Clinical trial NCT00993499: Trial of Continuous Once Daily Oral Treatment Using BIBW 2992 (Afatinib) Plus Sirolimus (Rapamune®) in Patients With Non-small Cell Lung Cancer Harbouring an EGFR Mutation and/or Disease Progression Following Prior Erlotinib or Gefitinib
Official title: A Phase Ib Open Label Clinical Trial of Continuous Once Daily Oral Treatment Using BIBW 2992 Plus Sirolimus in Patients With Non-small Cell Lung Cancer Harbouring an EGFR Mutation and/or Disease Progression Following Prior Erlotinib or Gefitinib
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Carcinoma, Non-Small-Cell Lung
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2009-10-12
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The primary objective of this trial is to identify the Maximum Tolerated Dose of BIBW 2992 therapy when given continuously in combination with Sirolimus.

The MTD will be based on the Dose Limiting Toxicity information collected during the first two cycles.

Overall safety, pharmacokinetics and anti-tumour efficacy will be evaluated as secondary objectives.


Eligibility criteria: Inclusion criteria:

1. Pathologically or cytologically confirmed diagnosis of Stage IIIB or Stage IV NSCLC
2. Patients who have failed conventional treatment (at least 1 prior treatment line), or for whom no therapy of proven efficacy exists
3. Patients whose tumors:

   * are EGFR mutation-positive or
   * are EGFR mutation-negative or unknown provided they had disease progression after achieving either response or stable disease for at least 6 months from a previous treatment with erlotinib (Tarceva®) or gefitinib (Iressa®)
4. Patients aged 18 years or older
5. Life expectancy of at least three (3) months
6. Eastern Cooperative Oncology Group (ECOG, R01-0787) performance score 0-2
7. Written informed consent that is consistent with ICH-GCP guidelines

Exclusion criteria:

1. Prior major surgery, chemotherapy or radiation therapy within 4 weeks before start of therapy.
2. Prior treatment with an mTOR inhibitor within the past 4 weeks before start of therapy or concomitantly with this study
3. Use of erlotinib (Tarceva®) or gefitinib (Iressa®) within 14 days of run-in treatment with Sirolimus
4. Active CNS metastases (defined as stable for \<4 weeks and/or symptomatic and/or requiring treatment with anticonvulsants or steroids)
5. Severe alteration in serum fasting cholesterol (equal or more than 350 mg/dL) or triglycerides (equal or more than 400 mg/dL). Patients may be allowed to enrol on the trial after initiation of lipid lowering agents.
6. Requirement for treatment with any of the prohibited concomitant medications:

   * Concomitant CYP3A4 inhibitors within the past 7 days before start of therapy or concomitantly with this study.
   * Concomitant CYP3A4 inducers within the past 14 days before start of therapy or concomitantly with this study.
7. Any contraindications for therapy with Sirolimus.
8. Known hypersensitivity to BIBW 2992, Sirolimus or other rapamycin analogues (everolimus, temsirolimus, deforolimus, etc.) or the excipients of any of the trial drugs.
9. Use of any investigational drug within 4 weeks before start of therapy.

Primary outcomes:
measure: Occurrence of Dose Limiting Toxicities (DLT)
timeFrame: 2 first cycles, 56 days
Secondary outcomes:
measure: Best Overall Response
timeFrame: From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days
measure: Objective Response
timeFrame: From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days
measure: Rate of Disease Control
timeFrame: From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days
measure: Exploratory Examination of EGFR Mutations (Exons 19, 20 and 21 and Others) in Serum/Plasma DNA and Tumour DNA.
timeFrame: Multiple time points during the trial
measure: Maximum Measured Plasma Concentration of Afatinib at Steady State (Cmax,ss)
timeFrame: 24 hours (h), 311h 55minutes (min), 312h, 313h, 314h, 315h, 316h, 317h, 318h, 320h and 336h after first administration of afatinib
measure: AUC of Afatinib at Steady State Over the Dosing Interval τ (AUCτ,ss)
timeFrame: 24 hours (h), 311h 55minutes (min), 312h, 313h, 314h, 315h, 316h, 317h, 318h, 320h and 336h after first administration of afatinib
measure: Maximum Measured Plasma Concentration of Sirolimus at Steady State (Cmax,ss)
timeFrame: 24 hours (h) 5 minutes (min), 24h, 23h, 22h, 20h, 18h, 16h, 5min before first afatinib administration and 144h, 311h 55min, 312h, 313h, 314h, 315h, 316h, 317h, 318h, 320h, 336h, 480h after first administration of afatinib
measure: AUC of Sirolimus at Steady State Over the Dosing Interval τ (AUCτ,ss)
timeFrame: 24 hours (h) 5 minutes (min), 24h, 23h, 22h, 20h, 18h, 16h, 5min before first afatinib administration and 144h, 311h 55min, 312h, 313h, 314h, 315h, 316h, 317h, 318h, 320h, 336h, 480h after first administration of afatinib
measure: Occurrence of Adverse Events According to CTCAE, Version 3.0
timeFrame: From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days
measure: Percentage of Patients With Drug-related AEs
timeFrame: From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days
measure: Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin
timeFrame: From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days
Other outcomes:
Locations:
city: Badalona (Barcelona)
country: Spain
facility: 1200.70.34001 Boehringer Ingelheim Investigational Site
city: Barcelona
country: Spain
facility: 1200.70.34008 Boehringer Ingelheim Investigational Site
city: Barcelona
country: Spain
facility: 1200.70.34009 Boehringer Ingelheim Investigational Site
city: Girona
country: Spain
facility: 1200.70.34006 Boehringer Ingelheim Investigational Site
city: L'Hospitalet de Llobregat (Barcelona)
country: Spain
facility: 1200.70.34007 Boehringer Ingelheim Investigational Site
city: Majadahonda (Madrid)
country: Spain
facility: 1200.70.34005 Boehringer Ingelheim Investigational Site
city: Valencia
country: Spain
facility: 1200.70.34004 Boehringer Ingelheim Investigational Site
city: Zaragoza
country: Spain
facility: 1200.70.34002 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: Moran T, Palmero R, Provencio M, Insa A, Majem M, Reguart N, Bosch-Barrera J, Isla D, Costa EC, Lee C, Puig M, Kraemer S, Schnell D, Rosell R. A phase Ib trial of continuous once-daily oral afatinib plus sirolimus in patients with epidermal growth factor receptor mutation-positive non-small cell lung cancer and/or disease progression following prior erlotinib or gefitinib. Lung Cancer. 2017 Jun;108:154-160. doi: 10.1016/j.lungcan.2017.03.009. Epub 2017 Mar 22.