Pharmacokinetic Study of Avastin and Doxil in Ovarian Cancer

Sponsor

NYU Langone Health (Other)

Overall Status

Completed

CT.gov ID

NCT00846612

Collaborator

Genentech, Inc. (Industry), University of New Mexico Cancer Center (Other)

Enrollment

Locations

Arm

Duration (Months)

3.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study is to study pharmacokinetics of Doxil using Doxil and Avastin on ovarian cancer patients who are resistant to or have relapsed from platinum-based therapy.

Condition or Disease	Intervention/Treatment	Phase
Ovarian Cancer	Drug: Doxil Drug: Bevacizumab (Avastin)	Phase 1

Detailed Description

This study registration at clinicaltrials.gov 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).

Study Design

Study Type:

Interventional

Actual Enrollment :

15 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jan 1, 2008

Actual Primary Completion Date :

Sep 1, 2010

Actual Study Completion Date :

Jun 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Avastin-Doxil	Drug: Doxil 1 cycle: 3 weeks; 30 mg/m^2, IV, every cycle Other Names: pegylated doxorubicin liposome Drug: Bevacizumab (Avastin) 1 cycle: every 3 weeks; 15 mg/kg, IV, beginning on cycle 2 and every cycle 20-24 hours following Doxil administration Other Names: Avastin

Arm

Intervention/Treatment

Experimental: Avastin-Doxil

Drug: Doxil

1 cycle: 3 weeks; 30 mg/m^2, IV, every cycle

Other Names:

pegylated doxorubicin liposome

Drug: Bevacizumab (Avastin)

1 cycle: every 3 weeks; 15 mg/kg, IV, beginning on cycle 2 and every cycle 20-24 hours following Doxil administration

Other Names:

Avastin

Outcome Measures

Primary Outcome Measures

change in peak plasma concentration of Doxil without and with Avastin [1 hour, 1, 4, 7, 10, 14, and 21 days post-dose in cycle 1 and cycle 2]
In cycle 1, patients were treated only with Doxil; in cycle 2, patients were treated with Doxil and Avastin.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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 medications)
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 enrollment
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 eligible).
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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Univ. of New Mexico cancer research and treatment center	Albuquerque	New Mexico	United States	87131
2	Bellevue Hospital	New York	New York	United States	10016
3	NYU Cancer Center	New York	New York	United States	10016
4	NYU medical center (Tisch Hospital)	New York	New York	United States	10016