ADAM-Afatinib Diarrhea Assessment and Management

Study Overview
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Brief Summary
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This is a non-randomized, open label, two-cohort, multi-institutional study to evaluate the use of diarrheal management tools intended to facilitate timely intervention and treatment modifications due to afatinib treatment-related diarrhea in patients with EGFR mutations-positive adenocarcinoma of the lung. Patients in Cohort 1 will follow diarrhea management. Patients in Cohort 2 will receive prophylactic loperamide starting the fist day of afatinib treatment.

Official Title
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A Phase IIIb, Non-randomized, Open-label, Two-cohort Study in Patients With EGFR Mutations-positive Advanced Adenocarcinoma of the Lung, Assessing the Utility of the Afatinib Diarrhea Assessment and Management Guidelines (ADAM)

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: afatinib
* Drug: loperamide


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Pathologically confirmed diagnosis of Stage IIIB or Stage IV adenocarcinoma of the lung, with EGFR mutations-positive status, who are not eligible to receive surgery or chemoradiotherapy. Patients with mixed histology are eligible if adenocarcinoma is the predominant histology, and is a suitable candidate for EGFR-TKI monotherapy, in the opinion of the investigator. Patients must have Epidermal Growth Factor Receptor (EGFR) mutation-positive status according to the institutional standard of care. Patient received no more than one (1) prior chemotherapy for locally advanced or metastatic adenocarcinoma of the lung. Male or female patients Age 18 years and older. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Adequate organ function, defined as all of the following: Left Ventricular Ejection Fraction (LVEF) of above 50% or within institution normal values Absolute neutrophil count (ANC) above 1500 / mm3. Platelet count above 75,000 / mm3. Estimated creatinine clearance more than 45ml / min. Total Bilirubin less than 1.5 times upper limit of (institutional/central) normal Aspartate amino transferase (AST) or alanine amino transferase (ALT) less than three times the upper limit of (institutional/central) normal (ULN) (if related to liver metastases less than five times ULN). Recovered from any previous therapy related toxicity to Grade 0 or 1 at study entry Able and willing to follow diarrhea management guidelines provided under this study and to complete Diarrhea Management Worksheet as instructed. Exclusion criteria: Chemotherapy, biological therapy or investigational agents within four weeks prior to the start of study treatment. Prior treatment with EGFR directed small molecules or antibodies. Hormonal treatment within 2 weeks prior to start of study treatment (continued use of anti-androgens and/or gonadorelin analogues for treatment of prostate cancer permitted). Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the projected course of the study. Known hypersensitivity to afatinib or the excipients of any of the trial drugs. History or presence of clinically relevant cardiovascular abnormalities. Any history of or concomitant condition that, in the opinion of the Investigator, would compromise the patient¿s ability to comply with the study or interfere with the evaluation of the efficacy and safety of the test drug. Previous or concomitant invasive malignancies at other sites. Known pre-existing interstitial lung disease (ILD). Any history or presence of poorly controlled gastrointestinal disorders that could affect the absorption of the study drug. 14. Active hepatitis B infection, active hepatitis C infection and/or known HIV carrier, who are determined by the investigator as not a suitable candidate to receive EGFR-TKI treatment. 15. Patients with meningeal carcinomatosis. 16. Patients with brain or subdural metastases.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Afatinib 40 mg + Loperamide (Cohort 1)<br>afatinib starting 40 mg daily; Cohort 1 will receive loperamide at first sign of diarrhea; Cohort 2 will receive loperamide starting C1D1. | Drug: afatinib<br>* Daily treatment starting 40 mg per day<br>Drug: loperamide<br>* Follow cohort assignment and diarrhea management guidelines<br>|
| Experimental: Afatinib 40 mg + loperamide prophylactic (Cohort 2)<br>afatinib starting 40 mg daily; Cohort 1 will receive loperamide at first sign of diarrhea; Cohort 2 will receive loperamide starting C1D1. | Drug: afatinib<br>* Daily treatment starting 40 mg per day<br>Drug: loperamide<br>* Follow cohort assignment and diarrhea management guidelines<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurence of CTCAE Grade >= 2 Diarrhea | Overall incidence of patients who experienced diarrhea during the first three courses of afatinib treatment. | From first drug administration until 28 days after the end of third treatment course, up to 84 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Initial Onset of Diarrhea Grade 2 or Higher | Time to initial onset of diarrhea grade 2 or higher | From first drug administration until end of third treatment course, up to 84 days. | 
| Duration of First Episode of Diarrhea Grade 2 or Higher | Duration of first episode of diarrhea grade 2 or higher. Please note that the nine patients experienced diarrhea episodes that were not managed according to the protocol specified afatinib treatment interruptions and dose reductions. No patients were excluded from the primary analysis. | From first drug administration until end of third treatment course, up to 84 days. | 
| Changes in Intensity of Diarrhea Over Time | Percentage of participants with grade 2 or higher diarrhea each week for the first 3 cycles of afatinib treatment | Up to 12 weeks (equivalent to 3 courses) | 
| PFS | Progression-free survival (PFS). PFS was defined as the time from the start of treatment to an event occurred. In the analyses for the PFS endpoint, an event was defined as disease progression or death, whichever occurred earlier. Data for patients who did not die or progress during the trial were censored at the time of afatinib discontinuation or transition to commercially available afatinib. Median PFS is estimated using Kaplan-Meier method. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1). | Every 08 weeks during the first 6 months of treatment, and every 12 weeks thereafter until the end of treatment. |