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

Carcinoma, Non-Small-Cell Lung Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00993499
• Other study ID #: 1200.70
• Secondary ID: 2009-010432-18
• Status: Completed
• Phase: Phase 1
• First received: October 8, 2009
• Last updated: September 4, 2015
• Start date: October 2009
• Est. completion date: September 2014

Study information

• Verified date: September 2015
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Spanish Agency of Medicines
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 44
• Est. completion date: September 2014
• Est. primary completion date: September 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Disease Progression

Intervention

Drug:
• BIBW 2992
Dose escalation (19-40 patients): low or high dose oral + 12 addit. pat. at MTD, until progression or undue AEs
• Sirolimus (rapamycin)
Dose escalation (19-40 patients): several dose levels + 12 addit. pat. at MTD until progression or undue AEs.

Locations

Country	Name	City	State
Spain	1200.70.34001 Boehringer Ingelheim Investigational Site	Badalona (Barcelona)
Spain	1200.70.34008 Boehringer Ingelheim Investigational Site	Barcelona
Spain	1200.70.34009 Boehringer Ingelheim Investigational Site	Barcelona
Spain	1200.70.34006 Boehringer Ingelheim Investigational Site	Girona
Spain	1200.70.34007 Boehringer Ingelheim Investigational Site	L'Hospitalet de Llobregat (Barcelona)
Spain	1200.70.34005 Boehringer Ingelheim Investigational Site	Majadahonda (Madrid)
Spain	1200.70.34004 Boehringer Ingelheim Investigational Site	Valencia
Spain	1200.70.34002 Boehringer Ingelheim Investigational Site	Zaragoza

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Occurrence of Dose Limiting Toxicities (DLT)	Number of participants with of dose limiting toxicities (DLT)	2 first cycles, 56 days	No
Secondary	Best Overall Response	Best overall response (unconfirmed) according to RECIST v1.1	From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days	No
Secondary	Objective Response	Rate of (unconfirmed) objective response, defined as complete response (CR) or partial response (PR) according to RECIST v1.1	From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days	No
Secondary	Rate of Disease Control	Rate of (unconfirmed) disease control defined as CR, PR, or stable disease (SD), according to RECIST v1.1	From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days	No
Secondary	Exploratory Examination of EGFR Mutations (Exons 19, 20 and 21 and Others) in Serum/Plasma DNA and Tumour DNA.	Exploratory examination of Epidermal growth factor (receptor)(EGFR) mutations (Exons 19, 20 and 21 and others) in serum/plasma DNA and tumour DNA.; This endpoint was not analysed in the study report as the available data was too limited.	Multiple time points during the trial	No
Secondary	Maximum Measured Plasma Concentration of Afatinib at Steady State (Cmax,ss)	Maximum measured plasma concentration of Afatinib at steady state (Cmax,ss)	24 hours (h), 311h 55minutes (min), 312h, 313h, 314h, 315h, 316h, 317h, 318h, 320h and 336h after first administration of afatinib	No
Secondary	AUC of Afatinib at Steady State Over the Dosing Interval t (AUCt,ss)	Area under the curve (AUC) of Afatinib at steady state over the dosing interval t (AUCt,ss) for afatinib.	24 hours (h), 311h 55minutes (min), 312h, 313h, 314h, 315h, 316h, 317h, 318h, 320h and 336h after first administration of afatinib	No
Secondary	Maximum Measured Plasma Concentration of Sirolimus at Steady State (Cmax,ss)	Maximum measured plasma concentration of sirolimus at steady state (Cmax,ss)	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	No
Secondary	AUC of Sirolimus at Steady State Over the Dosing Interval t (AUCt,ss)	Area under the curve (AUC) of sirolimus at steady state over the dosing interval t (AUCt,ss) for afatinib.	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	No
Secondary	Occurrence of Adverse Events According to CTCAE, Version 3.0	Percentage of participants with adverse events according to highest Common Terminology Criteria for Adverse Events (CTCAE) grade, version 3.0	From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days	No
Secondary	Percentage of Patients With Drug-related AEs	Percentage of patients with drug-related adverse events (AEs).	From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days	No
Secondary	Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin	Evaluation of laboratory parameters included assessment of the frequency of patients with ALT and AST elevations concurrent with elevated bilirubin and indicative of Hy's law cases.	From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days	No

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