A Safety and Efficacy Study of Carboplatin, Paclitaxel, Bevacizumab and CA4P in Non-Small Cell Lung Cancer (FALCON)

A Phase II Study to Assess the Safety and Efficacy of the Combination of Carboplatin, Paclitaxel, and Bevacizumab ± Combretastatin A4 Phosphate (CA4P) Followed by Bevacizumab ± CA4P in Subjects With Chemotherapy Naïve Stage IIIB/IV Non-Squamous Cell Histology Non-Small Cell Lung Cancer (NSCLC)

The purpose of this study is to determine the safety, tolerability and efficacy of combretastatin A4 phosphate (CA4P), also known as fosbretabulin, in combination with bevacizumab (Avastin), carboplatin and paclitaxel in patients with chemotherapy naïve non-small cell lung cancer (NSCLC). This is a randomized parallel arm study. All participants will receive carboplatin, paclitaxel and bevacizumab, and half will additionally receive CA4P. Patients who complete the first 6 cycles of therapy and have not experienced disease progression will receive maintenance therapy with bevacizumab alone or with bevacizumab plus CA4P.

The rationale for this study is the potential additive or synergistic actions of vascular disrupting agents like CA4P with anti-angiogenic agents like bevacizumab.

Study Overview

• Status: Completed
• Conditions: Tumors
• Intervention / Treatment: Drug: Carboplatin; Drug: Paclitaxel; Drug: Bevacizumab; Drug: Fosbretabulin

Detailed Description

Lung cancer has become the leading cause of cancer death in both men and women in the US and Europe, accounting for 29% of all cancer deaths. Non-Small Cell Lung cancer (NSCLC) accounts for approximately 80% of all lung cancer cases. Currently, no curative treatment is available for advanced stages of the disease (stages III and IV), which comprise the majority of cases. Treatment with the combination of carboplatin and paclitaxel has been shown to be effective and well tolerated in advanced stage NSCLC. Targeted therapies, such as bevacizumab, often act synergistically with chemotherapy. Bevacizumab inhibits vascular endothelial growth factor (VEGF), necessary for endothelial cell proliferation and new blood vessel formation. CA4P targets existing abnormal vasculature of tumors, impeding tumor blood flow and leading to extensive tumor cell death as a consequence of oxygen and nutrient deprivation.

This study will compare the effect of CA4P when combined with chemotherapy and bevacizumab on progression free survival (PFS) to PFS after chemotherapy and bevacizumab alone.

• Study Type: Interventional
• Enrollment (Actual): 63
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Campbell, California, United States, 95008
      • Southbay Oncology Hematology
    • Fountain Valley, California, United States, 92708
      • Pacific Coast Hematology and Oncology Medical Group
    • Los Angeles, California, United States, 90095
      • UCLA Division of Hematology and Oncology
    • Pleasant Hill, California, United States, 94523
      • Bay Area Cancer Research Group, LLC
  • Florida
    • Boca Raton, Florida, United States, 21020
      • Boca Raton Comprehensive Cancer Center
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Kentuckiana Cancer Institute
  • Massachusetts
    • Burlington, Massachusetts, United States, 01805
      • Lahey Clinic Medical Center
  • New Jersey
    • Cherry Hill, New Jersey, United States, 08003
      • The Center for Cancer and Hematologic Disease
  • New Mexico
    • Farmington, New Mexico, United States, 87401
      • San Juan Oncology Associates
  • Ohio
    • Canton, Ohio, United States, 44718
      • Gabrail Cancer Center
    • Columbus, Ohio, United States, 43219
      • The Mark H. Zangmeister Center
    • Middletown, Ohio, United States, 45042
      • Signal Point Clinical Research
  • Virginia
    • Salem, Virginia, United States, 24153
      • Blueridge Cancer Care
  • Washington
    • Tacoma, Washington, United States, 98405
      • Northwest Medical Specialties
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • Mary Babb Randolph Cancer Center-Clinical Trials Unit

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Pathologically confirmed Stage IIIB NSCLC with malignant pleural effusion, or Stage IV disease
• Measurable disease on CT scan (by the Response Evaluation Criteria in Solid Tumors [RECIST] criteria)
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 (which means able to independently care for self and to perform light work) .
• Adequate blood counts
• Adequate liver and kidney function
• Subjects or their legal representatives must be able to read, understand and provide written informed consent to participate in the trial.

Exclusion Criteria:

• Predominant Squamous Cell NSCLC histology.
• History of treatment for NSCLC with chemotherapy, biological therapy, immunotherapy (surgery or radiation therapy are accepted)
• Brain (CNS) metastasis by head CT scan or MRI
• Subjects with history of prior malignancy except for curatively treated basal cell carcinoma of the skin; cervical intra-epithelial neoplasia; or localized prostate cancer with a current prostate specific antigen (PSA) of < 4.0 mg/dL. Subjects with other curatively treated malignancies who have no evidence of metastatic disease and >2 year disease free interval may be entered after discussion with the Medical Monitor.
• History of bleeding disorders, particularly coughing up ≥ ½ teaspoon bright red blood during the last 3 months
• Certain cardiac disorders such as recent myocardial infarction (MI), severe congestive heart failure, certain types of abnormal cardiac rhythm
• Uncontrolled high blood pressure despite medications
• Uncontrolled, clinically significant active infection.
• Known HIV
• Known hypersensitivity to any of the components of CA4P, paclitaxel, carboplatin, bevacizumab, or radiologic contrast dyes.

Details of the above and additional inclusion and exclusion criteria can be discussed with an investigator.

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
Active Comparator: Arm 1: Chemotherapy+Bevacizumab; Carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg)administered intravenously on Day 1 of a 21-day cycle for up to six treatment cycles. After 6 cycles, subjects who have not progressed may continue to receive bevacizumab (15 mg/kg) alone on Day 1 every 3 weeks until progression or until 12 months from randomization.	Drug: Carboplatin; Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles.; Other Names: Paraplatin; Drug: Paclitaxel; Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles.; Other Names: Taxol; Drug: Bevacizumab; Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.; Other Names: Avastin
Experimental: Arm 2: Active Comparator+Fosbretabulin; Carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg), administered intravenously Day 1 of a 21-day cycle and fosbretabulin (60 mg/m2) on Days 7, 14, and 21 for up to six treatment cycles. After 6 cycles, subjects who have not progressed may continue to receive bevacizumab (15 mg/kg) on Day 1 and fosbretabulin on Days 1, 7 and 14 every 3 weeks until progression or until 12 months from randomization.	Drug: Carboplatin; Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles.; Other Names: Paraplatin; Drug: Paclitaxel; Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles.; Other Names: Taxol; Drug: Bevacizumab; Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.; Other Names: Avastin; Drug: Fosbretabulin; Arm 2 only: Fosbretabulin (60 mg/m2) on Days 7,14 and 21 for 6 cycles.; Other Names: Combretastatin A4 Phosphate; Zybrestat; CA4P

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS) in the Intent-to-Treat Population	Progression was defined using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0. Based on 20% increase of the longest diameter of target lesions or appearance of one or more new non-target lesions or/and progression of non-target lesions since the treatment started.	Six 21-day cycles

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best Overall Tumor Response Rate (RR) in the Intent-to-Treat Population	Based on Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0 for target lesions (assessed by MRI or CT scan): Complete Response (CR) is defined as the disappearance of all target lesions, Partial Response (PR) is defined as at least a 30% decrease in the sum of the longest diameter of target lesions, Progressive Disease is defined as at least 20% increase in the sum of the longest diameter of target lesions, Stable Disease (SD) is defined as neither shrinkage to qualify for a PR or increase to qualify for a PD.	Six 21-day cycles
Overall Survival (OS) Using a Multivariate Cox Regression Model in the Intent-to-Treat Population		Until death or lost to follow-up, up to 12 months since randomization
Chemistry NCI-CTCAE Toxicity Grade of 3 or 4 (Safety Population)		Days 1 (pretreatment) per 21-day Cycle (6 Cycles)
Hematology NCI-CTCAE Grade 3 or 4 (Safety Population)		Days 1 (pretreatment), 7, 14, and 21 per 21-day Cycle (6 Cycles)
Coagulation NCI-CTCAE Grade 3 or 4 (Safety Population)		Day 1 (pretreatment) per 21-day Cycle (6 Cycles)

Collaborators and Investigators

• Sponsor: Mateon Therapeutics
• Investigators: Study Director: Jai Balkissoon, MD, FACS, Mateon Therapeutics

Publications and helpful links

General Publications

• Lin CM, Singh SB, Chu PS, Dempcy RO, Schmidt JM, Pettit GR, Hamel E. Interactions of tubulin with potent natural and synthetic analogs of the antimitotic agent combretastatin: a structure-activity study. Mol Pharmacol. 1988 Aug;34(2):200-8.
• Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. doi: 10.1056/NEJMoa061884. Erratum In: N Engl J Med. 2007 Jan 18;356(3):318.
• Monestiroli S, Mancuso P, Burlini A, Pruneri G, Dell'Agnola C, Gobbi A, Martinelli G, Bertolini F. Kinetics and viability of circulating endothelial cells as surrogate angiogenesis marker in an animal model of human lymphoma. Cancer Res. 2001 Jun 1;61(11):4341-4.
• Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997 Feb;18(1):4-25. doi: 10.1210/edrv.18.1.0287. No abstract available.
• Chaplin DJ, Pettit GR, Hill SA. Anti-vascular approaches to solid tumour therapy: evaluation of combretastatin A4 phosphate. Anticancer Res. 1999 Jan-Feb;19(1A):189-95.
• Siemann DW, Mercer E, Lepler S, Rojiani AM. Vascular targeting agents enhance chemotherapeutic agent activities in solid tumor therapy. Int J Cancer. 2002 May 1;99(1):1-6. doi: 10.1002/ijc.10316.
• Shaked Y, Ciarrocchi A, Franco M, Lee CR, Man S, Cheung AM, Hicklin DJ, Chaplin D, Foster FS, Benezra R, Kerbel RS. Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science. 2006 Sep 22;313(5794):1785-7. doi: 10.1126/science.1127592.

Study record dates

Study Major Dates

• Study Start: March 1, 2008
• Primary Completion (Actual): July 1, 2011
• Study Completion (Actual): October 1, 2011

Study Registration Dates

• First Submitted: March 18, 2008
• First Submitted That Met QC Criteria: April 4, 2008
• First Posted (Estimate): April 7, 2008

Study Record Updates

• Last Update Posted (Estimate): February 9, 2015
• Last Update Submitted That Met QC Criteria: January 22, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Keywords: NSCLC; lung cancer; non-small cell lung cancer; non-small cell lung carcinoma; neoplasms, lung; tumors
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; 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; Fosbretabulin; Combretastatin
• Other Study ID Numbers: OXC401-216

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