<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03774472</url>
  </required_header>
  <id_info>
    <org_study_id>2017-0071</org_study_id>
    <secondary_id>NCI-2018-01050</secondary_id>
    <secondary_id>2017-0071</secondary_id>
    <nct_id>NCT03774472</nct_id>
  </id_info>
  <brief_title>Hydroxychloroquine, Palbociclib, and Letrozole Before Surgery in Treating Patients With Estrogen Receptor Positive, HER2 Negative Breast Cancer</brief_title>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>M.D. Anderson Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>M.D. Anderson Cancer Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase I/II trial studies the side effects and best dose of hydroxychloroquine when given&#xD;
      together with palbociclib and letrozole before surgery in treating patients with estrogen&#xD;
      receptor positive, HER2 negative breast cancer. Hydroxychloroquine is a substance that&#xD;
      decreases immune responses in the body. Palbociclib may stop the growth of tumor cells by&#xD;
      blocking some of the enzymes needed for cell growth. Estrogen can cause the growth of breast&#xD;
      cancer cells. Drugs, such as letrozole, may lessen the amount of estrogen made by the body.&#xD;
      Giving hydroxychloroquine, palbociclib, and letrozole before surgery may work better than&#xD;
      palbociclib and letrozole in treating patients with breast cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To determine the safety of adding hydroxychloroquine (HCQ) to continuous low dose&#xD;
      palbociclib and letrozole and to determine the recommended phase II dose (RP2D) for&#xD;
      hydroxychloroquine (HCQ) for the subsequent Phase II study. (Phase I) II. To determine the&#xD;
      dose responsiveness of 2 dose levels (400 mg and recommended phase II dose [RP2D]) of&#xD;
      hydroxychloroquine added to low dose palbociclib and letrozole on pre and post HCQ breast&#xD;
      tumor proliferation index (Ki67), autophagy, senescence and cell cycle control. (Phase II,&#xD;
      Part I) III. To determine whether hydroxychloroquine added to low dose palbociclib and&#xD;
      letrozole can increase the proportion of patients whose tumors achieve complete cell cycle&#xD;
      arrest (CCCA, defined as the Ki67 =&lt; 2.7%) comparing T2 to T1. (Phase II, Part II)&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To determine the response rate and clinical benefit rate at 8 weeks of the assigned dose&#xD;
      of hydroxychloroquine (HCQ) plus continuous low dose palbociclib and letrozole. (Phase I) II.&#xD;
      Determine longer term clinical tumor responsiveness (tumor volume) and tumor biomarker&#xD;
      indices (for patients who have extended pre-operative therapy, maximum 24 weeks). (Phase II,&#xD;
      Part I) III. Perform exploratory studies on blood-based tumor protein, deoxyribonucleic acid&#xD;
      (DNA) and ribonucleic acid (RNA) biomarkers with a focus on pathways of cell proliferation,&#xD;
      autophagy, senescence and cell cycle control. (Phase II, Part I) IV. To determine the impact&#xD;
      of adding hydroxychloroquine to low dose palbociclib and letrozole on breast tumor indices of&#xD;
      proliferation, autophagy, senescence, cell cycle control and other intersecting pathways.&#xD;
      (Phase II, Part II) V. Determine longer term clinical tumor responsiveness and tumor&#xD;
      biomarkers indices (for patients who have extended pre-operative therapy, maximum 24 weeks).&#xD;
      (Phase II, Part II) VI. To determine the dose responsiveness of HCQ (400 mg vs. RP2D) on the&#xD;
      primary (proportion with CCCA) and secondary clinical/biological endpoints. (Phase II, Part&#xD;
      II) VII. To perform exploratory studies on blood-based tumor protein, DNA and RNA biomarkers.&#xD;
      (Phase II, Part II) VIII. Obtain additional safety information for the combination of low&#xD;
      dose palbociclib, letrozole and hydroxychloroquine. (Phase II, Part II)&#xD;
&#xD;
      OUTLINE: This is a phase I, dose-escalation study of hydroxychloroquine followed by a phase&#xD;
      II study.&#xD;
&#xD;
      PHASE I: Patients with advanced, metastatic (stage IV) breast cancer receive&#xD;
      hydroxychloroquine orally (PO) once daily (QD), palbociclib PO QD, and letrozole PO QD on&#xD;
      days 1-28. Cycles repeat every 28 days for up to 1 year in the absence of disease progression&#xD;
      or unacceptable toxicity.&#xD;
&#xD;
      PHASE II: Patients with early stage (stage I-III) breast cancer receive hydroxychloroquine PO&#xD;
      QD on days 15-28 of cycle 1 and on days 1-28 of subsequent cycles. Patients also receive&#xD;
      palbociclib PO QD, and letrozole PO QD on days 1-28, followed by standard of care surgery at&#xD;
      week 5. If there is a proliferative benefit with complete cell cycle arrest (CCCA) by biopsy&#xD;
      at 4 weeks, cycles may repeat every 28 days for up to 20-24 weeks in the absence of disease&#xD;
      progression or unacceptable toxicity, followed by standard of care surgery during weeks&#xD;
      20-24.&#xD;
&#xD;
      After completion of study treatment, patients are followed up within 30 days or every 4&#xD;
      weeks.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">August 20, 2018</start_date>
  <completion_date type="Anticipated">December 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of adverse events (Phase I)</measure>
    <time_frame>Up to 30 days post-treatment</time_frame>
    <description>Assessed continuously using Common Terminology Criteria for Adverse Events version 4.03, with physical examination and laboratory assessments.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in breast tumor proliferation index (Ki67) (Phase II, Part I)</measure>
    <time_frame>Baseline up to 30 days post-treatment</time_frame>
    <description>Will determine the dose responsiveness of 2 dose levels (400 mg and recommended phase 2 dose) of hydroxychloroquine added to low dose palbociclib and letrozole.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in autophagy (Phase II, Part I)</measure>
    <time_frame>Baseline up to 30 days post-treatment</time_frame>
    <description>Will determine the dose responsiveness of 2 dose levels (400 mg and recommended phase 2 dose) of hydroxychloroquine added to low dose palbociclib and letrozole.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in senescence (Phase II, Part I)</measure>
    <time_frame>Baseline up to 30 days post-treatment</time_frame>
    <description>Will determine the dose responsiveness of 2 dose levels (400 mg and recommended phase 2 dose) of hydroxychloroquine added to low dose palbociclib and letrozole.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in cell cycle control (Phase II, Part I)</measure>
    <time_frame>Baseline up to 30 days post-treatment</time_frame>
    <description>Will determine the dose responsiveness of 2 dose levels (400 mg and recommended phase 2 dose) of hydroxychloroquine added to low dose palbociclib and letrozole.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in proportion of patients achieving tumoral complete cell cycle arrest (Phase II, Part II)</measure>
    <time_frame>At weeks 2 and 4</time_frame>
    <description>Defined as the Ki67 =&lt; 2.7%.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Longer term clinical tumor responsiveness (tumor volume) (Phase II Part I)</measure>
    <time_frame>Up to 1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tumor biomarker indices (for patients who have extended pre-operative therapy, maximum 24 weeks) (Phase II Part I and II)</measure>
    <time_frame>Up to 1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood-based tumor protein, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) biomarkers (Phase II Part I and II)</measure>
    <time_frame>Up to 1 year</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Breast tumor indices of proliferation, autophagy, senescence, cell cycle control and other intersecting pathways (Phase II Part II)</measure>
    <time_frame>Up to 1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Dose responsiveness hydroxychloroquine (400 mg versus recommended phase 2 dose) (Phase II Part II)</measure>
