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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks better treatment options for individuals with ovarian cancer that resists standard chemotherapy. It tests a combination of two treatments, E7777 (also known as Denileukin diftitox, an experimental treatment) and pembrolizumab, which together enhance the body's immune response against cancer cells. Participants should have ovarian cancer that has recurred or stopped responding to platinum-based treatments, a common chemotherapy type. This trial may suit those who have tried other treatments without success and seek new options. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of E7777 and pembrolizumab is promising in early studies. In one study, 27% of patients with recurring solid tumors saw their tumors shrink, indicating that over a quarter of patients responded positively. Additionally, 33% of patients experienced a clinical benefit, with their disease either stabilizing or improving. Importantly, the combination had manageable side effects, suggesting that most patients did not encounter severe issues.

Regarding safety, this treatment is generally well-tolerated. The study did not report any unexpected severe side effects, which reassures those considering joining a trial. Pembrolizumab, one of the drugs in this combination, has already received FDA approval for other conditions, demonstrating its safety for humans.

Overall, existing research suggests that this treatment is safe with manageable side effects, but ongoing studies will provide more detailed information as they continue. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about E7777 combined with Pembrolizumab for ovarian cancer because this combination offers a unique approach. Most treatments for ovarian cancer, like chemotherapy, attack rapidly dividing cells but can come with significant side effects. E7777 is a modified diphtheria toxin that specifically targets cancer cells by homing in on the IL-2 receptor, potentially sparing healthy ones. When paired with Pembrolizumab, an immune checkpoint inhibitor that revs up the immune system to recognize and fight cancer cells, this combination could enhance effectiveness and potentially provide a more targeted, less toxic treatment option. This dual action makes the treatment particularly promising compared to existing therapies.

What evidence suggests that this trial's treatments could be effective for ovarian cancer?

This trial will evaluate the combination of E7777 and pembrolizumab for treating ovarian cancer. Studies have shown promising results for using these two drugs together to treat cancer. In one study, about 27% of patients, or roughly one in four, saw their tumors shrink. Additionally, 33% of patients experienced some improvement in their condition. Research suggests that E7777 helps the immune system fight cancer by targeting cells that usually weaken the immune response. When combined with pembrolizumab, which also helps the immune system attack cancer, this treatment shows significantly better results in shrinking tumors and extending patients' lives compared to using each drug alone. These findings offer hope for better outcomes in treating recurrent ovarian cancer. ^{2 3 4 6 7}

Who Is on the Research Team?

Alexander B. Olawaiye

Principal Investigator

UPMC Hillman Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05200559

NCT05200559 | T-regulatory Cell Depletion with E7777 ... This open label study will investigate the safety and efficacy of a combined regimen of pembrolizumab with T-regulatory cell depletion and E7777 in patients ...

2. targetedonc.com targetedonc.com/view/pembrolizumab-plus-denileukin-diftitox-shows-promise-in-solid-tumors

Pembrolizumab Plus Denileukin Diftitox Shows Promise in ... A phase 1 trial of pembrolizumab plus denileukin diftitox shows 27% response and 33% clinical benefit in recurrent solid tumors, with manageable toxicity.

3. cancernetwork.com cancernetwork.com/view/denileukin-diftitox-combo-shows-promising-orr-and-cbr-in-solid-tumors

Denileukin Diftitox Combo Shows Promising ORR and ... Denileukin diftitox plus pembrolizumab yields objective responses and clinical benefit in patients with recurrent solid tumors.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10646188/

Targeting regulatory T cells by E7777 enhances CD8 ... E7777 administered in combination with anti-PD-1 led to significantly increased anti-tumor activity and durable, extended overall survival compared to either ...

5. prnewswire.com prnewswire.com/news-releases/citius-pharmaceuticals-inc-and-citius-oncology-inc-announce-promising-preliminary-results-of-an-investigator-initiated-phase-i-clinical-trial-of-pembrolizumab-keytruda-and-lymphir-in-cancer-patients-with-recurrent-solid-tu-302300516.html

Citius Pharmaceuticals, Inc. and Citius Oncology, Inc. ... The study aims to identify an optimal dose for future trials and explore the impact of a treatment regimen combining pembrolizumab and LYMPHIR on the tumor ...

6. s204.q4cdn.com s204.q4cdn.com/372710200/files/doc_news/Citius-Pharmaceuticals-Inc.-and-Citius-Oncology-Inc.-Announce-Promising-Preliminary-Results-of-an-Investigator-Initiated-Phase-I-Clin-Y8Z9P.pdf

Citius Pharmaceuticals, Inc. and Citius Oncology, Inc. The data was summarized in a poster presentation titled "T-regulatory Cell Depletion with E7777. (denileukin diftitox-xcdl) Combined with ...

7. citiuspharma.com citiuspharma.com/pipeline/clinical-trials/default.aspx

Pipeline - Clinical Trials & Publications This study is an open label, Phase 1/1b study to investigate the safety and efficacy of a combined regimen of pembrolizumab with T-regulatory cell depletion and ...