E7777 + Pembrolizumab for Ovarian Cancer

Overseen By Lucia Borasso, RN

Age: 18+

Sex: Female

Trial Phase: Phase 1 & 2

Sponsor: Alexander B Olawaiye, MD

Must not be taking: Antibiotics, Immunosuppressants

Disqualifiers: Autoimmune disease, Cardiovascular disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 42

70 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, certain treatments like systemic immunosuppressive medications and some antibiotics must be stopped before starting the trial. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug pembrolizumab for ovarian cancer?

Research shows that pembrolizumab, when used alone or with other drugs like carboplatin, has shown some activity in treating recurrent ovarian cancer, especially in cases where the cancer is resistant to platinum-based treatments. ^{1 2 3 4 5}

Is the combination of E7777 and Pembrolizumab safe for humans?

Pembrolizumab, also known as KEYTRUDA, has been studied in various cancers and is generally considered safe in humans. In studies, it has shown no significant toxic effects in nonhuman primates, and clinical trials in humans have demonstrated its safety profile. However, specific safety data for the combination with E7777 is not provided in the available research. ^{1 2 4 5 6}

How is the drug E7777 + Pembrolizumab unique for treating ovarian cancer?

The combination of E7777 and Pembrolizumab is unique because it combines a novel agent, E7777, with Pembrolizumab, a PD-1 inhibitor that helps the immune system recognize and attack cancer cells. This approach may offer a new option for ovarian cancer, especially for cases that are resistant to standard treatments. ^{1 2 3 6 7}

What is the purpose of this trial?

Epithelial ovarian cancer (OC) is the most lethal gynecologic cancer: nearly 22,000 women are diagnosed with OC in the US annually and 63% are expected to die from their disease. The 5-year overall survival rate is unacceptably low at 20-30%, with \> 50% of patients experiencing recurrence of their disease. Recurrent, platinum-resistant OC is characterized by a low response to chemotherapy (\<10-15%) and poor prognosis, with overall survival estimated to be \<12 months. Thus, there is an urgent need to identify novel therapies to improve outcomes for patients with recurrent, platinum resistant OC. The primary focus in this trial is targeting tumor associated immunosuppressive T-regs with E7777 combined with PD-1 inhibitor, pembrolizumab. This trial will enroll patients with solid tumors in the dose escalation portion and specified cohorts in the dose expansion portion. In the Phase I portion, 18-30 patients will be enrolled. In the dose expansion portion, approximately 40 patients (20 in each cohort) will be enrolled. Given the relatively poor prognosis and limited treatment options for these patients, this population is considered appropriate for trials of novel therapeutic candidates.

Research Team

Alexander B. Olawaiye

Principal Investigator

UPMC Hillman Cancer Center

Eligibility Criteria

This trial is for adults with recurrent ovarian cancer resistant to platinum-based chemotherapy or post-PD1/PDL1 MSI-H cancers. Participants must have a life expectancy of at least 6 months, manageable health status (ECOG 0-1), and adequate organ function. Those with HIV can join if stable on therapy. Women who can bear children and men must agree to use contraception.

Inclusion Criteria

There is a sample of your tumor available for research purposes.

My ovarian cancer is resistant to platinum-based treatments, or I have MSI-H cancer after PD1/PDL1 therapy.

For women of childbearing potential: agreement to remain abstinent or use contraceptive methods, and agreement to refrain from donating eggs

Exclusion Criteria

I have had cancer spread to the lining of my brain and spinal cord.

I am allergic to certain medication ingredients, including those from Chinese hamster ovary cells.

I haven't taken any immune-boosting drugs in the last 4 weeks or 5 half-lives of the drug.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive E7777 and pembrolizumab in escalating doses to determine the recommended Phase 2 dose

Up to 8 cycles (21-day cycle each)

Visits every 21 days for each cycle

Dose Expansion

Participants receive E7777 and pembrolizumab at the recommended Phase 2 dose to evaluate efficacy

Up to 8 cycles (21-day cycle each)

Visits every 21 days for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Treatment Details

Interventions

• E7777
• Pembrolizumab

Trial Overview The study tests E7777, aimed at depleting immunosuppressive T-cells, combined with pembrolizumab, an immune checkpoint inhibitor. It includes a dose escalation phase for various solid tumors and a dose expansion specifically for certain cancer types.

Participant Groups

Group I: E7777 + Pembrolizumab Experimental Treatment 2 Interventions

Phase l: E7777: Dose Level 1, 3 µg/kg; Dose Level 2, 6 µg/kg; Dose Level 3, 9 µg/kg; Dose Level 4, 12 µg/kg Day 1-3 - given up to 8 cycles (dose-limiting toxicities assessed for first two cycles, only) Pembrolizumab: 200 mg, IV on Day 1 (21-day cycle) Phase ll: E7777: administered on Day 1-3 at Phase 2 Recommended Dose (P2RD); Day 1-3 up to 8 cycles Pembrolizumab: 200 mg, IV on Day 1 (21-day cycle)

E7777 is already approved in United States for the following indications:

Approved in United States as Ontak for:

• Cutaneous T-cell lymphoma

Who Is Running the Clinical Trial?

Alexander B Olawaiye, MD

Lead Sponsor

Trials

4

Recruited

130+

Haider Mahdi

Lead Sponsor

Trials

6

Recruited

130+

Dr. Reddys Laboratories, SA

Industry Sponsor

Trials

2

Recruited

120+

Findings from Research

In a phase Ib trial involving 26 patients with advanced PD-L1-positive ovarian cancer, pembrolizumab demonstrated a confirmed objective response rate of 11.5%, indicating some level of antitumor activity, with 1 complete response and 2 partial responses observed.

The treatment was generally well-tolerated, with 73.1% of patients experiencing treatment-related adverse events, but no deaths or treatment discontinuations due to these events, suggesting that pembrolizumab has a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028. Varga, A., Piha-Paul, S., Ott, PA., et al.[2019]

The combination of pembrolizumab and carboplatin was found to be well-tolerated and showed activity in patients with recurrent platinum-resistant ovarian cancer, with a median overall survival of 11.3 months.

Patients with a higher ratio of peripheral CD8+PD1+Ki67+ T cells to tumor burden had significantly longer overall survival, suggesting this ratio could help identify those who may benefit more from this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab with low-dose carboplatin for recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer: survival and immune correlates. Liao, JB., Gwin, WR., Urban, RR., et al.[2022]

In a study involving patients with recurrent platinum-resistant ovarian cancer, the combination of pembrolizumab, cisplatin, and gemcitabine resulted in an overall response rate of 60%, but the duration of response was relatively short at 4.9 months.

The addition of pembrolizumab did not show a significant benefit over chemotherapy alone, leading to the decision to close the trial for further accrual after an interim analysis indicated modest outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of cisplatin, gemcitabine and pembrolizumab for platinum-resistant ovarian cancer. Walsh, CS., Kamrava, M., Rogatko, A., et al.[2022]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Pembrolizumab (Keytruda) effectively blocks the PD-1 pathway, enhancing T-cell activity against tumors, which supports its role in promoting tumor regression and immune rejection.

Preclinical studies in cynomolgus monkeys showed that pembrolizumab has a favorable safety profile with no significant toxicological findings, aligning with its demonstrated safety and efficacy in human clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. Hutchins, B., Starling, GC., McCoy, MA., et al.[2021]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

In a study of 317 patients with advanced recurrent ovarian cancer treated with pembrolizumab, no significant associations were found between gene expression signatures and clinical outcomes, indicating that these markers may not be reliable predictors of treatment response.

However, higher densities of specific myeloid cell phenotypes (CD11c+ and CD11c+/MHCII-/CD163-/CD68-) in the tumor microenvironment were positively associated with better outcomes, suggesting that these immune cell populations could play a role in enhancing the efficacy of pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular determinants of clinical outcomes of pembrolizumab in recurrent ovarian cancer: Exploratory analysis of KEYNOTE-100. Ledermann, JA., Shapira-Frommer, R., Santin, AD., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab with low-dose carboplatin for recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer: survival and immune correlates. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Phase II trial of cisplatin, gemcitabine and pembrolizumab for platinum-resistant ovarian cancer. [2022]

4. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]

7. United States pubmed.ncbi.nlm.nih.gov

Molecular determinants of clinical outcomes of pembrolizumab in recurrent ovarian cancer: Exploratory analysis of KEYNOTE-100. [2023]