APL-2 + Pembrolizumab +/- Bevacizumab for Ovarian Cancer

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Roswell Park Cancer Institute

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Immunodeficiency, Autoimmune disease, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

Duration: 21 weeks for initial cycles, up to 2 years for extended pembrolizumab treatment

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether combining APL-2 (Pegcetacoplan) with pembrolizumab, with or without bevacizumab, can more effectively treat recurrent ovarian, fallopian tube, or primary peritoneal cancer with fluid buildup compared to bevacizumab alone. APL-2 may slow tumor growth and enhance the immune system. This trial may suit individuals with this cancer type who have recently experienced fluid buildup requiring drainage. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on any additional cancer therapy or investigational drugs within 3 weeks of starting the trial, and you should not be on systemic steroid therapy or other immunosuppressive treatments within 7 days prior to the trial.

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

Previous studies have tested pegcetacoplan (APL-2) both alone and with pembrolizumab. These studies initially assessed the safety of pegcetacoplan alone before introducing pembrolizumab. So far, patients have generally tolerated this combination well. Common side effects include fatigue, nausea, and injection site reactions, but these are usually not serious.

When combined with pembrolizumab and bevacizumab, the safety profile remains similar. Some patients might experience more side effects with this combination, but studies suggest the treatment is mostly safe. Fatigue and high blood pressure may occur, but these side effects are often manageable.

Since this trial is in Phase 2, earlier studies have already checked safety, indicating the treatment is reasonably safe. However, monitoring for any new side effects remains important as more participants join the trials. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments in this trial because they combine innovative immunotherapy and complement inhibition strategies to tackle ovarian cancer. Pegcetacoplan is unique as it specifically targets the complement system, which plays a role in inflammation and tumor growth, potentially offering a novel way to disrupt cancer progression. Pembrolizumab, known for its immune checkpoint inhibition, boosts the body’s immune response against cancer cells. When combined with bevacizumab, which inhibits blood vessel growth in tumors, these treatments offer a multi-faceted approach that could enhance effectiveness beyond standard chemo-based therapies. This combination approach has the potential to improve outcomes by targeting different aspects of cancer biology simultaneously.

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

Research has shown that using APL-2 (pegcetacoplan) with pembrolizumab and bevacizumab might improve treatment for ovarian cancer. In this trial, some participants will receive the combination of pegcetacoplan, pembrolizumab, and bevacizumab, while others will receive pegcetacoplan and pembrolizumab without bevacizumab. APL-2 may slow tumor growth and enhance the immune system's ability to fight cancer. Pembrolizumab helps the immune system attack cancer cells and can improve survival rates. Bevacizumab has been effective in 16–21% of recurring ovarian cancer cases by slowing tumor growth. Together, these drugs aim to provide better results than bevacizumab alone, which is also under study in this trial. ^{6 7 8 9 10}

Who Is on the Research Team?

Emese Zsiros

Principal Investigator

Roswell Park Cancer Institute

Are You a Good Fit for This Trial?

This trial is for adults over 18 with recurrent ovarian, fallopian tube, or primary peritoneal cancer who haven't had Bevacizumab or immune checkpoint inhibitors in the last 9 weeks. They should have a life expectancy of at least 3 months and be able to self-administer APL-2 (Pegcetacoplan). Pregnant women and those on recent cancer therapy or immunosuppressants can't participate.

Inclusion Criteria

Understands the investigational nature of the study and signs an approved informed consent form

You are expected to live for at least 3 more months.

My cancer has returned in the ovary, fallopian tube, or peritoneum, or I have both ovarian and uterine cancer.

Exclusion Criteria

I am currently on medication for an infection.

I have been treated for an autoimmune disease in the last 3 months.

I have a serious heart condition.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive pegcetacoplan, pembrolizumab, and/or bevacizumab in various combinations. Treatment repeats every 3 weeks for up to 7 cycles, with pembrolizumab potentially continuing for up to 35 cycles.

21 weeks for initial cycles, up to 2 years for extended pembrolizumab treatment

1 visit every 3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with assessments including tumor biopsy and blood sample collection.

30 days post-treatment, then every 12 weeks

1 visit at 30 days, then every 12 weeks

Long-term Follow-up

Participants are monitored for overall survival, progression-free survival, and quality of life measures.

