APL-2 and Pembrolizumab Versus APL-2, Pembrolizumab and Bevacizumab Versus Bevacizumab Alone for the Treatment of Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Cancer and Malignant Effusion

Study Overview
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Brief Summary
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This phase randomized phase 2 clinical trial to study the safety and effect of C3 complement inhibitor APL-2 (Pegcetacoplan) alone and in combination with Pembrolizumab, as well as APL-2 in combination with both Bevacizumab and Pembrolizumab in patients with recurrent ovarian, fallopian tube or primary peritoneal cancer with symptomatic malignant effusion (ascites or pleural effusion). APL-2 (Pegcetacoplan) is the lead drug in the class of compstatins, which are synthetic peptides that bind to C3 and inhibit the classical and alternative pathway C3 convertase formation required for complement activation. The rationale for using APL-2 in recurrent ovarian, fallopian tube and primary peritoneal cancer with recurrent malignant effusion is two-fold: (1) to decrease the immune system suppressing neutrophil cell accumulation in tumor tissue thereby making immune check point blockade more effective; and (2) to prevent generation of anaphylatoxins (C3a, C4a, and C5a) that increase vessel permeability and lead to malignant fluid accumulation. The current standard for palliation of ascites and/or pleural effusions in recurrent ovarian/fallopian tube/primary peritoneal cancer involves the use of bevacizumab alone or combined with a chemotherapy drug as well as repeated drainage of the fluid.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the safety of APL-2 (Pegcetacoplan) alone and in combination with pembrolizumab, and APL-2 in combination with both bevacizumab and pembrolizumab in patients with recurrent ovarian cancer with symptomatic malignant effusion II. Effect of therapy on of malignant effusion measured by total volume of effusion drained every 3 weeks (patient diary and/or drained volume). SECONDARY OBJECTIVES: I. Determine progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and overall survival (OS) II. Changes in quality of life measures during the clinical trial This is a single center, randomized, Phase 2 clinical trial of APL-2 in combination with Pembrolizumab or in combination with Bevacizumab and Pembrolizumab vs. Bevacizumab alone in patients with recurrent ovarian/fallopian tube/primary peritoneal cancer and persistent malignant effusions. A safety-lead in cohort of 3-5 patients, (patients will receive APL-2 alone for 2 weeks prior to adding pembrolizumab or pembrolizumab and bevacizumab) will be recruited to assess the safety of APL-2 alone, determine PK/PD levels is serum and malignant effusion and to test the short-term single-agent APL-2 effects on malignant effusion. If no concerning treatment limiting toxicity signal is seen, the randomized expansion cohorts (2B) are allowed to start. Patients will be randomized to 1 of 3 cohorts (2 experimental arms and 1 standard of care control arm). COHORT 2B-1: APL-2 (Pegcetacoplan) and pembrolizumab (experimental arm) COHORT 2B-2: Pegcetacoplan, pembrolizumab and bevacizumab (experimental arm) COHORT 2B-3: Bevacizumab only (control arm) Treatment repeats every 3 weeks and treatment will continue until disease progression, patient withdrawal or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 12 weeks thereafter up to 3 years.

Official Title
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Randomized Phase 2 Trial of APL-2 With Pembrolizumab vs. APL-2 With Pembrolizumab and Bevacizumab vs. Bevacizumab Alone in Patients With Recurrent Ovarian Cancer and Persistent Malignant Effusion

Conditions
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Fallopian Tube Carcinosarcoma, Fallopian Tube Adenocarcinoma, Fallopian Tube Serous Adenocarcinoma, Ovarian Carcinosarcoma, Ovarian Clear Cell Adenocarcinoma, Ovarian Endometrioid Adenocarcinoma, Ovarian Serous Adenocarcinoma, Primary Peritoneal Adenocarcinoma, Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma

Intervention / Treatment
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* Biological: Bevacizumab
* Biological: Pegcetacoplan
* Biological: Pembrolizumab
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 18 years of age on day of signing informed consent Recurrent epithelial ovarian/fallopian tube or primary peritoneal cancer (serous, clear cell, endometrioid, mixed or poorly differentiated or carcinosarcoma) based on imaging or synchronous primary ovarian and uterine cancer patients with any of the histology subtypes mentioned above regardless of platinum sensitivity, prior stage or number of prior treatment lines Symptomatic ascites or pleural effusion or both requiring >= 1 drainage within 4-weeks of study entry or has a peritoneal/pleural drainage catheter in place to control symptoms Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Patient has not received bevacizumab or pembrolizumab or other immune checkpoint inhibitor treatment for 9 weeks prior to enrollment Life expectancy of >= 3 months Have the following clinical laboratory values: Absolute neutrophil count (ANC): ≥ 1,500/µL Platelets: ≥ 75,000/µL Hemoglobin: ≥ 9 g/dL or 5.6 mmol/L (within 7 days of assessment) Creatinine: ≤1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance ≥ 60 mL/min (Cockcroft-Gault Equation) for participant with creatinine levels > 1.5 X institutional ULN. GFR can also be used in place of creatinine or CrCl. Total bilirubin: ≤ 1.5 X ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 ULN AST (SGOT) and ALT (SGPT): ≤ 2.5 X ULN OR ≤ 5 X ULN for participants with liver metastases Albumin: >2.5gm/dL International Normalized Ratio (INR) or Prothrombin Time (PT): ≤1.5 unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants Activated Partial Thromboplastin Time (aPTT): ≤1.5 X ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants Participants of childbearing potential must have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required Participants of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 90 days after the last dose of study medication (participants of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year). Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately Willing and able to self-administer APL-2 (Pegcetacoplan) (administration by caregiver will be allowed) No known absolute contraindication to bevacizumab and/or pembrolizumab treatment per enrolling provider Willing to receive vaccination against Neisseria meningitidis, Streptococcus pneumoniae, and Hemophilus influenzae if randomized into an APL-2 (Pegcetacoplan) receiving arm, and if not already vaccinated Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure Exclusion Criteria: Is currently receiving any additional cancer therapy or participating or used an investigational drug or device within 3 weeks of the first dose of treatment Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment or, is taking any other medication that might affect immune function Has active autoimmune disease that has required systemic treatment in the past 3 months (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) is not considered a form of systemic treatment Has an active infection requiring systemic therapy Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator Participant has clinically significant cardiovascular disease including: Uncontrolled hypertension, defined as systolic >150 mmHg or diastolic >90 mmHg Myocardial infarction or unstable angina within 6 months prior to enrollment New York Heart Association (NYHA) Grade II or greater congestive heart failure Participant has a Grade II (NYHA) or greater peripheral vascular disease Participant has a clinically significant peripheral artery disease (e.g. those with claudication), within 6 months prior to study enrollment Pregnancy or lactation Unwilling or unable to follow protocol requirements Any condition which in the investigator's opinion deems the participant an unsuitable candidate to receive study drug

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 2B-1 (pegcetacoplan, pembrolizumab)<br> | Biological: Pegcetacoplan<br>* Given IV (only for loading dose) and SC<br>* Other names: APL2;Biological: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Cohort 2B-2 (pegcetacoplan, pembrolizumab, bevacizumab)<br> | Biological: Bevacizumab<br>* Given IV<br>* Other names: Zirabev;Biological: Pegcetacoplan<br>* Given IV (only for loading dose) and SC<br>* Other names: APL2;Biological: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Cohort 2B-3 (bevacizumab)<br> | Biological: Bevacizumab<br>* Given IV<br>* Other names: Zirabev;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Accumulation of effusion (Phase 2b) | Will determine the effect of therapy on accumulation of effusion measured by total volume removed every 3 weeks. The change in accumulation of effusion (relative to pre-treatment) will be modeled as a function of cohort, time-point, their two-way interaction, baseline levels, and a random subject effect using a linear mixed model. The change will be compared: a) over-time within each cohort, and b) between the control cohort (cohort C) and each dosing cohort (cohorts A and B) using two-sided Bonferroni or Dunnet adjusted tests about the appropriate contrasts of model estimates. The model assumptions will be evaluated graphically, and transformations will be applied as appropriate. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Will be summarized by cohort using standard Kaplan-Meier methods. As an exploratory analysis, the two dosing cohorts (cohorts A and B) may be compared to the control cohort (cohort C) compared using one-sided log-rank tests. | From treatment until death or last follow-up, assessed up to 3 years | 
| Progression free survival (PFS) | Will be summarized by cohort using standard Kaplan-Meier methods, where estimates of median PFS are obtained with 90% confidence intervals. As an exploratory analysis, the two dosing cohorts (cohorts A and B) may be compared to the control cohort (cohort C) compared using one-sided log-rank tests. | From treatment initiation until disease progression, death, or last disease assessment (censored), assessed up to 3 years | 
| Best response | Will be summarized by cohort using frequencies and relative frequencies. | Up to 3 years | 
| Overall response rate | Defined as the proportion of patients who have a partial or complete response to therapy. Will be estimated by cohort using 95% confidence intervals obtained by Jeffrey's prior method. | Up to 3 years | 
| Disease control rate | Defined as the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease. Will be estimated by cohort using 95% confidence intervals obtained by Jeffrey's prior method. | Up to 3 years | 
| Quality of life (QOL) scores | The QoL scores will be summarized by cohort and time-point using the appropriate descriptive statistics. Each QoL score will be model as a function of cohort, time, their two-way interaction, and a random subject effect using a linear mixed model. Comparisons between cohorts within timepoint or between timepoints within cohort will be made using tests about the appropriate contrasts of model estimates. All model assumptions will be evaluated graphically, and transformations will be applied as appropriate. | Up to 3 years |