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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Cancer Stage IIB
• Intervention / Treatment: Drug: Hydroxychloroquine; Drug: Everolimus

• Study Type: Interventional
• Enrollment (Actual): 53
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Abramson Cancer Center of The University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HCQ alone (Arm A)	Drug: Hydroxychloroquine; Hydroxychloroquine
Experimental: EVE alone (Arm B)	Drug: Everolimus; Everolimus
Experimental: combination HCQ and EVE (Arm C+D)	Drug: Hydroxychloroquine; Hydroxychloroquine; Drug: Everolimus; Everolimus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility: Number of Participants Who Completed 6 Cycles of Protocol Treatment Without Grade 3 or 4 Toxicity	For the primary endpoint of feasibility, we employed ongoing Bayesian toxicity monitoring after every 3 participants completed cycle 6, assuming a Beta (1,2) prior, equivalent to one DLT observed in 3 treated participants. Early termination of a treatment arm for toxicity (non-feasibility) would occur if the posterior probability that the toxicity rate exceeds the target maximum of 30% was greater than 75%. Trial enrollment and conduct was significantly impacted by the COVID pandemic, including shortage of HCQ and inability of enrolled patients to travel. To address this, we amended the protocol to allow study Arms C and D to be combined for feasibility assessment, given that the investigational treatment was the same in the two arms, enabling enrollment to be halted when the sample size needed for feasibility assessment was complete for all study treatments. Toxicity was assessed using CTCAE v4.0.	3 years

Collaborators and Investigators

• Sponsor: Abramson Cancer Center at Penn Medicine
• Investigators: Principal Investigator: Angela DeMichele, MD, Abramson Cancer Center at Penn Medicine

Study record dates

Study Major Dates

• Study Start (Actual): January 23, 2017
• Primary Completion (Actual): May 17, 2022
• Study Completion (Estimated): January 1, 2026

Study Registration Dates

• First Submitted: January 24, 2017
• First Submitted That Met QC Criteria: January 25, 2017
• First Posted (Estimated): January 26, 2017

Study Record Updates

• Last Update Posted (Actual): July 22, 2025
• Last Update Submitted That Met QC Criteria: July 10, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Breast Neoplasms; MTOR Inhibitors; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Protein Kinase Inhibitors; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Everolimus; Hydroxychloroquine
• Other Study ID Numbers: UPCC 24116

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No