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

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).

Study Overview

• Status: Recruiting
• Conditions: Ovarian Cancer Recurrent
• Intervention / Treatment: Drug: Rintatolimod; Drug: Pembrolizumab; Drug: Cisplatin

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.

• Study Type: Interventional
• Enrollment (Anticipated): 45
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Robert Edwards, MD; Phone Number: 412-641-4212; Email: edwarp@upmc.edu
• Study Contact Backup: Name: Brenda Steele, RN; Phone Number: 412-641-3418; Email: steeleb@upmc.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • Magee-Womens Hospital of UPMC
      • Contact: Robert Edwards, MD; Phone Number: 412-641-4212; Email: edwarp@upmc.edu
      • Contact: Brenda Steele, RN; Phone Number: 412-641-3418; Email: steeleb@upmc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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-Women's Hospital of UPMC Cancer Centers if the patient did not have their initial surgery at Magee. Original tumor blocks may be reviewed after registration (informed consent and enrollment). Tumor block should be held until study is completed.
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 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 28 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 28days prior to the start of study treatment.

Exclusion Criteria :

1. A WOCBP 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 with previous pelvic radiation therapy.
6. 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.

7. 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.

8. 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.
9. Patients with tumors of low malignant potential, except ovarian pseudomyxomas, or with no peritoneal disease.
10. Concurrent malignancy or malignancy within 3 years prior to starting study drug, with the exception of adequately treated basal or squamous cell carcinoma, non- melanomatous skin cancer or curatively resected cervical cancer or per physician discretion that the previous cancer was adequately treated with curative intent and unlikely to recur (the study PI must concur with this determination).
11. 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.
12. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
13. 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.
14. 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.
15. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
16. Has an active infection requiring systemic therapy.
17. Has a known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is required unless mandated by local health authority.
18. 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.
19. Has a known history of active TB (Bacillus Tuberculosis)
20. 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.
21. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
22. 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.

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: cisplatin + rintatolimod + pembrolizumab; Intraperitoneal (IP) cisplatin 50mg/m^2 solution with IP rintatolimod 200 mg solution and IV pembrolizumab 200 mg solution.	Drug: Rintatolimod; 200 mg by IP administration over 1-2 hours; Other Names: Ampligen; Drug: Pembrolizumab; 200 mg will be administered as a 30 minute IV infusion; Other Names: Keytruda; Drug: Cisplatin; 50mg/m^2 solution; Other Names: Platinol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	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.	At 13 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	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.	up to 4 years
Change in number of CD8+ cells	Within-patient changes in number of CD8+ cells present in tumor tissue and peritoneal fluid.	At baseline (pre-treatment) and at 8 weeks (after the start of treatment)
Change in number of CD3+ cells	Within-patient changes in number of CD3+ cells present in tumor tissue and peritoneal fluid.	at baseline (pre-treatment) and at 12 weeks (after the start of treatment)

Other Outcome Measures

Outcome Measure	Time Frame
NK Cells	at baseline (pre-treatment) and at 12 weeks (after the start of treatment)
Grandzyme B	at baseline (pre-treatment) and at 12 weeks (after the start of treatment)
CD4 Tbet	at baseline (pre-treatment) and at 12 weeks (after the start of treatment)

Collaborators and Investigators

• Sponsor: Robert Edwards
• Collaborators: Merck Sharp & Dohme LLC; AIM ImmunoTech Inc.
• Investigators: Principal Investigator: Robert Edwards, MD, UPMC Hillman Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): January 28, 2019
• Primary Completion (Anticipated): December 1, 2024
• Study Completion (Anticipated): December 1, 2024

Study Registration Dates

• First Submitted: November 6, 2018
• First Submitted That Met QC Criteria: November 6, 2018
• First Posted (Actual): November 8, 2018

Study Record Updates

• Last Update Posted (Actual): March 28, 2023
• Last Update Submitted That Met QC Criteria: March 25, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Disease Attributes; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Recurrence; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Pembrolizumab; poly(I).poly(c12,U)
• Other Study ID Numbers: HCC 18-087

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No