Clinical Trials /

Bevacizumab and Anetumab Ravtansine or Paclitaxel in Treating Participants With Refractory Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

NCT03587311

Description:

This phase II trial studies the side effects of bevacizumab and anetumab ravtansine or paclitaxel in treating participants with ovarian, fallopian tube, or primary peritoneal cancer that does not respond to treatment. Monoclonal antibodies, such as bevacizumab and anetumab ravtansine, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving bevacizumab and anetumab ravtansine or paclitaxel may work better in treating participants with ovarian, fallopian tube, or primary peritoneal cancer.

Related Conditions:
  • Fallopian Tube Endometrioid Adenocarcinoma
  • High Grade Fallopian Tube Serous Adenocarcinoma
  • High Grade Ovarian Serous Adenocarcinoma
  • Ovarian Endometrioid Adenocarcinoma
  • Primary Peritoneal Serous Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Bevacizumab and Anetumab Ravtansine or Paclitaxel in Treating Participants With Refractory Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
  • Official Title: A Randomized Phase 2 Study of Bevacizumab and Either Weekly Anetumab Ravtansine or Weekly Paclitaxel in Platinum-Resistant or Platinum Refractory Ovarian Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2018-01503
  • SECONDARY ID: NCI-2018-01503
  • SECONDARY ID: 10150
  • SECONDARY ID: 10150
  • SECONDARY ID: UM1CA186644
  • NCT ID: NCT03587311

Conditions

  • Fallopian Tube Endometrioid Adenocarcinoma
  • High Grade Fallopian Tube Serous Adenocarcinoma
  • High Grade Ovarian Serous Adenocarcinoma
  • Ovarian Endometrioid Adenocarcinoma
  • Platinum-Resistant Ovarian Carcinoma
  • Primary Peritoneal High Grade Serous Adenocarcinoma
  • Refractory Fallopian Tube Carcinoma
  • Refractory Ovarian Carcinoma
  • Refractory Primary Peritoneal Carcinoma

Interventions

DrugSynonymsArms
Anetumab RavtansineBAY 94-9343GROUP I (anetumab ravtansine, bevacizumab)
BevacizumabAnti-VEGF, Anti-VEGF Humanized Monoclonal Antibody, Anti-VEGF rhuMAb, Avastin, Bevacizumab Biosimilar BEVZ92, Bevacizumab Biosimilar BI 695502, Bevacizumab Biosimilar CBT 124, Bevacizumab Biosimilar FKB238, Bevacizumab Biosimilar HD204, Bevacizumab Biosimilar HLX04, Bevacizumab Biosimilar IBI305, Bevacizumab Biosimilar LY01008, Bevacizumab Biosimilar MIL60, Bevacizumab Biosimilar QL 1101, Bevacizumab Biosimilar SCT501, 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, Recombinant Humanized Anti-VEGF Monoclonal Antibody, rhuMab-VEGF, SCT501GROUP I (anetumab ravtansine, bevacizumab)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratGROUP II (paclitaxel, bevacizumab)

Purpose

This phase II trial studies the side effects of bevacizumab and anetumab ravtansine or paclitaxel in treating participants with ovarian, fallopian tube, or primary peritoneal cancer that does not respond to treatment. Monoclonal antibodies, such as bevacizumab and anetumab ravtansine, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving bevacizumab and anetumab ravtansine or paclitaxel may work better in treating participants with ovarian, fallopian tube, or primary peritoneal cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess the safety and tolerability of the combination of weekly anetumab ravtansine
      (anetumab) and bi-weekly bevacizumab.

      II. To determine whether the progression free survival (PFS) of the combination weekly
      anetumab and bi-weekly bevacizumab is superior to weekly paclitaxel and bi-weekly
      bevacizumab.

      SECONDARY OBJECTIVES:

      I. To determine the overall response rate (ORR) according to Response Evaluation Criteria in
      Solid Tumors (RECIST) version (v)1.1.

      II. To evaluate the pharmacokinetic (PK) profiles of weekly anetumab in serum and in
      peripheral blood mononuclear cells (PBMCs).

      III. To evaluate anti-drug antibody (ADA) titers (only for patients receiving anetumab).

      IV. To evaluate mononuclear phagocyte system (MPS) function, Fc-gamma receptors (FcgammaRs),
      hormone and chemokine mediators.

      V. To correlate the expression of CA125 (immunohistochemistry [IHC] & serum) with mesothelin
      expression in archival tissue and circulating megakaryocyte potentiating factor (MPF).

      VI. To investigate blood-based angiome profiling as a potential biomarker. VII. To
      characterize the molecular profile of archival tumor tissue using the Oncomine panel, and
      explore whether genomic mutations such as BRCA1/2 and homologous repair deficiency status are
      associated with clinical outcome.

      EXPLORATORY OBJECTIVES:

      I. To assess tumor tissue-based VEGF-dependent gene expression signature as a biomarker of
      response.

      OUTLINE:

      PHASE I: Participants receive anetumab ravtansine intravenously (IV) over 1 hour on days 1,
      8, 15, and 22 and bevacizumab over 30-90 minutes IV on days 1 and 15. Courses repeat every 28
      days in the absence of disease progression or unacceptable toxicity.

      PHASE II: Participants are randomized to 1 of 2 groups.

      GROUP I: Participants receive anetumab ravtansine and bevacizumab as in Phase I.

      GROUP II: Participants receive paclitaxel on days 1, 8, 15, and 22 and bevacizumab over 30-90
      minutes IV on days 1 and 15. Courses repeat every 28 days in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, participants are followed up at 30-37 days and then
      every 8 weeks thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
GROUP I (anetumab ravtansine, bevacizumab)ExperimentalParticipants receive anetumab ravtansine IV over 1 hour on days 1, 8, 15, and 22 and bevacizumab over 30-90 minutes IV on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Anetumab Ravtansine
  • Bevacizumab
GROUP II (paclitaxel, bevacizumab)ExperimentalParticipants receive paclitaxel on days 1, 8, 15, and 22 and bevacizumab over 30-90 minutes IV on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Bevacizumab
  • Paclitaxel

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically or cytologically confirmed high grade serous or high
             grade endometrioid ovarian, fallopian tube, primary peritoneal cancer

          -  Patients must have platinum resistant (platinum-free interval < 6 months) or platinum
             refractory disease as per Gynecological Cancer Intergroup (GCIC) criteria

          -  Patients must have radiologic evidence of disease progression

          -  Criteria only for the randomized phase 2 part: patients must have measurable disease,
             defined as at least one lesion that can be accurately measured in at least one
             dimension (longest diameter to be recorded for non-nodal lesions and short axis for
             nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral
             computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by
             clinical exam

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Leukocytes >= 3 x 10^9/L

          -  Absolute neutrophil count >= 1.5 x 10^9/L

          -  Platelets >= 100 x 10^9/L

          -  Total bilirubin =< upper limit of normal (ULN) (except in Gilbert's syndrome)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =<
             2.5 x institutional upper limit of normal (ULN)

          -  Serum creatinine =< 1.5 x ULN

          -  Creatinine clearance >= 50 mL/min/1.73 m^2 for patients with creatinine levels above
             1.5 x institutional normal (using the Cockcroft Gault formula)

          -  Urine protein / creatinine ratio (UPCR) =< 1

          -  Ongoing prior toxicities related to previous treatments must be recovered to < grade 2
             at the time of registration (with the exception of alopecia, grade 2 peripheral
             neuropathy or lymphopenia)

          -  Criteria only for the randomized phase 2 part: mesothelin screen positive determined
             from archival tumor tissue and to be performed centrally. MSLN-positive is defined as
             >= 30% of tumor cells with membrane staining intensities >= 2+

               -  For the run-in-phase 1, patients will not be selected based on the mesothelin
                  expression

          -  Patients with known brain metastases are not excluded from this clinical trial.
             Patients who received palliative radiation (for brain metastases) are eligible if they
             have been asymptomatic for at least 4 weeks without use of maintenance steroid
             therapy, and last received radiation at least 4 weeks prior to proposed start of
             therapy

          -  Ability to understand and the willingness to sign a written informed consent document.
             Patients with Impaired Decision Making Capacity (IDMC) can have a Legally Authorized
             Representative sign on their behalf. Documentation, such as a Power of Attorney, must
             be presented in order for a substitute decision maker to be allowed

