Clinical Trials /

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

NCT04919629

Description:

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.

Related Conditions:
  • Fallopian Tube Carcinosarcoma
  • Fallopian Tube Clear Cell Adenocarcinoma
  • Fallopian Tube Endometrioid Adenocarcinoma
  • Fallopian Tube Serous Adenocarcinoma
  • Malignant Ovarian Mixed Epithelial Tumor
  • Ovarian Carcinosarcoma
  • Ovarian Clear Cell Adenocarcinoma
  • Ovarian Endometrioid Adenocarcinoma
  • Ovarian Serous Adenocarcinoma
  • Primary Peritoneal Carcinosarcoma
  • Primary Peritoneal Clear Cell Carcinoma
  • Primary Peritoneal Endometrioid Adenocarcinoma
  • Primary Peritoneal Serous Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: I 798120
  • SECONDARY ID: NCI-2021-04265
  • SECONDARY ID: I 798120
  • NCT ID: NCT04919629

Conditions

  • 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

Interventions

DrugSynonymsArms
BevacizumabABP 215, Anti-VEGF, Anti-VEGF Humanized Monoclonal Antibody, Anti-VEGF rhuMAb, Avastin, Bevacizumab awwb, Bevacizumab Biosimilar ABP 215, Bevacizumab Biosimilar BEVZ92, Bevacizumab Biosimilar BI 695502, Bevacizumab Biosimilar CBT 124, Bevacizumab Biosimilar CT-P16, Bevacizumab Biosimilar FKB238, Bevacizumab Biosimilar GB-222, Bevacizumab Biosimilar HD204, Bevacizumab Biosimilar HLX04, Bevacizumab Biosimilar IBI305, Bevacizumab Biosimilar LY01008, Bevacizumab Biosimilar MIL60, Bevacizumab Biosimilar Mvasi, Bevacizumab Biosimilar QL 1101, Bevacizumab Biosimilar RPH-001, Bevacizumab Biosimilar SCT501, Bevacizumab Biosimilar Zirabev, Bevacizumab-awwb, Bevacizumab-bvzr, BP102, BP102 Biosimilar, HD204, Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer, Mvasi, Recombinant Humanized Anti-VEGF Monoclonal Antibody, rhuMab-VEGF, SCT501, ZirabevCohort 2B-2 (pegcetacoplan, pembrolizumab, bevacizumab)
PegcetacoplanAPL 2, APL-2, APL2Cohort 2B-1 (pegcetacoplan, pembrolizumab)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Cohort 2B-1 (pegcetacoplan, pembrolizumab)

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 2B-1 (pegcetacoplan, pembrolizumab)Experimental
  • Pegcetacoplan
  • Pembrolizumab
Cohort 2B-2 (pegcetacoplan, pembrolizumab, bevacizumab)Experimental
  • Bevacizumab
  • Pegcetacoplan
  • Pembrolizumab
Cohort 2B-3 (bevacizumab)Experimental
  • Bevacizumab

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 0-2

          -  Patient has not received bevacizumab or pembrolizumab or other immune checkpoint
             inhibitor treatment for 3 months prior to enrollment

          -  Life expectancy of >= 3 months

          -  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

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Accumulation of effusion (Phase 2b)
Time Frame:Up to 3 years
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Overall survival
Time Frame:From treatment until death or last follow-up, assessed up to 3 years
Safety Issue:
Description: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.
Measure:Progression free survival (PFS)
Time Frame:From treatment initiation until disease progression, death, or last disease assessment (censored), assessed up to 3 years
Safety Issue:
Description: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.
Measure:Best response
Time Frame:Up to 3 years
Safety Issue:
Description:Will be summarized by cohort using frequencies and relative frequencies.
Measure:Overall response rate
Time Frame:Up to 3 years
Safety Issue:
Description: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.
Measure:Disease control rate
Time Frame:Up to 3 years
Safety Issue:
Description: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.
Measure:Quality of life (QOL) scores
Time Frame:Up to 3 years
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Roswell Park Cancer Institute

Last Updated

June 28, 2021