    <time_frame>Up to 1 year</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">54</enrollment>
  <condition>Anatomic Stage I Breast Cancer AJCC v8</condition>
  <condition>Anatomic Stage IA Breast Cancer AJCC v8</condition>
  <condition>Anatomic Stage IB Breast Cancer AJCC v8</condition>
  <condition>Anatomic Stage II Breast Cancer AJCC v8</condition>
  <condition>Anatomic Stage IIA Breast Cancer AJCC v8</condition>
  <condition>Anatomic Stage IIB Breast Cancer AJCC v8</condition>
  <condition>Anatomic Stage III Breast Cancer AJCC v8</condition>
  <condition>Anatomic Stage IIIA Breast Cancer AJCC v8</condition>
  <condition>Anatomic Stage IIIB Breast Cancer AJCC v8</condition>
  <condition>Anatomic Stage IIIC Breast Cancer AJCC v8</condition>
  <condition>Anatomic Stage IV Breast Cancer AJCC v8</condition>
  <condition>Prognostic Stage I Breast Cancer AJCC v8</condition>
  <condition>Prognostic Stage IA Breast Cancer AJCC v8</condition>
  <condition>Prognostic Stage IB Breast Cancer AJCC v8</condition>
  <condition>Prognostic Stage IIA Breast Cancer AJCC v8</condition>
  <condition>Prognostic Stage IIB Breast Cancer AJCC v8</condition>
  <condition>Prognostic Stage III Breast Cancer AJCC v8</condition>
  <condition>Prognostic Stage IIIA Breast Cancer AJCC v8</condition>
  <condition>Prognostic Stage IIIB Breast Cancer AJCC v8</condition>
  <condition>Prognostic Stage IIIC Breast Cancer AJCC v8</condition>
  <condition>Prognostic Stage IV Breast Cancer AJCC v8</condition>
  <arm_group>
    <arm_group_label>Treatment (hydroxychloroquine, palbociclib, letrozole)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>PHASE I: Patients with advanced, metastatic (stage IV) breast cancer receive hydroxychloroquine PO QD, palbociclib PO QD, and letrozole PO QD on days 1-28. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.&#xD;
PHASE II: Patients with early stage (stage I-III) breast cancer receive hydroxychloroquine PO QD on days 15-28 of cycle 1 and on days 1-28 of subsequent cycles. Patients 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, cycles 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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Hydroxychloroquine</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (hydroxychloroquine, palbociclib, letrozole)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Letrozole</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (hydroxychloroquine, palbociclib, letrozole)</arm_group_label>
    <other_name>CGS 20267</other_name>
    <other_name>Femara</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Palbociclib</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (hydroxychloroquine, palbociclib, letrozole)</arm_group_label>
    <other_name>6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-8h-pyrido(2,3-d)pyrimidin-7-one</other_name>
    <other_name>Ibrance</other_name>
    <other_name>PD 0332991</other_name>
    <other_name>PD 332991</other_name>
    <other_name>PD 991</other_name>
    <other_name>PD-0332991</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Signed written informed consent&#xD;
&#xD;
          -  Diagnosis of estrogen positive breast cancer, estrogen receptor-positive and&#xD;
             HER2-negative by American Society of Clinical Oncology (ASCO)/College of American&#xD;
             Pathologists (CAP) criteria&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1&#xD;
&#xD;
          -  Postmenopausal defined by: a. Age &gt;= 55 years and 1 year or more of amenorrhea b. Age&#xD;
             &lt; 55 years and 1 year or more of amenorrhea with luteinizing hormone (LH) and/or&#xD;
             follicle stimulating hormone (FSH) levels in the postmenopausal range c. Age &lt; 55 with&#xD;
             prior hysterectomy but intact ovaries with LH and/or FSH levels in the postmenopausal&#xD;
             range d. Chemotherapy or medically induced ovarian suppression with 1 year or more of&#xD;
             amenorrhea and with LH and/or FSH levels in the postmenopausal range e. Status after&#xD;
             bilateral oophorectomy (&gt;= 28 days prior to first study treatment)&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt;= 1500 cells/ul&#xD;
