A Phase 1, Open-Label, Dose Escalation Study to Evaluate Safety, Pharmacokinetics and Pharmacodynamics of Combined Oral C-Met/ALK Inhibitor (PF-02341066) and Pan-Her Inhibitor (PF-0299804) in Patients With Advanced Non-Small Cell Lung Cancer
- Approximately 85% of lung cancer is defined histologically as NSCLC and the majority of
patients present with inoperable locally advanced (Stage IIIB) or metastatic (Stage IV)
disease for which no curative treatment is available.
- Patients with disease progression on or after first-line treatment with platinum-based
doublets may be candidates for second-line treatment.
- Recent evidence strongly implicates EGFR activating somatic mutations as a mechanism of
tumorigenesis and a determinant of sensitivity to EGFR TKIs in NSCLC.
- Despite the dramatic initial response to gefitinib and erlotinib, about 50% of NSCLC
tumors develop resistance due to secondary activating mutations in EGFR itself,
including the EGFR T790M gatekeeper mutation, and more than 20% of acquired
resistance is due to an increase in mesenchymal-epithelial transition factor (c-Met)
- There is evidence from a limited number of tumors from patients with acquired
resistance to EGFR-TKIs that both T790M and cMET resistance mechanisms can occur in the
same patient at different metastatic sites and even in different fractions of the same
- Tumors with acquired resistance to erlotinib and gefitinib might be vulnerable to a
combination of PF-00299804 a second generation EGFR TKI which is also an inhibitor of
T790M mutation, and PF-02341066 which is an inhibitor of c- Met/Hepatocyte Growth
Factor Receptor (HGFR).
- To define the recommended Phase 2 dose (RP2D) of combined PF-02341066 plus
PF-00299804 in patients with advanced Non-Small Cell Lung Cancer (NSCLC).
- To assess the overall safety and tolerability, plasma pharmacokinetics (PK) and
clinical activity of combined PF-02341066 plus PF-00299804.
- To analyze potential predictive and pharmacodynamic biomarkers in tumor and blood in
patients with advanced NSCLC who have acquired resistance to erlotinib or gefitinib
- Dose Escalation Phase: Adults with histologically documented diagnosis of NSCLC that is
locally advanced or metastatic, after failure of either at least one chemotherapy regimen or
treatment with erlotinib or gefitinib.
Expansion Phase: Adults with histologically documented diagnosis of NSCLC that is locally
advanced or metastatic, with acquired resistance to erlotinib or gefitinib, and must have
one lesion amendable to biopsy.
- All pathology samples will be reviewed at the NCI.
- Phase 1, multi-center, open-label, non-randomized trial of combined oral PF- 02341066
and oral PF-00299804 in patients with advanced NSCLC. Trial consists of two phases.
- Dose Escalation Phase: Patients will be treated with varying doses of combined PF-
02341066 plus PF-00299804. Tumor biopsy is not required.
- Expansion Phase: Two expansion cohorts will run concurrently following completion of
the Dose Escalation Phase. Both cohorts will enroll patients with locally advanced or
metastatic NSCLC with acquired resistance to erlotinib or gefitinib, which is defined
as progression following an initial response (complete or partial) or stable disease
for at least six months while on erlotinib or gefitinib.
- The dose escalation phase and the dose expansion phase can run concurrently insofar as
the dose expansion phase can enroll before completion of the dose escalation phase
provided that the dose used in the expansion phase has already been tested in the
escalation phase and has been declared safe; i.e., for each specific safe dose the
escalation phase is followed by the expansion phase.
- Tumor biopsy is mandatory for Expansion Phase entrance, however, all patients will be
treated with study drugs irrespective of the biomarker identified which will be
analyzed retrospectively. The mandatory biopsy in the Expansion Phase is necessary in
order to identify acquired mutations that change over time.
- Expansion cohort 1 will continue to evaluate safety, tolerability and PK of the drug
combination PF-02341066 plus PF-00299804.
- Expansion cohort 2 will enroll patients who are either untreated by prior PF- 00299804
or who have progressed on single agent PF-00299804 administered in an ongoing clinical
trial. Patients who are previously untreated with PF-00299804 will be treated
sequentially; i.e., first with single agent PF-00299804 until progression, then with
the combination of PF-02341066 plus PF-00299804. Those who progressed with single agent
PF-00299804 on another clinical trial will be treated with the combination PF-02341066
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Overall safety profile of combined PF-0234 1066 plus PF-00299804 including adverse events.
Arun Rajan, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|