Breast Neoplasms
Conditions
Brief summary
The purpose of the study is to compare the efficacy of treatment with afatinib plus letrozole to treatment with letrozole alone in women diagnosed with a specific type of breast cancer.
Detailed description
This is an open-label, multicenter, international, randomized, Phase II clinical trial that will assess the efficacy and safety of letrozole in combination with afatinib(oral epidermal growth factor receptor (EGFR ) inhibitor) versus letrozole monotherapy for the first-line treatment of postmenopausal women with ER+, Human Epidermal Growth Factor Receptor 2 (HER2) negative advanced breast cancer with low ER expression. In order to assess the level of estrogen receptor (ER) expression we will use a semi-quantitative scoring system (McClelland, 1990) defined as : H-score = (% of cells stained at intensity category 1x1) + (% of cells stained at intensity category 2x2) + (% of cells stained at intensity category 3x3). This formula results in an H-score in the range of 0-300 where 300 equals 100% of tumor cells stained strongly (i.e., 3+). Low ER expression will be defined as tumor sample with H-score below 160 (Finn, 2009). All subjects who consented for the study must submit a tumor sample to the designated central laboratory for central confirmation of ER / Progesterone receptor (PR) and HER2 statuses and determination of the H-score. This will be assessed prior to randomization. Subjects with HER2 negative, ER+ advanced breast cancer with low ER expression defined as H-score between 1 and 159 will enter screening phase and perform the required screening assessments. Eligible subjects will be randomly assigned in a 1:1 ratio and stratified according to sites of disease (bone only disease vs. other) and prior administration of hormonal therapy in neo/adjuvant setting (Yes vs. No) to either: Arm A : Continuous regimen of oral letrozole 2.5 mg until progression of disease or any other study treatment discontinuation criteria. or Arm B : Continuous regimen of oral letrozole 2.5 mg daily plus oral afatinib 30 mg daily until progression of disease or any other study treatment discontinuation criteria. IN ADDITION the following applies whichever comes first: * If the patients treated with the combination of afatinib and letrozole (arm B) discontinue the trial treatment (whatever the reason) before 30 November 2018, the patients from the other arm (arm A, letrozole alone) still on treatment will also be discontinued from the trial at the same time. They may continue receiving letrozole using commercial drug as standard of care according to their treating physician discretion. * If the patients treated with afatinib and letrozole (arm B) have not discontinued the trial treatment by 30 November 2018, all patients currently on treatment in the trial (including the ones only treated by letrozole alone (arm A)) will be discontinued from the trial at that time. They may continue receiving their treatment if in alignment with their treating physician judgment as follows: * Patients in arm A: may continue receiving letrozole using commercial drug as standard of care according to their treating physician discretion. * Patients in arm B: may continue receiving afatinib in the context of alternative drug supply outside the clinical trial as appropriate according to local legislation. Additionally, they may continue receiving letrozole using commercial drug as standard of care according to their treating physician discretion. Once the patient is discontinued from trial treatment and has undergone the End of Treatment Visit, she will be permanently discontinued from the trial and treated as per local clinical practice.
Interventions
DRUGLetrozole
DRUGAfatinib
Sponsors
Boehringer Ingelheim
Translational Research in Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed and dated informed consent. * Postmenopausal females, 18 years of age or older. * Histologically or cytologically proven diagnosis of adenocarcinoma of the breast with evidence of locally recurrent disease not amenable to resection or radiation therapy with curative intent, or metastatic disease. * HER2 negative breast cancer. Central testing (required for all subjects) must demonstrate that the tumor is HER2 negative by FISH or Immunohistochemistry (IHC). * ER positive breast cancer. Central testing (required for all subjects) must demonstrate that the tumor is ER+ with low expression (H-score \[1-159\]). * Paraffin-embedded tumor block(s) or 15 to 20 unstained slides available for centralized assessment of ER, PR, and HER2. * Measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 or bone-only non measurable disease. * Eastern Cooperative Oncology Group (ECOG) Performance status 0 or 1. * Adequate hematological, hepatic and renal functions. * Baseline left ventricular ejection fraction (LVEF) 50%. * Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.
Exclusion criteria
* Brain metastases, spinal cord compression, carcinomatous meningitis, or leptomeningeal disease. * Prior treatment with any type of systemic therapy for advanced disease. * Prior treatment with letrozole in (neo)adjuvant setting with disease-free interval ≤ 12 months from completion of treatment until randomization. * Prior treatment with any anti HER-family targeted therapy in (neo)adjuvant setting. * Any concurrent or previous malignancy within 5 years prior to randomization, except for adequately and radically treated basal or squamous skin cancer, or carcinoma in situ of the cervix, or other non-invasive/in-situ neoplasm. * Non-measurable disease according to RECIST 1.1, with the exception of bone-only non-measurable disease. * Known pre-existing interstitial lung disease. * Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom. * History or presence of clinically relevant cardiovascular abnormalities as per investigator assessment. * Any other concomitant serious illness or organ system dysfunction as per investigator assessment * Any contraindication to oral agents. * Active hepatitis B infection, active hepatitis C infection or known HIV carrier. * Known or suspected active drug or alcohol abuse. * Known hypersensitivity to afatinib or letrozole or the excipients of any of the trial drugs. * Concomitant treatment with strong inhibitor of P-gp. * Any ongoing acute clinically significant toxic effect of prior anticancer therapy or any persisting complication of prior surgery. * Subjects with known history of keratitis, ulcerative keratitis or severe dry eye. * Participation in the active phase of other clinical trials of investigational agents in which last study treatment was administered within 2 weeks prior to randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Tumor assessments were every 12 weeks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B. | Progression Free Survival (PFS) is defined as the time from randomization until date of progression (assessed by Response Evaluation Criteria in Solid Tumors - RECIST) or death due to any cause, whichever occurs first. For evaluation of PFS, the randomization date for each patient was the start date. If the status at the last assessment date was Non-complete response/ Non-progressive disease or Complete response, then the patient was considered censored. If the status at the last assessment for any tumor was Progressive disease, then the patient was considered as having an event. Progressive disease is defined using RECIST v1 .1 as a ≥ 20% increase in the sum of the longest diameter of target lesions compared with the smallest-sum longest diameter recorded or the appearance of one or more target or non-target new lesions and/or unequivocal progression of existing non-target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Under treatment: every 4 wks up to 9 months (average) for subject in the Arm A or up to 14 months (average) for subjects in Arm B. After documentation of disease progression up to the end of the study: every 6 months up to 42 months | Overall Survival is defined as the time from randomization until death to any cause. For subjects in which treatment is discontinued for reasons different than Progression Disease: after treatment and up to documentation of disease progression: Overall Survival is assessed every 12 weeks |
| Objective Response Rate (ORR) | Tumor assessment: every 12 weeks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B. | Objective response rate (ORR) is defined as the proportion of randomized subjects achieving a best overall response of complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST). As per RECIST (version 1.1): CR is defined as disappearance of all target and non target lesions - lymph node (LN) \<10mm. PR is defined as at least a 30% decrease in the Sum of Diameters, taking as reference the Baseline Sum of Diameters |
| Time to Tumor Progression (TTP) | Tumor assessments: every 12 weeks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B. | As per Response Evaluation Criteria In Solid Tumors (RECIST). Time to progression (TTP) is defined as the time interval from date of randomization to date of the first documented objective tumor progression. |
| Number of Participants With Adverse Events | Under treatment: every 4 wks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B. After documentation of disease progression up to the end of the study: every 6 months up to 42 months | Participants who experienced at least one Treatment Emergent Adverse Event (TEAE) are presented. Participants with at least one serious TEAE, those who had at least one TEAE related to letrozole or afatinib (serious/non-serious), including participants who experienced a grade 3/4 TEAE, or who discontinued/died as a result of their TEAE are listed by treatment arm. Adverse events were tabulated by system organ class, preferred term and toxicity grade by treatment arm. For subjects in which treatment was discontinued for reasons different than progression of disease, the assessment was conducted every 12 weeks following treatment, and up to documentation of disease progression. \*\* Enrollment was closed prematurely due to low recruitment (only 44 participants enrolled) compared to what was initially planned (150 participants), therefore no statistical evaluations were completed. Adverse event data collected are described per arm but no statistical comparison was made. |
Countries
Bosnia and Herzegovina, Romania, Spain, United States
Participant flow
Pre-assignment details
For all patients consented on the trial, a tumor sample was sent to the central lab for testing of ER/PR and HER2 and determination of the H-score. This was assessed prior to randomization. Patients with HER2 negative, ER+ advanced breast cancer with low ER expression defined as H-score between 1 and 159 entered screening phase.