Up to 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Bevacizumab
• Pegcetacoplan
• Pembrolizumab

Trial Overview The study tests APL-2 (Pegcetacoplan) alone, combined with Pembrolizumab, and alongside both Bevacizumab and Pembrolizumab against Bevacizumab alone. It aims to improve immune response and reduce fluid buildup in patients with symptomatic malignant effusion due to certain cancers.

How Is the Trial Designed?

Group I: Cohort 2B-3 (bevacizumab) Experimental Treatment 4 Interventions

Patients receive bevacizumab IV on day 1 of each cycle. Treatment repeats every 3 weeks for up to 7 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy and blood sample collection throughout the study.

Group II: Cohort 2B-2 (pegcetacoplan, pembrolizumab, bevacizumab) Experimental Treatment 6 Interventions

Patients receive pegcetacoplan IV over 20-40 minutes on day 1 of cycle 1 and then SC BIW of each cycle. Patients also receive pembrolizumab IV and bevacizumab IV on day 1 of each cycle. Treatment repeats every 3 weeks for up to 7 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive pembrolizumab for up to 35 21-day cycles in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy and blood sample collection throughout the study.

Group III: Cohort 2B-1 (pegcetacoplan, pembrolizumab) Experimental Treatment 5 Interventions

(Expansion) Patients receive pegcetacoplan IV over 20-40 minutes on day 1 of cycle 1 and then SC BIW of each cycle. Treatment repeats every 3 weeks for up to 7 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV on day 1 of each cycle. Treatment repeats every 21 days for 6 cycles, followed by every 42 days for up to 35 total cycles in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy and blood sample collection throughout the study.

Group IV: Cohort 2A-2 (pegcetacoplan, pembrolizumab, bevacizumab) Experimental Treatment 6 Interventions

Patients receive pegcetacoplan IV over 20-40 minutes on day 1 of cycle 1 and then SC BIW of each cycle. Patients also receive pembrolizumab IV and bevacizumab IV on day 1of each cycle. Treatment repeats every 3 weeks for up to 7 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive pembrolizumab for up to 35 21-day cycles in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy and blood sample collection throughout the study.

Group V: Cohort 2A-1 (pegcetacoplan, pembrolizumab) Experimental Treatment 5 Interventions

Patients receive pegcetacoplan IV over 20-40 minutes on day 1 of cycle 1 and then SC BIW of each cycle. Patients also receive pembrolizumab IV on day 1 of each cycle. Treatment repeats every 3 weeks for up to 7 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive pembrolizumab for up to 35 21-day cycles in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy and blood sample collection throughout the study.

Pegcetacoplan is already approved in United States, European Union for the following indications:

Approved in United States as Empaveli for:

• Paroxysmal Nocturnal Hemoglobinuria (PNH)

Approved in European Union as Aspaveli for:

• Paroxysmal Nocturnal Hemoglobinuria (PNH)

Who Is Running the Clinical Trial?

Roswell Park Cancer Institute

Lead Sponsor

Trials

427

Recruited

40,500+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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 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 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]

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, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

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]

The JAVELIN Ovarian 200 trial is the first Phase III study to investigate the effectiveness of avelumab, a PD-L1 checkpoint inhibitor, in treating women with platinum-resistant ovarian cancer, involving multiple treatment arms to assess its efficacy.

The trial will measure overall survival and progression-free survival as primary outcomes, providing valuable insights into the potential benefits of avelumab alone or in combination with doxorubicin compared to doxorubicin alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab (anti-PD-L1) in platinum-resistant/refractory ovarian cancer: JAVELIN Ovarian 200 Phase III study design. Pujade-Lauraine, E., Fujiwara, K., Dychter, SS., et al.[2022]

In a small case series of three patients with recurrent ovarian clear cell carcinoma (OCCC), the combination of lenvatinib and pembrolizumab resulted in a remarkable overall response rate of 100%.

Patients experienced progression-free survival ranging from 10 months to not-yet-reached, indicating that this treatment may be effective for those with platinum-resistant disease, although two patients ultimately succumbed to their illness after 14 and 27 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination lenvatinib plus pembrolizumab in the treatment of ovarian clear cell carcinoma: A case series. Calo, CA., Levine, MD., Brown, MD., et al.[2023]

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]

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