E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
non-small cell lung cancer
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niet-kleincellig longkanker
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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. |
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E.2.2 | Secondary objectives of the trial |
- 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
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 |
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E.4 | Principal 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Incidence of dose-limiting toxicities (DLTs)
Progression free survival (PFS) per RECIST version 1.1 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | 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
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E.5.2.1 | 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 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
First administration to humans of the combination of dacomitinib + PD-0325901 |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study will be upon completion of the follow-up period of the last patient. This will occur when either all the patients in each arm of PART B (phase II) are deceased, every patient in PART B has completed the end of treatment assessments and has been followed for at least 18 months for overall survival after initiation of the last study treatment, or have been lost to follow-up or withdrew consent, whichever occurs first. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |