Phase 1b Study of PD-0332991 in Combination With T-DM1(Trastuzumab-DM1)

Study ID
042013-042

Cancer Related
Yes

Healthy Volunteers
No

Study Sites

  • Clements University Hospital
  • UT Southwestern Ambulatory Services
  • Zale Lipshy University Hospital
  • Parkland Health & Hospital System

Contact
Joyce Bolluyt
214/648-7007
joyce.bolluyt@utsouthwestern.edu

Principal Investigator
Barbara Haley

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

Brief Overview


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.

Summary


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

Participant Eligibility


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.