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Phase I Trial of Afatinib and Trastuzumab in HER2 Overexpressing Cancer.

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ClinicalTrials.gov Identifier: NCT01649271
Recruitment Status : Completed
First Posted : July 25, 2012
Results First Posted : November 6, 2017
Last Update Posted : December 22, 2017
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Brief Summary:
The aim of the study is to determine the Maximum Tolerated Dose (MTD) of afatinib in combination with 3-weekly trastuzumab in HER2 overexpressing cancer and to assess the efficacy of afatinib given at the MTD dosage, with 3-weekly trastuzumab in HER2 overexpressing metastatic breast cancer.

Condition or disease Intervention/treatment Phase
Breast Neoplasms Stomach Neoplasms Drug: Herceptin Drug: afatinib Drug: trastuzumab Phase 1

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 13 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Trial of Afatinib in Combination With 3 Weekly Trastuzumab in Patients With Tumours Overexpressing HER2. Once the MTD of Afatinib With 3 Weekly Trastuzumab Was Established the Safety of This Dose Will be Assessed Also in Combination With Weekly Trastuzumab.
Actual Study Start Date : July 23, 2012
Actual Primary Completion Date : June 23, 2016
Actual Study Completion Date : June 23, 2016

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Experimental: Phase Ia, group 1
afatinib escalating dose with 3-weekly trastuzumab
Drug: Herceptin
3-weekly
Drug: afatinib
escalating dose
Experimental: Phase Ia, group 2
afatinib at MTD dose with weekly trastuzumab
Drug: afatinib
at MTD level
Drug: Herceptin
weekly
Experimental: Phase Ib
afatinib at MTD level with 3-weekly trastuzumab
Drug: trastuzumab
3-weekly
Drug: afatinib
at MTD level



Primary Outcome Measures :
  1. MTD of Afatinib in Combination With Trastuzumab Based on the Number of Patients With DLTs During the First Treatment Cycle (Afatinib). [ Time Frame: First 21 days treatment cycle ]

    Maximum Tolerated Dose (MTD) of Afatinib in combination with trastuzumab based on the number of patients with dose limiting toxicity (DLT) during the first treatment cycle (Dose escalation part). The MTD was defined as the highest dose studied at which the incidence of a DLT was less than 17% (i.e. 1/6 patients) during the first cycle.

    One patient in the Afa30+Trast8 cohort developed tumour lysis syndrome during the first course of treatment and was therefore not evaluable for the primary endpoint.


  2. Dose Limiting Toxicities During cycle1 [ Time Frame: First 21-day treatment cycle ]

    Number of Patients With Dose Limiting Toxicity (DLT) occurring during Cycle 1 based on the investigator assessment.

    One patient in the Afa30+Trast8 cohort developed tumour lysis syndrome during the first course of treatment and was therefore not evaluable for the primary endpoint.



Secondary Outcome Measures :
  1. Best Overall Response (BOR) [ Time Frame: Post baseline tumour-imaging was performed at every 6 weeks (in the week preceding the start of Cycles 3, 5, 7, 9, 11, etc.) until End of Treatment (EOT); up to 33 months ]
    BOR represents the best response a patient had during their time in study from start of treatment until progression, the last evaluable assessment in absence of progression or start of subsequent anticancer therapy. For patients that died, BOR was to be calculated based on data up to last evaluable RECIST,v1.1 assessment prior to death. Death did not contribute as PD for BOR. As per RECIST v1.1 for target lesions (TL) & assessed by MRI: CR: Disappearance of all TL,all non-TL, & no new lesion. Any pathological lymph nodes must have had reduction in the short axis to <10 mm. PR: At least 30% decrease in sum of the longest diameter (SLD) of TL taking as reference the baseline SLD. PD: At least a 20% increase in SLD of TL taking as reference the smallest SLD recorded since treatment started, together with an absolute increase in SLD of at least 5mm. SD: Neither sufficient shrinkage to qualify for PR, taking as reference the baseline SLD, nor sufficient increase to qualify for PD.

  2. Objective Response [ Time Frame: Post baseline tumour-imaging was performed at every 6 weeks (in the week preceding the start of Cycles 3, 5, 7, 9, 11, etc.) until EOT; up to 33 months ]
    Objective Response (OR) was defined as best overall response of complete response (CR) or partial response (PR), where best overall response was determined according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 from first administration of study medication until the earliest of disease progression, death or last evaluable tumour assessment before start of subsequent anti-cancer therapy. As Per RECIST v1.1 for target lesions (TL) & assessed by MRI: CR: Disappearance of all TL,all non-TL, & no new lesion. Any pathological lymph nodes must have had reduction in the short axis to <10 mm. PR: At least 30% decrease in sum of the longest diameter (SLD) of TL taking as reference the baseline SLD.

  3. Clinical Benefit [ Time Frame: Post baseline tumour-imaging was performed at every 6 weeks (in the week preceding the start of Cycles 3, 5, 7, 9, 11, etc.) until EOT; up to 33 months ]

    Clinical benefit was defined as best overall response of CR or PR or stable disease (SD) where best overall response is defined according to RECIST version 1.1 from first treatment administration until the earliest of disease progression, death or last evaluable tumour assessment before start of subsequent anti-cancer therapy.

    As Per RECIST v1.1 for target lesions (TL) & assessed by MRI: CR: Disappearance of all TL,all non-TL, & no new lesion. Any pathological lymph nodes must have had reduction in the short axis to <10 mm. PR: At least 30% decrease in sum of the longest diameter (SLD) of TL taking as reference the baseline SLD. SD: Neither sufficient shrinkage to qualify for PR, taking as reference the baseline SLD, nor sufficient increase to qualify for PD.




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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  1. Patients aged 18 years and older
  2. Patients with cancers overexpressing HER2 by Immunohistochemistry test( IHC) 3+ and/or IHC 2+ with positive gene amplification by FISH (confirmation on archived tissue needed)
  3. Written informed consent that is consistent with ICH-GCP guidelines.
  4. Patients must be eligible for treatment with trastuzumab.
  5. Patients must have adequate organ function (kidney, liver, bone marrow, cardiac)
  6. Eastern Cooperative Oncology Group (ECOG) = 0 or 1.
  7. Measurable disease according to RECIST 1.1 (Phase Ib).

Exclusion criteria:

  1. Active brain metastases.
  2. Prior treatment with erbB family targeting therapies within the past four weeks before start of therapy or concomitantly with the trial other than trastuzumab and/or lapatinib.
  3. Patients having more than 2 lines of chemotherapy for the treatment of metastatic breast cancer (Phase Ib).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01649271


Locations
France
CTR Georges-François Leclerc
Dijon, France, 21079
CTR René Gauducheau, Onco, St Herblain
Saint Herblain Cedex, France, 44805
INS Claudius Regaud
Toulouse, France, 31059
Sponsors and Collaborators
Boehringer Ingelheim
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim

Additional Information:
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01649271     History of Changes
Other Study ID Numbers: 1200.134
2012-001753-10 ( EudraCT Number )
First Posted: July 25, 2012    Key Record Dates
Results First Posted: November 6, 2017
Last Update Posted: December 22, 2017
Last Verified: November 2017

Additional relevant MeSH terms:
Neoplasms
Breast Neoplasms
Stomach Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Trastuzumab
Antineoplastic Agents