non-small cell lung cancer
Conditions
Interventions
Product Name: Dacomitinib
Pharmaceutical Form: Coated tablet
INN or Proposed INN: dacomitinib
Other descriptive name: DACOMITINIB
Concen
Sponsors
The Netherlands Cancer Institute
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Histological or cytological proof of metastatic NSCLC 2. Written documentation of a known pathogenic KRAS (exon 2, 3 or 4) mutation and PIK3CA wildtype (exon 9 and 20). 3. Age >= 18 years. 4. Able and willing to give written informed consent. 5. WHO performance status of 0, 1. 6. Able and willing to undergo blood sampling for PK and PD analysis. 7. Able and willing to undergo tumor biopsies prior to start, while on study treatment and upon progression of disease 8. All toxicities related to prior treatment should have resolved to CTCAE grade 1 or less (excluding alopecia) 9. Life expectancy >= 3 months allowing adequate follow up of toxicity evaluation and antitumor activity. 10. Measurable disease according to RECIST 1.1 criteria 11. Adequate organ system function Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 100 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 32
Exclusion criteria
Exclusion criteria: 1. Any treatment with investigational drugs within 30 days prior to receiving the first dose of investigational treatment. 2. History of additional primary malignancies 3. Two or more prior lines of therapy for advanced disease (PART B only). 4. Symptomatic or untreated leptomeningeal disease. 5. Symptomatic brain metastasis. 6. Patients previously treated with any targeted drug combination known to interfere with EGFR, HER-2, HER-3, HER-4 or MAPK- and PI3K-pathway components, including inhibitors of PTEN, PI3K, AKT, mTOR, BRAF, MEK and ERK. 7. History of interstitial lung disease or pneumonitis 8. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral dacomitinib/PD-0325901 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection). 9. Woman who are pregnant or breast feeding. 10. Unreliable contraceptive methods. 11. Radio-, immuno- or chemotherapy within the last 4 weeks prior to receiving the first dose of investigational treatment. Palliative radiation (1x 8Gy) is allowed. 12. Patients who have undergone any major surgery within the last 2 weeks prior to starting study drug or who would not have fully recovered from previous surgery. 13. Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients. 14. Patients with a known history of hepatitis B or C. 15. Patients with retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), or with a history of uveitis, retinal vein occlusion, central serous retinopathy or retinal detachment.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To determine the recommended phase 2 dose (RP2D) of the dacomitinib-PD-0325901 combination in patients with KRASm NSCLC. To determine the progression free survival of the dacomitinib/PD-0325901 combination compared to standard of care therapy in patients with KRASm NSCLC. ; Secondary Objective: - To characterize the safety and tolerability of dacomitinib in combination with PD-0325901. - To asses anti-tumor activity of dacomitinib in combination with PD-0325901. - To determine the pharmacokinetic profile of dacomitinib and PD-0325901 in this combination. - To explore genetic determinants of response to the dacomitinib-PD-0325901 combination - To evaluate pharmacodynamic biomarkers of the dacomitinib-PD-0325901 combination as measured by expression levels of relevant proteins (e.g. pERK, pAKT and pS6). - To explore the potential mechanism of resistance to dacomitinib in combination with PD-0325901, as measured by gene alterations/expression profiles (baseline, relapse) in tumor tissue upon progression ; Primary end point(s): Incidence of dose-limiting toxicities (DLTs) Progression free survival (PFS) per RECIST version 1.1 ; Timepoint(s) of evaluation of this end point: Continuous Every 8 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Incidence and severity of adverse events Overall response rate, duration of response, time to response and overall survival (phase II only) Plasma concentrations of dacomitinib, PD-0325901 and relevant metabolites Baseline molecular status of potential predictive markers of tumor response (BRAF, HRAS, KRAS, NRAS, PTEN, PIK3CA, MAPK1, MAPK2, ARAF, c-MET, EGFR etc.) RNA and protein expression levels of relevant proteins (e.g. pERK, pAKT and pS6) Gene alteration (baseline, relapse) in tumor tissue ; Timepoint(s) of evaluation of this end point: continuous Every 8 weeks / continuous Cycle 1 Day 1,2, 4, 7, Cycle 2 Day 1, 2, Day 1 of subsequent cycles Baseline Baseline, on treatment and upon progrssive disease | — |
Countries
Netherlands
Contacts
Public ContactCarla Vianen
The Netherlands Cancer Institute
Outcome results
None listed