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

Carcinoma, Non-Small-Cell Lung Clinical Trial

— 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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02450656
• Other study ID #: M14AFS
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: June 2015
• Est. completion date: December 2019

Study information

• Verified date: August 2018
• Source: The Netherlands Cancer Institute
• Contact: F Opdam, MD, PhD
• Phone: +31 20 512 2446
• Email: f.opdam[@]nki.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 320
• Est. completion date: December 2019
• Est. primary completion date: May 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

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

Intervention

Drug:
• Afatinib
Tablet
• Selumetinib
Capsule
• Docetaxel

Locations

Country	Name	City	State
Netherlands	Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital	Amsterdam
Netherlands	UMC St. Radboud Nijmegen	Nijmegen	Gelderland

Sponsors (3)

Lead Sponsor	Collaborator
The Netherlands Cancer Institute	AstraZeneca, Boehringer Ingelheim

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Determinants and mode of response - Target proteins	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)
Other	Pharmacogenetics profiling to assess predictors of response and resistance- inducing mutations	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)
Primary	Dose Limiting Toxicities (Phase I)	Incidence of DLTs in the first treatment cycle	Cycle 1 (4 weeks)
Primary	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	Tolerability (Incidence and severity of adverse events per CTCAE v4.03)	Incidence and severity of adverse events per CTCAE v4.03	Up to 28 days after last study drug intake
Secondary	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.	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
Secondary	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	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.