Carboplatin-Paclitaxel ± Bevacizumab in Advanced (Stage III-IV) or Recurrent Endometrial Cancer (MITOBEVAEND2)

A Randomized Phase II Trial of Carboplatin-Paclitaxel Compared to Carboplatin-Paclitaxel-Bevacizumab in Advanced (Stage III-IV) or Recurrent Endometrial Cancer

Wright et al (Anticancer Res, 2000) reported the results of a retrospective study on 11 patients with advanced/recurrent endometrial cancers. All patients had multi-site disease and were heavily pretreated with a median of 3 prior chemotherapy regimens. All received bevacizumab combination therapy which was well-tolerated. Two patients had partial responses, 3 had stable disease, while 5 patients progressed. One subject was not assessable for response. The median progression-free interval was 5.4 months for the entire cohort and 8.7 months for those who achieved clinical benefit (PR or SD). The authors concluded that Bevacizumab was well-tolerated and displayed promising anti-neoplastic activity in patients with endometrial cancer.The rationale for combining anti-angiogenic agents, including anti-VEGF antibodies, with cytotoxic chemotherapy stems from a number of preclinical studies showing additive and synergistic anti-tumour activity in a number of solid tumour types. By combining VEGF-targeting agents such as bevacizumab with conventional chemotherapies, it is hoped that these agents will act synergistically, thereby enhancing their anti-tumour efficacy and controlling disease progression.

The addition of bevacizumab to chemotherapy has been shown to improve PFS and/or OS in a series of large, randomized Phase III clinical trials in a wide range of tumour types, including mCRC, non-squamous NSCLC, metastatic BC (mBC) and mRCC.

Study Overview

• Status: Unknown
• Conditions: Stage III-IV or Recurrent Endometrial Cancer
• Intervention / Treatment: Drug: Bevacizumab; Drug: Carboplatin AUC 5+Paclitaxel 175 mg/mq q 21 for 6-8 cycles

• Study Type: Interventional
• Enrollment (Anticipated): 108
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Rome
    • Rome,, Rome, Italy, 00100
      • Recruiting
      • Catholic University of Sacred Heart Rome,

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. ≥18 years of age.
2. ECOG Performance Status of 0-2.
3. Life expectancy of at least 12 weeks.
4. Patients must have advanced stage III or IV, or recurrent histologically-confirmed endometrial cancer.
5. Endometrial cancer will include all carcinomas, including endometrioid carcinoma, papillary serous carcinoma, clear cell carcinoma.
6. One previous chemotherapy lines is allowed if platinum free interval is more than six mounths (previous radiotherapy is allowed).

7 Measurable and not measurable disease. 8 Adequate renal and hepatic function, defined as:

• Total serum bilirubin ≤ institutional ULN unless patient has Gilbert's syndrome in which case direct bilirubin must be < ULN for the institution.
• AST and/or ALT ≤ 2.5 x ULN for the institution. (or ≤ 5 x ULN if liver metastases are present)
• Alkaline phosphatase < 1.5 x ULN for the institution (if > 1.5 x ULN, then alkaline phosphatase liver fraction must be < 1.5 ULN).
• Serum creatinine ≤ 1.5 x ULN for the institution (or calculated creatinine clearance ≥ 50 mL/min/1.73 m2) 9 Adequate bone marrow function, defined as:
• Total leukocytes ³ 3.0 x 109/L.
• ANC ³ 1.5 x 109/L.
• Platelet count ³ 100 x 109/L. Able to understand and give written informed consent. 10 Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to study enrollment.

Exclusion Criteria:

1. Previous cytotoxic chemotherapy.
2. Women who are pregnant or lactating.
3. Presence of brain or other central nervous system metastases.
4. Anticancer treatment within 4 weeks prior to randomization.
5. Ongoing toxicity associated with prior anticancer therapy.
6. Inadequate recovery from any prior surgical procedure or having undergone any major surgical procedure within 4 weeks prior to randomization. Patients who have recovered from placement of a central venous access port within 2 weeks of Cycle 1 Day 1 will be considered eligible.
7. Another primary malignancy within the past five years (except for non-melanoma skin cancer and cervical carcinoma in situ).
8. Current or recent (within 10 days prior to the first study drug dose) chronic daily treatment with aspirin (>325 mg/day).
9. Current or recent (within 10 days prior to the first study drug dose) use of full-dose oral or parenteral anticoagulant or thrombolytic agent for therapeutic purposes.
10. Inadequate coagulation parameters:activated partial thromboplastin time (APTT) >1.5 xULN or INR >1.5.
11. Known HIV infection.
12. Known hepatitis B or C infection.
13. Concurrent treatment with immunosuppressive or investigational agents.
14. History or evidence of thrombotic or hemorrhagic disorders; including cerebrovascular accident (CVA) / stroke or transient ischemic attack (TIA) or subarachnoid haemorrhage within _6 months prior to the first study treatment).
15. Uncontrolled hypertension (sustained systolic >150 mm Hg and/or diastolic >100 mm Hg despite antihypertensive therapy) or clinically significant (i.e. active) cardiovascular disease, including.
16. Myocardial infarction or unstable angina within _6 months prior to the first study treatment.
17. New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF).
18. Serious cardiac arrhythmia requiring medication (with the exception of atrial fibrillation or paroxysmal supraventricular tachycardia).
19. Peripheral vascular disease _grade 3 (i.e.symptomatic and interfering with activities of daily living requiring repair or revision).
20. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to the first study treatment.
21. Non-healing wound, ulcer or bone fracture. Patients with granulating incisions healing by secondary intention with no evidence of facial dehiscence or infection are eligible but require three weekly wound examinations.
22. Serious active infection requiring i.v. antibiotics at enrolment.
23. Significant traumatic injury during the 4 weeks preceding the first dose of bevacizumab.
24. Known hypersensitivity to any of the study drugs or excipients (including cremophor and hamster Ovary cell products).
25. Evidence of any other medical conditions (such as psychiatric illness, peptic ulcer, etc.), physical examination or laboratory findings that may interfere with the planned treatment, affect patient compliance or place the patient at high risk from treatment related complications.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Carboplatin-paclitaxel-bevacizumab; Carboplatin AUC 5+ Paclitaxel 175 mg/mq+Bevacizumab 15 mg/kg q 21 for 6 -8 cycles + Bevacizumab 15 mg/kg every 3 weeks until disease progression	Drug: Bevacizumab; Carboplatin AUC 5+ Paclitaxel 175 mg/mq+Bevacizumab 15 mg/kg q 21 for 6 -8 cycles + Bevacizumab 15 mg/kg
Active Comparator: carboplatin-paclitaxel; Carboplatin AUC 5+Paclitaxel 175 mg/mq q 21 for 6-8 cycles	Drug: Carboplatin AUC 5+Paclitaxel 175 mg/mq q 21 for 6-8 cycles; Carboplatin AUC 5+Paclitaxel 175 mg/mq q 21 for 6-8 cycles

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	• Progression-free survival, defined as the time from the date of randomization to the date of documented progressive disease, recurrence or death (whichever occurs first)	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	• Overall survival defined as the time from the date of randomization to the date of death	3 months
Best target lesion response	Best target lesion response, defined as best change in sum of the target lesions from baseline to disease progression.	6 months
Duartion of Response	Duration of response Safety and tolerability	3 months
Quality of life	Changes Quality of Life parameters as measured using EORTC QLQ-30 & EORTC-QLQ-EN-24	3 cycle

Collaborators and Investigators

• Sponsor: Catholic University of the Sacred Heart
• Investigators: Principal Investigator: Giovanni Scambia, Prof, Catholic University of Sacred Heart; Principal Investigator: Domenica Lorusso, MD, National Cancer Institute, Milan

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Anticipated): December 1, 2017
• Study Completion (Anticipated): December 1, 2017

Study Registration Dates

• First Submitted: December 10, 2012
• First Submitted That Met QC Criteria: January 15, 2013
• First Posted (Estimate): January 17, 2013

Study Record Updates

• Last Update Posted (Estimate): January 17, 2013
• Last Update Submitted That Met QC Criteria: January 15, 2013
• Last Verified: December 1, 2012

More Information

Terms related to this study

• Keywords: endometrial cancer; recurrent endometrial cancer; bevacizumab
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Diseases; Disease Attributes; Recurrence; Endometrial Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Carboplatin; Paclitaxel; Bevacizumab
• Other Study ID Numbers: MITOBEVAEND2

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No