Abemaciclib Alone or in Combination with Hydroxychloroquine for the Treatment of Patients with Breast Cancer, ABBY Trial
This phase II trial studies the side effects of abemaciclib alone or in combination with hydroxychloroquine in treating patients with breast cancer and to see how well they work in reducing or eliminating disseminated tumor cells in the bone marrow. Disseminated tumor cells are breast cancer cells that are asleep (dormant) in the bone marrow. There are multiple ways in which these cells stay alive and two of these mechanisms are inhibited by abemaciclib and hydroxychloroquine. First, dormant cancer cells need a protein pathway called CDK 4/6 to wake up from sleep and to survive as an active cancer cell. Abemaciclib works by blocking the CDK 4/6 protein and by doing so may limit the dormant cancer cell from waking up or surviving. Second, dormant cancer cells also use a process called "autophagy" to generate their own nutrition, which can allow them to stay asleep. Hydroxychloroquine has been shown to prevent autophagy, which leads to starvation of the cells. Because both abemaciclib and hydroxychloroquine work on the mechanisms that keep the dormant cells alive, giving abemaciclib alone or in combination with hydroxychloroquine may be able to eliminate disseminated tumor cells.
Inclusion Criteria
- Histologically-confirmed, primary, invasive breast cancer diagnosed within 5 years of entry into the companion DTC screening protocol UPCC 28115 (NCT02732171)
- Qualifying risk status, at diagnosis utilizing receptor testing by American Society of Clinical Oncology (ASCO)/ (College of American Pathologists (CAP) guidelines, meeting at least one of the following: * Histologically positive axillary lymph nodes, regardless of receptors * Primary tumor that is ER/PR/Her2 negative: estrogen receptor (ER) < 10%, progesterone receptor (PR) < 10% and negative Her2-overexpression by ASCO-CAP guidelines, regardless of lymph node status * Primary tumor that is ER+/Her2 negative/lymph node negative with Breast Cancer Recurrence Score of >= 25 per the Genomic Health Oncotype DX breast cancer test and/or high risk MammaPrint * Evidence of residual disease in the breast on pathologic assessment after neoadjuvant chemotherapy
- Patients must have completed all primary therapy (definitive surgery, (neo)adjuvant chemotherapy adjuvant radiation and/or Her2-directed therapy) for the index malignancy at least 4 weeks prior to study entry. Prior treatment-related toxicity must be resolved or improving to grade 1 with the exception of alopecia and up to grade 3 peripheral neuropathy, prior to study enrollment. Concurrent receipt of adjuvant endocrine and bone modifying agents is allowed per standard of care guidelines. Tamoxifen is not allowed due to drug-drug interactions with HCQ
- Bone marrow aspirate obtained via research trial UPCC 28115 after completion of therapy (except endocrine therapy) demonstrates detectable DTCs (via IHC)
- No evidence of recurrent local or distant breast cancer by physical examination, blood tests (complete blood count [CBC], liver function test [LFTs], alkaline phosphatase [Alk Phos]), or imaging. Assessment for overt metastatic disease by radiologic testing per institutional guidelines (computed tomography [CT] chest, abdomen and pelvis, bone scan, magnetic resonance imaging [MRI] and/or positron emission tomography [PET]/CT) will only be done in patients with DTCs detected on bone marrow aspirate who are being screening for this trial
- Age >= 18 years
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Ability to swallow oral medications
- No contraindications to the study medications or uncontrolled medical illness
- Absolute neutrophil count (ANC) >= 1.5 x10^9/L
- Platelets >= 100 x 10^9/L
- Hemoglobin (Hb) > 9 g/dL
- Serum bilirubin =< 1.5 x upper limit of normal (ULN)
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x ULN
- International normalized ratio (INR) =< 1.5
- Anticoagulation is allowed if target INR =< 1.5 on a stable dose of warfarin or on a stable dose of anticoagulant for > 2 weeks at time of randomization. For patients on therapeutic anti-coagulants, medication must be clinically held peri-procedure (bone marrow aspirate) per standard clinical management
- Serum creatinine =< 1.5 x ULN
- Creatine phosphokinase (CPK) =< 2.5 ULN
- Ability to provide informed consent
Exclusion Criteria
- Concurrent enrollment on another investigational therapy
- Prior treatment with a CDK 4/6 inhibitor
- Known hypersensitivity to hydroxychloroquine or any of its derivatives
- Patients with hormone-receptor positive breast cancer may not be receiving tamoxifen due to drug-drug interactions with hydroxychloroquine
- Patients who have received bone modifying agents within 3 months
- Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study including: * History or evidence of increased cardiovascular risk including any of the following: ** Current clinically significant uncontrolled arrhythmias. Exception: Subjects with rate controlled atrial fibrillation ** History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to enrollment ** Current >= class II congestive heart failure as defined by New York Heart Association * Severely impaired lung function with a previously documented spirometry and diffusing capacity for carbon monoxide (DLCO) that is 50% of the normal predicted value and/or oxygen (O2) saturation that is 88% or less at rest on room air * Interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy * Uncontrolled diabetes as defined by fasting serum glucose > 1.5 x ULN. For eligibility assessment, if non-fasting serum glucose =< 1.5 x ULN, then a fasting serum glucose does not need to be obtained * Active (acute or chronic) or uncontrolled severe infection including but not limited to active bacterial or fungal infection requiring intravenous (IV) antibiotics/antifungals at time of initiating study treatment (testing is not required for enrollment) * Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis, because it is unknown whether abemaciclib could reactivate hepatitis * A known history of human immunodeficiency virus (HIV) seropositivity, because there are concerns with drug-drug interactions between abemaciclib and HIV antiretroviral therapy. Controlling HIV infection is more important than patients participating in this trial. * History of major surgical resection involving the stomach or small bowel, or pre-existing impairment of gastrointestinal function or gastrointestinal disease (e.g., ulcerative disease, Crohn’s disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or a pre-existing chronic condition resulting in baseline grade 2 or higher diarrhea) * Patients with an active, bleeding diathesis * History of retinopathy or retinal vein occlusion
- Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods
- If barrier contraceptives are being used, these must be continued throughout the trial and for 3 weeks following the last dose of Abema
- Hormonal contraceptives are not acceptable as a sole method of contraception
- Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose of Abema. Pregnancy testing and contraception is required unless age >= 60, prior hysterectomy, prior oophorectomy, or >= 24 months amenorrhea. Patients on anti-estrogen therapy who are between 12-24 months of amenorrhea do not require pregnancy testing and contraception if estradiol < 30 pg/mL and follicle-stimulating hormone (FSH) in post-menopausal range
Additional locations may be listed on ClinicalTrials.gov for NCT04523857.
Locations matching your search criteria
United States
Pennsylvania
Philadelphia
PRIMARY CLINICAL OBJECTIVES:
I. To evaluate the safety of combination hydroxychloroquine (HCQ) and abemaciclib (Abema) in a safety cohort of 12 patients during cycle 1 (4 weeks) of therapy.
II. To evaluate the efficacy of Abema +/- HCQ in eliminating bone marrow disseminated tumor cells (DTCs).
SECONDARY CLINICAL OBJECTIVES:
I. To evaluate the safety and tolerability of administering Abema +/- HCQ with or without endocrine therapy in early stage breast cancer patients with DTCs.
II. To explore the patterns of response between different receptor subtypes of breast cancer (BC).
III. To estimate the risk of recurrence after treatment with Abema +/- HCQ.
TRANSLATIONAL OBJECTIVES:
I. To assess the utility of a novel DTC assay, DTC-Flow, as a pharmacodynamic marker in trial participants to detect DTCs and their response to study therapy, compared to DTC-immunohistochemistry (IHC).
II. To determine whether patient DTCs biologically reflect primary tumor and predict response to study therapy.
III. To determine whether patient circulating tumor cells (CTCs) biologically reflect primary tumor, accurately identify patients with bone marrow DTCs at baseline, predict for the elimination of DTCs with therapy, and/or predict for improved clinical outcomes relative to therapy.
IV. To determine whether plasma tumor deoxyribonucleic acid (DNA) (ptDNA) biologically reflects primary tumor, accurately identifies patients with bone marrow DTCs, or predicts response to therapy.
OUTLINE:
SAFETY COHORT: Patients receive abemaciclib orally (PO) twice daily (BID) and hydroxychloroquine PO BID for 28 days in the absence of disease progression or unacceptable toxicity.
Patients are randomized to 1 of 2 arms.
ARM A: Patients receive abemaciclib PO BID on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients with detectable DTCs then receive abemaciclib PO BID and hydroxychloroquine PO BID on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive abemaciclib PO BID and hydroxychloroquine PO BID on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients with detectable DTCs continue to receive abemaciclib PO BID and hydroxychloroquine PO BID on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 6 months for 3 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationUniversity of Pennsylvania/Abramson Cancer Center
Principal InvestigatorAmy S. Clark
- Primary IDUPCC 10119
- Secondary IDsNCI-2021-12420
- ClinicalTrials.gov IDNCT04523857