Afatinib In Combination With Cisplatin Or Carboplatin + Pemetrexed In Patients With EGFR-Mutant Lung Cancers Undergoing Definitive Chemoradiation

A Dose-Finding Study Of Afatinib In Combination With Cisplatin Or Carboplatin + Pemetrexed In Patients With EGFR-Mutant Lung Cancers Undergoing Definitive Chemoradiation

The purpose of this Phase I study is to test the safety of combining afatinib with standard chemotherapy and radiation. The drug afatinib will be given before the chemotherapy and radiation therapy to shrink the tumor and evaluate how afatinib affects the patient. This study will then test the safety of afatinib at different dose levels when combined with the chemotherapy drugs cisplatin or carboplatin, and pemetrexed. These treatments will be given during radiation treatment and the drug afatinib will be continued after chemotherapy and radiation.

Study Overview

• Status: Withdrawn
• Conditions: Non-small Cell Lung Cancer
• Intervention / Treatment: Drug: Cisplatin; Drug: Pemetrexed; Radiation: Radiation therapy; Drug: Carboplatin; Drug: Afatinib

• Study Type: Interventional
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Unresectable or inoperable, stage III or locoregional recurrence without evidence of distant, metastatic disease
• Pathologic confirmation of NSCLC at MSKCC
• Documentation of a sensitizing EGFR mutation
• Age ≥ 18 years
• No contraindication to definitive thoracic radiation therapy with concurrent chemotherapy

Adequate organ function as defined by:

• Calculated creatinine clearance≥ 45 mL/min (by Cockcroft-Gault)
• Total bilirubin less than 1.5 x ULN (unless known Gilbert's disease) and AST/ALT less than 3 x ULN
• Absolute neutrophil count greater than 1500/mm3
• Platelet count greater than 100,000/mm3
• Women of childbearing age must have a negative blood pregnancy test
• Men and women of childbearing potential must be willing to use effective contraception while on treatment and for at least 3 months there after

Exclusion Criteria:

• Prior chemotherapy or radiation therapy for this lung cancer (history of prior lung cancer that has been treated and deeded inactive by the clinician is acceptable)
• Ineligible for cisplatin or carboplatin per medical oncologist
• Ineligible for pemetrexed per medical oncologist
• Greater than minimal, exudative, or malignant pleural effusion
• Calculated creatinine clearance by Cockcroft & Gault method ≤45 ml/min
• Unstable congestive heart failure
• Ejection fraction <50% as assessed by MUGA or echocardiogram
• Interstitial lung disease
• Patient requiring on-going treatment with a potent inhibitor (cyclosporin, erythromycin, ketoconazole, itraconazole, quinidine, phenobarbital with quinidine, ritonavir, valspodar, verapamil) or inducer of P-gp (St. John's wort or rifampin)
• Women who are breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Afatinib w Cisplatin Pemetrexed Chemoradiation; induction afatinib 40mg daily x 28days Cisplatin or Carboplatin (can be used if patient is not eligible for cisplatin) + Pemetrexed + 50Gy to pretreatment field boost to 60Gy to residual tumor + afatinib dose escalation* *afatinib dose levels: 20mg daily, 30mg daily & 40mg daily (3+3 design) Then adjuvant afatinib x 2 years	Drug: Cisplatin; Drug: Pemetrexed; Radiation: Radiation therapy; Drug: Carboplatin; Drug: Afatinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
maximum tolerated dose	This will be defined as the dose at which fewer than 1:6 patients experiences a dose-limiting toxicity.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
local control rate	will be determined as the proportion of patients who start the concurrent phase who are alive and free of local failure.	at 1 year and at 2 years
tolerability of adjuvant afatinib	Tolerability will be defined by in terms of dose reductions, delays and discontinuations of patients who have not had disease progression or death.	at 3 months
median progression free survival	PFS is defined as the duration of time from start of treatment to time of progression of disease or death, whichever occurs first.	2 years
median overall survival	will be calculated using Kaplan-Meier estimates among all patients enrolled.	2 years

Collaborators and Investigators

• Sponsor: Memorial Sloan Kettering Cancer Center
• Collaborators: Boehringer Ingelheim; National Comprehensive Cancer Network

Publications and helpful links

Helpful Links

• Memorial Sloan-Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Anticipated): April 1, 2015
• Study Completion (Anticipated): April 1, 2015

Study Registration Dates

• First Submitted: April 17, 2013
• First Submitted That Met QC Criteria: April 17, 2013
• First Posted (Estimate): April 19, 2013

Study Record Updates

• Last Update Posted (Estimate): December 19, 2013
• Last Update Submitted That Met QC Criteria: December 18, 2013
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Keywords: Cisplatin; Carboplatin; Pemetrexed; Radiation therapy; EGFR mutation; Afatinib; 12-279
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Folic Acid Antagonists; Carboplatin; Pemetrexed; Afatinib
• Other Study ID Numbers: 12-279