Breast Cancer, Breast Cancer Stage, HER2-positive Breast Cancer, HER2 Positive Breast Carcinoma, Metastatic Breast Cancer, Recurrent Breast Cancer
Conditions
Keywords
Breast Cancer, HER2-positive, T-DM1, HER2-positive Breast Cancer, Recurrent Breast Cancer, Metastatic Breast Cancer
Brief summary
This is a single arm, phase II study to evaluate if the combination of T-DM1 with palbociclib improves progression-free survival in patients with metastatic HER2 positive breast cancer. All patients will be treated with T-DM1 with palbociclib.
Detailed description
This is a multi-center, single arm, phase II study of T-DM1 with palbociclib in the treatment of patients with metastatic HER2-positive breast cancer. Hypotheses: Combination of T-DM1 with palbociclib improves progression free survival Primary objective: Progression free survival of the combination of T-DM1 with palbociclib Secondary objectives i) Response rates ii) Overall survival Correlative objectives i) Investigate predictive biomarkers of response in blood and archived tumor tissue ii) Investigate mechanisms of resistance for palbociclib in blood and tumor tissue
Interventions
DRUGPalbociclib
Palbociclib is to be taken orally on days 5-18 (14 days) of each cycle (each cycle length is 21 days). The starting dose will be 125mg.
DRUGT-DM1
The recommended dose of T-DM1 is 3.6 mg/kg and is given as an intravenous infusion on Day 1 of every cycle (every 21 days).
Sponsors
Pfizer
University of Arizona
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Be informed of the investigational nature of the study and all pertinent aspects of the trial 2. Sign and provide written consent in accordance with institutional and federal guidelines. 3. ECOG Performance status of 0-2 4. Recurrent or metastatic HER2-positive breast cancer (HER2 positive is defined per ASCO-CAP guidelines) 5. Adequate cardiac reserve (EF≥50%) 6. Serum creatinine ≤ 1.5 x institutional upper limit of normal (IULN), bilirubin ≤ 2.0, and an SGOT/SGPT/alkaline phosphatase ≤ 2.0 x IULN 7. Adequate bone marrow function (ANC ≥1000, Platelets ≥100,000/ml, Hemoglobin ≥10gm/dL) 8. Be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other trial procedures 9. Been treated with pertuzumab previously (neoadjuvant or metastatic setting). Patients who weren't able to tolerate pertuzumab due to side effects can be eligible for study upon discussion with the study PI 10. No more than 2 lines of therapy in the metastatic disease setting
Exclusion criteria
1. HER2 negative tumors 2. Prior treatment with T-DM1 3. Prior treatment with CDK 4/6 inhibitors 4. Known active CNS metastases or carcinomatous meningitis. Patients with stable CNS metastases including brain metastases who have completed a course of radiotherapy are eligible for the study provided they are clinically stable. However, oral corticosteroids for control of CNS symptoms are not allowed on study 5. Known documented or suspected hypersensitivity to the components of the study drug(s) or analogs. 6. Uncontrolled systemic illness, including but not limited to ongoing or active infection 7. Symptomatic congestive heart failure, unstable angina pectoris, stroke or myocardial infarction within 3 months 8. Be pregnant or breast feeding. Female subjects must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of therapy. All female subjects with reproductive potential must have a negative pregnancy test (serum or urine) prior to enrollment and must agree to use effective contraception during the period of therapy 9. Concurrent hormonal or other anti-neoplastic therapy is not allowed. Patients can receive supportive therapy like bone-directed therapy including bisphosphonates or denosumab
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Estimate Progression-free Survival | Up to 4 years | Progression Free Survival (PFS) is defined as the time from date of first treatment to the date of investigator-determined objective disease progression as defined by Response Evaluation Criteria In Solid Tumors Criteria (RECIST) 1.1 or death from any cause. Per RECIST 1.1 for target lesions: Complete Response (CR) is the disappearance of all target lesions; Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; Progressive Disease (PD) is at least a 20% increase in the sum of diameters of target lesions; Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Patients who have neither progressed nor died will be censored at the day of their last radiographic tumor assessment (if available) or date of randomization if no post initiation (that is post baseline) radiographic assessment is available. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Response | Up to 4 years | Per RECIST 1.1 for target lesions: Complete Response (CR) is the disappearance of all target lesions; Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; Progressive Disease (PD) is at least a 20% increase in the sum of diameters of target lesions; Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Overall response rate (ORR) is defined as the proportion of patients with CR or PR per RECIST 1.1. Disease control rate (DCR) is defined as the proportion of patients with CR, PR or SD per RECIST 1.1. The data shown is the number of participants with ORR, DCR, CR, PR, PD, and SD. |
| Estimate Overall Survival | Up to 4 years | Estimate overall survival of T-DM1+Palbociclib treatment regimen. Overall survival (OS) is defined as the time from date of first treatment to date of death due to any cause. Patients last known to be alive are censored at their last contact date. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| T-DM1 With Palbociclib T-DM1 is given intravenously every 21 days (day 1 of each cycle) Palbociclib is administered orally on days 5-18 of each cycle
Palbociclib: Palbociclib is to be taken orally on days 5-18 (14 days) of each cycle (each cycle length is 21 days). The starting dose will be 125mg.
T-DM1: The recommended dose of T-DM1 is 3.6 mg/kg and is given as an intravenous infusion on Day 1 of every cycle (every 21 days). | 38 |
| Single Agent T-DM1 T-DM1 is given intravenously every 21 days (day 1 of each cycle)
T-DM1: The recommended dose of T-DM1 is 3.6 mg/kg and is given as an intravenous infusion on Day 1 of every cycle (every 21 days). | 14 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Excluded for not meeting eligibility criteria upon further review | 1 | 2 |
Baseline characteristics
| Characteristic | T-DM1 With Palbociclib | Single Agent T-DM1 | Total |
|---|---|---|---|
| Age, Continuous | 56.5 Years STANDARD_DEVIATION 12.6 | 57.8 Years STANDARD_DEVIATION 11.4 | 56.8 Years STANDARD_DEVIATION 12.2 |
| Bone Metastasis No | 22 Participants | 9 Participants | 31 Participants |
| Bone Metastasis Yes | 15 Participants | 5 Participants | 20 Participants |
| Central Nervous System (CNS) Metastases No | 7 Participants | 0 Participants | 7 Participants |
| Central Nervous System (CNS) Metastases Yes | 30 Participants | 14 Participants | 44 Participants |
| Current HER2+ Breast Cancer Diagnosis Metastatic | 37 Participants | 14 Participants | 51 Participants |
| Current HER2+ Breast Cancer Diagnosis Recurrent | 1 Participants | 0 Participants | 1 Participants |
| Estrogen Receptor (ER) Status Negative | 25 Participants | 9 Participants | 34 Participants |
| Estrogen Receptor (ER) Status Positive | 13 Participants | 5 Participants | 18 Participants |
| Menopausal Status Post-Menopausal | 25 Participants | 12 Participants | 37 Participants |
| Menopausal Status Pre-Menopausal | 10 Participants | 1 Participants | 11 Participants |
| Menopausal Status Surgical Menopause | 3 Participants | 1 Participants | 4 Participants |
| Pertuzumab Prior to Study No | 11 Participants | 4 Participants | 15 Participants |
| Pertuzumab Prior to Study Yes | 27 Participants | 10 Participants | 37 Participants |
| Prior Treatment Lines in Metastatic Setting 0 | 13 Participants | 4 Participants | 17 Participants |
| Prior Treatment Lines in Metastatic Setting 1 | 14 Participants | 3 Participants | 17 Participants |
| Prior Treatment Lines in Metastatic Setting 2 | 8 Participants | 6 Participants | 14 Participants |
| Prior Treatment Lines in Metastatic Setting 3 | 3 Participants | 1 Participants | 4 Participants |
| Progesterone Receptor (PR) Status Negative | 20 Participants | 5 Participants | 25 Participants |
| Progesterone Receptor (PR) Status Positive | 18 Participants | 9 Participants | 27 Participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian or Pacific Islander | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Black | 4 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized Hispanic | 4 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 24 Participants | 10 Participants | 34 Participants |
| Region of Enrollment United States | 38 participants | 14 participants | 52 participants |
| Sex: Female, Male Female | 38 Participants | 14 Participants | 52 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 38 | 4 / 14 |
| other Total, other adverse events | 38 / 38 | 14 / 14 |
| serious Total, serious adverse events | 8 / 38 | 3 / 14 |
Outcome results
Primary
Estimate Progression-free Survival
Progression Free Survival (PFS) is defined as the time from date of first treatment to the date of investigator-determined objective disease progression as defined by Response Evaluation Criteria In Solid Tumors Criteria (RECIST) 1.1 or death from any cause. Per RECIST 1.1 for target lesions: Complete Response (CR) is the disappearance of all target lesions; Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; Progressive Disease (PD) is at least a 20% increase in the sum of diameters of target lesions; Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Patients who have neither progressed nor died will be censored at the day of their last radiographic tumor assessment (if available) or date of randomization if no post initiation (that is post baseline) radiographic assessment is available.
Time frame: Up to 4 years
Population: Number of patients included for PFS analysis:~T-DM1 with Palbociclib Arm: n=36 T-DM1 Arm: n=11~5 patients lack data on response because they discontinued study participation (or withdrew consent) before the first scan. Thus, the final sample size for responses is n = 47.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| T-DM1 With Palbociclib | Estimate Progression-free Survival | 16.9 Months |
| Single Agent T-DM1 | Estimate Progression-free Survival | 8.3 Months |
Secondary
Estimate Overall Survival
Estimate overall survival of T-DM1+Palbociclib treatment regimen. Overall survival (OS) is defined as the time from date of first treatment to date of death due to any cause. Patients last known to be alive are censored at their last contact date.
Time frame: Up to 4 years
Population: We used date of study discontinuation as the censoring date for patients excluded from the survival follow-up file. There are not enough deaths recorded to calculate median OS in the T-DM1 only arm (nor the upper bound of the confidence interval for the T-DM1 + Palbociclib arm).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| T-DM1 With Palbociclib | Estimate Overall Survival | 35.1 Months |
| Single Agent T-DM1 | Estimate Overall Survival | NA Months |
Secondary
Number of Participants With Response
Per RECIST 1.1 for target lesions: Complete Response (CR) is the disappearance of all target lesions; Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; Progressive Disease (PD) is at least a 20% increase in the sum of diameters of target lesions; Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Overall response rate (ORR) is defined as the proportion of patients with CR or PR per RECIST 1.1. Disease control rate (DCR) is defined as the proportion of patients with CR, PR or SD per RECIST 1.1. The data shown is the number of participants with ORR, DCR, CR, PR, PD, and SD.
Time frame: Up to 4 years
Population: 5 patients lack data on response because they discontinued study participation (or withdrew consent) before the first scan and 1 additional patient died before the first scan. Thus, the final sample size for responses is n = 46 (T-DM1 only: n = 11; T-DM1 + Palbociclib: n = 35).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| T-DM1 With Palbociclib | Number of Participants With Response | Overall Response Rate | 15 Participants |
| T-DM1 With Palbociclib | Number of Participants With Response | Disease Control Rate | 30 Participants |
| T-DM1 With Palbociclib | Number of Participants With Response | Partial Response | 12 Participants |
| T-DM1 With Palbociclib | Number of Participants With Response | Stable Disease | 15 Participants |
| T-DM1 With Palbociclib | Number of Participants With Response | Progressive Disease | 5 Participants |
| T-DM1 With Palbociclib | Number of Participants With Response | Complete Response | 3 Participants |
| Single Agent T-DM1 | Number of Participants With Response | Partial Response | 2 Participants |
| Single Agent T-DM1 | Number of Participants With Response | Overall Response Rate | 2 Participants |
| Single Agent T-DM1 | Number of Participants With Response | Progressive Disease | 4 Participants |
| Single Agent T-DM1 | Number of Participants With Response | Disease Control Rate | 7 Participants |
| Single Agent T-DM1 | Number of Participants With Response | Complete Response | 0 Participants |
| Single Agent T-DM1 | Number of Participants With Response | Stable Disease | 5 Participants |