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

NCT02450656 | Unknown Phase 1

• 1 other identifier: M14AFS
• Study Type: interventional
• Target: 320
• Locations: 1 country
• Sites: 2

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.

Conditions

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

Outcome Measures

Primary Outcomes (2)

• Dose Limiting Toxicities (Phase I)

  Incidence of DLTs in the first treatment cycle

  Cycle 1 (4 weeks)

• Progression Free Survival (Phase II)

  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 Outcomes (3)

• Tolerability (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

  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)

  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 (2)

• Determinants and mode of response - Target proteins

  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

  Before treatment, every 6 weeks and at treatment discontinuation (expected 6-9 months after start)

Study Arms (2)

Afatinib plus selumetinib

EXPERIMENTAL

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

Drug: Afatinib; Drug: Selumetinib

Control

ACTIVE COMPARATOR

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

Drug: Docetaxel

Interventions

Afatinib DRUG

Tablet

Also known as: BIBW2992

Afatinib plus selumetinib

Selumetinib DRUG

Capsule

Also known as: AZD6244

Afatinib plus selumetinib

Docetaxel DRUG

Control

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• The Netherlands Cancer Institute: lead
• AstraZeneca: collaborator
• Boehringer Ingelheim: collaborator

Study Sites (2)

UMC St. Radboud Nijmegen

Nijmegen, Gelderland, 6525GA, Netherlands

RECRUITING

Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital

Amsterdam, 1066CX, Netherlands

RECRUITING

MeSH Terms

Conditions

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

Interventions

Afatinib; AZD 6244; Docetaxel

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Endocrine System Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Amides; Organic Chemicals; Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes

Study Officials

• F Opdam, MD, PhD

  NKI-AvL

  PRINCIPAL INVESTIGATOR

Central Study Contacts

F Opdam, MD, PhD

CONTACT

+31 20 512 2446; f.opdam@nki.nl

S huijberts, MD

CONTACT

0031205129111; s.huijberts@nki.nl

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 13, 2014
• First Posted: May 21, 2015
• Study Start: June 1, 2015
• Primary Completion: May 1, 2019
• Study Completion: December 1, 2019
• Last Updated: August 27, 2018

Record last verified: 2018-08

Locations

NL (2)