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Phase II and Pharmacokinetic Study of Avastin and Doxil in the Treatment of Platinum-resistant or Refractory Ovarian Cancer

Phase 1
18 Years
Not Enrolling
Ovarian Cancer

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Trial Information

Phase II and Pharmacokinetic Study of Avastin and Doxil in the Treatment of Platinum-resistant or Refractory Ovarian Cancer

This study registration at is divided into 2 records. This record
(NCT00846612) is for pharmacokinetics of Doxil. Another record (NCT00945139) describes the
efficacy and safety of the combination treatment.

Treatment upon diagnosis of epithelial ovarian cancer (EOC) consists of surgery to achieve
maximal tumor debulking followed by platinum-based chemotherapy (carboplatin + paclitaxel).
Recently, optimally (e.g., < 1 cm residual disease) debulked patients appear to benefit from
regimens that include intraperitoneal administration of cisplatin. While complete response
(CR) is frequently achieved, by two years 50% of the patients show signs of recurrence.

When EOC presenting at an advanced stage recurs, even after a CR had been achieved, it can
no longer be totally eradicated. Nevertheless, a number of drugs lead to objective
responses, patients benefit with a prolongation of survival. Anti-tumor activity of Doxil
against ovarian cancer was noted in a phase I study, and this was followed by a phase II
study that demonstrated activity in platinum and paclitaxel refractory disease. In the
expanded phase II experience at the University of Southern California, responses to Doxil
occurred preferably in disease that was not bulky and after fewer prior treatments.
Typically, several cycles were required for maximum response, and some patients had
prolonged stable disease. Subsequently, the study of Gordon et al established the preferred
role of this drug formulation in the 2nd line-setting. It is logical, therefore, to build
on this agent in trying to improve the outcome of patients with recurrent ovarian cancer,
and in particular, to consider a combination with Avastin, since Avastin has shown agent
activity in retrospective data and recent studies in EOC.

A combination of Doxil with Avastin has several aspects of interest to ovarian cancer
treatment: 1) independent single-agent activity, 2) enhanced localization of Doxil is
possible via increased half-life (if liposomal egress is diminished) and decreased tumoral
interstitial pressure, 3) improved Doxil distribution, and 4) likely favorable toxicity
profile since Doxil's only common problematic toxicity is to the skin (palmar-plantar
erythrodysesthesia or PPE). Pharmacokinetic issues will be addressed in selected patients,
by comparing cycle 1 (without Avastin) with cycle 2 (with Avastin).

Inclusion Criteria:

- Patients must be platinum resistant

- No prior anthracycline use

- PS ≤ 2

- Lab values within certain limits (ANC > 1000, platelets > 100,000; ALT, AST 2x ULN,
creatinine < 2.0);

- No more than 3 prior chemotherapy regimens, only 2 of which can have included
platinum-containing regimens.

- Use of effective means of contraception in subjects of child-bearing potential

Exclusion Criteria:

- Disease-Specific Exclusions:

- Evidence of complete or partial bowel obstruction

- Need for IV hydration or TPN

- > 2 prior abdominal surgeries

- History of gastrointestinal perforation

- Gastrointestinal perforation due to any other cause within the last 6 months

- General Medical Exclusions:

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

- Life expectancy of less than 12 weeks

- 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
Avastin cancer study

- Avastin-Specific Exclusions:

- Inadequately controlled hypertension (defined as systolic blood pressure greater
than 150 and/or diastolic blood pressure > 100 mmHg on antihypertensive

- Any prior history of hypertensive crisis or hypertensive encephalopathy

- New York Heart Association (NYHA) Grade II or greater congestive heart failure
(see Appendix E of the protocol)

- History of myocardial infarction or unstable angina within 6 months prior to
study enrollment

- History of stroke or transient ischemic attack within 6 months prior to study

- Known CNS disease

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

- Symptomatic peripheral vascular disease

- Evidence of bleeding diathesis or coagulopathy

- Major surgical procedure, open biopsy, or significant traumatic injury within 28
days prior to study enrollment 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 study enrollment

- History of abdominal fistula, or intra-abdominal abscess within 6 months prior
to study enrollment

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

- Proteinuria at screening as demonstrated by either

- Urine protein:creatinine (UPC) ratio no less than 1.0 at screening OR

- 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

- Known hypersensitivity to any component of Avastin

- Pregnant (positive pregnancy test) or lactating. No effective means of
contraception (men and women) in subjects of child-bearing potential

Type of Study:


Study Design:

Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

change in peak plasma concentration of Doxil without and with Avastin

Outcome Description:

In cycle 1, patients were treated only with Doxil; in cycle 2, patients were treated with Doxil and Avastin.

Outcome Time Frame:

1 hour, 1, 4, 7, 10, 14, and 21 days post-dose in cycle 1 and cycle 2

Safety Issue:


Principal Investigator

Franco Muggia, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

New York University School of Medicine


United States: Institutional Review Board

Study ID:




Start Date:

January 2008

Completion Date:

June 2012

Related Keywords:

  • Ovarian Cancer
  • refractory
  • avastin
  • doxil
  • relapsed
  • ovarian cancer
  • platinum-resistant
  • Ovarian Neoplasms



Bellevue Hospital New York, New York  10016
NYU Cancer Center New York, New York  10016
Univ. of New Mexico cancer research and treatment center Albuquerque, New Mexico  87131
NYU medical center (Tisch Hospital) New York, New York  10016