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

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

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.

Study Overview

• Status: Completed
• Conditions: Non-Small Cell Lung Cancer
• Intervention / Treatment: Drug: oral vinorelbine; Drug: sorafenib

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 Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 1

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore, 169610
    • National Cancer Centre, Singapore

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: Nexavar

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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	every 1-2 monthly with DCE-MR and circulating endothelial cells apart from routine CT scans

Secondary Outcome Measures

Outcome Measure	Time Frame
To determine the response rate to the combination of metronomic oral vinorelbine and sorafenib in advanced NSCLC	CT scan every 2 months while on treatment

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Actual): August 1, 2013
• Study Completion (Actual): September 1, 2013

Study Registration Dates

• First Submitted: June 9, 2008
• First Submitted That Met QC Criteria: March 26, 2009
• First Posted (Estimate): March 27, 2009

Study Record Updates

• Last Update Posted (Estimate): November 3, 2013
• Last Update Submitted That Met QC Criteria: November 1, 2013
• Last Verified: November 1, 2013

More Information

Terms related to this study

• Keywords: Sorafenib; Phase I; Combination; Anti-angiogenic; Metronomic oral vinorelbine
• 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; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Protein Kinase Inhibitors; Sorafenib; Vinorelbine
• Other Study ID Numbers: 08-3-LUN