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Trial of Pemetrexed and Bevacizumab for Recurrent Ovarian Primary Peritoneal Carcinoma

Sponsor
Washington University School of Medicine (Other)
Overall Status
Completed
CT.gov ID
NCT00868192
Collaborator
Columbia University (Other)
38
Enrollment
1
Location
1
Arm
55
Duration (Months)
0.7
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if the combination of bevacizumab and pemetrexed have an effect on recurrent ovarian and primary peritoneal carcinoma by looking at progression and survival at 6 months.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

Patients will be treated with pemetrexed 500 mg/m2 IV and Bevacizumab 15 mg/kg IV every 3 weeks.The patient is treated indefinitely until side effects are deemed severe by the investigator or until progression. Disease progression is measured every 6 weeks using RECIST criteria.

Study Design

Study Type:
Interventional
Actual Enrollment :
38 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase II Trial of Pemetrexed and Bevacizumab for Recurrent Ovarian and Primary Peritoneal Carcinoma
Study Start Date :
May 1, 2008
Actual Primary Completion Date :
Dec 1, 2012
Actual Study Completion Date :
Dec 1, 2012

Arms and Interventions

Arm Intervention/Treatment
Experimental: Pemetrexed and bevacizumab

Pemetrexed 500 mg/m2 IV on Day 1 of each 21 day cycle Bevacizumab 15 mg/kg IV on Day 1 of each 21 day cycle

Drug: Pemetrexed
Other Names:
  • Alimta

    • Drug: Bevacizumab
    Other Names:
  • Avastin

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Progression-free Survival (PFS) [6 months]

      PFS = Period from study entry until disease progression, death, or date of last contact

    Secondary Outcome Measures

    1. Distribution of Progression-free Survival (PFS) [Median follow-up was 25.7 months (range 3.0-47.2 months)]

      PFS = Period from study entry until disease progression, death, or date of last contact

    2. Distribution of Overall Survival (OS) [Median follow-up was 25.7 months (range 3.0-47.2 months)]

      OS = observed length of time from entry into the study to death or date of last contact

    3. Toxicity Associated With Bevacizumab and Pemetrexed [6 months]

      Detailed serious adverse events and other adverse events are shown in the adverse event module of the results.

    4. Frequency of Clinical Response [6 months]

      As measured by RECIST criteria

    5. Gene Expression as Assessed by Illumina cDNA Mediated Annealing, Selection, Extension and Ligation (DASL) Microarray From Paraffin-embedded Tumor Specimens With Response to Pemetrexed and Bevacizumab [6 months]

    6. Association Between Levels of Thymidylate Synthase, Dihydrofolate Reductase, and Glycinamide Ribonucleotide Formyl Transferase and Ovarian Response to Pemetrexed and Bevacizumab [6 months]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Recurrent epithelial ovarian or primary peritoneal carcinoma. Histologic confirmation of the primary tumor is required. Patients with borderline tumors are not eligible.

    • Patients must have measurable disease. Measurable disease is defined as at least one lesion that can be accurately measured in one dimension (longest dimension to be recorded). Each lesion must by > 20 mm when measured by conventional imaging techniques, including plain radiography, computed tomography and MRI or > 10 mm when measured by spiral CT.

    • Patients must have at least one "target lesion" to assess response by RECIST criteria. Lesions within a previously irradiated field will be considered "non-target" lesions.

    • Patients must have a GOG performance status of 0 or 1.

    • Patients must have the ability to interrupt non-steroidal anti-inflammatory (NSAID) treatment 2 days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of pemetrexed.

    • Patients must have the ability to take folic acid, vitamin B12 and dexamethasone as described per protocol.

    • Recovery from effects of recent surgery, radiotherapy or chemotherapy.

    • Patients should be free of active infection requiring antibiotics.

    • Any hormonal therapy directed at the tumor must be discontinued at least one week prior to registration. Continuation of hormone replacement therapy (HRT) is permitted.

    • Any other prior therapy directed at the malignant tumor, including immunologic agents and cytotoxic agents, must be discontinued at least three weeks prior to registration.

    • Patients must have had one prior platinum-based chemotherapeutic regimen for management of primary disease containing carboplatin, cisplatin, or another organoplatinum compound. This initial treatment may have included high-dose therapy, consolidation, or extended therapy administered after surgical or non-surgical assessment.

    • Patients must have had one prior regimen containing a taxane compound. Patient may have received first-line treatment either intravenously or intraperitoneally.

    • Patients must NOT have received prior therapy with pemetrexed or bevacizumab.

    • Patients may have received a total of < 2 prior cytotoxic chemotherapy regimens (adjuvant therapy plus one additional regimen). Consolidation or extended therapy as part of first line treatment will be considered as a single regimen.

    • Bone marrow function: absolute neutrophil count (ANC) greater than or equal to 1,500/ul, equivalent to Common Toxicity Criteria (CTC) grade 1; Platelets greater than or equal to 100,000/ul.

    • Creatinine clearance must be greater than 45 ml/min.

    • Hepatic function: bilirubin less than or equal to 1.5 x ULN. AST and alkaline phosphatase less than or equal to 2.5 x ULN.

    • Neurologic function: neuropathy (sensory and motor) less than or equal to CTC grade 1.

    • Coagulation: prothrombin time (PT) such that the international normalized ratio (INR) is < 1.5 (INR may be between 2 and 3 if a patient is on stable dose of therapeutic warfarin) and a PTT < 1.2 times control.

    • Patients must have signed informed consent.

    • Patients must meet pre-entry requirements.

    • Patients of childbearing potential must have a negative serum pregnancy test prior to study entry, be practicing an effective form of contraception, and cannot be lactating.

    • Patients may have received prior radiotherapy (to less than 25% of bone marrow), but must start at a Level 1 dose reduction.

    Exclusion Criteria:

    • Patients with serious, non-healing wound, ulcer or bone fracture.

    • Patients with clinically significant cardiovascular disease:

    • Inadequately controlled hypertension (defined as systolic blood pressure > 150 and/or diastolic blood pressure > 100 mmHg on antihypertensive medications)

    • Any prior history of hypertensive crisis or hypertensive encephalopathy.

    • Unstable angina within 6 months prior to study enrollment.

    • New York Heart Association (NYHA) grade II or greater congestive heart failure.

    • Serious cardiac arrhythmia requiring medication.

    • Grade II or greater peripheral vascular disease. Patients with claudication within 6 months.

    • History of myocardial infarction within 6 months.

    • Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels.

    • Patients with the presence of ascites or other third space fluid which cannot be controlled by drainage.

    • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to day 1 of study or anticipation of need for major surgical procedure during the course of the study.

    • Patients with history or evidence upon physical examination of central nervous system disease, including primary brain tumor, brain metastases, seizure not controlled with standard medical therapy, history of cerebrovascular accident (CVA, stroke), or transient ischemic attack (TIA) or subarachnoid hemorrhage within 6 months of the first date of treatment on this study.

    • Minor surgical procedures, other than central venous access placement, such as fine needle aspiration or core biopsy within 7 days prior to day 1 of study.

    • Patients with proteinuria. At baseline patients will undergo a urine protein-creatinine ratio (UPCR) (Appendix IV). Patients with a UPCR > 1.0 at screening should be excluded. Urine dipstick for proteinuria may also be used. Urine dipstick for proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible).

    • Patients whose circumstances do not permit completion of the study or the required follow-up.

    • Patients who are pregnant or nursing.

    • Patients under the age of 18.

    • Patients with other invasive malignancies, with the exception of non-melanoma skin cancer, who had (or have) any evidence of other cancer within the last 5 years or whose previous cancer treatment contraindicates this protocol.

    • Prior therapy with anti-angiogenic agents or pemetrexed.

    • Patients with active infection requiring parenteral antibiotics.

    • History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months.

    • Partial or complete small or large bowel obstruction demonstrated radiographically within 3 months prior to study.

    • Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study other than a Genentech-sponsored bevacizumab cancer study.

    • Known hypersensitivity to any component of bevacizumab.

    • Inability to comply with study and/or follow-up procedures.

    • Life expectancy of less than 12 weeks.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Washington University School of Medicine St. Louis Missouri United States 63110

    Sponsors and Collaborators

    • Washington University School of Medicine
    • Columbia University

    Investigators

    • Principal Investigator: David G Mutch, M.D., Washington University School of Medicine

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    Responsible Party:
    Washington University School of Medicine
    ClinicalTrials.gov Identifier:
    NCT00868192
    Other Study ID Numbers:
    • 08-0508 / 201102272
    First Posted:
    Mar 24, 2009
    Last Update Posted:
    Oct 20, 2014
    Last Verified:
    Oct 1, 2014
    Additional relevant MeSH terms:
    Carcinoma
    Bevacizumab
    Pemetrexed

    Study Results

    Participant Flow

    Recruitment Details The study was open to participant enrollment on 05/28/2008 and closed to participant enrollment on 11/30/2010.
    Pre-assignment Detail
    Arm/Group Title Pemetrexed and Bevacizumab
    Arm/Group Description Pemetrexed 500 mg/m2 IV on Day 1 of each 21 day cycle Bevacizumab 15 mg/kg IV on Day 1 of each 21 day cycle
    Period Title: Overall Study
    STARTED 38
    COMPLETED 34
    NOT COMPLETED 4

    Baseline Characteristics

    Arm/Group Title Pemetrexed and Bevacizumab
    Arm/Group Description Pemetrexed 500 mg/m2 IV on Day 1 of each 21 day cycle Bevacizumab 15 mg/kg IV on Day 1 of each 21 day cycle
    Overall Participants 34
    Age (years) [Mean (Full Range) ]
    Mean (Full Range) [years]
    61.5
    Sex: Female, Male (Count of Participants)
    Female
    34
    100%
    Male
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    34
    100%
    Stage (participants) [Number]
    Stage I/II
    1
    2.9%
    Stage III
    27
    79.4%
    Stage IV
    6
    17.6%
    Histology (participants) [Number]
    Serous
    24
    70.6%
    Endometriod
    2
    5.9%
    Mixed
    3
    8.8%
    Other
    5
    14.7%
    Tumor grade (participants) [Number]
    Grade 1
    3
    8.8%
    Grade 2
    1
    2.9%
    Grade 3
    30
    88.2%
    Pathologic diagnosis (participants) [Number]
    Ovarian
    27
    79.4%
    Fallopian tube
    1
    2.9%
    Primary peritoneal
    6
    17.6%
    Gynecologic Oncology Group (GOG) Performance Status (participants) [Number]
    0
    22
    64.7%
    1
    12
    35.3%
    Prior number of chemotherapy regimens (participants) [Number]
    1
    20
    58.8%
    2
    14
    41.2%
    Platinum-free interval (participants) [Number]
    <6 months
    12
    35.3%
    6-12 months
    11
    32.4%
    >12 months
    11
    32.4%

    Outcome Measures

    1. Primary Outcome
    Title Progression-free Survival (PFS)
    Description PFS = Period from study entry until disease progression, death, or date of last contact
    Time Frame 6 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pemetrexed and Bevacizumab
    Arm/Group Description Pemetrexed 500 mg/m2 IV on Day 1 of each 21 day cycle Bevacizumab 15 mg/kg IV on Day 1 of each 21 day cycle
    Measure Participants 34
    Number (95% Confidence Interval) [percentage of participants]
    56
    164.7%
    2. Secondary Outcome
    Title Distribution of Progression-free Survival (PFS)
    Description PFS = Period from study entry until disease progression, death, or date of last contact
    Time Frame Median follow-up was 25.7 months (range 3.0-47.2 months)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pemetrexed and Bevacizumab
    Arm/Group Description Pemetrexed 500 mg/m2 IV on Day 1 of each 21 day cycle Bevacizumab 15 mg/kg IV on Day 1 of each 21 day cycle
    Measure Participants 34
    Platinum-free interval of <6 months
    6.7
    Platinum-free interval of 6-12 months
    4.7
    Platinum-free interval of >12 months
    16.8
    3. Secondary Outcome
    Title Distribution of Overall Survival (OS)
    Description OS = observed length of time from entry into the study to death or date of last contact
    Time Frame Median follow-up was 25.7 months (range 3.0-47.2 months)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pemetrexed and Bevacizumab
    Arm/Group Description Pemetrexed 500 mg/m2 IV on Day 1 of each 21 day cycle Bevacizumab 15 mg/kg IV on Day 1 of each 21 day cycle
    Measure Participants 34
    Platinum-free interval of <6 months
    16.7
    Platinum-free interval of 6-12 months
    24.9
    Platinum-free interval of >12 months
    28.0
    4. Secondary Outcome
    Title Toxicity Associated With Bevacizumab and Pemetrexed
    Description Detailed serious adverse events and other adverse events are shown in the adverse event module of the results.
    Time Frame 6 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pemetrexed and Bevacizumab
    Arm/Group Description Pemetrexed 500 mg/m2 IV on Day 1 of each 21 day cycle Bevacizumab 15 mg/kg IV on Day 1 of each 21 day cycle
    Measure Participants 34
    Grade 3/4 hematologic toxicity
    53
    155.9%
    Most common non-hematologic toxicity - fatigue
    94
    276.5%
    Grade 3 renal toxicity
    6
    17.6%
    Gastrointestinal toxicity
    91
    267.6%
    Subsequently developed hematologic malignancies
    6
    17.6%
    5. Secondary Outcome
    Title Frequency of Clinical Response
    Description As measured by RECIST criteria
    Time Frame 6 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pemetrexed and Bevacizumab
    Arm/Group Description Pemetrexed 500 mg/m2 IV on Day 1 of each 21 day cycle Bevacizumab 15 mg/kg IV on Day 1 of each 21 day cycle
    Measure Participants 34
    Complete response
    0
    0%
    Partial response
    14
    41.2%
    Stable disease
    18
    52.9%
    Progressive disease
    2
    5.9%
    6. Secondary Outcome
    Title Gene Expression as Assessed by Illumina cDNA Mediated Annealing, Selection, Extension and Ligation (DASL) Microarray From Paraffin-embedded Tumor Specimens With Response to Pemetrexed and Bevacizumab
    Description
    Time Frame 6 months

    Outcome Measure Data

    Analysis Population Description
    This outcome was not analyzed. Columbia University was to participate in this study but did not. They were to perform the correlative studies.
    Arm/Group Title Pemetrexed and Bevacizumab
    Arm/Group Description Pemetrexed 500 mg/m2 IV on Day 1 of each 21 day cycle Bevacizumab 15 mg/kg IV on Day 1 of each 21 day cycle
    Measure Participants 0
    7. Secondary Outcome
    Title Association Between Levels of Thymidylate Synthase, Dihydrofolate Reductase, and Glycinamide Ribonucleotide Formyl Transferase and Ovarian Response to Pemetrexed and Bevacizumab
    Description
    Time Frame 6 months

    Outcome Measure Data

    Analysis Population Description
    This outcome was not analyzed. Columbia University was to participate in this study but did not. They were to perform the correlative studies.
    Arm/Group Title Pemetrexed and Bevacizumab
    Arm/Group Description Pemetrexed 500 mg/m2 IV on Day 1 of each 21 day cycle Bevacizumab 15 mg/kg IV on Day 1 of each 21 day cycle
    Measure Participants 0
    8. Post-Hoc Outcome
    Title Overall Survival (OS)
    Description OS = observed length of time from entry into the study to death or date of last contact
    Time Frame 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pemetrexed and Bevacizumab
    Arm/Group Description Pemetrexed 500 mg/m2 IV on Day 1 of each 21 day cycle Bevacizumab 15 mg/kg IV on Day 1 of each 21 day cycle
    Measure Participants 34
    Number (95% Confidence Interval) [percentage of participants]
    79
    232.4%
    9. Post-Hoc Outcome
    Title Progression-free Survival (PFS)
    Description PFS = Period from study entry until disease progression, death, or date of last contact
    Time Frame Median follow-up was 25.7 months (range 3.0-47.2 months)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pemetrexed and Bevacizumab
    Arm/Group Description Pemetrexed 500 mg/m2 IV on Day 1 of each 21 day cycle Bevacizumab 15 mg/kg IV on Day 1 of each 21 day cycle
    Measure Participants 34
    Median (95% Confidence Interval) [months]
    7.9
    10. Post-Hoc Outcome
    Title Overall Survival (OS)
    Description OS = observed length of time from entry into the study to death or date of last contact
    Time Frame Median follow-up was 25.7 months (range 3.0-47.2 months)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pemetrexed and Bevacizumab
    Arm/Group Description Pemetrexed 500 mg/m2 IV on Day 1 of each 21 day cycle Bevacizumab 15 mg/kg IV on Day 1 of each 21 day cycle
    Measure Participants 34
    Median (95% Confidence Interval) [months]
    25.7
    11. Post-Hoc Outcome
    Title Overall Response Rate
    Description Overall response rate = complete response + partial response Complete response = disappearance of all target and non-target lesions and no evidence of new lesions documented by two disease assessments at least 4 weeks apart. Partial response = at least a 30% decrease in the sum of the longest dimensions (LD) of all target measurable lesions taking as reference the baseline sum of LD. There can be non unequivocal progression of non-target lesions and no new lesions.
    Time Frame 6 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pemetrexed and Bevacizumab
    Arm/Group Description Pemetrexed 500 mg/m2 IV on Day 1 of each 21 day cycle Bevacizumab 15 mg/kg IV on Day 1 of each 21 day cycle
    Measure Participants 34
    Number (95% Confidence Interval) [percentage of participants]
    41
    120.6%
    12. Post-Hoc Outcome
    Title CA-125 Response
    Description A CA-125 response was defined as at least a 50% reduction in CA-125 levels from a pretreatment sample following guidelines described by the Gynecological Cancer Intergroup.
    Time Frame 6 months

    Outcome Measure Data

    Analysis Population Description
    7 participants were not evauable by CA-125 criteria.
    Arm/Group Title Pemetrexed and Bevacizumab
    Arm/Group Description Pemetrexed 500 mg/m2 IV on Day 1 of each 21 day cycle Bevacizumab 15 mg/kg IV on Day 1 of each 21 day cycle
    Measure Participants 27
    50% CA-125 response
    17
    50%
    75% CA-125 response
    8
    23.5%
    No CA-125 response
    2
    5.9%

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Pemetrexed and Bevacizumab
    Arm/Group Description Pemetrexed 500 mg/m2 IV on Day 1 of each 21 day cycle Bevacizumab 15 mg/kg IV on Day 1 of each 21 day cycle
    All Cause Mortality
    Pemetrexed and Bevacizumab
    Affected / at Risk (%) # Events
    Total / (NaN)
    Serious Adverse Events
    Pemetrexed and Bevacizumab
    Affected / at Risk (%) # Events
    Total 5/34 (14.7%)
    Gastrointestinal disorders
    Nausea 1/34 (2.9%)
    Vomiting 2/34 (5.9%)
    Small bowel obstruction 1/34 (2.9%)
    Vascular disorders
    Thromobolic event 1/34 (2.9%)
    Septic embolism 1/34 (2.9%)
    Other (Not Including Serious) Adverse Events
    Pemetrexed and Bevacizumab
    Affected / at Risk (%) # Events
    Total 34/34 (100%)
    Blood and lymphatic system disorders
    Anemia 28/34 (82.4%)
    Impaired coagulation 6/34 (17.6%)
    Lymphatics 1/34 (2.9%)
    Cardiac disorders
    Cardiovascular 11/34 (32.4%)
    Ear and labyrinth disorders
    Auditory 1/34 (2.9%)
    Endocrine disorders
    Endocrine 1/34 (2.9%)
    Eye disorders
    Ocular 6/34 (17.6%)
    Gastrointestinal disorders
    Gastrointestinal 27/34 (79.4%)
    General disorders
    Constitutional 32/34 (94.1%)
    Hemorrhage 4/34 (11.8%)
    Pain 29/34 (85.3%)
    Immune system disorders
    Allergy 11/34 (32.4%)
    Infections and infestations
    Infection/febrile neutropenia 14/34 (41.2%)
    Investigations
    Leukopenia 28/34 (82.4%)
    Thrombocytopenia 15/34 (44.1%)
    Neutropenia 33/34 (97.1%)
    Metabolism and nutrition disorders
    Metabolic 31/34 (91.2%)
    Musculoskeletal and connective tissue disorders
    Musculoskeletal 2/34 (5.9%)
    Nervous system disorders
    Neurologic 21/34 (61.8%)
    Renal and urinary disorders
    Genitourinary 6/34 (17.6%)
    Respiratory, thoracic and mediastinal disorders
    Pulmonary 16/34 (47.1%)
    Skin and subcutaneous tissue disorders
    Rash 23/34 (67.6%)
    Vascular disorders
    Vascular 1/34 (2.9%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title David G. Mutch, M.D.
    Organization Washington University School of Medicine
    Phone 314-362-2181
    Email mutchd@wudosis.wustl.edu
    Responsible Party:
    Washington University School of Medicine
    ClinicalTrials.gov Identifier:
    NCT00868192
    Other Study ID Numbers:
    • 08-0508 / 201102272
    First Posted:
    Mar 24, 2009
    Last Update Posted:
    Oct 20, 2014
    Last Verified:
    Oct 1, 2014