Clinical Trials /

Hydroxychloroquine (HCQ) in Combination With Abemaciclib and Endocrine Therapy in HR+/Her 2- Advanced Breast Cancer After a Lead in Dose Escalation Cohort of HCQ and Abemaciclib in Advanced Solid Tumors

NCT04316169

Description:

The hypothesis is that abemaciclib synergizes with autophagy inhibitor hydroxychloroquine (HCQ/ Plaquenil), inducing apoptosis leading to tumor regression.

Related Conditions:
  • Breast Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Hydroxychloroquine (HCQ) in Combination With Abemaciclib and Endocrine Therapy in HR+/Her 2- Advanced Breast Cancer After a Lead in Dose Escalation Cohort of HCQ and Abemaciclib in Advanced Solid Tumors
  • Official Title: Hydroxychloroquine (HCQ) in Combination With Abemaciclib and Endocrine Therapy in HR+/Her 2- Advanced Breast Cancer After a Lead in Dose Escalation Cohort of HCQ and Abemaciclib in Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: PRO00035701
  • NCT ID: NCT04316169

Conditions

  • Solid Tumor
  • Advanced Breast Cancer

Interventions

DrugSynonymsArms
AbemaciclibVerzenioAbemaciclib + HCQ (Optimal Dose) + endocrine therapy
HydroxychloroquinePlaquenilAbemaciclib + HCQ (Optimal Dose) + endocrine therapy
FaslodexFulvestrantAbemaciclib + HCQ (Optimal Dose) + endocrine therapy
AnastrazoleArimidexAbemaciclib + HCQ (Optimal Dose) + endocrine therapy
LetrozoleFemaraAbemaciclib + HCQ (Optimal Dose) + endocrine therapy

Purpose

The hypothesis is that abemaciclib synergizes with autophagy inhibitor hydroxychloroquine (HCQ/ Plaquenil), inducing apoptosis leading to tumor regression.

Detailed Description

      Part 1: 3+3 dose escalation of HCQ combined with abemaciclib in advanced solid tumors.

      Part 2: HCQ at top-dose level from part one is combined with abemaciclib and endocrine
      therapy in HR+/Her 2- advanced breast cancer (ABC) and divided into two cohorts based on
      prior exposure to endocrine therapy.

      Primary Objective

        1. Dose-escalation cohort: To determine safety and tolerability of HCQ combined with
           abemaciclib.

        2. Dose-expansion cohort: To determine safety and tolerability of HCQ combined with
           abemaciclib and endocrine therapy in HR+/Her2- ABC.

      Secondary Objectives

        1. To assess the clinical efficacy of HCQ in combination with abemaciclib and hormone
           blockade in the dose- expansion cohort of advanced ER- positive breast cancer
           participants.

        2. To assess the clinical efficacy of HCQ in combination with abemaciclib in the dose-
           escalation cohort
    

Trial Arms

NameTypeDescriptionInterventions
Abemaciclib and HCQ 200 mg b.i.d.ExperimentalHCQ will have a dose escalation of a 3 + 3 design.
  • Abemaciclib
  • Hydroxychloroquine
Abemaciclib and HCQ 400 mg b.i.d.ExperimentalHCQ will have a dose escalation of a 3 + 3 design.
  • Abemaciclib
  • Hydroxychloroquine
Abemaciclib and HCQ 600 mg b.i.d.ExperimentalHCQ will have a dose escalation of a 3 + 3 design.
  • Abemaciclib
  • Hydroxychloroquine
Abemaciclib + HCQ (Optimal Dose) + endocrine therapyExperimentalThis group will be divided into two cohorts: eligible participants who are endocrine therapy naive. eligible participants who had one prior line of endocrine therapy.
  • Abemaciclib
  • Hydroxychloroquine
  • Faslodex
  • Anastrazole
  • Letrozole

Eligibility Criteria

        Inclusion Criteria for Dose-escalation Phase

          1. Participants (men and women) with advanced or metastatic cancers who are refractory to
             standard therapy, relapsed after standard therapy, or who have no standard therapy
             available that improves progression-free or overall survival by at least three months.

          2. Intact G1/S checkpoint in tumor tissue defined by positive-Rb staining and
             negative-low-molecule weight isoforms of cyclin E (LMWE) with staining done on
             formalin-fixed paraffin embedded slides from archival tissue or cell blocks.

          3. Demonstrate measurable disease as defined by Response Evaluation Criteria in Solid
             Tumors (RECIST) 1.1 criterion.

          4. Age ≥ 18 years.

          5. Estimated life expectancy of three months.

          6. Eastern Cooperative Oncology Group (ECOG) performance status ≤2.

          7. Participants who received chemotherapy must have recovered (Common Terminology
             Criteria for Adverse Events (CTCAE) Grade ≤1) from the acute effects of chemotherapy
             except for residual alopecia or Grade 2 peripheral neuropathy prior to randomization.
             A washout period of at least 21 days is required between the last chemotherapy dose
             and the first dose of the study drug/s (provided the participant did not receive
             radiotherapy).

          8. Participants who received palliative radiotherapy must have completed and fully
             recovered from the acute effects of radiotherapy. A washout period of at least 14 days
             is required between the end of radiotherapy and the first dose of the study drug/s.

          9. Participants must be >/= 3 weeks from major surgery. For biologic/targeted agents,
             participants must be >/= 5 half-lives or >/= 3 weeks from the last dose (whichever
             comes first).

         10. The participant is able to swallow oral medications.

         11. Documented ophthalmic exam within the last 12 months demonstrating no evidence of
             retinopathy. Participants with retinal changes will be considered for enrollment with
             written clearance from a board-certified ophthalmologist.

         12. The participant must sign informed consent prior to registration.

         13. The participant has adequate organ function for all of the following criteria, as
             defined in below.

             Hematologic:

             Absolute Neutrophil Count (ANC) >/=1.5 × 10^9/L Platelets: >/=100 × 10^9/L Hemoglobin:
             >/= 8 g/dL Participants may receive erythrocyte transfusions to achieve this
             hemoglobin level at the discretion of the investigator. Initial treatment must not
             begin earlier than the day after the erythrocyte transfusion.

             Hepatic:

             Total bilirubin: ≤ 1.5 × upper limit of normal (ULN) Participants with Gilbert's
             syndrome with a total bilirubin ≤ 2 times ULN and direct bilirubin within normal
             limits are permitted.

             Alanine Aminotransferase (ALT) and aspartate aminotransferase (AST): ≤ 3 × ULN Renal
             Serum creatinine: ≤ 1.5 × ULN

         14. Female participants must meet one of the following:

               -  Postmenopausal for at least one year before enrollment, OR

               -  Surgically sterile (i.e., undergone a hysterectomy or bilateral oophorectomy), OR

               -  If participant is of childbearing potential (defined as not satisfying either of
                  the above two criteria), agrees to practice two acceptable methods of
                  contraception (combination methods require use of two of the following: diaphragm
                  with spermicide, cervical cap with spermicide, contraceptive sponge, male or
                  female condom, hormonal contraceptive) from the time of signing of the informed
                  consent form through 21 days after the last dose of study agent, OR o Agrees to
                  practice true abstinence when this is in line with the preferred and usual
                  lifestyle of the participant. (Periodic abstinence [e.g., calendar, ovulation,
                  symptothermal, postovulation methods] and withdrawal are not acceptable
                  contraception methods.)

         15. Male participants, even if surgically sterilized (i.e., status postvasectomy), must
             agree to one of the following:

               -  Practice effective barrier contraception during the entire study period and
                  through 60 calendar days after the last dose of study agent, OR o Agree to
                  practice true abstinence when this is in line with the preferred and usual
                  lifestyle of the participant. (Periodic abstinence [e.g., calendar, ovulation,
                  symptothermal, post ovulation methods] and withdrawal are not acceptable methods
                  of contraception.)

        Exclusion Criteria for Dose-escalation Phase

          1. Serious concomitant systemic disorder that would compromise the safety of the
             participant or compromise the participant's ability to complete the study, as
             determined by the treating physician or the principal investigator (for example,
             interstitial lung disease, severe dyspnea at rest, history of major surgical resection
             involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative
             colitis or a preexisting chronic condition resulting in baseline grade 2 or higher
             diarrhea).

          2. Second primary malignancy except most in situ carcinomas (e.g., adequately treated
             non-melanomatous carcinoma of the skin) or other malignancy treated at least five
             years previously with no evidence of recurrence.

          3. Uncontrolled or symptomatic central nervous system (CNS) metastases.

          4. Known history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.

          5. Taking other commercially available medications, which may theoretically either
             stimulate or inhibit autophagy; these include calcitriol and chloroquine.

          6. Taking medications which may lead to interactions with HCQ, including penicillamine,
             telbivudine, botulinum toxin, digoxin and propafenone.

          7. Must not be taking HCQ at baseline.

          8. Females who are pregnant or lactating.

          9. The participant has a history of active bacterial infection (requiring intravenous
             [IV] antibiotics at time of initiating study treatment), fungal infection or
             detectable viral infection (such as known human immunodeficiency virus positivity or
             with known active hepatitis B or C [for example, hepatitis B surface antigen
             positive]. Screening tests are NOT required for this criterion.

         10. The participant has a personal history of any of the following conditions: syncope of
             cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but
             not limited to, ventricular tachycardia and ventricular fibrillation), or sudden
             cardiac arrest.

         11. Participant receiving treatment with strong and moderate Cytochrome P450, family 3,
             subfamily A (CYP3A) inducers within seven days prior to the first dose of study drugs.

         12. Participant receiving treatment with tamoxifen within seven days prior to the first
             dose of study drugs.

         13. Participant receiving treatment with live vaccines within 30 days prior to the first
             dose of study drugs.

         14. Participant receiving medications which may prolong the QT interval.

        Eligibility criteria- Part 2 (Enrollment criteria for the dose-expansion phase)

        Inclusion Criteria

          1. Postmenopausal women with HR+/ Her2- advanced breast cancer with endocrine naïve
             disease will be enrolled in Cohort A. Endocrine naïve participants are defined as
             advanced breast cancer participants eligible for first-line aromatase inhibitor in
             combination with cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor therapy. Prior
             endocrine therapy in the neoadjuvant or adjuvant setting is permitted if the
             participant had a disease-free interval of more than 12 months.

          2. Postmenopausal women with HR +/ Her 2 -advanced breast cancer with endocrine
             pretreated disease will be enrolled in Cohort B. Endocrine pretreated participants are
             defined as advanced breast cancer participants who progressed while receiving
             endocrine therapy as first-line therapy or who had prior endocrine therapy in the
             neoadjuvant or adjuvant setting with a disease-free interval of less than 12 months
             and who are otherwise eligible to receive a combination of Faslodex® and CDK 4/6
             inhibitor may be enrolled in Cohort B.

          3. Intact G1/S checkpoint in tumor tissue defined by positive-Rb staining and
             negative-low-molecule weight isoforms of cyclin E (LMWE) with staining done on
             formalin-fixed paraffin embedded slides from archival tissue or cell blocks.

          4. Age ≥ 18 years.

          5. Peri or premenopausal women may be enrolled in Cohort A or B, if they are receiving a
             gonadotropin-releasing agonist and meet eligibility criteria as above for
             postmenopausal women.

          6. Female participants must meet one of the following:

               -  Postmenopausal for at least one year before enrollment, OR

               -  Surgically sterile (i.e., undergone a hysterectomy or bilateral oophorectomy), OR

               -  If participant is of childbearing potential (defined as not satisfying either of
                  the above two criteria), agrees to practice two acceptable methods of
                  contraception (combination methods requires use of two of the following:
                  diaphragm with spermicide, cervical cap with spermicide, contraceptive sponge,
                  male or female condom, hormonal contraceptive) from the time of signing of the
                  informed consent form through 21 days after the last dose of study agent, OR o
                  Agree to practice true abstinence when this is in line with the preferred and
                  usual lifestyle of the participant. (Periodic abstinence [e.g., calendar,
                  ovulation, symptothermal, postovulation methods] and withdrawal are not
                  acceptable contraception methods.)

          7. Estimated life expectancy of at least six months.

          8. ECOG performance status ≤2.

          9. Demonstrates measurable disease as defined by RECIST 1.1 criteria or non-measurable
             bone-only disease.

         10. Documented ophthalmic exam within the last 12 months demonstrating no evidence of
             retinopathy. Participants with retinal changes will be considered for enrollment with
             written clearance from a board-certified ophthalmologist.

         11. Must sign informed consent prior to registration.

         12. The participant has adequate organ function for all of the following criteria, as
             defined below.

             Hematologic:

             Absolute Neutrophil Count (ANC) >/=1.5 × 10^9/L Platelets: >/=100 × 10^9/L Hemoglobin:
             >/= 8 g/dL Participants may receive erythrocyte transfusions to achieve this
             hemoglobin level at the discretion of the investigator. Initial treatment must not
             begin earlier than the day after the erythrocyte transfusion.

             Hepatic:

             Total bilirubin: ≤ 1.5 × upper limit of normal (ULN) Participants with Gilbert's
             syndrome with a total bilirubin ≤ 2 times ULN and direct bilirubin within normal
             limits are permitted.

             Alanine Aminotransferase (ALT) and aspartate aminotransferase (AST): ≤ 3 × ULN Renal
             Serum creatinine: ≤ 1.5 × ULN

         13. Participants who previously received chemotherapy must have recovered (Common
             Terminology Criteria for Adverse Events (CTCAE) grade ≤1) from the acute effects of
             chemotherapy except for residual alopecia or grade 2 peripheral neuropathy prior to
             randomization. A washout period of at least 21 days is required between last
             chemotherapy dose and first dose of the study drug/s (provided the participant did not
             receive radiotherapy).

         14. Participants who received palliative radiotherapy must have completed and fully
             recovered from the acute effects of radiotherapy. A washout period of at least 14 days
             is required between end of palliative radiotherapy and first dose of the study drug/s.

         15. The participant is able to swallow oral medications.

        Exclusion Criteria

          1. Presence of visceral crisis, lymphangitic spread, leptomeningeal carcinomatosis or
             inflammatory breast cancer.

          2. Prior therapy with a CDK4/6 inhibitor.

          3. Serious concomitant systemic disorder that would compromise the safety of the
             participant or compromise the participant's ability to complete the study, as
             determined by the treating physician or the principal investigator (for example,
             interstitial lung disease, severe dyspnea at rest, history of major surgical resection
             involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative
             colitis or a preexisting chronic condition resulting in baseline grade 2 or higher
             diarrhea).

          4. Second primary malignancy except most in situ carcinoma (e.g., adequately treated
             non-melanomatous carcinoma of the skin) or other malignancy treated at least five
             years previously with no evidence of recurrence.

          5. Uncontrolled or symptomatic CNS metastases.

          6. Known history of G6PD deficiency.

          7. Taking other commercially available medications which may theoretically either
             stimulate or inhibit autophagy; these include calcitriol and chloroquine.

          8. Taking medications which may lead to interactions with HCQ, including penicillamine,
             telbivudine, botulinum toxin, digoxin, and propafenone.

          9. Must not be taking HCQ at baseline.

         10. Females who are pregnant or lactating.

         11. The participants has active bacterial infection (requiring intravenous [IV]
             antibiotics at time of initiating study treatment), fungal infection, or detectable
             viral infection (such as known human immunodeficiency virus positivity or with known
             active hepatitis B or C [for example, hepatitis B surface antigen positive]). No
             screening tests is required for this criterion.

         12. The participant has a personal history of any of the following conditions: syncope of
             cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but
             not limited to, ventricular tachycardia and ventricular fibrillation), or sudden
             cardiac arrest.

         13. The participant receiving treatment with strong and moderate CYP3A inducers within
             seven days prior to the first dose of study drugs.

         14. Participant receiving treatment with tamoxifen within seven days prior to the first
             dose of study drugs.

         15. Participant receiving treatment with live vaccines within 30 days prior to the first
             dose of study drugs.

         16. Participant receiving medications which may prolong the QT interval.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose-limiting toxicities during dose-escalation phase.
Time Frame:28 days for each cohort
Safety Issue:
Description:The number of participants with dose-limiting toxicities during the dose-escalation phase (HCQ in combination with abemaciclib).

Secondary Outcome Measures

Measure:Progression-free survival.
Time Frame:1 Year
Safety Issue:
Description:This measure is the number of months participants remain free from evidence of disease. Participants will undergo imaging every eight weeks and results will be reported annually.
Measure:Overall response rate.
Time Frame:1 Year
Safety Issue:
Description:The number of participants who have a partial or complete response based on tumor measurement by CT or MRI using RECIST 1.1. Participants will be imaged every eight weeks and reported annually.
Measure:Clinical benefit rate.
Time Frame:1 Year
Safety Issue:
Description:The percentage of participants who have a complete response, partial response and stable disease as measurement by CT or MRI using RECIST 1.1. Participants will be imaged every eight weeks and reported annually.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Medical College of Wisconsin

Last Updated

March 18, 2020