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

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ClinicalTrials.gov Identifier: NCT02450656
Recruitment Status : Recruiting
First Posted : May 21, 2015
Last Update Posted : August 27, 2018
Sponsor:
Collaborators:
AstraZeneca
Boehringer Ingelheim
Information provided by (Responsible Party):
The Netherlands Cancer Institute

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.

Condition or disease Intervention/treatment Phase
Colorectal Neoplasms Gastrointestinal Neoplasms Pancreatic Neoplasms Carcinoma, Non-Small-Cell Lung Drug: Afatinib Drug: Selumetinib Drug: Docetaxel Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated 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 : June 2015
Estimated Primary Completion Date : May 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine


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 Name: BIBW2992

Drug: Selumetinib
Capsule
Other Name: AZD6244

Active Comparator: Control
Standard-of-care second line treatment for non small cell lung cancer (docetaxel)
Drug: Docetaxel



Primary Outcome Measures :
  1. Dose Limiting Toxicities (Phase I) [ Time Frame: Cycle 1 (4 weeks) ]
    Incidence of DLTs in the first treatment cycle

  2. 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


Secondary Outcome Measures :
  1. 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

  2. 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.

  3. 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


Other Outcome Measures:
  1. 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

  2. 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



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02450656


Contacts
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Contact: F Opdam, MD, PhD +31 20 512 2446 f.opdam@nki.nl
Contact: S huijberts, MD 0031205129111 s.huijberts@nki.nl

Locations
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Netherlands
UMC St. Radboud Nijmegen Recruiting
Nijmegen, Gelderland, Netherlands, 6525GA
Contact: Carla ML van Herpen, MD, PhD    +31243610353    Carla.vanHerpen@radboudumc.nl   
Principal Investigator: Carla ML van Herpen, MD, PhD         
Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital Recruiting
Amsterdam, Netherlands, 1066CX
Contact: F Opdam, MD, PhD         
Principal Investigator: F Opdam, MD, PhD         
Sponsors and Collaborators
The Netherlands Cancer Institute
AstraZeneca
Boehringer Ingelheim
Investigators
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Principal Investigator: F Opdam, MD, PhD NKI-AvL

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Responsible Party: The Netherlands Cancer Institute
ClinicalTrials.gov Identifier: NCT02450656     History of Changes
Other Study ID Numbers: M14AFS
First Posted: May 21, 2015    Key Record Dates
Last Update Posted: August 27, 2018
Last Verified: August 2018
Additional relevant MeSH terms:
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Colorectal Neoplasms
Pancreatic Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Intestinal Neoplasms
Digestive System Diseases
Endocrine Gland Neoplasms
Pancreatic Diseases
Endocrine System Diseases
Carcinoma, Non-Small-Cell Lung
Carcinoma, Bronchogenic
Lung Diseases
Respiratory Tract Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Docetaxel
Afatinib
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action