Phase 1B study of PD-0332991 in combination with T-DM1 in the treatment of patients with advanced HER2-positive breast cancer

Study ID
STU 042013-042

Cancer Related
Yes

Healthy Volunteers
No

Study Sites

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

Principal Investigator
Barbara Haley

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 [Greater Than]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-hisotone 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 pharmacokinectic (PK) parameters for PD-0332991 and T-DM1 including Cmax, auC, t1/2

Participant Eligibility

1.All subjects must be informed about the study and have signed a current IRB 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 and a taxane, separately or in combination and have received prior therapy for metastatic disease.
4.Tumor must be HER2-positive and RB-proficient. RB-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. RB-proficiency will be done locally as standard of care and made available for central review at later time points in the study.
5. Subjects must have a performance status of <= 2 on the ECOG 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 >=1,000/mcL, and Platelets >=100,000/mcL.
7. Subjects must be willing to use dual forms of contraception from the time of consent until 6 months after completion fo the study as TDM1 is known to be embryo-fetal toxic and palbociclib was found to be aneugenic in preclinical studies.
8. Age > 18 years.
9. 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.

10. Left ventricular ejection fraction (LVEF) must be within institutional limits of normal as assessed by ECHO or MUGA documented within four weeks prior to first dose of study drug. Adequate cardia reserve EF >= 50%
11. Patients must have a Hemoglobin >= 9 g/dL,

12. Patients must have a baseline QTc < 480 ms

13. Patients with measurable or non-measurable disease are eligible

All screening procedures must occur within 28 days before registration