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

Trial Summary

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.

What data supports the effectiveness of the drug pembrolizumab in treating 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 patients whose tumors express certain proteins (PD-L1). ^{1 2 3 4 5}

What safety information is available for Pembrolizumab in clinical trials?

Pembrolizumab, also known as Keytruda, has been studied in various cancers and is generally considered less toxic than traditional chemotherapy, but it can cause side effects like pneumonitis (lung inflammation) in 1%-5% of patients. It has been evaluated for safety in ovarian cancer and other conditions, showing some adverse effects, but overall it is considered to have a manageable safety profile. ^{1 3 6 7 8}

How is the drug combination of APL-2, Pembrolizumab, and Bevacizumab unique for treating ovarian cancer?

This treatment is unique because it combines Pegcetacoplan (APL-2), which targets the complement system (part of the immune system), with Pembrolizumab, an immunotherapy drug that helps the immune system recognize and attack cancer cells, and optionally Bevacizumab, which inhibits blood vessel growth in tumors. This combination aims to enhance the immune response against ovarian cancer, offering a novel approach compared to traditional chemotherapy. ^{1 3 4 5 9}

What is the purpose of this trial?

This trial tests APL-2 alone or with other drugs in patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer that causes fluid buildup. APL-2 aims to slow tumor growth, reduce fluid buildup, and enhance the immune response. The study aims to determine the most effective treatment.

Research Team

Emese Zsiros

Principal Investigator

Roswell Park Cancer Institute

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

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 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]

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 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]

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]

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]

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]

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

Avelumab (anti-PD-L1) in platinum-resistant/refractory ovarian cancer: JAVELIN Ovarian 200 Phase III study design. [2022]

3. 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]

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

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

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

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

6. 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]

7. England pubmed.ncbi.nlm.nih.gov

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

8. England pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Combination lenvatinib plus pembrolizumab in the treatment of ovarian clear cell carcinoma: A case series. [2023]