Neoadjuvant Bevacizumab and Carboplatin Followed by Concurrent Bevacizumab, Carboplatin and Radiotherapy in the Primary Treatment of Cervix Cancer

Summary

This trial is designed to study the safety and efficacy of the combination of carboplatin, bevacizumab, and pelvic radiation therapy.

Rationale for substituting cisplatin with carboplatin:

Five landmark trials in cervical cancer prompted the National Cancer Institute in February of 1999 to issue a clinical announcement stating that "strong consideration should be given to adding concurrent chemotherapy in the treatment of invasive cervical cancer". The chemotherapeutic agent which was a common denominator to all 5 trials was cisplatin, and ever since it has become part of the standard of care for the treatment of stage IIB, III, and IVA cervical cancers. In addition, chemoradiotherapy with cisplatin is also considered one of the standard treatment options for IB2 and IIA tumors greater than 4 cm in diameter.

The most recent Gynecologic Oncology Group protocols for cervical cancer have used cisplatin and radiation therapy as in two of the five landmark trials. However, the benefit in survival given by cisplatin has not been without toxicity. In summary, in the trial by Keys 35% of patients receiving cisplatin and radiotherapy experienced moderate or severe toxicities. In the one by Rose, only 49 % completed the intended 6 cycles of chemotherapy.

Based on the toxicity profile of cisplatin, Higgins performed a phase II study of concurrent carboplatin with pelvic radiation therapy in the primary treatment of cervix cancer. He demonstrated the ability to administer carboplatin with concurrent radiation therapy with significantly less toxicity and with 94 % of the planned treatments delivered.

A comprehensive analysis of the literature from 1998 which compared the efficacy of carboplatin versus cisplatin in solid tumors concluded that for ovarian cancer and lung cancer the effectiveness of carboplatin was comparable to cisplatin, while for germ cell tumors, bladder cancer, and head and neck cancer cisplatin appeared superior. There was no mention of cervical cancer in this review, since at present there is no phase III trial comparing carboplatin versus cisplatin in cervix cancer.

Rationale for bevacizumab:

Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of vascular endothelial growth factor (VEGF) which stimulates tumor and tumor blood vessel growth. Targeting VEGF with bevacizumab could potentially be of benefit in cervical cancer patients by starving the tumor's blood supply and potentially enhancing the effect of radiotherapy and carboplatin chemotherapy.

Conditions

• Cervical Cancer

Interventions

DRUG

Bevacizumab

Bevacizumab will be delivered intravenously on day -7 at a dose of 10 mg/kg followed by carboplatin AUC 2.0 intravenously. This will allow therapy to start one week before starting radiotherapy to assess the initial tolerability of the combination without having radiation as a confounding factor, to start treatment while the patient's radiation is being planned, and to possibly optimize the tumor vasculature and allow optimal carboplatin delivery by the time chemoradiotherapy starts. Thereafter, bevacizumab will be given intravenously at 10 mg/kg every two weeks. Carboplatin will be given intravenously weekly at AUC 2.0. On weeks where both drugs are given, bevacizumab will be given first since it could help sensitize the tumor cells to carboplatin.

DRUG

Carboplatin

Bevacizumab will be delivered intravenously on day -7 at a dose of 10 mg/kg followed by carboplatin AUC 2.0 intravenously. This will allow therapy to start one week before starting radiotherapy to assess the initial tolerability of the combination without having radiation as a confounding factor, to start treatment while the patient's radiation is being planned, and to possibly optimize the tumor vasculature and allow optimal carboplatin delivery by the time chemoradiotherapy starts. Thereafter, bevacizumab will be given intravenously at 10 mg/kg every two weeks. Carboplatin will be given intravenously weekly at AUC 2.0. On weeks where both drugs are given, bevacizumab will be given first since it could help sensitize the tumor cells to carboplatin.

RADIATION

Radiation Therapy

Whole pelvis will be treated to a total dose of 45 Gy in 5 weeks. Cesium will be used with standard intracavitary systems preferably in two intracavitary applications. An effort should be made to deliver a minimum cumulative external and intracavitary dose to Point A of 85 Gy in 2 insertions.

Sponsors & Collaborators

• Genentech, Inc.

  collaborator INDUSTRY

• Leo W. Jenkins Cancer Center

  lead OTHER

Principal Investigators

• Gloria Frelix, MD · East Carolina University School of Medicine

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2008-01-31

Primary Completion

2011-04-30

Completion

2011-04-30

Countries

• United States

Study Locations