Description:
Standard of care:
Treatment with Trastuzumab
Experimental:
21-Day Cycle of Combination therapy with T-DM1 intravenously on Day 1 and oral PD-0332991 on
Days 5-18
Study Design and Methodology:
This is a phase 1B inter-patient dose escalation study of PD-0332991 in combination with
T-DM1 in patients with recurrent or metastatic HER2-positive breast cancer after prior
trastuzumab or other HER2-directed therapies.
The subjects will be administered T-DM1 by intravenous infusion at 3.6 mg/kg for 90 minutes
on day 1 of each 21 day cycle. Infusion timing may vary from 30-90 minutes depending on how
well the subject tolerates the treatment.
A standard 3+3 trial design will be used for PD-0332991 dose escalation cohorts.The dosing of
PD-0332991 will be divided into 3 cohorts, the subjects will receive PD-0332991 on days 5-18
of each 21 day cycle.
Cohort 1 : PD-0332991 - 100 mg daily (oral) Cohort 2 : PD-0332991 - 150 mg daily (oral)
Cohort 3 : PD-0332991 - 200 mg daily (oral)
The 3+3 design entails that if one patient out of the first three patients has a DLT, up to
three additional patients will be entered at that dose level
Treatment cycles will continue until disease progression or withdrawal from study.
Title
- Brief Title: Phase 1b Study of PD-0332991 in Combination With T-DM1(Trastuzumab-DM1)
- Official Title: Phase 1B Study of PD-0332991 in Combination With T-DM1 in the Treatment of Patients With Advanced HER2 (Human Epidermal Growth Factor Receptor 2)-Positive Breast Cancer
Clinical Trial IDs
- ORG STUDY ID:
STU 042013-042
- NCT ID:
NCT01976169
Conditions
Interventions
| Drug | Synonyms | Arms |
|---|
| PD-0332991 and T-DM1 | KADCYLA=T-DM1, Palbociclib=PD-0332991 | PD-0332991 and T-DM1 |
Purpose
Standard of care:
Treatment with Trastuzumab
Experimental:
21-Day Cycle of Combination therapy with T-DM1 intravenously on Day 1 and oral PD-0332991 on
Days 5-18
Study Design and Methodology:
This is a phase 1B inter-patient dose escalation study of PD-0332991 in combination with
T-DM1 in patients with recurrent or metastatic HER2-positive breast cancer after prior
trastuzumab or other HER2-directed therapies.
The subjects will be administered T-DM1 by intravenous infusion at 3.6 mg/kg for 90 minutes
on day 1 of each 21 day cycle. Infusion timing may vary from 30-90 minutes depending on how
well the subject tolerates the treatment.
A standard 3+3 trial design will be used for PD-0332991 dose escalation cohorts.The dosing of
PD-0332991 will be divided into 3 cohorts, the subjects will receive PD-0332991 on days 5-18
of each 21 day cycle.
Cohort 1 : PD-0332991 - 100 mg daily (oral) Cohort 2 : PD-0332991 - 150 mg daily (oral)
Cohort 3 : PD-0332991 - 200 mg daily (oral)
The 3+3 design entails that if one patient out of the first three patients has a DLT, up to
three additional patients will be entered at that dose level
Treatment cycles will continue until disease progression or withdrawal from study.
Detailed Description
This is a phase 1B inter-patient dose escalation study of PD-0332991 in combination with
T--DM1 in patients with recurrent or metastatic HER2-positive breast cancer after prior
trastuzumab or other HER2-directed therapies. A standard 3+3 trial design will be used for
PD-0332991 dose escalation cohorts. The 3+3 design entails that if one patient out of the
first three patients has a dose-limiting toxicity (DLT), three additional patients will be
entered at that dose level. The PD-0332991 dose levels will start at 100 mg po daily; the
second cohort will receive 150mg po daily; the third cohort 200mg po daily. Patients receive
PD-0332991 on days 5-18 of each 21 day cycle. T-DM1 will be given intravenously at 3.6 mg/kg
on day 1 of each 21 day cycle.
Toxicity will be assessed using the Common Terminology Criteria of Adverse Events (CTCAE)
version 4.0 grading scale. Dose- limiting toxicity-DLT is defined as any drug-related grade 3
non-hematologic toxicity or grade 4 hematologic toxicity lasting >28 days after the last day
of therapy. If two patients experience drug-related DLT, the maximal tolerated dose (MTD) for
the combination in HER2-positive breast cancer patients has been exceeded, enrollment to that
dose will stop, and the next lower dose will be designated the MTD. An additional 15 patients
will be treated at the MTD or the maximal 200mg po daily PD-0332991 dose in combination with
T-DM1 to confirm safety. Treatment cycles will continue until disease progression or
withdrawal from study.
Study End-points:
1. To evaluate and assess Dose Limiting Toxicities (DLT).
2. To determine the toxicity profile.
3. To determine the clinical response rate.
4. To determine the duration of response.
5. To evaluate baseline HER2 positivity biomarkers by analyzing pretreatment tumor Ki67,
phospho-RB, cleaved caspase 3, phospho-histone H3, cycline E, MCM7, HER2, p27Kip1.
6. To evaluate post-treatment Ki67, phospho-RB, cleaved caspase 3, phospho-histone H3,
cyclin E, MCM7, HER2, p27Kip1, Rb, p16ink4c, CDK4, CDK6 in order to establish biomarker
response to treatment.
7. To evaluate pharmacokinetic (PK) parameters for PD-0332991 and T-DM1 including Cmax,
AUC, t1/2
Trial Arms
| Name | Type | Description | Interventions |
|---|
| PD-0332991 and T-DM1 | Experimental | The subjects will be administered T-DM1 by intravenous infusion at 3.6 mg/kg for 90 minutes on day 1 of each 21 day cycle. Infusion timing may vary from 30-90 minutes depending on how well the subject tolerates the treatment.
A standard 3+3 trial design will be used for PD-0332991 dose escalation cohorts.The dosing of PD-0332991 will be divided into 3 cohorts, the subjects will receive PD-0332991 on days 5-18 of each 21 day cycle.
Cohort 1 : PD-0332991 - 100 mg daily (oral) Cohort 2 : PD-0332991 - 150 mg daily (oral) Cohort 3 : PD-0332991 - 200 mg daily (oral) | |
Eligibility Criteria
Inclusion Criteria:
- 1.All subjects must be informed about the study and have signed a current IRB
(Institutional Review Board) approved informed consent.
2. All subjects must have recurrent or metastatic HER2-positive breast cancer.
diagnosed by biopsy.
3. All subjects must have previously received trastuzumab or other HER2 targeted
therapies.
4.Tumor must be HER2-positive and RB-proficient. RB (Retinoblastoma
protein)-proficiency is determined by tumor biopsy demonstrating RB normal and p16in4a
low by immunohistochemistry. RB proficiency means that there is an intact RB pathway
indicative of responsiveness to PD-0332991. RB staining is scored on an absent (no
nuclear staining), weak (nuclear staining less than observed in endothelial cells and
stromal cells surrounding the tumor), positive (nuclear staining at or above
surrounding tissue) (0, 0.5, 1 respectively). P16ink4a is a routine clinical stain
that is scored using absent, weak, positive, strong (0,1,2,3 respectively). Tumors
will be scored using [p16]/[RB], where a score of less than 3 is required for
inclusion. RB loss is expected to occur in less than 15% of cases.
5. Subjects must have a performance status of ≤ 2 on the ECOG (Eastern Cooperative
Oncology Group)Performance scale.
6. Subjects must have bilirubin <1.5 mg/dl, transaminases <2.5x upper limit of normal,
albumin >3gm/dl, creatinine <1.3mg/dl, adequate cardiac reserve (EF>50%), ANC
(Absolute neutrophil count) >1,000/mcL (microliter), and Platelets >100,000/mcL.
7. Must be willing to be treated at the University of Texas Southwestern Hospital,
University of Pennsylvania and affiliated clinics.
8. Subjects must be willing to use an approved form of birth control while on this
study and for 90 days after completion.
9. Age > 18 years. 10. Subject must be able to swallow capsules and have no surgical
or anatomic condition that will preclude the subject from swallowing and absorbing
oral medications on an ongoing basis.
Exclusion Criteria:
- 1. Chemotherapy, radiotherapy or hormonal therapy within 3 weeks ( 6 weeks for
nitrosoureas, mitomycin C or bevacizumab), or who have not recovered from the adverse
events to < grade 2 due to previous agents administered more than 4 weeks prior to
Study Day 1.
2. Subjects less than 4 weeks post major surgery. 3. Known active CNS metastases or
carcinomatous meningitis. Subjects with CNS (Central Nervous System) 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.
4. Known documented or suspected hypersensitivity to the components of the study
drug(s) or analogs.
5. Uncontrolled systemic illness, including but not limited to ongoing or active
infection.
6. Symptomatic congestive heart failure, unstable angina pectoris, stroke or
myocardial infarction within 3 months.
7. Baseline neuropathy >grade 1. 8. Known positive for human immunodeficiency virus
(HIV). Baseline HIV screening is not required.
9. Pregnant or breast-feeding subjects. 10. Subjects who are unable or unwilling to
abide by the study protocol or to cooperate fully with the investigator or designee.
| Maximum Eligible Age: | 90 Years |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Maximum Tolerated Dose (MTD) |
| Time Frame: | 42 days at the end of Cycle 2 |
| Safety Issue: | |
| Description: | A standard 3+3 trial design will be used for PD-0332991 dose escalation cohorts.The dosing of PD-0332991 will be divided into 3 cohorts, the subjects will receive PD-0332991 on days 5-18 of each 21 day cycle.
Cohort 1 : PD-0332991 - 100 mg daily (oral) Cohort 2 : PD-0332991 - 150 mg daily (oral) Cohort 3 : PD-0332991 - 200 mg daily (oral) |
Details
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Active, not recruiting |
| Lead Sponsor: | Barbara Haley |
Trial Keywords
- Breast Cancer
- Advanced Breast Cancer
Last Updated
January 12, 2021