        Exclusion Criteria:

          -  Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering the study or those who have not
             recovered from adverse events due to agents administered more than 4 weeks earlier

          -  Patients who are receiving any other investigational agents

          -  History of severe allergic reactions attributed to compounds of similar chemical or
             biologic composition to bevacizumab, anetumab ravtansine or paclitaxel

          -  Patients receiving any medications or substances that are strong inhibitors or
             inducers of CYP3A4 are ineligible. As part of the enrollment/informed consent
             procedures, the patient will be counseled on the risk of interactions with other
             agents, and what to do if new medications need to be prescribed or if the patient is
             considering a new over-the-counter medicine or herbal product. Strong inhibitors and
             inducers of CYP3A4 are prohibited within 2 weeks before the start of and during
             treatment. Strong inhibitors and inducers of CYP2C8 should be used with caution; the
             PI of the study is to be consulted regarding their use

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, or psychiatric illness/social
             situations that would limit compliance with study requirements

          -  Pregnant women are excluded from this study because of the potential for teratogenic
             or abortifacient effects. Because there is an unknown but potential risk for adverse
             events in nursing infants secondary to treatment of the mother, breastfeeding should
             be discontinued during the study and for at least 6 months after last dose of study
             drugs. These potential risks may also apply to other agents used in this study. Women
             of child-bearing potential who do not agree to use adequate contraceptive measures
             during study therapy and for at least 6 months after the completion of study therapy
             will be excluded. Should a patient become pregnant or suspect she is pregnant while
             she is participating in this study, the patient should inform the treating physician
             immediately

          -  Serious or non-healing wound, ulcer or bone fracture

          -  History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
             within 6 months prior to day 1

          -  Invasive procedures defined as follows:

               -  Major surgical procedure or significant traumatic injury within 28 days prior to
                  day 1 therapy, or open biopsy within 7 days prior to day 1 therapy

               -  Anticipation of need for major surgical procedures during the course of the study

          -  Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or
             recent peripheral arterial thrombosis) within 6 months prior to day 1

          -  Patients with clinically significant cardiovascular disease are excluded

               -  Inadequately controlled hypertension (HTN) (systolic blood pressure [SBP] > 160
                  mmHg and/or diastolic blood pressure [DBP] > 90 mmHg despite antihypertensive
                  medication)

               -  History of cerebrovascular accident (CVA) within 6 months

               -  Myocardial infarction or unstable angina within 6 months

               -  Serious and inadequately controlled cardiac arrhythmia

               -  Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection)

               -  Clinically significant peripheral vascular disease

          -  Evidence of bleeding diathesis or coagulopathy

          -  Patients with known hypersensitivity to Chinese hamster ovary cell products or other
             recombinant human antibodies

          -  Current symptom of keratitis or retinopathy at >= grade 2

          -  Resting electrocardiogram (ECG) with corrected QT interval by Fridericia (QTcF) > 470
             msec or family history of long QT syndrome

          -  History of bowel obstruction within 28 days from proposed start of treatment

          -  History or evidence of arterial thrombotic or hemorrhagic disorders within 3 months
             before proposed start of treatment, non-healing wound, ulcer, or bone fracture

          -  Prior use of weekly paclitaxel or bevacizumab in the platinum resistant (disease
             progression within 6 months of platinum based chemotherapy)/refractory (disease
             progression during or following the 3 months of the first line platinum based
             chemotherapy) setting

          -  Known active human immunodeficiency virus (HIV) or hepatitis B or C infection
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:From the time of treatment start assessed up to 1 year
Safety Issue:
Description:PFS will be estimated using the Kaplan-Meier method and compared between groups with log rank test. Summary statistics will be provided, such as the median, 6-month and estimates, along with 95% confidence intervals. Plots will also be constructed which show the PFS estimate and 95% confidence intervals.

Secondary Outcome Measures

Measure:Response rate assessed using Response Evaluation Criteria in Solid Tumors
Time Frame:Up to 1 year
Safety Issue:
Description:Only one, single, final analysis is planned and statistical significance will be defined at the alpha = 0.05 level. All tests will be two-sided and 95% confidence levels will be constructed for outcomes of interest.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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