Participants by arm
| Arm | Count |
|---|---|
| Arm A Letrozole 2.5 mg | 23 |
| Arm B Letrozole 2.5 mg + Afatinib 30 mg | 21 |
| Total | 44 |
Baseline characteristics
| Characteristic | Arm A | Arm B | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 11 Participants | 20 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 10 Participants | 24 Participants |
| ECOG Performance Status 0 | 12 Participants | 14 Participants | 26 Participants |
| ECOG Performance Status 1 | 11 Participants | 7 Participants | 18 Participants |
| Menopausal Status Post-Menopausal | 23 Participants | 21 Participants | 44 Participants |
| Menopausal Status Pre-Menopausal | 0 Participants | 0 Participants | 0 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Bosnia and Herzegovina | 4 participants | 3 participants | 7 participants |
| Region of Enrollment Romania | 3 participants | 5 participants | 8 participants |
| Region of Enrollment Spain | 7 participants | 7 participants | 14 participants |
| Region of Enrollment United States | 9 participants | 6 participants | 15 participants |
| Sex: Female, Male Female | 23 Participants | 21 Participants | 44 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Weight (kg) | 77.39 kg STANDARD_DEVIATION 16.25 | 69.59 kg STANDARD_DEVIATION 11.14 | 73.67 kg STANDARD_DEVIATION 14.44 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 23 | 0 / 21 |
| other Total, other adverse events | 16 / 23 | 20 / 21 |
| serious Total, serious adverse events | 5 / 23 | 2 / 21 |
Outcome results
Primary
Progression Free Survival (PFS)
Progression Free Survival (PFS) is defined as the time from randomization until date of progression (assessed by Response Evaluation Criteria in Solid Tumors - RECIST) or death due to any cause, whichever occurs first. For evaluation of PFS, the randomization date for each patient was the start date. If the status at the last assessment date was Non-complete response/ Non-progressive disease or Complete response, then the patient was considered censored. If the status at the last assessment for any tumor was Progressive disease, then the patient was considered as having an event. Progressive disease is defined using RECIST v1 .1 as a ≥ 20% increase in the sum of the longest diameter of target lesions compared with the smallest-sum longest diameter recorded or the appearance of one or more target or non-target new lesions and/or unequivocal progression of existing non-target lesions.
Time frame: Tumor assessments were every 12 weeks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B.
Population: The timeframe specifies when tumor assessments were performed. Enrollment was closed prematurely due to low recruitment (only 44 participants enrolled) compared to what was initially planned (150 participants), therefore no statistical evaluations were completed (including PFS).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Progression Free Survival (PFS) | Failed (Progressed or Died) | 4 Participants |
| Arm A | Progression Free Survival (PFS) | Censored | 14 Participants |
| Arm B | Progression Free Survival (PFS) | Censored | 16 Participants |
| Arm B | Progression Free Survival (PFS) | Failed (Progressed or Died) | 2 Participants |
Secondary
Number of Participants With Adverse Events
Participants who experienced at least one Treatment Emergent Adverse Event (TEAE) are presented. Participants with at least one serious TEAE, those who had at least one TEAE related to letrozole or afatinib (serious/non-serious), including participants who experienced a grade 3/4 TEAE, or who discontinued/died as a result of their TEAE are listed by treatment arm. Adverse events were tabulated by system organ class, preferred term and toxicity grade by treatment arm. For subjects in which treatment was discontinued for reasons different than progression of disease, the assessment was conducted every 12 weeks following treatment, and up to documentation of disease progression. \*\* Enrollment was closed prematurely due to low recruitment (only 44 participants enrolled) compared to what was initially planned (150 participants), therefore no statistical evaluations were completed. Adverse event data collected are described per arm but no statistical comparison was made.
Time frame: Under treatment: every 4 wks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B. After documentation of disease progression up to the end of the study: every 6 months up to 42 months
Population: Participants who experienced at least one Treatment Emergent Adverse Event (TEAE) are listed. Participants with at least one serious TEAE, those who had at least one TEAE related to letrozole or afatinib (serious/non-serious), including participants who experienced a grade 3/4 TEAE, or who discontinued/died as a result of their TEAE are presented.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Number of Participants With Adverse Events | At least one TEAE related to letrozole | 6 Participants |
| Arm A | Number of Participants With Adverse Events | At least one serious TEAE related to afatinib | 0 Participants |
| Arm A | Number of Participants With Adverse Events | Patient having at least one serious TEAE | 5 Participants |
| Arm A | Number of Participants With Adverse Events | Patient having at least one grade 3/4 TEAE | 7 Participants |
| Arm A | Number of Participants With Adverse Events | At least one TEAE related to afatinib | 0 Participants |
| Arm A | Number of Participants With Adverse Events | TEAE leading to discontinuation - letrozole | 1 Participants |
| Arm A | Number of Participants With Adverse Events | Patient having at least one TEAE | 16 Participants |
| Arm A | Number of Participants With Adverse Events | TEAE leading to discontinuation - afatinib | 0 Participants |
| Arm A | Number of Participants With Adverse Events | At least one serious TEAE related to letrozole | 0 Participants |
| Arm A | Number of Participants With Adverse Events | Fatal TEAE | 0 Participants |
| Arm B | Number of Participants With Adverse Events | At least one serious TEAE related to letrozole | 0 Participants |
| Arm B | Number of Participants With Adverse Events | Patient having at least one TEAE | 20 Participants |
| Arm B | Number of Participants With Adverse Events | Patient having at least one serious TEAE | 2 Participants |
| Arm B | Number of Participants With Adverse Events | At least one TEAE related to letrozole | 11 Participants |
| Arm B | Number of Participants With Adverse Events | At least one TEAE related to afatinib | 18 Participants |
| Arm B | Number of Participants With Adverse Events | Fatal TEAE | 0 Participants |
| Arm B | Number of Participants With Adverse Events | At least one serious TEAE related to afatinib | 1 Participants |
| Arm B | Number of Participants With Adverse Events | Patient having at least one grade 3/4 TEAE | 3 Participants |
| Arm B | Number of Participants With Adverse Events | TEAE leading to discontinuation - letrozole | 1 Participants |
| Arm B | Number of Participants With Adverse Events | TEAE leading to discontinuation - afatinib | 1 Participants |
Secondary
Objective Response Rate (ORR)
Objective response rate (ORR) is defined as the proportion of randomized subjects achieving a best overall response of complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST). As per RECIST (version 1.1): CR is defined as disappearance of all target and non target lesions - lymph node (LN) \<10mm. PR is defined as at least a 30% decrease in the Sum of Diameters, taking as reference the Baseline Sum of Diameters
Time frame: Tumor assessment: every 12 weeks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B.
Population: The timeframe specifies when tumor assessments were performed. Enrollment was closed prematurely due to low recruitment (only 44 participants enrolled) compared to what was initially planned (150 participants), therefore no statistical evaluations were completed (including ORR).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Objective Response Rate (ORR) | Complete Response (CR) | 2 Participants |
| Arm A | Objective Response Rate (ORR) | Death | 2 Participants |
| Arm A | Objective Response Rate (ORR) | Progessive Disease (PD) | 2 Participants |
| Arm A | Objective Response Rate (ORR) | Non-CR / Non-PD | 12 Participants |
| Arm B | Objective Response Rate (ORR) | Non-CR / Non-PD | 15 Participants |
| Arm B | Objective Response Rate (ORR) | Complete Response (CR) | 1 Participants |
| Arm B | Objective Response Rate (ORR) | Progessive Disease (PD) | 2 Participants |
| Arm B | Objective Response Rate (ORR) | Death | 0 Participants |
Secondary
Overall Survival (OS)
Overall Survival is defined as the time from randomization until death to any cause. For subjects in which treatment is discontinued for reasons different than Progression Disease: after treatment and up to documentation of disease progression: Overall Survival is assessed every 12 weeks
Time frame: Under treatment: every 4 wks up to 9 months (average) for subject in the Arm A or up to 14 months (average) for subjects in Arm B. After documentation of disease progression up to the end of the study: every 6 months up to 42 months
Population: The timeframe specifies when tumor assessments were performed. Enrollment was closed prematurely due to low recruitment (only 44 participants enrolled) compared to what was initially planned (150 participants), therefore no statistical evaluations were completed (including OS).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Overall Survival (OS) | Died | 2 Participants |
| Arm A | Overall Survival (OS) | Censored | 16 Participants |
| Arm B | Overall Survival (OS) | Died | 0 Participants |
| Arm B | Overall Survival (OS) | Censored | 18 Participants |
Secondary
Time to Tumor Progression (TTP)
As per Response Evaluation Criteria In Solid Tumors (RECIST). Time to progression (TTP) is defined as the time interval from date of randomization to date of the first documented objective tumor progression.
Time frame: Tumor assessments: every 12 weeks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B.
Population: The timeframe specifies when tumor assessments were performed. Enrollment was closed prematurely due to low recruitment (only 44 participants enrolled) compared to what was initially planned (150 participants), therefore data for TTP was not produced due to the small number of patients (evaluation would not produce meaningful data).