Hydroxychloroquine, Abemaciclib and Endocrine Therapy in Hormone Receptor Positive (HR+)/Her 2 Negative Breast Cancer

NCT04316169 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: PRO00035701
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Solid Tumor; Advanced Breast Cancer

Outcome Measures

Primary Outcomes (2)

• Dose-limiting toxicities during dose-escalation phase.

  The number of participants with dose-limiting toxicities during the dose-escalation phase (HCQ in combination with abemaciclib).

  28 days for each cohort

• Dose-limiting toxicities in dose-expansion phase.

  The number of participants with dose-limiting toxicities during the dose-expansion phase (maximum-tolerated dose of HCQ and abemaciclib in combination with endocrine therapy.

  28 days for each cohort

Secondary Outcomes (2)

• Progression-free survival.

  1 Year

• Overall response rate.

  1 Year

Study Arms (4)

Abemaciclib and HCQ 200 mg b.i.d.

EXPERIMENTAL

HCQ will have a dose escalation of a 3 + 3 design.

Drug: Abemaciclib; Drug: Hydroxychloroquine 200 mg

Abemaciclib and HCQ 400 mg b.i.d.

EXPERIMENTAL

HCQ will have a dose escalation of a 3 + 3 design.

Drug: Abemaciclib; Drug: Hydroxychloroquine 400 mg

Abemaciclib and HCQ 600 mg b.i.d.

EXPERIMENTAL

HCQ will have a dose escalation of a 3 + 3 design.

Drug: Abemaciclib; Drug: Hydroxychloroquine 600 mg

Abemaciclib + HCQ (Optimal Dose) + endocrine therapy

EXPERIMENTAL

This group will be divided into two cohorts: 1. eligible participants who are endocrine therapy naive. 2. eligible participants who had one prior line of endocrine therapy.

Drug: Abemaciclib; Drug: Hydroxychloroquine 200 mg; Drug: Faslodex; Drug: Anastrazole; Drug: Letrozole; Drug: Hydroxychloroquine 400 mg; Drug: Hydroxychloroquine 600 mg

Interventions

Abemaciclib DRUG

150 mg b.i.d

Also known as: Verzenio

Abemaciclib + HCQ (Optimal Dose) + endocrine therapy; Abemaciclib and HCQ 200 mg b.i.d.; Abemaciclib and HCQ 400 mg b.i.d.; Abemaciclib and HCQ 600 mg b.i.d.

Hydroxychloroquine 200 mg DRUG

Dose level: 200 mg b.i.d.

Also known as: Plaquenil

Abemaciclib + HCQ (Optimal Dose) + endocrine therapy; Abemaciclib and HCQ 200 mg b.i.d.

Faslodex DRUG

Cohort B will receive Faslodex.

Also known as: Fulvestrant

Abemaciclib + HCQ (Optimal Dose) + endocrine therapy

Anastrazole DRUG

Cohort A will receive anastrazole or letrozole.

Also known as: Arimidex

Abemaciclib + HCQ (Optimal Dose) + endocrine therapy

Letrozole DRUG

Cohort A will receive anastrazole or letrozole.

Also known as: Femara

Abemaciclib + HCQ (Optimal Dose) + endocrine therapy

Hydroxychloroquine 400 mg DRUG

Dose level: 400 mg. b.i.d.

Also known as: Plaquenil

Abemaciclib + HCQ (Optimal Dose) + endocrine therapy; Abemaciclib and HCQ 400 mg b.i.d.

Hydroxychloroquine 600 mg DRUG

Dose level: 600 mg b.i.d.

Also known as: Plaquenil

Abemaciclib + HCQ (Optimal Dose) + endocrine therapy; Abemaciclib and HCQ 600 mg b.i.d.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients 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.
• 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.
• Demonstrate measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST)1.1 criterion.
• Age ≥ 18 years.
• Estimated life expectancy of three months.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
• Patients with asymptomatic central nervous system (CNS) metastases not requiring use of corticosteroids will be allowed.
• Patients 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 patient did not receive radiotherapy).
• Patients 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.
• Patients must be \>/= 3 weeks from major surgery. For biologic/targeted agents, patients must be \>/= 5 half-lives or \>/= 3 weeks from the last dose (whichever comes first).
• The patient is able to swallow oral medications.
• Documented ophthalmic exam within the last 12 months demonstrating no evidence of retinopathy. Patients with retinal changes will be considered for enrollment with written clearance from a board-certified ophthalmologist.
• The patient must sign informed consent prior to registration.
• The patient has adequate organ function for all of the following criteria, as defined below.
• Laboratory Value Guidance to Establish Adequate Organ Function

You may not qualify if:

• Serious concomitant systemic disorder that would compromise the safety of the patient or compromise the patient'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).
• 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.
• Uncontrolled or symptomatic CNS metastases.
• Known history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.
• Taking other commercially available medications, which may theoretically either stimulate or inhibit autophagy; these include calcitriol and chloroquine.
• Taking medications which may lead to interactions with HCQ, including penicillamine, telbivudine, botulinum toxin, digoxin and propafenone.
• Must not be taking HCQ at baseline.
• Females who are pregnant or lactating.
• Uncontrolled infections including and not limited to active bacterial infection (requiring intravenous \[IV\] antibiotics at time of initiating study treatment), fungal infection, human immunodeficiency virus infection with cluster of differentiation 4 (CD4) counts less than 350 and/or AIDS defining opportunistic illnesses known active hepatitis B \[for example, hepatitis B surface antigen positive\], patients with hepatitis C antibody with detectable hepatitis C viral load.. Screening tests are NOT required for this criterion.
• The patient has a marked baseline prolongation of QT/QTc interval \>470 millisecond using Fridericia's QT correction formula or 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), sudden cardiac arrest, family history of Long QT syndrome.
• Patients with symptomatic heart failure, uncontrolled arrhythmia, hypokalemia that does not respond to supplementation
• Patient 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.
• Patient receiving treatment with tamoxifen within seven days prior to the first dose of study drugs.
• Patient receiving treatment with live vaccines within 30 days prior to the first dose of study drugs.
• Patients receiving medications including herbal supplements which may prolong the QT interval.

Sponsors & Collaborators

• Medical College of Wisconsin: lead

Study Sites (1)

Froedtert Hospital and the Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

MeSH Terms

Interventions

abemaciclib; Hydroxychloroquine; Fulvestrant; Anastrozole; Letrozole

Intervention Hierarchy (Ancestors)

Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring

Study Officials

• Smitha Menon, MD

  Medical College of Wisconsin

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: March 18, 2020
• First Posted: March 20, 2020
• Study Start: October 21, 2021
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2028
• Last Updated: December 23, 2022

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)