Hydroxychloroquine, Palbociclib, and Letrozole Before Surgery in Treating Participants With Estrogen Receptor Positive, HER2 Negative Breast Cancer

Summary

Participation Requirements

Description

PRIMARY OBJECTIVES: I. To determine the safety of adding hydroxychloroquine (HCQ) to continuous low dose palbociclib and letrozole and to determine the recommended phase II dose (RP2D) for hydroxychloroquine (HCQ) for the subsequent Phase II study. (Phase I) II. To determine the dose responsiveness ...

PRIMARY OBJECTIVES: I. To determine the safety of adding hydroxychloroquine (HCQ) to continuous low dose palbociclib and letrozole and to determine the recommended phase II dose (RP2D) for hydroxychloroquine (HCQ) for the subsequent Phase II study. (Phase I) II. To determine the dose responsiveness of 2 dose levels (400 mg and recommended phase II dose [RP2D]) of hydroxychloroquine added to low dose palbociclib and letrozole on pre and post HCQ breast tumor proliferation index (Ki67), autophagy, senescence and cell cycle control. (Phase II, Part I) III. To determine whether hydroxychloroquine added to low dose palbociclib and letrozole can increase the proportion of patients whose tumors achieve complete cell cycle arrest (CCCA, defined as the Ki67 =< 2.7%) comparing T2 to T1. (Phase II, Part II) SECONDARY OBJECTIVES: I. To determine the response rate and clinical benefit rate at 8 weeks of the assigned dose of hydroxychloroquine (HCQ) plus continuous low dose palbociclib and letrozole. (Phase I) II. Determine longer term clinical tumor responsiveness (tumor volume) and tumor biomarker indices (for patients who have extended pre-operative therapy, maximum 24 weeks). (Phase II, Part I) III. Perform exploratory studies on blood-based tumor protein, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) biomarkers with a focus on pathways of cell proliferation, autophagy, senescence and cell cycle control. (Phase II, Part I) IV. To determine the impact of adding hydroxychloroquine to low dose palbociclib and letrozole on breast tumor indices of proliferation, autophagy, senescence, cell cycle control and other intersecting pathways. (Phase II, Part II) V. Determine longer term clinical tumor responsiveness and tumor biomarkers indices (for patients who have extended pre-operative therapy, maximum 24 weeks). (Phase II, Part II) VI. To determine the dose responsiveness of HCQ (400 mg vs. RP2D) on the primary (proportion with CCCA) and secondary clinical/biological endpoints. (Phase II, Part II) VII. To perform exploratory studies on blood-based tumor protein, DNA and RNA biomarkers. (Phase II, Part II) VIII. Obtain additional safety information for the combination of low dose palbociclib, letrozole and hydroxychloroquine. (Phase II, Part II) OUTLINE: This is a phase I, dose-escalation study of hydroxychloroquine followed by a phase II study. PHASE I: Participants with advanced, metastatic (stage IV) breast cancer receive hydroxychloroquine orally (PO) once daily (QD), palbociclib PO QD, and letrozole PO QD on days 1-28. Courses repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. PHASE II: Participants with early stage (stage I-III) breast cancer receive hydroxychloroquine PO QD on days 15-28 of course 1 and on days 1-28 of subsequent courses. Participants also receive palbociclib PO QD, and letrozole PO QD on days 1-28, followed by standard of care surgery at week 5. If there is a proliferative benefit with complete cell cycle arrest (CCCA) by biopsy at 4 weeks, courses may repeat every 28 days for up to 20-24 weeks in the absence of disease progression or unacceptable toxicity, followed by standard of care surgery during weeks 20-24. After completion of study treatment, participants are followed up within 30 days or every 4 weeks.

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