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

This study has been withdrawn prior to enrollment.
(low patient accrual)
Sponsor:
Collaborator:
Genentech
Information provided by (Responsible Party):
Leo W. Jenkins Cancer Center
ClinicalTrials.gov Identifier:
NCT00600210
First received: January 11, 2008
Last updated: September 23, 2013
Last verified: September 2013
  Purpose

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.


Condition Intervention Phase
Cervical Cancer
Drug: Bevacizumab
Drug: Carboplatin
Radiation: Radiation Therapy
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: AVF3963s Neoadjuvant Bevacizumab and Carboplatin Followed by Concurrent Bevacizumab, Carboplatin and Radiotherapy in the Primary Treatment of Cervix Cancer

Resource links provided by NLM:


Further study details as provided by Leo W. Jenkins Cancer Center:

Primary Outcome Measures:
  • To determine the safety of the proposed treatment in this patient population. [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Progression Free Survival [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]

Enrollment: 0
Study Start Date: January 2008
Study Completion Date: April 2011
Primary Completion Date: April 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: I 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.


  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have IB2 and IIA tumors greater than 4 cm in diameter, IIB, IIIB without hydronephrosis or non-functioning kidney, and IVA without invasion to the bladder or rectum, primary, previously untreated, and histologically confirmed invasive squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix.
  • Negative, non-suspicious para-aortic nodes determined by CT lymphangiogram, MRI or lymphadenectomy.
  • Adequate bone marrow function: ANC greater ≥ 1,500/mm3, platelets ≥ 100,000/mm3.
  • Adequate renal function: serum creatinine ≤ 1.5 mg/100 mL.
  • Adequate hepatic function: bilirubin less than or equal to 1.5 x upper limit of normal (ULN) and SGOT and alkaline phosphatase less than or equal to 3 x ULN.
  • Zubrod Performance Status of 0 or 1
  • Patients of childbearing potential must have a negative serum pregnancy test within14 days of enrolling in this study and use an effective form of contraception during the study period.
  • Patients who are medically suitable for treatment with radical intent using concurrent chemotherapy and pelvic radiation.

Exclusion Criteria:

  • Patients with Stage IA, IB1, IB2 and IIa tumors less than 4 cm in diameter, IIIA or IVB disease.
  • Patients who have known metastases to para-aortic or scalene nodes or metastases to other organs outside the radiation field at the time of the original clinical and surgical staging.
  • Extensive tumor preventing intracavitary irradiation.
  • Distal vaginal involvement or any disease such that an interstitial implant might be necessary
  • Previous pelvic or abdominal radiation, cytotoxic chemotherapy, or previous therapy of any kind for this malignancy.
  • Patients who might require an emergency surgical procedure to relieve hydronephrosis, or who are at risk of perforating the bladder and might require surgery.
  • Patients with renal abnormalities, such as pelvic kidney, horseshoe kidney, or renal transplantation, that would require modification of radiation fields
  • 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 bevacizumab cancer study.
  • Septicemia or severe infection
  • Patients who have circumstances that will not permit completion of this study or the required follow-up.
  • Patients who are pregnant at the time of diagnosis and do not wish pregnancy termination prior to initiation of treatment.
  • Other concomitant malignancies, with the exception of nonmelanoma skin cancer, who had (or have) any evidence of other cancer present within the last 5 years.
  • Bevacizumab-Specific Exclusions
  • 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
  • New York Heart Association (NYHA) Grade II or greater congestive heart failure
  • 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, gastrointestinal perforation, 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 ≥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 bevacizumab
  • Pregnant (positive pregnancy test) or lactating. Use of effective means of contraception (men and women) in subjects of child-bearing potential
  • Any history of stroke or transient ischemic attack at any time
  • History of myocardial infarction or unstable angina within 6 months of study enrollment
  • Carboplatin-Specific Exclusions
  • History of severe allergic reactions to cisplatin or other platinum-containing compounds.
  • Patients with severe bone marrow depression or significant bleeding.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00600210

Locations
United States, North Carolina
East Carolina University School of Medicine
Greenville, North Carolina, United States, 27834
Sponsors and Collaborators
Leo W. Jenkins Cancer Center
Genentech
Investigators
Principal Investigator: Gloria Frelix, MD East Carolina University School of Medicine
  More Information

Publications:

Responsible Party: Leo W. Jenkins Cancer Center
ClinicalTrials.gov Identifier: NCT00600210     History of Changes
Other Study ID Numbers: AVF3963s
Study First Received: January 11, 2008
Last Updated: September 23, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Uterine Cervical Neoplasms
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Uterine Cervical Diseases
Uterine Diseases
Genital Diseases, Female
Bevacizumab
Carboplatin
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Growth Inhibitors
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 30, 2014