M14AFS: Afatinib and Selumetinib in Advanced KRAS Mutant and PIK3CA Wildtype Non-small Cell Lung Cancer

Sponsor
The Netherlands Cancer Institute (Other)
Overall Status
Unknown status
CT.gov ID
NCT02450656
Collaborator
AstraZeneca (Industry), Boehringer Ingelheim (Industry)
320
2
2
54
160
3

Study Details

Study Description

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.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
320 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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 Start Date :
Jun 1, 2015
Anticipated Primary Completion Date :
May 1, 2019
Anticipated Study Completion Date :
Dec 1, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Afatinib plus selumetinib

Combination of afatinib and selumetinib at the optimal dose and regimen as determined in the phase I part of this study

Drug: Afatinib
Tablet
Other Names:
  • BIBW2992
  • Drug: Selumetinib
    Capsule
    Other Names:
  • AZD6244
  • Active Comparator: Control

    Standard-of-care second line treatment for non small cell lung cancer (docetaxel)

    Drug: Docetaxel

    Outcome Measures

    Primary Outcome Measures

    1. Dose Limiting Toxicities (Phase I) [Cycle 1 (4 weeks)]

      Incidence of DLTs in the first treatment cycle

    2. 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 Outcome Measures

    1. 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

    2. 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.

    3. 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

    Other Outcome Measures

    1. 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

    2. 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

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts 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)

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 UMC St. Radboud Nijmegen Nijmegen Gelderland Netherlands 6525GA
    2 Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital Amsterdam Netherlands 1066CX

    Sponsors and Collaborators

    • The Netherlands Cancer Institute
    • AstraZeneca
    • Boehringer Ingelheim

    Investigators

    • Principal Investigator: F Opdam, MD, PhD, NKI-AvL

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    The Netherlands Cancer Institute
    ClinicalTrials.gov Identifier:
    NCT02450656
    Other Study ID Numbers:
    • M14AFS
    First Posted:
    May 21, 2015
    Last Update Posted:
    Aug 27, 2018
    Last Verified:
    Aug 1, 2018

    Study Results

    No Results Posted as of Aug 27, 2018