&#xD;
          -  Platelet count &gt;= 100,000/ul&#xD;
&#xD;
          -  Serum creatinine concentration &lt; 1.5 x upper limit of normal (ULN)&#xD;
&#xD;
          -  Bilirubin level &lt; 1.5 x ULN&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) &lt; 3 x ULN&#xD;
&#xD;
          -  Alkaline phosphatase =&lt; 2.5 ULN&#xD;
&#xD;
          -  Metastatic cohorts (Phase I): Diagnosis of stage IV estrogen positive breast cancer,&#xD;
             estrogen receptor-positive and HER2-negative by ASCO/CAP criteria&#xD;
&#xD;
          -  Metastatic cohorts (Phase I): Must be a candidate for treatment with CDK4/6 inhibitor&#xD;
             and hormonal therapy with an aromatase inhibitor as standard of care&#xD;
&#xD;
          -  Metastatic cohorts (Phase I): No prior exposure to CDK 4/6 inhibitors&#xD;
&#xD;
          -  Neoadjuvant cohorts (Phase II): Diagnosis of stage I-III estrogen positive breast&#xD;
             cancer, estrogen receptor-positive and HER2-negative by ASCO/CAP criteria. If stage I,&#xD;
             clinical tumor size must be &gt;= 1.5 cm&#xD;
&#xD;
          -  Neoadjuvant cohorts (Phase II): Baseline tumor Ki67 &gt; 5%&#xD;
&#xD;
          -  Neoadjuvant cohorts (Phase II): Surgical candidate and appropriate for pre-operative&#xD;
             endocrine therapy&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior exposure to CDK 4/6 inhibitor therapy&#xD;
&#xD;
          -  History of retinal disease or active visual disturbances (normal baseline&#xD;
             study-specified retinal exam required)&#xD;
&#xD;
          -  Acute illness, including infections requiring medical therapy, known bleeding&#xD;
             diathesis or need for anticoagulation&#xD;
&#xD;
          -  Treatment with any of the following medications within 4 weeks before the baseline&#xD;
             diagnostic biopsy is taken: a. Oral estrogens, including hormone replacement therapy&#xD;
             (but prior depot estrogen use not allowed). b. Investigational agents (or 5&#xD;
             half-lives, whichever is longer)&#xD;
&#xD;
          -  Required concomitant use of any drug that is a strong CYP3A inhibitor or inducer&#xD;
&#xD;
          -  Psychological, familial, sociological or geographical conditions that do not permit&#xD;
             compliance with the study protocol&#xD;
&#xD;
          -  Life expectancy of less than 6 months&#xD;
&#xD;
          -  Pregnancy, lactation or planning to be pregnant.&#xD;
&#xD;
          -  Neo-adjuvant cohorts (Phase II): Prior therapy for breast cancer (medical, surgical or&#xD;
             radiation therapy)&#xD;
&#xD;
          -  Neo-adjuvant cohorts (Phase II): Clinical T4 disease&#xD;
&#xD;
          -  Neo-adjuvant cohorts (Phase II): Inoperable or metastatic breast cancer based on&#xD;
             standard evaluation&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Debasish Tripathy</last_name>
    <role>Principal Investigator</role>
    <affiliation>M.D. Anderson Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>M D Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.mdanderson.org</url>
    <description>MD Anderson Cancer Center Website</description>
  </link>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>December 7, 2018</study_first_submitted>
  <study_first_submitted_qc>December 10, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 13, 2018</study_first_posted>
  <last_update_submitted>June 5, 2023</last_update_submitted>
  <last_update_submitted_qc>June 5, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hydroxychloroquine</mesh_term>
    <mesh_term>Letrozole</mesh_term>
    <mesh_term>Palbociclib</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03774472
org study id: 2017-0071
secondary id: NCI-2018-01050
secondary id: 2017-0071
nct id: NCT03774472
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
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 patients 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 than
      palbociclib and letrozole in treating patients with breast cancer.
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: Patients 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. Cycles repeat every 28 days for up to 1 year in the absence of disease progression
      or unacceptable toxicity.

      PHASE II: Patients with early stage (stage I-III) breast cancer receive hydroxychloroquine PO
      QD on days 15-28 of cycle 1 and on days 1-28 of subsequent cycles. Patients 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, cycles 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, patients are followed up within 30 days or every 4
      weeks.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of adverse events (Phase I)
time frame: Up to 30 days post-treatment
description: Assessed continuously using Common Terminology Criteria for Adverse Events version 4.03, with physical examination and laboratory assessments.
measure: Change in breast tumor proliferation index (Ki67) (Phase II, Part I)
time frame: Baseline up to 30 days post-treatment
description: Will determine the dose responsiveness of 2 dose levels (400 mg and recommended phase 2 dose) of hydroxychloroquine added to low dose palbociclib and letrozole.
measure: Change in autophagy (Phase II, Part I)
time frame: Baseline up to 30 days post-treatment
description: Will determine the dose responsiveness of 2 dose levels (400 mg and recommended phase 2 dose) of hydroxychloroquine added to low dose palbociclib and letrozole.
measure: Change in senescence (Phase II, Part I)
time frame: Baseline up to 30 days post-treatment
description: Will determine the dose responsiveness of 2 dose levels (400 mg and recommended phase 2 dose) of hydroxychloroquine added to low dose palbociclib and letrozole.
measure: Change in cell cycle control (Phase II, Part I)
time frame: Baseline up to 30 days post-treatment
description: Will determine the dose responsiveness of 2 dose levels (400 mg and recommended phase 2 dose) of hydroxychloroquine added to low dose palbociclib and letrozole.
measure: Change in proportion of patients achieving tumoral complete cell cycle arrest (Phase II, Part II)
time frame: At weeks 2 and 4
description: Defined as the Ki67 =< 2.7%.
measure: Longer term clinical tumor responsiveness (tumor volume) (Phase II Part I)
time frame: Up to 1 year
measure: Tumor biomarker indices (for patients who have extended pre-operative therapy, maximum 24 weeks) (Phase II Part I and II)
time frame: Up to 1 year
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
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
measure: Dose responsiveness hydroxychloroquine (400 mg versus recommended phase 2 dose) (Phase II Part II)
time frame: Up to 1 year
arm group label: Treatment (hydroxychloroquine, palbociclib, letrozole)
arm group type: Experimental
description: PHASE I: Patients with advanced, metastatic (stage IV) breast cancer receive hydroxychloroquine PO QD, palbociclib PO QD, and letrozole PO QD on days 1-28. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.
PHASE II: Patients with early stage (stage I-III) breast cancer receive hydroxychloroquine PO QD on days 15-28 of cycle 1 and on days 1-28 of subsequent cycles. Patients 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, cycles 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.
intervention type: Drug
intervention name: Hydroxychloroquine
description: Given PO
arm group label: Treatment (hydroxychloroquine, palbociclib, letrozole)
intervention type: Drug
intervention name: Letrozole
description: Given PO
arm group label: Treatment (hydroxychloroquine, palbociclib, letrozole)
other name: CGS 20267
other name: Femara
intervention type: Drug
intervention name: Palbociclib
description: Given PO
arm group label: Treatment (hydroxychloroquine, palbociclib, letrozole)
other name: 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-8h-pyrido(2,3-d)pyrimidin-7-one
other name: Ibrance
other name: PD 0332991
other name: PD 332991
other name: PD 991
other name: PD-0332991
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Debasish Tripathy
role: Principal Investigator
affiliation: M.D. Anderson Cancer Center
facility: 
country: United States
url: http://www.mdanderson.org
description: MD Anderson Cancer Center Website
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Hydroxychloroquine
mesh term: Letrozole
mesh term: Palbociclib