Carcinoma, Non-Small-Cell Lung, Colorectal Neoplasms, Gastrointestinal Neoplasms, Pancreatic Neoplasms
Conditions
Brief summary
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.
Interventions
DRUGAfatinib
Tablet
DRUGSelumetinib
Capsule
DRUGDocetaxel
Sponsors
AstraZeneca
Boehringer Ingelheim
The Netherlands Cancer Institute
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicities (Phase I) | Cycle 1 (4 weeks) | Incidence of DLTs in the first treatment cycle |
| Progression Free Survival (Phase II) | 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 | PFS measured by RECIST v 1.1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy (Phase II) (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. | Overall response rate (ORR), duration of response (DOR) , time to response (TTR) and overall survival (OS) per RECIST v1.1 |
| Plasma concentrations of afatanib and selumetinib | 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 | 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. |
| Tolerability (Incidence and severity of adverse events per CTCAE v4.03) | Up to 28 days after last study drug intake | Incidence and severity of adverse events per CTCAE v4.03 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Determinants and mode of response - Target proteins | At baseline, cycle 1 day 15 and at treatment discontinuation (expected 6-9 months after start) | Change in expression and/or phosphorylation status target proteins (e.g. pERK, pS6, heregulin, HER2) before, during and after treatment |
| Pharmacogenetics profiling to assess predictors of response and resistance- inducing mutations | Before treatment, every 6 weeks and at treatment discontinuation (expected 6-9 months after start) | Pharmacogenetic profiling to assess predictors of response and resistance- inducing mutations |
Countries
Netherlands
Contacts
Primary ContactF Opdam, MD, PhD
Backup ContactS huijberts, MD
Outcome results
None listed