Hydroxychloroquine Sulfate, Everolimus, or the Combination in Preventing Recurrence in Patients with Breast Cancer
This randomized phase II pilot trial studies how well hydroxychloroquine sulfate, everolimus, or the combination work in preventing recurrence in patients with breast cancer. Hydroxychloroquine sulfate and everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
- Histologically-confirmed, primary, invasive breast cancer diagnosed within 5 years of study entry
- Qualifying risk status, at diagnosis utilizing receptor testing by American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines, meeting one of the following: * Histologically positive axillary lymph nodes * Primary tumor that is estrogen receptor (ER)/progesterone receptor (PR)/Her2 negative * Primary tumor that is ER+/Her2 negative/lymph node negative with Breast Cancer Recurrence Score of >= 25 per the Genomic Health Oncotype diagnosis (DX) breast cancer test * Evidence of residual disease in the breast on pathological 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; all prior treatment-related toxicity must be resolved prior to study enrollment; concurrent receipt of adjuvant endocrine and bone modifying agents is allowed per standard of care guidelines
- Bone marrow aspirate after completion of 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 tests [LFTs], alkaline phosphatase [alk phos]), or symptom-directed imaging, per National Comprehensive Cancer Network (NCCN) guidelines
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- No contraindications to the study medications or uncontrolled medical illness
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/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) =< 2.5 x ULN
- Aspartate aminotransferase (AST) =< 2.5 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
- Adequate renal function: serum creatinine =< 2.0 x ULN or creatinine clearance (CrCl) >= 30mL/min obtained within 28 days prior to registration; a calculated creatinine clearance by Cockcroft-Gault formula is acceptable in lieu of a measured value
- Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND fasting triglycerides =< 2.5 x ULN; NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication
- Ability to provide informed consent
- Concurrent enrollment on another investigational therapy
- Prior treatment with an mTOR inhibitor (sirolimus, temsirolimus, everolimus)
- Known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or to its excipients
- Patients receiving chronic, high dose systemic treatment with corticosteroids defined as: chronic use of cortisone > 50mg; hydrocortisone > 40mg, prednisone > 10mg, methylprednisone > 8mg or dexamethasone > 1.5mg; or another immunosuppressive agent; topical or inhaled corticosteroids are allowed
- Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period
- Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study including: * Symptomatic congestive heart failure of New York heart Association class III or IV * Unstable angina pectoris, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease * Severely impaired lung function with a previously documented spirometry and Carbon Monoxide Diffusing Capability Test (DLCO) that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air * Uncontrolled diabetes as defined by fasting serum glucose > 1.5 x ULN * Active (acute or chronic) or uncontrolled severe infections * Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis * A known history of human immunodeficiency virus (HIV) seropositivity as reported by the patient * Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of EVE (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) * Patients with an active, bleeding diathesis * Active or latent, untreated hepatitis B or C; a detailed assessment of hepatitis B/C medical history and risk factors must be done at screening for all patients; hepatitis B virus (HBV) DNA and hepatitis C virus (HCV) ribonucleic acid (RNA) polymerase chain reaction (PCR) testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection
- 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 8 weeks after stopping study drug, by both sexes; hormonal contraceptives are not acceptable as a sole method of contraception; (women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to administration of EVE)
Locations & Contacts
Contact: Angela M. DeMichele
Trial Objectives and Outline
I. To evaluate the feasibility of administering hydroxychloroquine sulfate (HCQ), everolimus (EVE) or the combination in patients who have completed primary therapy for breast cancer and harbor bone marrow disseminated tumor cells.
I. To determine the safety of administering HCQ + EVE in combination with adjuvant endocrine therapy.
II. To evaluate preliminary efficacy of HCQ, EVE or the combination in reducing or eliminating disseminated tumor cells (DTCs).
III. To estimate the risk of recurrence after treatment with HCQ, EVE, or the combination.
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: Patients are randomized to 1 of 4 arms.
ARM A: Patients receive hydroxychloroquine sulfate orally (PO) twice per day (BID) on days 1-28. Treatment repeats every 4 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients who have detectable DTCs after week 24 crossover to combination therapy comprising of hydroxychloroquine sulfate PO BID and everolimus PO daily for an additional 24 weeks.
ARM B: Patients receive everolimus PO daily on days 1-28. Treatment repeats every 4 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients who have detectable DTCs after week 24 crossover to combination therapy comprising of hydroxychloroquine sulfate PO BID and everolimus PO daily for an additional 24 weeks.
ARM C: Patients receive hydroxychloroquine sulfate PO BID and everolimus PO daily on days 1-28. Treatment repeats every 4 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients who have detectable DTCs after week 24 continue treatment for an additional 24 weeks.
ARM D: Patients undergo observation for 24 weeks without study treatment. Patients who have detectable DTCs after week 24 crossover to combination therapy comprising of hydroxychloroquine sulfate PO BID and everolimus PO daily for an additional 24 weeks.
After completion of study treatment, patients are followed up at 30 days and then every 6 months for 3 years.
Trial Phase & Type
University of Pennsylvania / Abramson Cancer Center
Angela M. DeMichele
Secondary IDs NCI-2017-00108
Clinicaltrials.gov ID NCT03032406