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 lapatinib-
trametinib combination in patients with KRASm NSCLC
To determine the progression free survival of the lapatinib-trametinib 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 lapatinib in
combination with trametinib.
- To asses anti-tumor activity of lapatinib in combination with trametinib.
- To determine the pharmacokinetic profile of lapatinib and trametinib in this combination.
- To explore genetic determinants of response to the lapatinib-trametinib combination
- To explore the potential mechanism of resistance to lapatinib in
combination with trametinib, 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 ; for PART B: treated with first line therapy for metastatic disease only.
2. Written documentation of a known pathogenic KRAS (exon 2, 3 or 4) mutation and PIK3CA wild-type (exon 9 and 20).
3. Age ≥ 18 years.
4. Able and willing to give written informed consent.
5. WHO performance status of 0 or 1 (part A and B)
6. Able to swallow and retain orally administered medications and does not have clinically significant gastrointestinal abnormalities that may alter absorption (e.g. malabsorption syndrome or major resection of the stomach or bowel)
7. Able and willing to undergo blood sampling for PK and PD analysis.
8. Able and willing to undergo a tumor biopsy prior to start, after two weeks on therapy and upon progression of disease
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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 another primary malignancy
3. Symptomatic or untreated leptomeningeal disease.
4. Symptomatic brain metastasis. Patients previously treated or untreated for these conditions that are asymptomatic in the absence of corticosteroid and anticonvulsant therapy (for at least 6 weeks) are allowed to enrol. Radiotherapy for brain metastasis must have been completed at least 6 weeks prior to start of study treatment. Brain metastasis must be stable with verification by imaging (e.g. brain MRI or CT completed at screening demonstrating no current evidence of progressive brain metastases). Patients are not permitted to receive anti-epileptic drugs or corticosteroids.
5. 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 PI3K, AKT, mTOR, BRAF, MEK and ERK.
6. History of interstitial lung disease or pneumonitis
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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 lapatinib, trametinib 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.)
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, Cycle 2 Day 1, 2, Day 1 of subsequent cycles
Baseline
Baseline, on treatment, and upon progressive 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 of the combination lapatinib + trametinib to humans |
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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 | No |
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 | 4 |
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 | 2 |
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
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 | 4 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |