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

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ClinicalTrials.gov Identifier: NCT03774472
Recruitment Status : Recruiting
First Posted : December 13, 2018
Last Update Posted : December 13, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
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 Drug: Hydroxychloroquine Drug: Letrozole Drug: Palbociclib Phase 1 Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 54 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : August 20, 2018
Estimated Primary Completion Date : December 31, 2019
Estimated Study Completion Date : December 31, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Treatment (hydroxychloroquine, palbociclib, letrozole)

PHASE 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.

Drug: Hydroxychloroquine
given by mouth

Drug: Letrozole
given by mouth
Other Names:
  • CGS 20267
  • Femara

Drug: Palbociclib
given by mouth
Other Names:
  • Ibrance
  • PD-0332991
  • PD-332991




Primary Outcome Measures :
  1. Incidence of adverse events (Phase I) [ Time Frame: Up to 30 days post-treatment ]
    Assessed continuously using Common Terminology Criteria for Adverse Events version 4.03, with physical examination and laboratory assessments.

  2. Change in breast tumor proliferation index (Ki67) (Phase II, Part I) [ Time Frame: Baseline up to 30 days post-treatment ]
    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.

  3. Change in autophagy (Phase II, Part I) [ Time Frame: Baseline up to 30 days post-treatment ]
    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.

  4. Change in senescence (Phase II, Part I) [ Time Frame: Baseline up to 30 days post-treatment ]
    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.

  5. Change in cell cycle control (Phase II, Part I) [ Time Frame: Baseline up to 30 days post-treatment ]
    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.

  6. Change in proportion of patients achieving tumoral complete cell cycle arrest (Phase II, Part II) [ Time Frame: At weeks 2 and 4 ]
    Defined as the Ki67 =< 2.7%.


Secondary Outcome Measures :
  1. Longer term clinical tumor responsiveness (tumor volume) (Phase II Part I) [ Time Frame: Up to 1 year ]
  2. Blood-based tumor protein, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) biomarkers (Phase II Part I and II) [ Time Frame: Up to 1 year ]
    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.

  3. Breast tumor indices of proliferation, autophagy, senescence, cell cycle control and other intersecting pathways (Phase II Part II) [ Time Frame: Up to 1 year ]
  4. Dose responsiveness hydroxychloroquine (400 mg versus recommended phase 2 dose) (Phase II Part II) [ Time Frame: Up to 1 year ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03774472


Contacts
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Contact: Debasish Tripathy 713-794-4385 dtripathy@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Debasish Tripathy    713-794-4385      
Principal Investigator: Debasish Tripathy         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Debasish Tripathy M.D. Anderson Cancer Center

Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03774472     History of Changes
Other Study ID Numbers: 2017-0071
NCI-2018-01050 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2017-0071 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: December 13, 2018    Key Record Dates
Last Update Posted: December 13, 2018
Last Verified: December 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Hydroxychloroquine
Letrozole
Palbociclib
Estrogens
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Hormones
Protein Kinase Inhibitors
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Antirheumatic Agents