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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

Phase 1
21 Years
Open (Enrolling)
Non-Small Cell Lung Cancer

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Trial Information

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

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.

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

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

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

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

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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

Outcome Time Frame:

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

Safety Issue:


Principal Investigator

Eng-Huat Tan, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Centre, Singapore


Singapore: Health Sciences Authority

Study ID:




Start Date:

June 2008

Completion Date:

June 2013

Related Keywords:

  • Non-Small Cell Lung Cancer
  • Phase I
  • Combination
  • Anti-angiogenic
  • Sorafenib
  • Metronomic oral vinorelbine
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms