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

Study Overview
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Brief Summary
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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.

Official Title
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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.

Conditions
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Breast Neoplasms, Stomach Neoplasms

Intervention / Treatment
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* Drug: Herceptin
* Drug: afatinib
* Drug: trastuzumab
* Drug: Herceptin
* Drug: afatinib
* Drug: afatinib


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patients aged 18 years and older 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) Written informed consent that is consistent with ICH-GCP guidelines. Patients must be eligible for treatment with trastuzumab. Patients must have adequate organ function (kidney, liver, bone marrow, cardiac) Eastern Cooperative Oncology Group (ECOG) = 0 or 1. Measurable disease according to RECIST 1.1 (Phase Ib). Exclusion criteria: Active brain metastases. 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. Patients having more than 2 lines of chemotherapy for the treatment of metastatic breast cancer (Phase Ib).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase Ia, group 1<br>afatinib escalating dose with 3-weekly trastuzumab | Drug: Herceptin<br>* 3-weekly<br>Drug: afatinib<br>* escalating dose<br>|
| Experimental: Phase Ia, group 2<br>afatinib at MTD dose with weekly trastuzumab | Drug: afatinib<br>* at MTD level<br>Drug: Herceptin<br>* weekly<br>|
| Experimental: Phase Ib<br>afatinib at MTD level with 3-weekly trastuzumab | Drug: trastuzumab<br>* 3-weekly<br>Drug: afatinib<br>* at MTD level<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD of Afatinib in Combination With Trastuzumab Based on the Number of Patients With DLTs During the First Treatment Cycle (Afatinib). | 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. | First 21 days treatment cycle | 
| Dose Limiting Toxicities During cycle1 | 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. | First 21-day treatment cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response (BOR) | 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. | 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 | 
| Objective Response | 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. | 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 | 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. | 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 |