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Phase 1 Study of Oral Vinorelbine in Combination With Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Using Two Different Schedules

Phase 1
21 Years
Not Enrolling
Non-Small Cell Lung Cancer

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Trial Information

Phase 1 Study of Oral Vinorelbine in Combination With Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Using Two Different Schedules

Additive or supraadditive activity of an EGFR TK-I with vinorelbine has been demonstrated
in-vitro. Clinical synergism has also been described between gefitinib and vinorelbine in
NSCLC. The use of cytotoxics in a metronomic schedule has not been well investigated in the
clinical setting despite emerging pre-clinical data. Using an established oral cytotoxic
such as oral vinorelbine in a metronomic dose-schedule is attractive due to the oral route
of administration. Preclinical studies have shown that by using cytotoxics in a low-dose
protracted manner, endothelial cells are preferentially affected via inhibition of
proliferation and induction of apoptosis. In addition to this anti-angiogenic mechanism, an
anti-vasculogenic process may also be involved that acts by reducing circulating endothelial
progenitor mobilization and viability. Moreover, it has also been shown that tumours that
were selected for high levels of acquired resistance to cytotoxics can be induced to respond
by using metronomic doses of chemotherapy.

Continuous administration of metronomic oral vinorelbine, given three times a week, has been
reported as feasible and well tolerated at doses up to 180 mg total dose per week. Early
results showed activity against refractory solid tumors such as renal cancer, NSCLC, ovarian
cancer, prostate cancer, unknown primary and Kaposi sarcoma.

This phase I study combines erlotinib and oral vinorelbine on two different schedules. The
conventional schedule vinorelbine (CSV) aims to determine the MTD of conventional schedule
of oral vinorelbine given on days 1 and 8 every 21 days plus daily erlotinib and the
metronomic schedule vinorelbine (MSV) aims to determine the optimal metronomic dose of
vinorelbine given 3 times a week plus daily erlotinib.

Inclusion Criteria:

- Histologically or cytologically confirmed NSCLC

- At least one or two prior lines of chemotherapy for metastatic disease or locally
advanced unresectable disease. There should be at least 4 weeks since prior
chemotherapy or radiation therapy or 6 weeks if the last regimen included BCNU or
mitomycin C

- Age > 21 years.

- ECOG performance status <2 (Karnofsky >60%, see Appendix A).

- Life expectancy of greater than 3 months

- Patients must have normal organ and marrow function as defined below:

- leukocytes >3,000/mcL

- absolute neutrophil count >1,500/mcL

- platelets >100,000/mcL

- total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) <2.5 X institutional ULN

- creatinine within normal institutional limits OR

- creatinine clearance >60 mL/min/1.73 m2

- The effects of Oral Vinorelbine on the developing human fetus are unknown. For this
reason and because vinca alkaloids as well as other therapeutic agents used in this
trial are known to be teratogenic, women of child-bearing potential and men must
agree to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry and for the duration of study participation.

- Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier.

- Patients may not be receiving any other investigational agents.

- Patients who have received previous vinorelbine or oral EGFR tyrosine kinase

- Patients with progressive 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. However patients are eligible if they have brain metastases that have
been treated with whole brain radiotherapy and are stable and not on corticosteroids.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to Oral Vinorelbine or other agents used in study.

- Prior and / or concomitant treatment with drugs known to induce or inhibit cytochrome
P450 3A4, CYP1A1 & CYP1A2 : phenytoin, carbamazepine, barbiturates, rifampicin,
imidazole antifungals (such as ketoconazole, fluconazole, itraconazole,
metronidazole), omeprazole and ritonavir

- Significant malabsorption syndrome or disease affecting the gastro-intestinal tract

- 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.

- Pregnancy or breast feeding or women of child-bearing potential not using effective

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with Oral Vinorelbine. In addition,
these patients are at increased risk of lethal infections when treated with
marrow-suppressive therapy. Appropriate studies will be undertaken in patients
receiving combination antiretroviral therapy when indicated.

- History of organ allograft

- Patients with evidence or history of bleeding diatheses or coagulopathy

- Serious, non-healing wound, ulcer, or bone fracture

- Because of interaction risk on CYP3A4, patients with concomitant treatments with
vitamin K antagonists such as phenprocoumon or warfarin or heparin or heparinoids
should be excluded

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Define the recommended dose of oral navelbine with erlotinib

Outcome Time Frame:

3 weeks

Safety Issue:


Principal Investigator

Wan-Teck Lim, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Center Singapore


Singapore: Health Sciences Authority

Study ID:




Start Date:

April 2008

Completion Date:

October 2012

Related Keywords:

  • Non-Small Cell Lung Cancer
  • Lung Cancer
  • Vinorelbine
  • Erlotinib
  • Phase 1
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms