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

• ClinicalTrials.gov Identifier: NCT00653939
• Recruitment Status: Completed
• First Posted: April 7, 2008
• Results First Posted: February 9, 2015
• Last Update Posted: February 9, 2015
• Sponsor: Mateon Therapeutics
• Information provided by (Responsible Party): Mateon Therapeutics

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Tumors	Drug: Fosbretabulin; Drug: Carboplatin; Drug: Paclitaxel; Drug: Bevacizumab	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 63 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Study Start Date: March 2008
• Actual Primary Completion Date: July 2011
• Actual Study Completion Date: October 2011

Arms and Interventions

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 Name: Paraplatin; Drug: Paclitaxel; Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles.; Other Name: Taxol; Drug: Bevacizumab; Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.; Other Name: 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: Fosbretabulin; Arm 2 only: Fosbretabulin (60 mg/m2) on Days 7,14 and 21 for 6 cycles.; Other Names: Combretastatin A4 Phosphate; Zybrestat; CA4P; Drug: Carboplatin; Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles.; Other Name: Paraplatin; Drug: Paclitaxel; Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles.; Other Name: Taxol; Drug: Bevacizumab; Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.; Other Name: Avastin

Outcome Measures

Primary Outcome Measures :

1. Progression Free Survival (PFS) in the Intent-to-Treat Population [ Time Frame: Six 21-day cycles ]
   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.

Secondary Outcome Measures :

1. Best Overall Tumor Response Rate (RR) in the Intent-to-Treat Population [ Time Frame: Six 21-day cycles ]
   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.
2. Overall Survival (OS) Using a Multivariate Cox Regression Model in the Intent-to-Treat Population [ Time Frame: Until death or lost to follow-up, up to 12 months since randomization ]
3. Chemistry NCI-CTCAE Toxicity Grade of 3 or 4 (Safety Population) [ Time Frame: Days 1 (pretreatment) per 21-day Cycle (6 Cycles) ]
4. Hematology NCI-CTCAE Grade 3 or 4 (Safety Population) [ Time Frame: Days 1 (pretreatment), 7, 14, and 21 per 21-day Cycle (6 Cycles) ]
5. Coagulation NCI-CTCAE Grade 3 or 4 (Safety Population) [ Time Frame: Day 1 (pretreatment) per 21-day Cycle (6 Cycles) ]

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, California

Southbay Oncology Hematology

Campbell, California, United States, 95008

Pacific Coast Hematology and Oncology Medical Group

Fountain Valley, California, United States, 92708

UCLA Division of Hematology and Oncology

Los Angeles, California, United States, 90095

Bay Area Cancer Research Group, LLC

Pleasant Hill, California, United States, 94523

United States, Florida

Boca Raton Comprehensive Cancer Center

Boca Raton, Florida, United States, 21020

United States, Kentucky

Kentuckiana Cancer Institute

Louisville, Kentucky, United States, 40202

United States, Massachusetts

Lahey Clinic Medical Center

Burlington, Massachusetts, United States, 01805

United States, New Jersey

The Center for Cancer and Hematologic Disease

Cherry Hill, New Jersey, United States, 08003

United States, New Mexico

San Juan Oncology Associates

Farmington, New Mexico, United States, 87401

United States, Ohio

Gabrail Cancer Center

Canton, Ohio, United States, 44718

The Mark H. Zangmeister Center

Columbus, Ohio, United States, 43219

Signal Point Clinical Research

Middletown, Ohio, United States, 45042

United States, Virginia

Blueridge Cancer Care

Salem, Virginia, United States, 24153

United States, Washington

Northwest Medical Specialties

Tacoma, Washington, United States, 98405

United States, West Virginia

Mary Babb Randolph Cancer Center-Clinical Trials Unit

Morgantown, West Virginia, United States, 26506

Sponsors and Collaborators

Mateon Therapeutics

Investigators

• Study Director: Jai Balkissoon, MD, FACS; Mateon Therapeutics

More Information

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. 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. Review.

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.

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.

• Responsible Party: Mateon Therapeutics
• ClinicalTrials.gov Identifier: NCT00653939
• Other Study ID Numbers: OXC401-216
• First Posted: April 7, 2008
• Results First Posted: February 9, 2015
• Last Update Posted: February 9, 2015
• Last Verified: January 2015

Keywords provided by Mateon Therapeutics:

non-small cell lung cancer; non-small cell lung carcinoma; neoplasms, lung; lung cancer; tumors; NSCLC

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Paclitaxel; Fosbretabulin; Combretastatin; Bevacizumab; Carboplatin; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors