Ovarian Cancer Clinical Trial

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

Summary

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.

View Full Description

Full Description

PRIMARY OBJECTIVES:

I. Determine the safety of pegcetacoplan (APL-2) 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 (Common Terminology Criteria for Adverse Events [CTCAE] version 5.0).

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) per immune related response criteria (irRECIST).

II. Changes in quality of life measures during the clinical trial (European Organisation for the Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire [QLQ]-Core 30 [C30], EORTC QLQ-Ovarian version 28 [OV28] and Multidimensional Fatigue Symptom Inventory-Short Form [MFSI-SF]).

EXPLORATORY OBJECTIVES:

I. Evaluate the immunologic and phenotypic changes in malignant effusions and blood samples in all cohorts, which can include the following:

Ia. To understand the signaling mechanisms in ascites primed neutrophils and their effects on tumor cell growth.

Ib. To understand the changes in complement activation pathways. Ic. Functional assays of neutrophil, macrophage and T cells. Id. Flow cytometry for immune cell composition. Ie. Luminex assay for circulation inflammatory cytokines/chemokines, angiogenesis markers.

II. In patients with solid tumor lesions accessible by image-guided core biopsies the effects of therapy will be determined on the immune composition of tumor microenvironment. Studies on tumor may include immune cell infiltration, ribonucleic acid (RNA)-sequencing (Seq) and T cell receptor (TCR)-Seq for immune cell activation and exhaustion markers, complement deposits, genomic and transcriptomic profile.

III. Microbiome analysis from stool, tumor tissue and malignant effusions. IV. Determine the concentration (pharmacokinetics [PK]/pharmacodynamics [PD]) of APL-2 in serum and malignant effusion.

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP 2A: Patients are assigned to 1 of 2 cohorts.

COHORT 2A-1: Patients receive pegcetacoplan intravenously (IV) over 20-40 minutes on day 1 of cycle 1 and then subcutaneously (SC) twice weekly (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.

COHORT 2A-2: 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 2B: Patients are assigned to 1 of 3 cohorts.

COHORT 2B-1: 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.

COHORT 2B-2: 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.

COHORT 2B-3: 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.

After completion of study treatment, patients are followed up at 30 days and then every 12 weeks thereafter.

View Eligibility Criteria

Eligibility Criteria

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 0-1
Patient has not received pembrolizumab or other immune checkpoint inhibitor treatment for 9 weeks prior to enrollment
Life expectancy of >= 3 months
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 creatinine clearance (CrCl)
Total bilirubin: =< 1.5 X ULN OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 ULN
Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]): =< 2.5 X ULN OR =< 5 X ULN for participants with liver metastases
Albumin: > 2.5 gm/dL
International Normalized Ratio (INR) or Prothrombin Time (PT): =< 1.5 unless participant is receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (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
A woman 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 120 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 (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 receiving arm, 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
Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
Has a known history of human immunodeficiency virus (HIV) infection
Concurrent active hepatitis B (defined as hepatitis B surface antigen [HBsAg] positive and/or detectable HBV deoxyribonucleic acid [DNA]) and hepatitis C virus (HCV) (defined as anti-HCV Ab positive and detectable HCV ribonucleic acid [RNA]) infection. Note: Hepatitis B and C screening tests are not required unless known history of HBV and HCV infection
Has received any investigational vaccines (i.e., those not licensed or approved for emergency use). Note: Any licensed COVID-19 vaccine (including for Emergency Use) is allowed in the study as long as they are modified ribonucleic acid (mRNA) vaccines, adenoviral vaccines, or inactivated vaccines. These vaccines will be treated just as any other concomitant therapy. Investigational vaccines (i.e., those not licensed or approved for emergency use) are not allowed
Known additional malignancy that is progressing or has required active treatment within the past 2 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded

Study is for people with:

Ovarian Cancer

Phase:

Phase 2

Estimated Enrollment:

60

Study ID:

NCT04919629

Recruitment Status:

Recruiting

Sponsor:

Roswell Park Cancer Institute

Check Your Eligibility

Let’s see if you might be eligible for this study.

What is your age and gender ?

Submit

There is 1 Location for this study

See Locations Near You

Roswell Park Cancer Institute
Buffalo New York, 14263, United States More Info
Emese Zsiros
Contact
716-845-8337
[email protected]
Emese Zsiros
Principal Investigator

How clear is this clinincal trial information?

Study is for people with:

Ovarian Cancer

Phase:

Phase 2

Estimated Enrollment:

60

Study ID:

NCT04919629

Recruitment Status:

Recruiting

Sponsor:


Roswell Park Cancer Institute

How clear is this clinincal trial information?

×

Introducing, the Journey Bar

Use this bar to access information about the steps in your cancer journey.