A Phase I Dose Escalation Trial of Afatinib Plus Gemcitabine or Plus Docetaxel

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT01251653
First received: December 1, 2010
Last updated: April 22, 2016
Last verified: April 2016
  Purpose

To establish the maximum tolerated dose (MTD) of oral afatinib (BIBW2992) given in combination with gemcitabine or docetaxel in patients with relapsed or refractory tumors.

To assess the safety of the combination. To investigate the PK characteristics of docetaxel or gemcitabine and of oral afatinib (BIBW2992) in the tested treatment schedule. To assess antitumor activity.


Condition Intervention
Neoplasms
Drug: Afatinib
Drug: docetaxel
Drug: gemcitabine

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: A Phase I Dose Escalation Trial of Once Daily Oral Treatment Using Afatinib (BIBW2992) Plus Gemcitabine or Docetaxel in Patients With Relapsed or Refractory Solid Tumors.

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • Number of Participants With Dose Limiting Toxicities (DLTs) in Process for the Determination of the Maximum Tolerated Dose (MTD). [ Time Frame: 3 weeks ] [ Designated as safety issue: No ]
    DLT was based on following criterions: 1. Grade 4 uncomplicated (not associated with fever >38.5° C (Celsius)) neutropenia for ≥7 days. 2. Grade 3 or 4 neutropenia concomitant with fever >38.5º C or Grade ≥3 infection. 3. Platelet count of <25x 10^9/L or <50x 10^9/L with bleeding requiring whole blood transfusion. 4. Grade ≥3 non-haematological toxicity (except untreated nausea, untreated vomiting, or untreated diarrhoea). 5. Grade ≥2 decrease in cardiac left ventricular function. 6. Grade ≥2 worsening of renal function as measured by serum creatinine, newly developed proteinuria, or a newly developed decrease in glomerular filtration rate. Toxicity grading was based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0


Secondary Outcome Measures:
  • The Incidence and Intensity of AEs With Grading According to CTCAE. [ Time Frame: From first drug administration until 28 days after last drug administration, up to 717 days. ] [ Designated as safety issue: Yes ]
    The incidence and intensity of adverse events with grading according to CTCAE. The CTCAE grades are: 1 (mild AE), 2 (moderate AE), 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related to AE).

  • Best Overall Response According to RECIST v1.1 Criteria [ Time Frame: From first drug administration until 28 days after last drug administration, up to 717 days. ] [ Designated as safety issue: No ]
    Best overall response (according to Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) was the best response recorded at any time from the date of the first administration of afatinib or gemcitabine/docetaxel to the end of treatment (EOT). Partial response is for patients with measurable disease. Missing categories signifies that no tumour imaging has been performed post baseline, and therefore the response status could not be assessed.

  • Disease Control According to RECIST v1.1 [ Time Frame: From first drug administration until 28 days after last drug administration, up to 717 days. ] [ Designated as safety issue: No ]
    Disease control according to RECIST v1.1 Disease control is complete response, partial response or stable disease for measurable patients and complete response or non−CR/non−PD for non−measurable patients. Missing categories signify that no tumour imaging has been performed post baseline, and therefore the response status could not be assessed.

  • Objective Response According to RECIST v1.1 [ Time Frame: From first drug administration until 28 days after last drug administration, up to 717 days. ] [ Designated as safety issue: No ]
    Objective response according to RECIST v1.1. Objective response is complete response or partial response for patients with measurable disease. Missing categories signify that no tumour imaging has been performed post baseline, and therefore the response status could not be assessed.

  • Time to Objective Response According to RECIST v1.1 [ Time Frame: 6 weeks, 12 weeks and 24 weeks ] [ Designated as safety issue: No ]
    Objective response according to RECIST v1.1. Objective response is complete response or partial response for patients with measurable disease. Time to objective response is the time from the start of treatment to the date of first documented complete response or partial response. Descriptive analyses has been performed for the time to objective response (N(%) of patients with first occurrence of objective response at 6, 12 and 24 weeks). Onset of objective response is derived for patient with measurable disease.

  • Duration of Objective Response According to RECIST v1.1 [ Time Frame: From the first documented complete response or partial response to the time of disease progression or death ] [ Designated as safety issue: No ]
    Duration of objective response was the time from the first documented complete response or partial response to disease progression or death.

  • Duration of Disease Control According to RECIST v1.1 [ Time Frame: From the first administration of study medication to the time of disease progression or death ] [ Designated as safety issue: No ]
    Duration of disease control according to RECIST v1.1.

  • Progression Free Survival (PFS) [ Time Frame: From the first administration of study medication to the time of disease progression or death ] [ Designated as safety issue: No ]
    Progression-free survival was defined as the time from the first administration of study medication to the time of disease progression or death, whichever occurred first.

  • Overall Survival (OS) [ Time Frame: From the first administration of study medication to the time of death ] [ Designated as safety issue: No ]
    Overall survival was defined as the time from the first administration of study medication to the time of death from any cause.

  • Area Under the Concentration-time Curve (AUC) Tau,ss of Afatinib [ Time Frame: PK samples were taken at hours; 167:55, 479:55, 481:05, 482:05, 483:05, 485:05, 487:05 and on day 22 at hours; -0:10, 1, 2, 3, 5, 7, 23:55 ] [ Designated as safety issue: No ]
    Area under the concentration-time curve of Afatinib in plasma over a uniform dosing interval t at steady state.

  • Cmax,ss of Afatinib [ Time Frame: PK samples were taken at hours; 167:55, 479:55, 481:05, 482:05, 483:05, 485:05, 487:05 and on day 22 at hours; -0:10, 1, 2, 3, 5, 7, 23:55 ] [ Designated as safety issue: No ]
    Maximum concentration of Afatinib in plasma at steady state.

  • AUC 0-tz of Gemcitabine [ Time Frame: PK samples were taken on day 1 at hours; -0:05, 0:30, 1, 1:30, 2, 3 and on day 22 at hours; -0:10, 0:30, 1, 1:30, 2, 3 ] [ Designated as safety issue: No ]
    Area under the concentration-time curve of Gemcitabine in plasma over the time interval from 0 up to the last quantifiable data point

  • Cmax of Gemcitabine [ Time Frame: PK samples were taken on day 1 at hours; -0:05, 0:30, 1, 1:30, 2, 3 and on day 22 at hours; -0:10, 0:30, 1, 1:30, 2, 3 ] [ Designated as safety issue: No ]
    Maximum concentration of Gemcitabine in plasma.

  • Total Clearance (CL) of Gemcitabine [ Time Frame: PK samples were taken on day 1 at hours; -0:05, 0:30, 1, 1:30, 2, 3 and on day 22 at hours; -0:10, 0:30, 1, 1:30, 2, 3 ] [ Designated as safety issue: No ]
    Total Clearance (CL) of Gemcitabine from plasma.

  • Volume of Distribution at Steady State (Vss) of Gemcitabine [ Time Frame: PK samples were taken on day 1 at hours; -0:05, 0:30, 1, 1:30, 2, 3 and on day 22 at hours; -0:10, 0:30, 1, 1:30, 2, 3 ] [ Designated as safety issue: No ]
    Apparent volume of distribution at steady state (Vss) of Gemcitabine.

  • AUC 0-24 of Docetaxel [ Time Frame: PK samples were taken on day 1 at hours; -0:05, 1, 2, 3, 5, 7, 23:55 and on day 22 at hours; -0:10, 1, 2, 3, 5, 7, 23:55 ] [ Designated as safety issue: No ]
    Area under the concentration-time curve of docetaxel in plasma over the time interval from 0 up to 24 hours

  • Cmax of Docetaxel [ Time Frame: PK samples were taken on day 1 at hours; -0:05, 1, 2, 3, 5, 7, 23:55 and on day 22 at hours; -0:10, 1, 2, 3, 5, 7, 23:55 ] [ Designated as safety issue: No ]
    Maximum concentration of docetaxel in plasma.

  • Total Clearance (CL) of Docetaxel [ Time Frame: PK samples were taken on day 1 at hours; -0:05, 1, 2, 3, 5, 7, 23:55 and on day 22 at hours; -0:10, 1, 2, 3, 5, 7, 23:55 ] [ Designated as safety issue: No ]
    Total Clearance (CL) of Docetaxel from plasma.

  • Volume of Distribution at Steady State (Vss) of Docetaxel [ Time Frame: PK samples were taken on day 1 at hours; -0:05, 1, 2, 3, 5, 7, 23:55 and on day 22 at hours; -0:10, 1, 2, 3, 5, 7, 23:55 ] [ Designated as safety issue: No ]
    Apparent volume of distribution at steady state (Vss) of Docetaxel.


Biospecimen Retention:   Samples Without DNA
Pharmacokinetic samples

Enrollment: 94
Study Start Date: November 2010
Study Completion Date: April 2015
Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
Afatinib and docetaxel Drug: Afatinib
Maximum Tolerated Dose of Afatinib in combination with gemcitabine
Drug: docetaxel
Maximum Tolerated Dose of Afatinib in combination with docetaxel
Afatinib and gemcitabine Drug: Afatinib
Maximum Tolerated Dose of Afatinib in combination with gemcitabine
Drug: gemcitabine
Maximum Tolerated Dose of Afatinib in combination with gemcitabine

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
solid tumors
Criteria

Inclusion criteria:

1. histologically or cytologically confirmed diagnosis of any advanced or metastatic relapsed or refractory solid tumor.

Exclusion criteria:

  1. Active brain metastases
  2. Patients with known pre-existing interstitial lung disease
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01251653

Locations
France
1200.93.33002 Boehringer Ingelheim Investigational Site
Dijon, France
1200.93.33001 Boehringer Ingelheim Investigational Site
Saint-Herblain cedex, France
1200.93.33003 Boehringer Ingelheim Investigational Site
Toulouse, France
Sponsors and Collaborators
Boehringer Ingelheim
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  More Information

Additional Information:
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01251653     History of Changes
Other Study ID Numbers: 1200.93  2010-020560-37 
Study First Received: December 1, 2010
Results First Received: April 22, 2016
Last Updated: April 22, 2016
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Additional relevant MeSH terms:
Gemcitabine
Docetaxel
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators

ClinicalTrials.gov processed this record on August 25, 2016