Carcinosarcoma
  • Ovarian Adenocarcinoma
  • Ovarian Carcinosarcoma
  • Primary Peritoneal Carcinoma
  • Primary Peritoneal Carcinosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Systemic Immune Checkpoint Blockade and Intraperitoneal Chemo-Immunotherapy in Recurrent Ovarian Cancer
  • Official Title: Systemic Immune Checkpoint Blockade and Intraperitoneal Chemo-Immunotherapy in Recurrent Ovarian Cancer

Clinical Trial IDs

  • ORG STUDY ID: HCC 18-087
  • NCT ID: NCT03734692

Conditions

  • Ovarian Cancer Recurrent

Interventions

DrugSynonymsArms
RintatolimodAmpligencisplatin + rintatolimod + pembrolizumab
PembrolizumabKeytrudacisplatin + rintatolimod + pembrolizumab
CisplatinPlatinolcisplatin + rintatolimod + pembrolizumab

Purpose

This is a phase II single arm efficacy/safety trial that will evaluate the effectiveness of combining intensive locoregional intraperitoneal (IP) chemoimmunotherapy of cisplatin with IP rintatolimod (TLR-3 agonist) and IV infusion of the checkpoint inhibitor pembrolizumab (IVP) for patients with recurrent platinum-sensitive ovarian cancer (OC).

Detailed Description

      Patients will receive a total of six treatment cycles, at 3-week intervals. The study will
      use an IP neoadjuvant approach (IP chemoimmunotherapy of cisplatin with IP rintatolimod and
      IV infusion of pembrolizumab), followed by interval cytoreduction (usually laparoscopically)
      of residual tumor. Cytoreduction will occur approximately 4 weeks after the fourth treatment
      cycle. Post-surgery the investigators will consolidate with 2 additional courses of same
      chemo-immunotherapy regimen. Catheter will be removed 12 weeks after the last treatment. All
      surgical procedures, if done laparoscopically, are outpatient and will yield up to three
      serial biopsies of the tumor sites: 1) at catheter placement; 2) at interval cytoreduction
      which consists of removal of any visible tumor sites and the site biopsied initially whether
      tumor is present or not; 3) at catheter removal, when site of first tumor biopsy will be
      re-biopsied for pathologic response.
    

Trial Arms

NameTypeDescriptionInterventions
cisplatin + rintatolimod + pembrolizumabExperimentalIntraperitoneal (IP) cisplatin 50mg/m^2 solution with IP rintatolimod 200 mg solution and IV pembrolizumab 200 mg solution.
  • Rintatolimod
  • Pembrolizumab
  • Cisplatin

Eligibility Criteria

        Inclusion Criteria:

          1. Patients must be at least 18 years of age on the day of signing informed consent.

          2. Patients must have first or second peritoneal recurrence of epithelial adenocarcinoma
             or carcinosarcoma of ovarian, tubal or peritoneal origin:

               1. Histologic documentation of the original primary tumor is required via the
                  pathology report.

               2. Original tumor blocks from the primary diagnosis will be requested by our study
                  pathologist at Magee-Womens Hospital of UPMC Cancer Centers. Original tumor
                  blocks may be reviewed after registration (informed consent and enrollment).

          3. Patients must have completed prior platinum-based therapy. Response can be complete or
             partial if it otherwise meets platinum sensitive criteria, see below.

          4. Patients must be platinum-sensitive, defined as having a progression free interval
             (PFI) of more than 6 months (180 days) from any platinum therapy. Patients are allowed
             to have had other lines of therapy since last platinum if PFI after platinum therapy
             meets platinum sensitive criteria.

          5. Patients must have measurable disease in the peritoneal cavity, measurable per RECIST
             1.1 criteria:

               1. A mass with a length of 1.0 cm or greater and/or

               2. A lymph node with a length of 1.5 cm or greater in the shortest axis.

          6. Patients must be a reasonable candidate for laparoscopy and IP platinum regimen with
             no prior evidence of clinically significant intra-abdominal adhesions, persistent
             abdominal wall infections, renal toxicity or bowel obstruction.

          7. Patients of childbearing potential must:

               1. Have a negative pregnancy test prior to the study entry.

               2. Must discontinue breastfeeding prior to the first date of treatment on this study
                  if applicable.

               3. Agree to follow the contraceptive guidance in Appendix 3 during the treatment
                  period and for at least 120 days after the last dose of study treatment.

          8. Patients must agree to the protocol designated clinical monitoring to receive the
             study regimens.

          9. The participant (or legally acceptable representative if applicable) provides written
             informed consent for the trial.

         10. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
             Evaluation of ECOG is to be performed within 7 days prior to the date of
             allocation/randomization.

