Study of Combination of Metronomic Oral Vinorelbine and Sorafenib in Patients With Advanced Non-small Cell Lung Cancer

• ClinicalTrials.gov Identifier: NCT00870532
• Recruitment Status: Completed
• First Posted: March 27, 2009
• Last Update Posted: November 3, 2013
• Sponsor: National Cancer Centre, Singapore
• Information provided by (Responsible Party): Eng-Huat Tan, National Cancer Centre, Singapore

Study Description

Brief Summary:

Targeting the blood supply of cancer, called anti-angiogenesis is a new but proven treatment strategy. There are two ways of achieving this effect. The first way to specifically target the molecular pathways that promote new blood vessel formation in cancer. An example of such an agent is sorafenib, which is an oral agent and which is already in use worldwide for the treatment of kidney and liver cancers. The second way is to target the cells lining the blood vessels by using low dose of chemotherapy agents administered at frequent intervals. This strategy is called metronomic chemotherapy. It is possible that combining agents like sorafenib and metronomic chemotherapy may further enhance anti-cancer effects. This study aims to determine the optimal way of combining oral vinorelbine in metronomic doses and sorafenib. Oral vinorelbine is a chemotherapy agent that is already approved for use in cancer treatment such as lung cancer. By combining both oral anti-cancer agents to optimize their anti-angiogenic effects in this study, the potential benefit to the patients can be tremendous and far-reaching. Special radiologic imagings and blood tests will be incorporated into this study to help further the understanding of the anti-angiogenic processes of both agents.

Condition or disease	Intervention/treatment	Phase
Non-Small Cell Lung Cancer	Drug: oral vinorelbine; Drug: sorafenib	Phase 1

Detailed Description:

Phase I Dose-finding study: The patients will be divided into 3 cohorts (15 patients per cohort), each cohort receiving a fixed metronomic (thrice a week) dose of oral vinorelbine at 60 mg/week, 90 mg/week, and 120 mg/week respectively. Each patient within each cohort will receive a starting dose of sorafenib at 200 mg bid for 4 weeks. In the absence of dose-limiting toxicities, the dose of sorafenib will be escalated to 400 mg bid for another 4 weeks, 600 mg bid for 4 weeks and then finally 800 mg bid. We should arrive at 3 different MTDs from the 3 cohorts.

Once the MTD has been determined for each cohort, we will recruit an additional 12 patients for each cohort and study the PK profile of both drugs. The 12 patients in each cohort will be sequentially alternated to group 1 or group 2 treatment schedules. Group 1 (N=6 patients in each cohort) will receive vinorelbine three times per week starting on Monday (Day 1) followed by Wednesday (Day 3) and Friday (Day 5). In the subsequent weeks vinorelbine will be given on the same working days (i.e. Monday, Wednesday and Friday). The first PK profile of vinorelbine (without concomitant sorafenib) will be determined on Day 15 under steady state conditions.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 52 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Prospective Study of Metronomic Oral Vinorelbine in Combination With Sorafenib in Advanced Non-small Cell Lung Cancer a) A Phase I Dose-finding Study of the Combination of Metronomic Oral Vinorelbine and Sorafenib b) Pharmacokinetics Profiling of the Combination of Metronomic Oral Vinorelbine and Sorafenib at MTD
• Study Start Date: June 2008
• Actual Primary Completion Date: August 2013
• Actual Study Completion Date: September 2013

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1; 60 mg/week of vinorelbine + sorafenib	Drug: oral vinorelbine; The patients will be divided into 3 cohorts (15 patients per cohort), each cohort receiving a fixed metronomic (thrice a week) dose of oral vinorelbine at 60 mg/week, 90 mg/week, and 120 mg/week respectively. We should arrive at 3 different MTDs from the 3 cohorts.; Other Name: Navelbine Oral; Drug: sorafenib; Each patient within each cohort will receive a starting dose of sorafenib at 200 mg bid for 4 weeks. In the absence of dose-limiting toxicities, the dose of sorafenib will be escalated to 400 mg bid for another 4 weeks, 600 mg bid for 4 weeks and then finally 800 mg bid. We should arrive at 3 different MTDs from the 3 cohorts.; Other Name: Nexavar
Experimental: 2; 90 mg/week of vinorelbine + sorafenib	Drug: oral vinorelbine; The patients will be divided into 3 cohorts (15 patients per cohort), each cohort receiving a fixed metronomic (thrice a week) dose of oral vinorelbine at 60 mg/week, 90 mg/week, and 120 mg/week respectively. We should arrive at 3 different MTDs from the 3 cohorts.; Other Name: Navelbine Oral; Drug: sorafenib; Each patient within each cohort will receive a starting dose of sorafenib at 200 mg bid for 4 weeks. In the absence of dose-limiting toxicities, the dose of sorafenib will be escalated to 400 mg bid for another 4 weeks, 600 mg bid for 4 weeks and then finally 800 mg bid. We should arrive at 3 different MTDs from the 3 cohorts.; Other Name: Nexavar
Experimental: 3; 120 mg/week of vinorelbine + sorafenib	Drug: oral vinorelbine; The patients will be divided into 3 cohorts (15 patients per cohort), each cohort receiving a fixed metronomic (thrice a week) dose of oral vinorelbine at 60 mg/week, 90 mg/week, and 120 mg/week respectively. We should arrive at 3 different MTDs from the 3 cohorts.; Other Name: Navelbine Oral; Drug: sorafenib; Each patient within each cohort will receive a starting dose of sorafenib at 200 mg bid for 4 weeks. In the absence of dose-limiting toxicities, the dose of sorafenib will be escalated to 400 mg bid for another 4 weeks, 600 mg bid for 4 weeks and then finally 800 mg bid. We should arrive at 3 different MTDs from the 3 cohorts.; Other Name: Nexavar

Outcome Measures

Primary Outcome Measures :

1. to determine the optimal combination of metronomic oral vinorelbine with sorafenib to achieve anti-angiogenic and hence anti-tumour effect in patients with advanced NSCLC [ Time Frame: every 1-2 monthly with DCE-MR and circulating endothelial cells apart from routine CT scans ]

Secondary Outcome Measures :

1. To determine the response rate to the combination of metronomic oral vinorelbine and sorafenib in advanced NSCLC [ Time Frame: CT scan every 2 months while on treatment ]

Eligibility Criteria

• Ages Eligible for Study: 21 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Patients must have histologically or cytologically confirmed NSCLC
2. At least one or 2 prior lines of chemotherapy, including oral EGFR tyrosine-kinase inhibitor for metastatic disease or locally advanced unresectable disease. There should be at least 4 weeks since prior chemotherapy or radiation therapy; patients who decline conventional chemotherapy or oral EGFR tyrosine-kinase inhibitor as salvage 2nd or 3rd line treatment are also eligible.
3. Minimum body-surface area (BSA) of 1.4 m2 at point of recruitment. This is a safeguard against recruiting small-built patients who may experience adverse reaction on absolute dosing of oral vinorelbine. At this body surface area, the maximum dosing of oral vinorelbine at 120 mg/week is equivalent to 86 mg/m2/week for a patient with BSA of 1.4 m2.
4. Age >21 years
5. ECOG performance status <2 (Karnofsky >60%)
6. Patients must have normal organ and marrow function as defined here: leukocytes >3,000/mcL, absolute neutrophil count >1,500/mcL, platelet count > 100,000/mcL, serum bilirubin within normal institutional limits, AST(SGOT)/ALT(SGPT) <2.5 X upper limit of normal, and creatinine within normal institutional limits or creatinine clearance >60 mL/min/1.73 m2 for patients. These tests must be done within 1 week of study treatment.
7. Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

1. Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
2. Patients receiving any other investigational agents
3. Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
4. History of allergic reactions attributed to compounds of similar chemical or biologic composition to Oral Vinorelbine or other agents used in study
5. Prior and / or concomitant treatment with drugs known to induce or inhibit cytochrome P450 3A4: phenytoin, carbamazepine, barbiturates, rifampicin, imidazole antifungals (such as ketoconazole, fluconazole, itraconazole, metronidazole), omeprazole and ritonavir. Patients who are taking gastric acid-lowering agents such as H2 antagonist or antacids will be evaluated regarding the need to continue with these medications. If discontinuation of these medications is medically contraindicated, the patient will be excluded as these agents are known to lower the solubility of sorafenib and hence may limit their efficacy.
6. Significant malabsorption syndrome or disease affecting the gastro-intestinal tract function
7. Significant peripheral or autonomic neuropathy affecting sensation or bowel motility
8. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
9. Uncontrolled hypertension defined as systolic blood pressure >150 mmHg or diastolic pressure >90 mmHg despite optimal management
10. Pregnancy or breast-feeding or women of childbearing potential not using effective contraception
11. Evidence or history of bleeding diathesis or coagulopathy
12. Thrombotic or embolic events such as cerebrovascular accident including transient ischemic attacks within the past 6 months
13. Pulmonary hemorrhage/bleeding event >CTCAE grade 2 within 4 weeks of recruitment
14. Any other hemorrhage/bleeding event >CTCAE grade 3 within 4 weeks of recruitment

Contacts and Locations

Locations

Singapore

National Cancer Centre, Singapore

Singapore, Singapore, 169610

Sponsors and Collaborators

National Cancer Centre, Singapore

Investigators

• Principal Investigator: Eng-Huat Tan, MD; National Cancer Centre, Singapore

More Information

• Responsible Party: Eng-Huat Tan, Senior Consultant, National Cancer Centre, Singapore
• ClinicalTrials.gov Identifier: NCT00870532
• Other Study ID Numbers: 08-3-LUN
• First Posted: March 27, 2009
• Last Update Posted: November 3, 2013
• Last Verified: November 2013

Keywords provided by Eng-Huat Tan, National Cancer Centre, Singapore:

Phase I; Combination; Anti-angiogenic; Sorafenib; Metronomic oral vinorelbine

Additional relevant MeSH terms:

Sorafenib; 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; Vinorelbine; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Phytogenic; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators