Breast Neoplasms, Stomach Neoplasms
Conditions
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.
Interventions
DRUGHerceptin
3-weekly
DRUGafatinib
at MTD level
DRUGtrastuzumab
3-weekly
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MTD of Afatinib in Combination With Trastuzumab Based on the Number of Patients With DLTs During the First Treatment Cycle (Afatinib). | 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. |
| Dose Limiting Toxicities During cycle1 | 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
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response (BOR) | 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. |
| Objective Response | 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. |
| Clinical Benefit | 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. |
Countries
France
Participant flow
Recruitment details
HER2: Human Epidermal Growth Factor Receptor 2; RECIST,v1.1: Response Evaluation Criteria In Solid Tumors, version 1.1
Pre-assignment details
Phase Ia: Open label, uncontrolled, dose escalation study of afatinib given continuously in combination with trastuzumab administered every 3 weeks. Phase Ib: Open label, uncontrolled study to explore the efficacy, safety, pharmacokinetics & biomarkers of afatinib at the MTD dosage, with 3- weekly trastuzumab.
Participants by arm
| Arm | Count |
|---|---|
| Phase Ia: Afatinib 20mg+Trastuzumab 8 mg/kg In each 21 day treatment cycle, patients were administered orally 20 mg afatinib tablet from Day 2 continuous daily administration in combination with trastuzumab. An initial loading dose of trastuzumab 8 mg/kg was administered via intravenous infusion at Day1 Cycle1, followed by trastuzumab 6 mg/kg every 3 weeks. Trastuzumab intravenous infusion, 90 minutes, infusion duration could be reduced to 30 minutes if well tolerated. | 6 |
| Phase Ia: Afatinib 30mg+Trastuzumab 8 mg/kg In each 21 day treatment cycle, patients were administered orally 30 mg afatinib tablet from Day 2 continuous daily administration in combination with trastuzumab. An initial loading dose of trastuzumab 8 mg/kg was administered via intravenous infusion at Day1 Cycle1, followed by trastuzumab 6 mg/kg every 3 weeks. Trastuzumab intravenous infusion, 90 minutes, infusion duration could be reduced to 30 minutes if well tolerated. | 7 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Other Adverse Event | 0 | 2 |
| Overall Study | Other than stated above | 1 | 0 |
| Overall Study | Progressive disease | 4 | 5 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Phase Ia: Afatinib 20mg+Trastuzumab 8 mg/kg | Phase Ia: Afatinib 30mg+Trastuzumab 8 mg/kg | Total |
|---|---|---|---|
| Age, Continuous | 60.8 Years STANDARD_DEVIATION 3.7 | 48.4 Years STANDARD_DEVIATION 7.6 | 54.2 Years STANDARD_DEVIATION 8.7 |
| Sex: Female, Male Female | 4 Participants | 7 Participants | 11 Participants |
| Sex: Female, Male Male | 2 Participants | 0 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 7 / 7 |
| serious Total, serious adverse events | 4 / 6 | 4 / 7 |
Outcome results
Primary
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.
Time frame: First 21-day treatment cycle
Population: Treated set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase Ia: Afatinib +Trastuzumab 8 mg/kg | Dose Limiting Toxicities During cycle1 | 1 Participants |
| Phase Ia: Afatinib 30mg+Trastuzumab 8 mg/kg | Dose Limiting Toxicities During cycle1 | 2 Participants |
Primary
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.
Time frame: First 21 days treatment cycle
Population: Treated set: This analysis set includes all patients who were documented to have taken at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase Ia: Afatinib +Trastuzumab 8 mg/kg | MTD of Afatinib in Combination With Trastuzumab Based on the Number of Patients With DLTs During the First Treatment Cycle (Afatinib). | 20 mg |
Secondary
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.
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
Population: Treated set~Missing: First image time point not reached before discontinuation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase Ia: Afatinib +Trastuzumab 8 mg/kg | Best Overall Response (BOR) | Complete Response (CR) | 0.0 percentage of participants |
| Phase Ia: Afatinib +Trastuzumab 8 mg/kg | Best Overall Response (BOR) | Partial Response (PR) | 16.7 percentage of participants |
| Phase Ia: Afatinib +Trastuzumab 8 mg/kg | Best Overall Response (BOR) | Stable Disease (SD) | 16.7 percentage of participants |
| Phase Ia: Afatinib +Trastuzumab 8 mg/kg | Best Overall Response (BOR) | Progressive Disease (PD) | 50.0 percentage of participants |
| Phase Ia: Afatinib +Trastuzumab 8 mg/kg | Best Overall Response (BOR) | Missing | 16.7 percentage of participants |
| Phase Ia: Afatinib +Trastuzumab 8 mg/kg | Best Overall Response (BOR) | Not Evaluable | 0.0 percentage of participants |
| Phase Ia: Afatinib 30mg+Trastuzumab 8 mg/kg | Best Overall Response (BOR) | Missing | 0.0 percentage of participants |
| Phase Ia: Afatinib 30mg+Trastuzumab 8 mg/kg | Best Overall Response (BOR) | Complete Response (CR) | 0.0 percentage of participants |
| Phase Ia: Afatinib 30mg+Trastuzumab 8 mg/kg | Best Overall Response (BOR) | Progressive Disease (PD) | 0.0 percentage of participants |
| Phase Ia: Afatinib 30mg+Trastuzumab 8 mg/kg | Best Overall Response (BOR) | Partial Response (PR) | 0.0 percentage of participants |
| Phase Ia: Afatinib 30mg+Trastuzumab 8 mg/kg | Best Overall Response (BOR) | Not Evaluable | 0.0 percentage of participants |
| Phase Ia: Afatinib 30mg+Trastuzumab 8 mg/kg | Best Overall Response (BOR) | Stable Disease (SD) | 100.0 percentage of participants |
Secondary
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.
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
Population: Treated set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase Ia: Afatinib +Trastuzumab 8 mg/kg | Clinical Benefit | 33.3 percentage of participants |
| Phase Ia: Afatinib 30mg+Trastuzumab 8 mg/kg | Clinical Benefit | 100.0 percentage of participants |
Secondary
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.
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
Population: Treated set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase Ia: Afatinib +Trastuzumab 8 mg/kg | Objective Response | 16.7 percentage of participants |
| Phase Ia: Afatinib 30mg+Trastuzumab 8 mg/kg | Objective Response | 0.0 percentage of participants |