Afatinib and Selumetinib in Advanced KRAS Mutant and PIK3CA Wildtype Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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This is a multi-center open-label proof-of-concept study consisting of two parts: PART A - a phase I dose-finding study (3 + 3 classical design) evaluating the RP2D of afatinib in combination with selumetinib in KRASm NSCLC; and PART B - a randomized phase II study investigating the progression free survival and safety of selumetinib/afatinib combination therapy compared to standard of care chemotherapy in KRASm NSCLC.

Official Title
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Phase I/II Study With the Combination of Afatinib and Selumetinib in Advanced KRAS Mutant Positive and PIK3CA Wildtype Non-small Cell Lung Cancer

Conditions
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Colorectal Neoplasms, Gastrointestinal Neoplasms, Pancreatic Neoplasms, Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Afatinib
* Drug: Selumetinib
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological proof of advanced NSCLC; for PART B: treated with first line therapy for metastatic disease only. Written documentation of a known pathogenic KRAS (exon 2, 3 or 4) mutation and PIK3CA wildtype (defined as absence of mutations in exon 9 and 20) Able and willing to give written informed consent Able and willing to undergo blood sampling for PK and PD analysis Life expectancy >=3 months allowing adequate follow up of toxicity evaluation and antitumor activity. WHO performance status of 0 or 1. Able and willing to undergo a tumor biopsies prior to start, after two weeks (part A only) and upon progression of disease Measurable disease according to RECIST 1.1 Adequate organ system function measured by laboratory values Exclusion Criteria: Any treatment with investigational drugs within 30 days prior to receiving the first dose of investigational treatment. History of another malignancy Exception PART A: Patients who have been disease-free for at least 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent second malignancies are eligible. Exception PART B: Adequately treated carcinoma in situ of the cervix and adequately treated basal cell carcinoma of the skin. 3. Symptomatic or untreated leptomeningeal disease. Symptomatic brain metastasis. Patients previously treated with any drug combination known to interfere with EGFR, HER2, HER3, HER4 or MAPK- and PI3K-pathway components, including inhibitors of PTEN, PI3K, AKT, mTOR, BRAF, MEK and ERK. History of interstitial lung disease or pneumonitis Radio-, immuno- or chemotherapy within the last 2 weeks prior to receiving the first dose of investigational treatment. Palliative radiation (1x 8Gy) is allowed. Opthalmological diseases Patients with left ventricular ejection fraction (LVEF) < 55% Patients with cardiac comorbidities Concomitant or recent use (in the past 14 days) of strong inhibitors and inducers of CYP1A2, CYP2C19, CYP3A4, 3A5 and P-glycoprotein (P-gp)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Afatinib plus selumetinib<br>Combination of afatinib and selumetinib at the optimal dose and regimen as determined in the phase I part of this study | Drug: Afatinib<br>* Tablet<br>* Other names: BIBW2992;Drug: Selumetinib<br>* Capsule<br>* Other names: AZD6244;|
| Active Comparator: Control<br>Standard-of-care second line treatment for non small cell lung cancer (docetaxel) | Drug: Docetaxel<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicities (Phase I) | Incidence of DLTs in the first treatment cycle | Cycle 1 (4 weeks) | 
| Progression Free Survival (Phase II) | PFS measured by RECIST v 1.1 | CT scan every 6 weeks and monthly phone call until start of subsequent anticancer therapy or until all patients have been followed up for at least 18 months of have been lost to follow up, whichever occurs first | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerability (Incidence and severity of adverse events per CTCAE v4.03) | Incidence and severity of adverse events per CTCAE v4.03 | Up to 28 days after last study drug intake | 
| Plasma concentrations of afatanib and selumetinib | Plasma concentrations of afatanib and selumetinib will be measured at day 1,2,4,8,15, 22 in cycle 1, on day 1 and 2 in cycle 2 and subsequently before every treatment cycle to determine pharmacokinetics of both substances in combination and interindividual differences after a single dose and after multiple doses. | On day 1, 2, 4, 8, 15, 22 in cycle 1, on day 1 and 2 in cycle 2 and subsequently at every treatment cycle pre-dose | 
| Efficacy (Phase II) (Overall response rate (ORR), duration of response (DOR) , time to response (TTR) and overall survival (OS) per RECIST v1.1) | Overall response rate (ORR), duration of response (DOR) , time to response (TTR) and overall survival (OS) per RECIST v1.1 | Assessed by CT scans every 6 weeks and by monthly phone call until all patients have been followed up for at least 18 months or have been lost to follow up, whichever occurs first. |