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

Phase 1

Withdrawn

• Conditions: Non-small Cell Lung Cancer
• Interventions: Drug: Afatinib; Drug: Cisplatin; Drug: Carboplatin; Drug: Pemetrexed; Radiation: Radiation therapy

• Registration Number: NCT01836341
• Lead Sponsor: Memorial Sloan Kettering Cancer Center

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2013-04
• Study First Submitted: 2013-04-17
• Study First Submitted QC: 2013-04-17
• Study First Posted: 2013-04-19
• Status Verified: 2013-12
• Last Update Submitted: 2013-12-18
• Last Update Posted: 2013-12-19
• Primary Completion: 2015-04
• Study Completion: 2015-04

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Afatinib w Cisplatin Pemetrexed Chemoradiation	Afatinib	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
Afatinib w Cisplatin Pemetrexed Chemoradiation	Cisplatin	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
Afatinib w Cisplatin Pemetrexed Chemoradiation	Radiation therapy	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
Afatinib w Cisplatin Pemetrexed Chemoradiation	Carboplatin	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
Afatinib w Cisplatin Pemetrexed Chemoradiation	Pemetrexed	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

Primary Outcome Measures

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

Secondary Outcome Measures

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