         11. Have adequate organ function as defined in the following table (Table 1). Specimens
             must be collected within 14 days prior to the start of study treatment.

        Exclusion Criteria:

          1. A woman of child-bearing potential who has a positive urine pregnancy test within 72
             hours prior to infusion of treatment regimen (see Appendix 3). If the urine test is
             positive or cannot be confirmed as negative, a serum pregnancy test will be required.
             Note: in the event that 72 hours have elapsed between the screening pregnancy test and
             the first dose of study treatment, another pregnancy test (urine or serum) must be
             performed and must be negative in order for subject to start receiving study
             medication

          2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with
             an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g.,
             CTLA-4, OX 40, CD137).

          3. Has received prior systemic anti-cancer therapy including investigational agents
             within 4 weeks prior to allocation.

               -  Note: Participants must have recovered from all AEs due to previous therapies to
                  ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.

               -  Note: If participant received major surgery, they must have recovered adequately
                  from the toxicity and/or complications from the intervention prior to starting
                  study treatment.

          4. Has received prior radiotherapy within 2 weeks of start of study treatment.
             Participants must have recovered from all radiation-related toxicities, not require
             corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
             for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.

          5. Patients who received maintenance therapy after the prior platinum therapy. An
             exception to this exclusion would be if the PFI is greater than 6 months (180 days)
             off of the maintenance agent or a PFI greater than a 1 year (365 days) regardless of
             the duration of maintenance therapy.

          6. Patients with previous pelvic radiation therapy.

          7. Has received a live vaccine within 30 days prior to the first dose of study drug.
             Examples of live vaccines include, but are not limited to, the following: measles,
             mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
             Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
             are generally killed virus vaccines and are allowed; however, intranasal influenza
             vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.

          8. Is currently participating in or has participated in a study of an investigational
             agent or has used an investigational device within 4 weeks prior to the first dose of
             study treatment.

             o Note: Participants who have entered the follow-up phase of an investigational study
             may participate as long as it has been 4 weeks after the last dose of the previous
             investigational agent.

          9. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
             (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 7 days prior to the first dose of study drug.

         10. Patients with tumors of low malignant potential, except ovarian pseudomyxomas, or with
             no peritoneal disease.

         11. Has a known additional malignancy that is progressing or has required active treatment
             within the past 3 years.

             o Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of
             the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that
             have undergone potentially curative therapy are not excluded.

         12. Has known active CNS metastases and/or carcinomatous meningitis. Participants with
             previously treated brain metastases may participate provided they are radiologically
             stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging
             (note that the repeat imaging should be performed during study screening), clinically
             stable and without requirement of steroid treatment for at least 14 days prior to
             first dose of study treatment.

         13. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.

         14. Has a known allergy to cisplatin chemotherapy. Patients with carboplatin allergy may
             be included if they tolerate a test dose of IV cisplatin given in monitored floor
             conditions.

         15. Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.

         16. Has a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis.

         17. Has an active infection requiring systemic therapy.

         18. Has a known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is
             required unless mandated by local health authority.

         19. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
             reactive) or known active Hepatitis C virus (defined as HCV RNA qualitative is
             detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required
             unless mandated by local health authority.

         20. Has a known history of active TB (Bacillus Tuberculosis)

         21. Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the study, interfere with the subject's
             participation for the full duration of the study, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator.

         22. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

         23. Is pregnant or breastfeeding, or expecting to conceive or within the projected
             duration of the study, starting with the screening visit through 120 days after the
             last dose of trial treatment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate (ORR)
Time Frame:At 13 weeks
Safety Issue:
Description:The proportion of subjects with the best response of complete response (CR), or partial response (PR) per Response Evaluation Criteria for Solid Tumors (RECIST 1.1). Per RECIST 1.1 , CR is defined as all target lesions gone; PR is defined as a > 30% decrease in size of lesion from baseline.

Secondary Outcome Measures

Measure:Progression-Free Survival (PFS)
Time Frame:up to 4 years
Safety Issue:
Description:The length of time during and after study treatment that a patient remains alive without worsening disease. Per RECIST 1.1, progression is defined as a > 20% increase from smallest sum of longest (lesion) diameter recorded since treatment started (best response - target lesions) and/or, enlargement of non-target lesions.
Measure:Change in number of CD8+ cells
Time Frame:At baseline (pre-treatment) and at 8 weeks (after the start of treatment)
Safety Issue:
Description:Within-patient changes in number of CD8+ cells present in tumor tissue and peritoneal fluid.
Measure:Change in number of CD3+ cells
Time Frame:at baseline (pre-treatment) and at 12 weeks (after the start of treatment)
Safety Issue:
Description:Within-patient changes in number of CD3+ cells present in tumor tissue and peritoneal fluid.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Robert Edwards

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