Phase I Dose Escalation Study of Concomitant BIBF 1120 and BIBW 2992 in Patients With Advanced Solid Tumours.

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT00998296
First received: October 19, 2009
Last updated: July 23, 2015
Last verified: July 2015
  Purpose

The primary objective of this trial is to determine the Maximum Tolerated Dose (MTD) of the combination of BIBW 2992/BIBF 1120 therapy administered concomitantly. The MTD will provide dosing recommendation for subsequent phase II trials in patients with metastatic cancer.


Condition Intervention Phase
Neoplasms
Drug: BIBW 2992
Drug: BIBF 1120
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Dose Escalation Study of Concomitant BIBF 1120 and BIBW 2992 in Patients With Advanced Solid Tumours.

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities [ Time Frame: first treatment cycle, up to 28 days ] [ Designated as safety issue: No ]
    Maximum tolerated dose (MTD) of nintedanib and afatinib based on the Percentage of participants experienced dose limiting toxicities during the dose escalation phase.


Secondary Outcome Measures:
  • Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1 [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]

    The investigator evaluated whether complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) occurred in a patient.

    CR for target lesions: Disappearance of all target lesions. CR for non-target lesions: Disappearance of all non-target lesions and normalization of tumour marker level. All lymph nodes must be non-pathological in size (<10mm short axis).

    PR: At least a 30% decrease in the sum of diameters (SoD) of target lesions taking as reference the baseline sum diameters.

    SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as references the smallest SoD while on study.

    PD: At least a 20% increase in the SoD of target lesions, taking as references the smallest sum on study (this includes the baseline sum if that is the smallest on study). Also, the sum must also demonstrate an absolute increase of a least 5mm. Appearance of one or more new lesions


  • Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0 [ Time Frame: First treatment administration until cut-off date of 02Oct2014; up to 336 days ] [ Designated as safety issue: No ]
    Incidence and intensity of Adverse Events with grading according to the Common Terminology Criteria for Adverse Events (CTCAE version 3.0).

  • Changes in Safety Laboratory Parameters [ Time Frame: First treatment administration until cut-off date of 02 October 2014, up to 336 days ] [ Designated as safety issue: No ]
    Changes in safety laboratory Parameters reported as adverse events

  • Cpre,ss,Norm (Dose Normalized Trough Plasma Concentration of Nintedanib at Steady State) [ Time Frame: Day 8, Day 15, Day 22 and Day 28 ] [ Designated as safety issue: No ]

    Cpre,ss,norm (Dose normalized trough plasma concentration of nintedanib at steady state) are presented for the 2 MTD treatment groups (continuous administered nintedanib at 150 mg b.i.d. concomitantly with continuously administered afatinib 30 mg q.d. or with intermittently administered afatinib 40 mg q.d.)

    As nintedanib is given twice daily, samples are taken at Day 8, Day 15, Day 22 and Day 28; the Pharmacokinetic (PK) parameter names will be Cpre,ss,15,norm (Day 8), Cpre,ss,29,norm (Day 15), Cpre,ss,43,norm (Day 22) and Cpre,ss,55,norm (Day 28)


  • Trough Plasma Concentration of Afatinib at Steady State [ Time Frame: Day 7, Day 13, Day 15, Day 22, Day 27 and Day 28 ] [ Designated as safety issue: No ]

    C(pre,ss) is defined as pre-dose (trough) concentration of afatinib in plasma at steady state immediately before administration of the next dose.

    C24,7 corresponds to the plasma concentration at 24 hours on Day 7. C24,13 corresponds to the plasma concentration at 24 hours on Day 13. C24,27 corresponds to the plasma concentration at 24 hours on Day 27.


  • Objective Response (OR) During the Expansion Phase [ Time Frame: Tumour assessment was to be performed at Screening, every 6 weeks after starting study treatment until disease progression, and at the end-of-treatment (EOT) visit (up to 1117 days) ] [ Designated as safety issue: No ]

    OR is defined as a best overall response of complete response (CR) or partial response (PR) according to RECIST version 1.1, CR for target lesions (TL): Disappearance of all target lesions.

    CR for non-target lesions (NTL): Disappearance of all non-target lesions. All lymph nodes must be nonpathological in size (<10mm short axis). PR for TL: At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters.

    Other factors which add to the overall response of an imaging timepoint as PR are as below:

    CR in TL, but non-CR/Non-PD in NTL leads to PR CR in TL, but not evaluated NTL leads to PR PR in TL, but non-PD NTL or not all evaluated NTL leads to PR; All the above scenarios should also satisfy 'No occurrence of new lesions'.


  • Disease Control (DC) During the Expansion Phase [ Time Frame: Tumour assessment was to be performed at Screening, every 6 weeks after starting study treatment until disease progression, and at the end-of-treatment (EOT) visit (up to 1117 days) ] [ Designated as safety issue: No ]
    DC is defined as the best overall response of CR, PR, stable disease (SD) and non-CR/non-PD. CR for target lesions (TL): Disappearance of all target lesions. CR for non-target lesions (NTL): Disappearance of all non-target lesions . All lymph nodes must be non-pathological in size (<10mm short axis). PR for TL: At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. Other factors which add to the overall response of an imaging timepoint as PR are as below:- CR in TL, but non-CR/Non-PD in NTL leads to PR CR in TL, but not evaluated NTL leads to PR PR in TL, but non-PD NTL or not all evaluated NTL leads to PR; SD for TL: change in the sum of diameters does not satisfy PR or PD. SD in TL, non-PD in NTL lead to overall response of SD, provided there is no appearance of new lesions.

  • Stable Disease for at Least 12 Weeks During the Expansion Phase [ Time Frame: Tumour assessment was to be performed at Screening, every 6 weeks after starting study treatment until disease progression, and at the end-of-treatment (EOT) visit (up to 1117 days) ] [ Designated as safety issue: No ]

    SD: Neither sufficient shrinkage to qualify for PR (Partial response) nor sufficient increase to qualify for PD(Progressive disease), taking as references the smallest sum of diameters SoD while on study.

    PR: At least a 30% decrease in the sum of diameters (SoD) of target lesions taking as reference the baseline sum diameters.

    PD: At least a 20% increase in the SoD of target lesions, taking as references the smallest sum on study (this includes the baseline sum if that is the smallest on study). Also, the sum must also demonstrate an absolute increase of a least 5mm. Appearance of one or more new lesions.


  • Percentage Change in the Tumour Size From Baseline During the Expansion Phase [ Time Frame: Tumour assessment was to be performed at Screening, every 6 weeks after starting study treatment until disease progression, and at the end-of-treatment (EOT) visit (up to 1117 days) ] [ Designated as safety issue: No ]
    Percentage change in the tumour size from baseline is expressed as Number of subjects with maximum decrease from baseline in the sum of longest diameters of target lesions.


Enrollment: 70
Study Start Date: October 2009
Study Completion Date: July 2014
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: BIBW 2992 + BIBF 1120
This is a phase I dose escalation clinical trial and the data obtained shall determine the MTD for the combination of BIBW 2992/BIBF 1120 in 28-day of treatment.
Drug: BIBW 2992
EGFR inhibitor
Drug: BIBF 1120
VEGF inhibitor

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  1. Patients with confirmed histological or cytological diagnosis of advanced solid tumours and for whom no proven therapy exists or who are not amenable to established treatments.
  2. Age 18 years or older.
  3. Life expectancy of at least three months.
  4. Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1.
  5. Patients previously treated and with asymptomatic brain metastases are eligible
  6. Patients must have recovered from recent surgery.

Exclusion criteria:

  1. Active infectious disease
  2. Recent surgery within the last 4 weeks prior visit 1.
  3. Chronic diarrhoea or gastrointestinal tract disease resulting in an inability to take oral medication
  4. History of haemorrhagic or thrombotic events
  5. Significant cardiovascular diseases within
  6. Current peripheral neuropathy > Common Terminology Criteria for Adverse Events (CTCAE) grade 1 except due to trauma
  7. Untreated or symptomatic brain metastases or leptomeningeal disease.
  8. Treatment with an Epidermal growth Factor-receptor (EGFR)- or Heregulin Receptor 2 (HER2) inhibiting drug or antiangiogenic drug.
  9. Therapeutic anticoagulation.
  10. Female patients of childbearing potential.
  11. Known pre-existing interstitial lung disease
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00998296

Locations
France
1239.14.3301A Boehringer Ingelheim Investigational Site
Villejuif Cedex, France
Sponsors and Collaborators
Boehringer Ingelheim
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  More Information

Additional Information:
No publications provided

Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT00998296     History of Changes
Other Study ID Numbers: 1239.14, 2009-011321-14
Study First Received: October 19, 2009
Results First Received: November 14, 2014
Last Updated: July 23, 2015
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
United States: Food and Drug Administration

Additional relevant MeSH terms:
Nintedanib
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on August 31, 2015