A Study of Intermittent, High-dose Afatinib to Determine the Maximal Tolerated Dose and Assess Activity of This Dose Against Non-small Cell Lung Cancer With T790M Mutations

NCT01647711 | Completed Phase 1 Results

• 1 other identifier: 1200.121
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 2

Brief Summary

This trial is divided into Part A and Part B. The primary objective of Part A is to establish the Maximal Tolerated Dose of intermittent high dose afatinib. The primary objective of Part B is to assess the response rate of patients with non-small cell lung cancer with EGFR T790M mutations to a dose of intermittent afatinib established in Part A. The secondary objective is to explore tumor response and tumor-derived biological markers of response to afatinib, as well as pharmacokinetic parameters of afatinib.

Conditions

Carcinoma, Non-Small-Cell Lung

Outcome Measures

Primary Outcomes (2)

• Percentage of Participants With Dose Limiting Toxicities

  Percentage of participants with Dose Limiting Toxicities (DLTs), based on investigator assessment, for determination of Maximum Tolerated Dose (MTD). MTD was defined as the dose in which less than 2 of up to 6 patients developed a DLT.

  28 days

• Maximum Tolerated Dose

  Maximum Tolerated Dose (MTD) was defined as the dose in which less than 2 of up to 6 patients developed a Dose Limiting Toxicity (DLT).

  28 days

Secondary Outcomes (3)

• Objective Response Rate for Patients With EGFR T790M Mutations

  From first drug administration until last drug administration, up to 420 days

• Cmax of Afatinib on Day 3 of Course 1

  47 hours (h) 55 minutes (min), 49h, 50h, 51h, 52h, 53h, 54h, 55h after first dose administration (on day 3 of course 1)

• Determination of Dosage for Expansion Cohort in Part B

  28 days

Study Arms (1)

Afatinib

EXPERIMENTAL

Establish the Maximal Tolerated Dose of a pulsatile, high-dose regimen of afatinib in patients with advanced solid tumors followed by treatment at that dose or a lower dose in patients with stage IV non-small cell lung cancer harboring EGFR T790M mutations who have progressed on therapy with a reversible tyrosine kinase inhibitor

Drug: Dose escalation followed by treatment with MTD

Interventions

Dose escalation followed by treatment with MTD DRUG

Fixed 3+3 dose escalation; expansion of MTD cohort

Afatinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Part A only:
• Patients with histologically confirmed advanced solid tumours that are metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective. Patients who refuse standard therapy are also eligible.
• Part B only:
• Pathologically confirmed diagnosis of Stage IV (M1a or b) non-small cell lung cancer
• Documented Epidermal Growth Factor Receptor (EGFR) T790M mutation
• Progression of disease on a reversible tyrosine kinase inhibitor within 30 days of starting study drug. Loss of exposure to prior EGFR TKI should not be \>30 days; any procedural delay in confirmation of progression is to be discussed with the BI Clinical Monitor.
• Parts A and B:
• Evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
• Age \>/= to 18 years
• Eastern Cooperative Group (ECOG) performance status 0-1
• Adequate organ function
• Recovered from any previous therapy-related toxicity to \</= to Grade 1 at study entry (except for stable sensory neuropathy \</= Grade 2 and alopecia)
• Written informed consent
• Ability to take oral medication

You may not qualify if:

• Parts A and B:
• Chemotherapy, biological therapy, or investigational agents (except erlotinib or gefitinib) within 4 weeks prior to the start of study treatment
• Hormonal treatment within 2 weeks prior to the start of study treatment (continued use of anti-androgens and/or gonadorelin analogues for treatment of prostate cancer is permitted)
• Radiotherapy within two weeks prior to the start of study treatment (except palliative radiotherapy given for symptom control)
• Less than 3 days from prior treatment with gefitinib or erlotinib. Patients with adverse events related to gefitinib or erlotinib must recover to Grade 1 or less to be eligible.
• 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 such as uncontrolled hypertension, congestive heart failure New York Heart Association classification of 3, unstable angina or poorly controlled arrhythmia as determined by the investigator. Myocardial infarction within 6 months prior to starting study treatment
• Women of childbearing potential and men who are able to father a child, unwilling to be abstinent or use adequate contraception prior to study entry, for the duration of study participation and for at least 2 months after treatment has ended.
• Female patients of childbearing potential who are nursing; are pregnant; are not using an acceptable method of birth control, or do not plan to continue using this method throughout the study; and do not agree to submit to pregnancy testing required by this protocol
• 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 malignancies at other sites, except effectively treated non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ or effectively treated malignancy that has been in remission for more than 3 years and is considered to be cured
• Required treatment with any of the prohibited medications listed in this protocol that cannot be stopped for the duration of trial participation
• Known pre-existing Interstitial Lung Disease
• Any history or presence of poorly controlled gastrointestinal disorders that could affect the absorption of the study drug (for example, Crohn's disease, ulcerative colitis, chronic diarrhea, malabsorption) in the opinion of the investigator

Sponsors & Collaborators

• Boehringer Ingelheim: lead

Study Sites (2)

Boehringer Ingelheim Investigational Site

Aurora, Colorado, United States

Location

Boehringer Ingelheim Investigational Site

Boston, Massachusetts, United States

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Maximum Tolerated Dose

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Toxicity Tests; Investigative Techniques; Toxicological Phenomena; Pharmacological and Toxicological Phenomena; Physiological Phenomena

Limitations and Caveats

One patient was screened in part B of the study, the patient did not meet eligibility requirements and was not treated. The trial completed enrollment in Part A before any additional patients were screened for Part B.

Results Point of Contact

• Title: Boehringer Ingelheim Call Center
• Organization: Boehringer Ingelheim

clintriage.rdg@boehringer-ingelheim.com

1-800-243-0127

Study Officials

• Boehringer Ingelheim

  Boehringer Ingelheim

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 16, 2012
• First Posted: July 23, 2012
• Study Start: July 1, 2012
• Primary Completion: September 1, 2015
• Study Completion: September 1, 2015
• Last Updated: January 31, 2017
• Results First Posted: January 31, 2017

Record last verified: 2016-12

Locations

US (2)