Clinical trial NCT02450656: Afatinib and Selumetinib in Advanced KRAS Mutant and PIK3CA Wildtype Non-small Cell Lung Cancer
Official title: Phase I/II Study With the Combination of Afatinib and Selumetinib in Advanced KRAS Mutant Positive and PIK3CA Wildtype Non-small Cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Colorectal Neoplasms
Gastrointestinal Neoplasms
Pancreatic Neoplasms
Carcinoma, Non-Small-Cell Lung
Lead sponsor: The Netherlands Cancer Institute
Sponsor class: OTHER
Collaborators: name: AstraZeneca
name: Boehringer Ingelheim
First posted: 2015-05-21
Enrollment: 320
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.


Eligibility criteria: 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)

Primary outcomes:
measure: Dose Limiting Toxicities (Phase I)
timeFrame: Cycle 1 (4 weeks)
measure: Progression Free Survival (Phase II)
timeFrame: 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 outcomes:
measure: Tolerability (Incidence and severity of adverse events per CTCAE v4.03)
timeFrame: Up to 28 days after last study drug intake
measure: Plasma concentrations of afatanib and selumetinib
timeFrame: 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
measure: Efficacy (Phase II) (Overall response rate (ORR), duration of response (DOR) , time to response (TTR) and overall survival (OS) per RECIST v1.1)
timeFrame: 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.
Other outcomes:
measure: Determinants and mode of response - Target proteins
timeFrame: At baseline, cycle 1 day 15 and at treatment discontinuation (expected 6-9 months after start)
measure: Pharmacogenetics profiling to assess predictors of response and resistance- inducing mutations
timeFrame: Before treatment, every 6 weeks and at treatment discontinuation (expected 6-9 months after start)
Locations:
city: Nijmegen
country: Netherlands
facility: UMC St. Radboud Nijmegen
state: Gelderland
city: Amsterdam
country: Netherlands
facility: Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
Study officials:
affiliation: NKI-AvL
name: F Opdam, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: