Clinical Trials /

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

NCT03774472

Description:

This phase I/II trial studies the side effects and best dose of hydroxychloroquine when given together with palbociclib and letrozole before surgery in treating participants with estrogen receptor positive, HER2 negative breast cancer. Hydroxychloroquine is a substance that decreases immune responses in the body. Palbociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Estrogen can cause the growth of breast cancer cells. Drugs, such as letrozole, may lessen the amount of estrogen made by the body. Giving hydroxychloroquine, palbociclib, and letrozole before surgery may work better in treating participants with breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Hydroxychloroquine, Palbociclib, and Letrozole Before Surgery in Treating Participants With Estrogen Receptor Positive, HER2 Negative Breast Cancer
  • Official Title: Phase I/II Safety and Efficacy Study of Autophagy Inhibition With Hydroxychloroquine to Augment the Antiproliferative and Biological Effects of Pre-Operative Palbociclib Plus Letrozole for Estrogen Receptor-Positive and HER2-Negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: 2017-0071
  • SECONDARY ID: NCI-2018-01050
  • SECONDARY ID: 2017-0071
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03774472

Conditions

  • Anatomic Stage I Breast Cancer AJCC v8
  • Anatomic Stage IA Breast Cancer AJCC v8
  • Anatomic Stage IB Breast Cancer AJCC v8
  • Anatomic Stage II Breast Cancer AJCC v8
  • Anatomic Stage IIA Breast Cancer AJCC v8
  • Anatomic Stage IIB Breast Cancer AJCC v8
  • Anatomic Stage III Breast Cancer AJCC v8
  • Anatomic Stage IIIA Breast Cancer AJCC v8
  • Anatomic Stage IIIB Breast Cancer AJCC v8
  • Anatomic Stage IIIC Breast Cancer AJCC v8
  • Anatomic Stage IV Breast Cancer AJCC v8
  • Estrogen Receptor Positive
  • HER2/Neu Negative
  • MKI67 Positive
  • Postmenopausal
  • Prognostic Stage I Breast Cancer AJCC v8
  • Prognostic Stage IA Breast Cancer AJCC v8
  • Prognostic Stage IB Breast Cancer AJCC v8
  • Prognostic Stage IIA Breast Cancer AJCC v8
  • Prognostic Stage IIB Breast Cancer AJCC v8
  • Prognostic Stage III Breast Cancer AJCC v8
  • Prognostic Stage IIIA Breast Cancer AJCC v8
  • Prognostic Stage IIIB Breast Cancer AJCC v8
  • Prognostic Stage IIIC Breast Cancer AJCC v8
  • Prognostic Stage IV Breast Cancer AJCC v8

Interventions

DrugSynonymsArms
HydroxychloroquineTreatment (hydroxychloroquine, palbociclib, letrozole)
LetrozoleCGS 20267, FemaraTreatment (hydroxychloroquine, palbociclib, letrozole)
PalbociclibIbrance, PD-0332991, PD-332991Treatment (hydroxychloroquine, palbociclib, letrozole)

Purpose

This phase I/II trial studies the side effects and best dose of hydroxychloroquine when given together with palbociclib and letrozole before surgery in treating participants with estrogen receptor positive, HER2 negative breast cancer. Hydroxychloroquine is a substance that decreases immune responses in the body. Palbociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Estrogen can cause the growth of breast cancer cells. Drugs, such as letrozole, may lessen the amount of estrogen made by the body. Giving hydroxychloroquine, palbociclib, and letrozole before surgery may work better in treating participants with breast cancer.

