Clinical Trials /

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

NCT02450656

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: M14AFS
  • NCT ID: NCT02450656

Conditions

  • Colorectal Neoplasms
  • Gastrointestinal Neoplasms
  • Pancreatic Neoplasms
  • Carcinoma, Non-Small-Cell Lung

Interventions

DrugSynonymsArms
AfatinibBIBW2992Afatinib plus selumetinib
SelumetinibAZD6244Afatinib plus selumetinib
DocetaxelControl

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Afatinib plus selumetinibExperimentalCombination of afatinib and selumetinib at the optimal dose and regimen as determined in the phase I part of this study
  • Afatinib
  • Selumetinib
ControlActive ComparatorStandard-of-care second line treatment for non small cell lung cancer (docetaxel)
  • Docetaxel

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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Limiting Toxicities (Phase I)
Time Frame:Cycle 1 (4 weeks)
Safety Issue:
Description:Incidence of DLTs in the first treatment cycle

Secondary Outcome Measures

Measure:Tolerability (Incidence and severity of adverse events per CTCAE v4.03)
Time Frame:Up to 28 days after last study drug intake
Safety Issue:
Description:Incidence and severity of adverse events per CTCAE v4.03
Measure: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
Safety Issue:
Description: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.
Measure: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.
Safety Issue:
Description:Overall response rate (ORR), duration of response (DOR) , time to response (TTR) and overall survival (OS) per RECIST v1.1

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:The Netherlands Cancer Institute

Last Updated

November 8, 2017