-02341066 and PF-00299804 for Advanced Non-Small Cell Lung Cancer
- Conditions
- Carcinoma, Non-Small Cell LungCarcinoma, Squamous CellCarcinoma, Large CellAdenocarcinoma
- Interventions
- Drug: PF-02341066/PF-00299804
- Registration Number
- NCT01441128
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
- PF-02341066 and PF-00299804 are drugs that specifically target certain proteins that may be more active in cancer cells than normal cells, in particular in non-small cell lung cancer. Both drugs seem to be able to stop the growth of or kill cancer cells. Researchers want to combine them to see if they are a safe and effective treatment for advanced non-small cell lung cancer.
Objectives:
- To test the safety and effectiveness of PF-02341066 and PF-00299804 for advanced non-small cell lung cancer.
Eligibility:
- Individuals at least 18 years of age with advanced non-small cell lung cancer that has not responded to standard treatments.
Design:
* Participants will be screened with a medical history and physical exam. They will also have blood and urine tests, and imaging studies. Heart and lung function tests and an eye exam may also be given.
* The first cycle of treatment will be 28 days. Every cycle after the first will be 21 days. Participants may have up to 17 cycles of treatment.
* Participants will take both study drugs as tablets. Twelve hours after the first dose, participants will take only the PF-02341066. This dose schedule will remain the same throughout the study.
* Participants will be monitored with frequent blood and urine tests and imaging studies. Tumor biopsies will be taken as needed. Those in the study will keep a diary to record any symptoms or side effects of taking the study drugs.
* After 17 cycles of treatment, or after stopping the study drugs early for any other reason, participants will have a final followup visit.
- Detailed Description
BACKGROUND:
* 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) signaling.
* 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 lesion.
* 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).
OBJECTIVES:
- 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
ELIGIBILITY:
* 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.
DESIGN:
* 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 plus PF-00299804.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 20
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Arm 2 PF-02341066/PF-00299804 45 mg by mouth once a day of PF-00299804 in tablet form until progressive disease and then the maximum tolerated combined dose of PF-02341066 (given by mouth twice a day in tablet form) and PF-00299804 (given by mouth once a day in tablet form). Arm 1 PF-02341066/PF-00299804 The starting doses will be 200 mg by mouth, twice a day of PF 02341066 in tablet form and 30 mg by mouth once a day of PF 0029804 in tablet form. Thedose of each drug in the combination will be escalated or de-escalated until the maximum tolerated combined dose is reached. Patients will then be treated with the maximum tolerated combined dose.
- Primary Outcome Measures
Name Time Method Overall safety profile of combined PF 02341066 plus PF 00299804 including adverse events (AE), as defined and graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], and first cycle Dose Limiting Tox... 18 months
- Secondary Outcome Measures
Name Time Method Plasma concentrations and pharmacokinetic (PK) parameters of PF 02341066 and PF 00299804 including AUCtau, Cmax, Ctrough, Tmax, and CLss/F 18 months Pharmacodynamic biomarkers in tumor biopsies (e.g., phospho c Met, c Met, EGFR, phospho EGFR) and in blood (e.g., HGF and s Met) that are modulated following drug exposure. 12 months Clinical activity of combined PF 02341066 plus PF 00299804 including objective response (OR) and stable disease (SD) as defined by RECIST version 1.1, duration of response (DR) and progression free survival (PFS). 18 months Biomarkers in tumor and blood that are potentially predictive for drug activity: for example, KRAS mutations, EGFR mutations (eg, T790M), EGFR and HER2 amplifications, c Met amplification and mutations, ALK, PTEN and PIK3A status in tumor biopsi... 12 months
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center, 9000 Rockville Pike
🇺🇸Bethesda, Maryland, United States