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

• ClinicalTrials.gov Identifier: NCT03734692
• Recruitment Status: Recruiting
• First Posted: November 8, 2018
• Last Update Posted: March 4, 2022
• Sponsor: Robert Edwards
• Collaborators: AIM ImmunoTech Inc.; Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Robert Edwards, University of Pittsburgh

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Ovarian Cancer Recurrent	Drug: Rintatolimod; Drug: Pembrolizumab; Drug: Cisplatin	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 45 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Systemic Immune Checkpoint Blockade and Intraperitoneal Chemo-Immunotherapy in Recurrent Ovarian Cancer
• Actual Study Start Date: January 28, 2019
• Estimated Primary Completion Date: December 2024
• Estimated Study Completion Date: December 2024

Arms and Interventions

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 Name: Ampligen; Drug: Pembrolizumab; 200 mg will be administered as a 30 minute IV infusion; Other Name: Keytruda; Drug: Cisplatin; 50mg/m^2 solution; Other Name: Platinol

Outcome Measures

Primary Outcome Measures :

1. Objective Response Rate (ORR) [ Time Frame: At 13 weeks ]
   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 :

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

Other Outcome Measures:

1. NK Cells [ Time Frame: at baseline (pre-treatment) and at 12 weeks (after the start of treatment) ]
2. Grandzyme B [ Time Frame: at baseline (pre-treatment) and at 12 weeks (after the start of treatment) ]
3. CD4 Tbet [ Time Frame: at baseline (pre-treatment) and at 12 weeks (after the start of treatment) ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Ovarian cancer is limited to the female population.
• Accepts Healthy Volunteers: No

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-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.

Contacts and Locations

Contacts

Contact: Robert Edwards, MD; 412-641-4212; edwarp@upmc.edu

Contact: Brenda Steele, RN; 412-641-3418; steeleb@upmc.edu

Locations

United States, Pennsylvania

Magee-Womens Hospital of UPMC; Recruiting

Pittsburgh, Pennsylvania, United States, 15213

Contact: Robert Edwards, MD 412-641-4212 edwarp@upmc.edu

Contact: Brenda Steele, RN 412-641-3418 steeleb@upmc.edu

Sponsors and Collaborators

Robert Edwards

AIM ImmunoTech Inc.

Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Robert Edwards, MD; UPMC Hillman Cancer Center

More Information

• Responsible Party: Robert Edwards, Professor, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT03734692
• Other Study ID Numbers: HCC 18-087
• First Posted: November 8, 2018
• Last Update Posted: March 4, 2022
• Last Verified: March 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Recurrence; Disease Attributes; Pathologic Processes; Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Endocrine System Diseases; Gonadal Disorders; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; poly(I).poly(c12,U); Pembrolizumab; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antiviral Agents; Anti-Infective Agents