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A Phase I/II Study of Foretinib in Patients With Previously Treated Non-Small Cell Lung Cancer Receiving Standard Erlotinib Therapy

Phase 1/Phase 2
18 Years
Open (Enrolling)
Lung Cancer

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Trial Information

A Phase I/II Study of Foretinib in Patients With Previously Treated Non-Small Cell Lung Cancer Receiving Standard Erlotinib Therapy


- To determine the recommended phase II dose of MET/VEGFR2 inhibitor Foretinibin
combination with standard erlotinib hydrochloride therapy in patients with locally
advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one
prior chemotherapy regimen, and whose EGFR-expression status is positive or unknown.

- To determine the safety, tolerability, toxicity profile, dose-limiting toxicities, and
pharmacokinetic profile of MET/VEGFR2 inhibitor Foretinib and erlotinib hydrochloride
in this schedule.

- To determine the correlation, if any, between the toxicity profile and

- To assess the anti-tumor activity of MET/VEGFR2 inhibitor Foretinib in combination with
erlotinib hydrochloride as evidenced by response rates, clinical benefit (complete or
partial response or stable disease ≥ 8 weeks duration), and an exploratory endpoint of
early assessment of tumor size as a continuous variable (when compared to erlotinib
hydrochloride alone).

- To assess one-year survival rate in these patients.

- To investigate the correlation, if any, between response and biomarkers, including EGFR
gene mutation, EGFR gene amplification, EGFR gene polymorphisms, c-Met gene mutation,
amplification and expression, phospho-c-Met expression, K-Ras gene mutation, and
baseline serum HGF levels.

OUTLINE: This is a multicenter, dose-escalation phase I study of MET/VEGFR2 inhibitor
Foretinib followed by a randomized, open-label phase II study.

- Phase I (dose-escalation) : Patients receive oral erlotinib hydrochloride once daily on
days 1-28. Patients receive oral MET/VEGFR2 inhibitor GSK1363089 once daily on days
15-28 during course 1 and on days 1-28 during all other courses. Courses repeat every
28 days until the maximum-tolerated dose of MET/VEGFR2 inhibitor Foretinib is

Blood samples are collected on days 14 and 28 of course 1 for pharmacokinetics and day 1 of
courses 1 and 2 and post treatment for pharmacodynamic studies.

- Phase II: Patients are randomized to 1 of 2 treatment arms:

- Arm I (MET/VEGFR2 inhibitor Foretinib and erlotinib hydrochloride): Patients
receive oral MET/VEGFR2 inhibitor Foretinib (at the recommended phase II dose
determined in phase I) once daily and oral erlotinib hydrochloride once daily on
days 1-28. Courses repeat very 28 days in the absence of disease progression or
unacceptable toxicity.

- Arm II (erlotinib hydrochloride only): Patients receive oral erlotinib
hydrochloride once daily on days 1-28. Courses repeat every 28 days in the absence
of disease progression or unacceptable toxicity.

In both arms, samples are collected for pharmacodynamic studies as in phase I.

After completion of study treatment, patients are followed at week 4 and then every 3 months

Inclusion Criteria


- Histologically or cytologically confirmed non-small cell lung cancer (NSCLC), meeting
all of the following criteria:

- Locally advanced or metastatic disease

- Failed 1-2 prior chemotherapy regimen

- Must be eligible to receive erlotinib therapy (i.e., patients must have
received 1-2 prior chemotherapy regimen [combination unless patient is ≥ 70
years]) for advanced or metastatic disease

- No plan to receive further palliative cytotoxic chemotherapy

- EGFR-expression status positive or unknown

- Patients who are known to have tumors that are EGFR negative on IHC are not

- Presence of clinically and/or radiologically documented measurable disease

- At least 1 site of disease must be unidimensionally measurable as follows:

- Chest X-ray ≥ 20 mm

- CT scan (with slice thickness of ≤ 5 mm) ≥ 10 mm (longest diameter)

- Physical exam (using calipers) ≥ 10 mm

- Lymph nodes by CT scan ≥ 15 mm (measured in short axis)

- Measurable lesions must be outside a previous radiotherapy field unless disease
progression has been documented

- Must have archival tissue available or undergo a biopsy or FNA prior to registration/

- No appreciable cavitation in central thoracic lesions

- Patients with overt bleeding from any site (> 30 mL bleeding/episode) within 3
months of study entry are not eligible

- No untreated brain or meningeal metastases (CT scans are not required to rule this
out unless there is a clinical suspicion of CNS disease)

