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

August 24, 2018 updated by: The Netherlands Cancer Institute

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

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 Overview

Status

Unknown

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Anticipated)

320

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
      • Amsterdam, Netherlands, 1066CX
        • Recruiting
        • Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
        • Principal Investigator:
          • F Opdam, MD, PhD
        • Contact:
          • F Opdam, MD, PhD
    • Gelderland
      • Nijmegen, Gelderland, Netherlands, 6525GA
        • Recruiting
        • UMC St. Radboud Nijmegen
        • Principal Investigator:
          • Carla ML van Herpen, MD, PhD
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Dose Limiting Toxicities (Phase I)
Time Frame: Cycle 1 (4 weeks)
Incidence of DLTs in the first treatment cycle
Cycle 1 (4 weeks)
Progression Free Survival (Phase II)
Time Frame: 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
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)
Time Frame: Up to 28 days after last study drug intake
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
Time Frame: 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.
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)
Time Frame: 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
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Determinants and mode of response - Target proteins
Time Frame: 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
At baseline, cycle 1 day 15 and at treatment discontinuation (expected 6-9 months after start)
Pharmacogenetics profiling to assess predictors of response and resistance- inducing mutations
Time Frame: 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
Before treatment, every 6 weeks and at treatment discontinuation (expected 6-9 months after start)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The Netherlands Cancer Institute

Collaborators

AstraZeneca
Boehringer Ingelheim

Investigators

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

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2015

Primary Completion (Anticipated)

May 1, 2019

Study Completion (Anticipated)

December 1, 2019

Study Registration Dates

First Submitted

November 13, 2014

First Submitted That Met QC Criteria

May 18, 2015

First Posted (Estimate)

May 21, 2015

Study Record Updates

Last Update Posted (Actual)

August 27, 2018

Last Update Submitted That Met QC Criteria

August 24, 2018

Last Verified

August 1, 2018

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • M14AFS

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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