Detailed 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 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (hydroxychloroquine, palbociclib, letrozole)ExperimentalPHASE I: Participants with advanced, metastatic (stage IV) breast cancer receive hydroxychloroquine PO 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 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.
  • Hydroxychloroquine
  • Letrozole
  • Palbociclib

Eligibility Criteria

        Inclusion Criteria:

          -  Signed written informed consent

          -  Diagnosis of estrogen positive breast cancer, estrogen receptor-positive and
             HER2-negative by American Society of Clinical Oncology (ASCO)/College of American
             Pathologists (CAP) criteria

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1

          -  Postmenopausal defined by: a. Age >= 55 years and 1 year or more of amenorrhea b. Age
             < 55 years and 1 year or more of amenorrhea with luteinizing hormone (LH) and/or
             follicle stimulating hormone (FSH) levels in the postmenopausal range c. Age < 55 with
             prior hysterectomy but intact ovaries with LH and/or FSH levels in the postmenopausal
             range d. Chemotherapy or medically induced ovarian suppression with 1 year or more of
             amenorrhea and with LH and/or FSH levels in the postmenopausal range e. Status after
             bilateral oophorectomy (>= 28 days prior to first study treatment)

          -  Absolute neutrophil count (ANC) >= 1500 cells/ul

          -  Platelet count >= 100,000/ul

          -  Serum creatinine concentration < 1.5 x upper limit of normal (ULN)

          -  Bilirubin level < 1.5 x ULN

          -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x ULN

          -  Alkaline phosphatase =< 2.5 ULN

          -  Metastatic cohorts (Phase I): Diagnosis of stage IV estrogen positive breast cancer,
             estrogen receptor-positive and HER2-negative by American Society of Clinical Oncology
             (ASCO)/College of American Pathologists (CAP) criteria

          -  Metastatic cohorts (Phase I): Must be a candidate for treatment with CDK4/6 inhibitor
             and hormonal therapy with an aromatase inhibitor as standard of care

          -  Metastatic cohorts (Phase I): No prior exposure to CDK 4/6 inhibitors

          -  Neoadjuvant cohorts (Phase II): Diagnosis of stage I-III estrogen positive breast
             cancer, estrogen receptor-positive and HER2-negative by ASCO/CAP criteria. If stage I,
             clinical tumor size must be >= 1.5 cm

          -  Neoadjuvant cohorts (Phase II): Baseline tumor Ki67 > 5%

          -  Neoadjuvant cohorts (Phase II): Surgical candidate and appropriate for pre-operative
             endocrine therapy

        Exclusion Criteria:

          -  Prior exposure to CDK 4/6 inhibitor therapy

          -  History of retinal disease or active visual disturbances (normal baseline
             study-specified retinal exam required)

          -  Acute illness, including infections requiring medical therapy, known bleeding
             diathesis or need for anticoagulation

          -  Treatment with any of the following medications within 4 weeks before the baseline
             diagnostic biopsy is taken: a. Oral estrogens, including hormone replacement therapy
             (but prior depot estrogen use not allowed). b. Investigational agents (or 5
             half-lives, whichever is longer)

          -  Required concomitant use of any drug that is a strong CYP3A inhibitor or inducer

          -  Psychological, familial, sociological or geographical conditions that do not permit
             compliance with the study protocol

          -  Life expectancy of less than 6 months

          -  Pregnancy, lactation or planning to be pregnant.

          -  Neo-adjuvant cohorts (Phase II): Prior therapy for breast cancer (medical, surgical or
             radiation therapy)

          -  Neo-adjuvant cohorts (Phase II): Clinical T4 disease

          -  Neo-adjuvant cohorts (Phase II): Inoperable or metastatic breast cancer based on
             standard evaluation
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events (Phase I)
Time Frame:Up to 30 days post-treatment
Safety Issue:
Description:Assessed continuously using Common Terminology Criteria for Adverse Events version 4.03, with physical examination and laboratory assessments.

Secondary Outcome Measures

Measure:Longer term clinical tumor responsiveness (tumor volume) (Phase II Part I)
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Blood-based tumor protein, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) biomarkers (Phase II Part I and II)
Time Frame:Up to 1 year
Safety Issue:
Description:Will perform exploratory studies on blood-based tumor protein, DNA and RNA biomarkers with a focus on pathways of cell proliferation, autophagy, senescence and cell cycle control.
Measure:Breast tumor indices of proliferation, autophagy, senescence, cell cycle control and other intersecting pathways (Phase II Part II)
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Dose responsiveness hydroxychloroquine (400 mg versus recommended phase 2 dose) (Phase II Part II)
Time Frame:Up to 1 year
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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