Breast Cancer, HER-2 Positive Breast Cancer, Stage II Breast Cancer, Stage III Breast Cancer
Conditions
Brief summary
This research study is studying a combination of drugs as a possible treatment for breast cancer that has tested positive for a protein called HER2. The names of the study interventions involved in this study are: * Trastuzumab emtansine (also called T-DM1) * Pertuzumab
Detailed description
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied. The FDA (the U.S. Food and Drug Administration) has not approved T-DM1 for pre-operative use in breast cancer but it has been approved for other uses in breast cancer. The FDA has approved pertuzumab as a pre-operative treatment.
Interventions
DRUGT-DM1
Neoadjuvant treatment is for a total of 18 weeks.
DRUGPertuzumab
Neoadjuvant treatment is for a total of 18 weeks.
PROCEDUREExcision of tumor/mastectomy
Definitive breast cancer surgery (excision or mastectomy) marks the end of protocol mandated therapy.
Sponsors
Dana-Farber Cancer Institute
Genentech, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have HER2-positive Stage II or III histologically confirmed invasive carcinoma of the breast. A minimum tumor size of 2 cm determined by physical exam or imaging is required. * HER-2 positive, confirmed by central testing (Clarient labs): IHC 3+ and/or FISH positive based on one of the three following criteria: * Single-probe average HER2 copy number≥6.0 signals/cell OR * Dual-probe HER2/CEP17 \<2.0 with an average HER2 copy number ≥6.0 signals/cell OR * Dual-probe HER2/CEP17 ratio ≥2.0 * ER/PR determination is required. * Bilateral breast cancers are allowed if both cancers are HER2-positive. * Patients with multifocal or multicentric disease are eligible as long as one area meets eligibility criteria. * Breast imaging should include the ipsilateral axilla. For subjects with a clinically negative axilla, a sentinel lymph node biopsy will be performed either before or after preoperative therapy at the discretion of the subject's physicians. For subjects with a clinically positive axilla, a needle aspiration, core biopsy or SLN procedure will be performed to determine the presence of metastatic disease in the lymph nodes. * Men and women (with any menopausal status) ≥ 18 years of age * ECOG performance status 0 or 1 * Required laboratory values: * ANC ≥1500/mm3 * Hemoglobin ≥ 9 g/dl * Platelets ≥100,000/mm3 * Serum creatinine \< 1.5 X ULN (institutional) * Total bilirubin ≤ 1.0 X ULN (institutional) For patients with Gilbert syndrome, the direct bilirubin should be within the institutional normal range. * AST and ALT ≤ 1.5x ULN (institutional) * Alkaline phosphatase ≤1.5x ULN (institutional) * Documentation of hepatitis B virus (HBV) and hepatitis C virus (HCV) serologies is required: this includes hepatitis B surface antigen (HBsAg) and/or total hepatitis B core antibody (HBcAb) in addition to HCV antibody testing. * Only for patients who test positive for hep B/C virus: PTT/INR \< ULN (institutional) * Left ventricular ejection fraction (LVEF) ≥ 55% * Premenopausal women must have a negative serum pregnancy test, including women who have had a tubal ligation and for women less than 12 months after the onset of menopause. * Women of childbearing potential and men with partners of childbearing potential must be willing to use one highly effective form of non-hormonal contraception or two effective forms of non-hormonal contraception by the patient and/or partner and continue its use for the duration of the study treatment and for 7 months after the last dose of study treatment. * Potent CYP3A4 inhibitors, such as ketoconazole and erythromycin, should be avoided during the study treatment period with T-DM1. * Excessive alcohol intake should be avoided (occasional use is permitted). * Patients with a history of ipsilateral DCIS are eligible. * Patients undergoing breast conservation therapy (i.e. lumpectomy) must not have any contraindications to radiation therapy. * Willing and able to sign informed consent. * Willing to provide tissue for research purposes.
Exclusion criteria
* Pregnant or nursing women due to the teratogenic potential of the study drugs. * Active, unresolved infection. * Receipt of intravenous antibiotics for infection within 7 days prior to enrollment. * Patients with active liver disease, for example, due to hepatitis B virus, hepatitis C virus, autoimmune hepatic disorder, or sclerosing cholangitis. * Uncontrolled hypertension (systolic \>180 mm Hg and/or diastolic \>100 mm Hg) or clinically significant (i.e. active) cardiovascular disease: cerebrovascular accident/stroke or myocardial infarction within 6 months prior to first study medication, unstable angina, congestive heart failure (CHF) of New York Heart Association (NYHA) Grade II or higher, or serious cardiac arrhythmia requiring medication. * Significant symptoms (Grade ≥2) peripheral neuropathy. * Other concurrent serious diseases that may interfere with planned treatment, including severe pulmonary conditions/illness, uncontrolled infections, uncontrolled diabetes. * Any prior treatment for the current breast cancer, including chemotherapy, hormonal therapy, radiation or experimental therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Pathologic Complete Response (pCR) by HER2 Amplification Status Non-Heterogeneous | Evaluate upon completion of breast surgery, up to approximately 24 weeks from study enrollment. | The rate of pCR is the percentage of participants with Residual Cancer Burden (RCB)=0 as defined by established guidelines (Symmans et al. JCO 2007; M.D Anderson http://www.mdanderson.org/breastcancer\_RCB). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Pathologic Complete Response (pCR) | Evaluate upon completion of breast surgery, up to approximately 24 weeks from study enrollment. | The rate of pCR is the percentage of participants with Residual Cancer Burden (RCB)=0 as defined by established guidelines (Symmans et al. JCO 2007; M.D Anderson http://www.mdanderson.org/breastcancer\_RCB). |
| Hormone Receptor (HR) Status by HER2 Amplification Status | Day 0 (baseline/at study entry) | HR status classified by estrogen receptor (ER) and/or progesterone receptor (ER) positive versus ER negative and PR negative determined by immunohistochemical methods according to the local institution's standard protocol. |
| Median Disease-Free Survival | Post-surgery follow-up of disease and survival occurs every 6 months for 5 years and annually until year 10. | Disease-free survival (DFS) based on the Kaplan-Meier method is defined as the duration of time from study entry to the occurrence of the first of the following events: local/regional recurrence, contralateral invasive breast cancer, distant recurrence or death from any cause. In situ cancer is not included as DFS event. Participants alive without an event are censored at date of last disease assessment. |
| Median Overall Survival | Post-surgery follow-up of disease and survival occurs every 6 months for 5 years and annually until year 10. | Overall survival (OS) based on Kaplan-Meier methods is defined as the interval from the date of registration to death from any cause. Patients are censored at date last known alive. |
| Clinical Response Rate (Complete Response) | Evaluate upon completion of neoadjuvant therapy, up to approximately 18 weeks from study enrollment. | Clinical response rate was defined as the percentage of participants achieving complete response (CR) based on RECIST 1.1 criteria on treatment up to surgery. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions |
| Clinical Response Rate (Partial Response) | Evaluate upon completion of neoadjuvant therapy, up to approximately 18 weeks from study enrollment. | Clinical response rate was defined as the percentage of participants achieving partial response (PR) based on RECIST 1.1 criteria on treatment up to surgery. Per RECIST 1.1 for target lesions: PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. |
| Number of Participants With a Dose Reduction | Evaluate upon completion of neoadjuvant therapy, up to approximately 18 weeks from study enrollment. | Number of participants with ever having dose reduction on neoadjuvant therapy up to surgery. |
| Treatment-Emergent Fatigue Rate | Adverse events are assessed every cycle of neoadjuvant therapy prior to surgery, up to approximately 18 weeks (6 cycles) from study enrollment. | Treatment-emergent fatigue rate is the percentage of participants who experienced grade 1-2 fatigue based on the Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0 as reported on the adverse event case report form. CTCAE severity scale ranges from 0 (none) to 5 (death): Grade 1=mild and Grade 2=moderate. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATOROtto Metzger, MD
Dana-Farber Cancer Institute
Participant flow
Recruitment details
Patients were enrolled from January 2015 to January 2018.
Participants by arm
| Arm | Count |
|---|---|
| T-DM1 and Pertuzumab T-DM1 3.6 mg per kg of body weight via IV every 3 weeks for 6 doses and Pertuzumab loading dose of 840 mg via IV on Cycle 1 Day 1 followed by maintenance dose of 420 mg via IV every 3 weeks for 6 doses. Excision of tumor/mastectomy of biopsy residual tumor within 42 days of the last cycle of therapy. | 163 |
| Total | 163 |
Baseline characteristics
| Characteristic | T-DM1 and Pertuzumab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 32 Participants |
| Age, Categorical Between 18 and 65 years | 131 Participants |
| Clinical Stage Stage 1 | 1 Participants |
| Clinical Stage Stage 2 | 138 Participants |
| Clinical Stage Stage 3 | 24 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 147 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 15 Participants |
| HER2 Amplification Status Heterogenous | 16 Participants |
| HER2 Amplification Status Missing | 6 Participants |
| HER2 Amplification Status Non-Heterogenous | 141 Participants |
| HER-2 results by IHC (central confirmation) 2+ | 40 Participants |
| HER-2 results by IHC (central confirmation) 3+ | 121 Participants |
| HER-2 results by IHC (central confirmation) Unknown | 2 Participants |
| Histologic Grade Grade 1 | 3 Participants |
| Histologic Grade Grade 2 | 56 Participants |
| Histologic Grade Grade 3 | 103 Participants |
| Histologic Grade Missing | 1 Participants |
| Hormone Receptor Status ER+ and/or PR+ | 112 Participants |
| Hormone Receptor Status ER- and PR- | 41 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 10 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race (NIH/OMB) White | 139 Participants |
| Region of Enrollment United States | 163 participants |
| Sex: Female, Male Female | 163 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 163 |
| other Total, other adverse events | 162 / 163 |
| serious Total, serious adverse events | 11 / 163 |
Outcome results
Primary
Rate of Pathologic Complete Response (pCR) by HER2 Amplification Status Non-Heterogeneous
The rate of pCR is the percentage of participants with Residual Cancer Burden (RCB)=0 as defined by established guidelines (Symmans et al. JCO 2007; M.D Anderson http://www.mdanderson.org/breastcancer\_RCB). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: Evaluate upon completion of breast surgery, up to approximately 24 weeks from study enrollment.
Population: Patients treated with at least one dose of T-DM1 and Pertuzumab and evaluable (with invasive disease present on the research core biopsy for evaluation of HER-2 heterogeneity by central pathology evaluation).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Heterogeneous HER2 Amplification Status | Rate of Pathologic Complete Response (pCR) by HER2 Amplification Status Non-Heterogeneous | 0 percentage of participants |
| Non-Heterogeneous HER2 Amplification Status | Rate of Pathologic Complete Response (pCR) by HER2 Amplification Status Non-Heterogeneous | 54.6 percentage of participants |
Comparison: By estimating that the overall pCR with T-DM1 plus pertuzumab would be approximately 40%, and 20% of the population classified as heterogeneous, the study would have 80% power with 136 evaluable patients to detect a difference in pCR of 44.9% in the non-heterogenous versus 20.3% in the heterogenous subgroup. The study had a 90% power to detect difference in pCR of 43.4% in the non-heterogenous versus 8.8% in the heterogenous subgroup if the observed prevalence of HER2 heterogeneity was 10%.p-value: <0.001Mantel Haenszel
Secondary
Clinical Response Rate (Complete Response)
Clinical response rate was defined as the percentage of participants achieving complete response (CR) based on RECIST 1.1 criteria on treatment up to surgery. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions
Time frame: Evaluate upon completion of neoadjuvant therapy, up to approximately 18 weeks from study enrollment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Heterogeneous HER2 Amplification Status | Clinical Response Rate (Complete Response) | 62 Participants |
Secondary
Clinical Response Rate (Partial Response)
Clinical response rate was defined as the percentage of participants achieving partial response (PR) based on RECIST 1.1 criteria on treatment up to surgery. Per RECIST 1.1 for target lesions: PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD.
Time frame: Evaluate upon completion of neoadjuvant therapy, up to approximately 18 weeks from study enrollment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Heterogeneous HER2 Amplification Status | Clinical Response Rate (Partial Response) | 69 Participants |
Secondary
Hormone Receptor (HR) Status by HER2 Amplification Status
HR status classified by estrogen receptor (ER) and/or progesterone receptor (ER) positive versus ER negative and PR negative determined by immunohistochemical methods according to the local institution's standard protocol.
Time frame: Day 0 (baseline/at study entry)
Population: Patients treated with at least one dose of T-DM1 and Pertuzumab and evaluable (with invasive disease present on the research core biopsy for evaluation of HER-2 heterogeneity by central pathology evaluation).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Heterogeneous HER2 Amplification Status | Hormone Receptor (HR) Status by HER2 Amplification Status | HR-positive | 13 Participants |
| Heterogeneous HER2 Amplification Status | Hormone Receptor (HR) Status by HER2 Amplification Status | HR-negative | 3 Participants |
| Non-Heterogeneous HER2 Amplification Status | Hormone Receptor (HR) Status by HER2 Amplification Status | HR-positive | 96 Participants |
| Non-Heterogeneous HER2 Amplification Status | Hormone Receptor (HR) Status by HER2 Amplification Status | HR-negative | 45 Participants |
Secondary
Median Disease-Free Survival
Disease-free survival (DFS) based on the Kaplan-Meier method is defined as the duration of time from study entry to the occurrence of the first of the following events: local/regional recurrence, contralateral invasive breast cancer, distant recurrence or death from any cause. In situ cancer is not included as DFS event. Participants alive without an event are censored at date of last disease assessment.
Time frame: Post-surgery follow-up of disease and survival occurs every 6 months for 5 years and annually until year 10.
Secondary
Median Overall Survival
Overall survival (OS) based on Kaplan-Meier methods is defined as the interval from the date of registration to death from any cause. Patients are censored at date last known alive.
Time frame: Post-surgery follow-up of disease and survival occurs every 6 months for 5 years and annually until year 10.
Secondary
Number of Participants With a Dose Reduction
Number of participants with ever having dose reduction on neoadjuvant therapy up to surgery.
Time frame: Evaluate upon completion of neoadjuvant therapy, up to approximately 18 weeks from study enrollment.
Population: Patients treated with at least one dose of T-DM1 and Pertuzumab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Heterogeneous HER2 Amplification Status | Number of Participants With a Dose Reduction | 18 Participants |
Secondary
Rate of Pathologic Complete Response (pCR)
The rate of pCR is the percentage of participants with Residual Cancer Burden (RCB)=0 as defined by established guidelines (Symmans et al. JCO 2007; M.D Anderson http://www.mdanderson.org/breastcancer\_RCB).
Time frame: Evaluate upon completion of breast surgery, up to approximately 24 weeks from study enrollment.
Population: Patients treated with at least one dose of T-DM1 and Pertuzumab and evaluable (with invasive disease present on the research core biopsy for evaluation of HER-2 heterogeneity by central pathology evaluation).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Heterogeneous HER2 Amplification Status | Rate of Pathologic Complete Response (pCR) | 49.0 percentage of participants |
Secondary
Treatment-Emergent Fatigue Rate
Treatment-emergent fatigue rate is the percentage of participants who experienced grade 1-2 fatigue based on the Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0 as reported on the adverse event case report form. CTCAE severity scale ranges from 0 (none) to 5 (death): Grade 1=mild and Grade 2=moderate.
Time frame: Adverse events are assessed every cycle of neoadjuvant therapy prior to surgery, up to approximately 18 weeks (6 cycles) from study enrollment.
Population: Patients treated with at least one dose of T-DM1 and Pertuzumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Heterogeneous HER2 Amplification Status | Treatment-Emergent Fatigue Rate | 76.1 percentage of participants |