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

Primary Purpose

Colorectal Neoplasms, Gastrointestinal Neoplasms, Pancreatic Neoplasms

Status

Unknown status

Phase

Phase 1

Locations

Netherlands

Study Type

Interventional

Intervention

Afatinib

Selumetinib

Docetaxel

About this trial

This is an interventional treatment trial for Colorectal Neoplasms

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

UMC St. Radboud NijmegenRecruiting
Netherlands Cancer Institute - Antoni van Leeuwenhoek HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Afatinib plus selumetinib

Control

Arm Description

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

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

Outcomes

Primary Outcome Measures

Dose Limiting Toxicities (Phase I)

Incidence of DLTs in the first treatment cycle

Progression Free Survival (Phase II)

PFS measured by RECIST v 1.1

Secondary Outcome Measures

Tolerability (Incidence and severity of adverse events per CTCAE v4.03)

Incidence and severity of adverse events per CTCAE v4.03

Plasma concentrations of afatanib and selumetinib

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.

Efficacy (Phase II) (Overall response rate (ORR), duration of response (DOR) , time to response (TTR) and overall survival (OS) per RECIST v1.1)

Overall response rate (ORR), duration of response (DOR) , time to response (TTR) and overall survival (OS) per RECIST v1.1

Full Information

NCT ID

NCT02450656

First Posted

November 13, 2014

Last Updated

August 24, 2018

Sponsor

The Netherlands Cancer Institute

Collaborators

AstraZeneca, Boehringer Ingelheim

1. Study Identification

Unique Protocol Identification Number

NCT02450656

Brief Title

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

Acronym

M14AFS

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 Type

Interventional

2. Study Status

Record Verification Date

August 2018

Overall Recruitment Status

Unknown status

Study Start Date

June 2015 (undefined)

Primary Completion Date

May 2019 (Anticipated)

Study Completion Date

December 2019 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

The Netherlands Cancer Institute

Collaborators

AstraZeneca, Boehringer Ingelheim

4. Oversight

Data Monitoring Committee

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Crossover Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

320 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Afatinib plus selumetinib

Arm Type

Experimental

Arm Description

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

Arm Title

Control

Arm Type

Active Comparator

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Afatinib

Other Intervention Name(s)

BIBW2992

Intervention Description

Tablet

Intervention Type

Drug

Intervention Name(s)

Selumetinib

Other Intervention Name(s)

AZD6244

Intervention Description

Capsule

Intervention Type

Drug

Intervention Name(s)

Docetaxel

Primary Outcome Measure Information:

Title

Dose Limiting Toxicities (Phase I)

Description

Incidence of DLTs in the first treatment cycle

Time Frame

Cycle 1 (4 weeks)

Title

Progression Free Survival (Phase II)

Description

PFS measured by RECIST v 1.1

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

Secondary Outcome Measure Information:

Title

Tolerability (Incidence and severity of adverse events per CTCAE v4.03)

Description

Incidence and severity of adverse events per CTCAE v4.03

Time Frame

Up to 28 days after last study drug intake

Title

Plasma concentrations of afatanib and selumetinib

Description

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

Title

Efficacy (Phase II) (Overall response rate (ORR), duration of response (DOR) , time to response (TTR) and overall survival (OS) per RECIST v1.1)

Description

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.

Other Pre-specified Outcome Measures:

Title

Determinants and mode of response - Target proteins

Description

Change in expression and/or phosphorylation status target proteins (e.g. pERK, pS6, heregulin, HER2) before, during and after treatment

Time Frame

At baseline, cycle 1 day 15 and at treatment discontinuation (expected 6-9 months after start)

Title

Pharmacogenetics profiling to assess predictors of response and resistance- inducing mutations

Description

Pharmacogenetic 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)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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)

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

F Opdam, MD, PhD

Phone

+31 20 512 2446

f.opdam@nki.nl

First Name & Middle Initial & Last Name or Official Title & Degree

S huijberts, MD

Phone

0031205129111

s.huijberts@nki.nl

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

F Opdam, MD, PhD

Organizational Affiliation

NKI-AvL

Official's Role

Principal Investigator

Facility Information:

Facility Name

UMC St. Radboud Nijmegen

City

Nijmegen

State/Province

Gelderland

ZIP/Postal Code

6525GA

Country

Netherlands

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Carla ML van Herpen, MD, PhD

Phone

+31243610353

Carla.vanHerpen@radboudumc.nl

First Name & Middle Initial & Last Name & Degree

Carla ML van Herpen, MD, PhD

Facility Name

Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital

City

Amsterdam

ZIP/Postal Code

1066CX

Country

Netherlands

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

F Opdam, MD, PhD

First Name & Middle Initial & Last Name & Degree

F Opdam, MD, PhD

12. IPD Sharing Statement

Learn more about this trial

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

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