CLEVER Pilot Trial: A Phase II Pilot Trial of HydroxyChLoroquine, EVErolimus or the Combination for Prevention of Recurrent Breast Cancer

Study Overview
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Brief Summary
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To evaluate the feasibility of administering HCQ, EVE or the combination in patients who have completed primary therapy for breast cancer and harbor bone marrow disseminated tumor cells.

Official Title
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CLEVER Pilot Trial: A Phase II Pilot Trial of HydroxyChLoroquine, EVErolimus or the Combination for Prevention of Recurrent Breast Cancer

Conditions
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Breast Cancer Stage IIB

Intervention / Treatment
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* Drug: Hydroxychloroquine
* Drug: Everolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically-confirmed, primary, invasive breast cancer diagnosed within 5 years of study entry. Qualifying risk status, at diagnosis utilizing receptor testing by ASCO/CAP guidelines, meeting one of the following: Histologically positive axillary lymph nodes Primary tumor that is ER/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 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 (CBC, LFTs, Alk Phos), or symptom-directed imaging, per NCCN guidelines. Age ≥ 18 years ECOG performance status 2 No contraindications to the study medications or uncontrolled medical illness. Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hb >9 g/dL Adequate liver function as shown by: Serum bilirubin ≤ 1.5 x ULN, ALT and AST ≤ 2.5 x ULN, and 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 Exclusion criteria 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 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 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. HBV DNA and HCV RNA 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.)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HCQ alone (Arm A)<br> | Drug: Hydroxychloroquine<br>* Hydroxychloroquine<br>|
| Experimental: EVE alone (Arm B)<br> | Drug: Everolimus<br>* Everolimus<br>|
| Experimental: combination HCQ and EVE (Arm C)<br> | Drug: Hydroxychloroquine<br>* Hydroxychloroquine<br>Drug: Everolimus<br>* Everolimus<br>|
| Experimental: observation (Arm D)<br> | Drug: Hydroxychloroquine<br>* Hydroxychloroquine<br>Drug: Everolimus<br>* Everolimus<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events |  | 3 years |