- Patients with treated and radiologic or clinical evidence of stable brain
metastases, with no evidence of cavitation or hemorrhage in the brain lesion,
are eligible providing that they are asymptomatic and do not require
corticosteroids (must have discontinued steroids ≥ 1 week prior to entry)


- ECOG performance status 0-2

- Patients must have discontinued smoking for ≥ 2 weeks prior to registration, and must
be prepared to refrain from cigarette usage until completion of the pharmacokinetic
sampling at the end of study course 1 (approximately 6 weeks in total) (Phase I only)

- Granulocyte count (AGC) ≥ 1.5 times 10^9/L

- Platelet count ≥ 100 x 10^9/L

- Serum creatinine ≤ 1.5 times upper normal limit (UNL) OR calculated creatinine
clearance ≥ 50 mL/min (≥ 0.83 mL/sec)

- Bilirubin ≤ 1.5 times UNL

- ALT and AST ≤ 2 times UNL

- No clinically relevant hemoptysis (> 5 mL fresh blood) within 4 weeks prior to study

- Patients with only flecks of blood in sputum are permitted

- No other invasive malignancies, unless curatively treated with no evidence of disease

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 90 days after
completion of study therapy

- No untreated and/or uncontrolled cardiovascular conditions and/or have symptomatic
cardiac dysfunction, including any of the following:

- Unstable angina, congestive heart failure, or myocardial infarction within the
previous year

- Cardiac ventricular arrhythmias requiring medication

- History of 2nd or 3rd degree atrioventricular conduction defects

- Patients with a significant cardiac history (even if controlled) or prior doxorubicin
exposure are required to have a LVEF > 50%

- Patients with proliferative diabetic retinopathy, retinal arteritis, or hemorrhage
must undergo full ophthalmological examination prior to entry to this study

- Must have resting systolic BP ≤ 150 mm Hg and/or diastolic BP ≤ 100 mm Hg (in the
presence or absence of a stable dose of anti-hypertensive medication)

- No poorly controlled hypertension

- No history of labile hypertension or poor compliance with anti-hypertensive

- No GI tract disease resulting in an inability to absorb oral medication, including
any of the following situations:

- Uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis)

- Post-surgical malabsorption characterized by uncontrolled diarrhea that results
in weight loss and vitamin deficiency or requires IV hyperalimentation (use of
pancreatic enzyme supplementation is allowed)

- No active or uncontrolled infections

- No serious illnesses or medical conditions that would not permit the patient to be
managed according to the protocol

- No known hypersensitivity to the study drugs or their components


- See Disease Characteristics

- No more than two prior chemotherapy regimens for metastatic NSCLC (excluding adjuvant

- Recovered from any treatment-related toxicities prior to randomization

- Persistent cisplatin- or taxane-induced sensory neuropathy ≤ grade 2 is

- No prior therapy with agents acting on the EGFR pathway

- No prior therapy with a c-Met inhibitor

- At least 21 days since the last dose of chemotherapy

- At least 21 days since last fraction of prior radiation therapy

- Exceptions may be made for non-myelosuppressive radiation to peripheral areas

- More than 14 days since prior major surgery, provided that wound healing has occurred

- More than 3 weeks since prior and no other concurrent investigational drugs or
anti-cancer therapy

- No concurrent CYP3A4 enzyme inducing or inhibiting drugs known to interact with
erlotinib hydrochloride, including any of the following:

- Enzyme-inducing anticonvulsants

- Rifampicin

- Rifabutin

- St. John wort

- Atazanavir

- Ketoconazole

- Patients with a history of pulmonary embolus or a deep vein thrombosis diagnosed
and/or treated within 6 months prior to registration will be excluded.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The recommended phase II dose of daily oral MET/VEGFR2 inhibitor Foretinib when given in combination with standard erlotinib hydrochloride therapy (phase I)

Outcome Description:

After completion of Phase I portion of the study

Outcome Time Frame:

3 years

Safety Issue:


Principal Investigator

Natasha Leighl, MD, FRCPC

Investigator Role:

Study Chair

Investigator Affiliation:

Princess Margaret Hospital, Canada


Canada: Health Canada

Study ID:




Start Date:

December 2009

Completion Date:

December 2013

Related Keywords:

  • Lung Cancer
  • recurrent non-small cell lung cancer
  • stage IIIA non-small cell lung cancer
  • stage IIIB non-small cell lung cancer
  • stage IV non-small cell lung cancer
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms