Sequential Angiogenic Blockade for the Treatment of Recurrent Mullerian Malignancies

NCT00856180 | Completed Phase 2 Results DMC

• 1 other identifier: 08-148
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 2

Brief Summary

The goals of this study were to evaluate the efficacy and safety of sequentially blocking the angiogenesis pathway via known antiangiogenic mechanisms, first with bevacizumab and then addition of oral cyclophosphamide upon progression of cancer through bevacizumab. The drugs used in this study were chosen because of their known antiangiogenic properties, tolerability, and anti-ovarian cancer effects.

Conditions

Ovarian Cancer; Peritoneal Cancer; Fallopian Tube Cancer

Keywords

avastin; bevacizumab; cyclophosphamide; cytoxan; mullerian malignancies

Outcome Measures

Primary Outcomes (2)

• Therapy Completion Rate

  The therapy completion rate is defined as the proportion of participants who completed at least 3 months/4 cycles of therapy. Participants were treated until disease progression on the combination regimen or unacceptable toxicity. Clinical response was evaluated based on RECIST 1.0 criteria for measurable disease (MD) participants and Gynecologic Cancer Intergroup (GCIG) CA-125 (Rustin) criteria for non-MD participants. Per RECIST 1.0 for target lesions, PD is at least a 20% increase in sum LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or appearance of new lesions. For non-target lesions, PD is the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Serologic PD is rise in CA-125 or previously normal CA125 that rises to \>/=2xULN documented, both requiring 2nd confirmation.

  Serologic and radiologic disease assessments occurred every 2 cycles/6 weeks on treatment. Median treatment duration for this study cohort was 7.5 months (range 0.7-20.7).

• Grade 3-5 Gastrointestinal Perforation

  All grade 3-5 gastrointestinal perforation events based on CTCAEv3 as reported on case report forms.

  Assessed each cycle/3 weeks throughout treatment from time of first dose and up to day 30 post-treatment. Median treatment duration for this study cohort was 7.5 months (range 0.7-20.7).

Secondary Outcomes (3)

• Clinical Benefit Response Rate

  Radiologic disease assessments occurred every 2 cycles/6 weeks on treatment. Median treatment duration for this study cohort was 7.5 months (range 0.7-20.7).

• Progression-Free Survival (PFS)

  Radiologic disease assessments occurred every 2 cycles/6 weeks on treatment and every 3 months in follow-up until PD, death or lost to follow-up. Median treatment duration was 7.5 months (range 0.7-20.7) and survival follow-up 23 months..

• Overall Survival (OS)

  Participants were followed long-term for survival every 3 months from the end of treatment until death or lost to follow-up. Median follow-up was 23 months in this study cohort.

Study Arms (1)

Bevacizumab then Cyclophosphamide with Bevacizumab

EXPERIMENTAL

Patients were given a regimen of sequential antiangiogenic blockade and disease assessed serologically and radiologically every 2 cycles/6 weeks. Patients started with bevacizumab 15 mg/kg IV every 3 weeks until they experienced progressive disease (PD) \[RECIST 1.0 or Rustin criteria\] or significant toxicity. If clinically stable as assessed by their treating physician, patients then received cyclophosphamide 50 mg orally (PO) daily continuously with bevacizumab treatment. If second PD occurred, patients discontinued the combination treatment.

Drug: Bevacizumab; Drug: Cyclophosphamide

Interventions

Bevacizumab DRUG

Also known as: Avastin

Bevacizumab then Cyclophosphamide with Bevacizumab

Cyclophosphamide DRUG

Also known as: cytoxan

Bevacizumab then Cyclophosphamide with Bevacizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed diagnosis of epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.
• Recurrent cancer and have received and failed a previous platinum-based chemotherapy regimen.
• Up to 2 prior lines of chemotherapy in the recurrent setting (either platinum-based or non-platinum regimens). Biologic therapies count as a prior line but hormonal therapies do not count.
• Platinum-resistant or platinum-sensitive recurrence.
• Must be able to take oral medications and have no evidence of bowel obstruction or partial bowel obstruction
• Measurable disease by either RECIST or Rustin criteria
• No chemotherapy, radiation therapy, nor biologic therapy within the last three weeks prior to initiating therapy
• ECOG score of 0 or 1
• Life expectancy of 12 weeks or greater
• years of age or older
• Laboratory values as outlined in the protocol
• Patients with treated limited stage basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the breast or cervix are eligible. Subjects with stage I or II cancer treated with curative intent and no evidence of recurrent disease are also eligible.
• No evidence of preexisting hypertension. If patient has hypertension, it must be controlled medically (less than 150/90) prior to starting bevacizumab
• Normal blood coagulation parameters
• No prior treatment with any other antiangiogenic agents or cyclophosphamide

You may not qualify if:

• Current, recent (within 4 weeks of the first study infusion), or planned participation in an experimental drug study other than a Genentech-sponsored bevacizumab cancer study
• Active malignancy, other than superficial basal cell and superficial squamous (skin) cell, or carcinoma in situ of the cervix within last five years
• Uncontrolled diarrhea
• Prior history of hypertensive crisis or hypertensive encephalopathy
• NYHA Grade II or greater congestive heart failure
• History of myocardial infarction or unstable angina within 6 months prior to Day 1
• History of stroke or transient ischemic attack within 6 months prior to day 1
• Known CNS disease, except for treated brain metastasis
• Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS: Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to day 1 will be excluded.
• Significant vascular disease within 6 months prior to day 1
• History of hemoptysis within 1 month prior to day 1
• Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to day 1 or anticipation of need for major surgical procedure during the course of the study
• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1
• History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Massachusetts General Hospital: collaborator
• Brigham and Women's Hospital: collaborator
• Genentech, Inc.: collaborator

Study Sites (2)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Related Publications (1)

• Matulonis UA, Pereira L, Liu J, Lee H, Lee J, Whalen C, Campos S, Atkinson T, Hill M, Berlin S. Sequential bevacizumab and oral cyclophosphamide for recurrent ovarian cancer. Gynecol Oncol. 2012 Jul;126(1):41-6. doi: 10.1016/j.ygyno.2012.04.003. Epub 2012 Apr 6.

  PMID: 22487536 RESULT

MeSH Terms

Conditions

Ovarian Neoplasms; Fallopian Tube Neoplasms

Interventions

Bevacizumab; Cyclophosphamide

Condition Hierarchy (Ancestors)

Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Fallopian Tube Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Results Point of Contact

• Title: Ursula A. Matulonis, MD
• Organization: Dana-Farber Cancer Institute

umatulonis@partners.org

617-632-2334

Study Officials

• Ursula Matulonis, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Medical Oncologist

Study Record Dates

• First Submitted: February 25, 2009
• First Posted: March 5, 2009
• Study Start: February 1, 2009
• Primary Completion: April 1, 2010
• Study Completion: January 1, 2014
• Last Updated: September 10, 2018
• Results First Posted: May 17, 2016

Record last verified: 2018-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)