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

NCT03032406 | Active Not Recruiting Phase 2 Results DMC FDA Drug

• 1 other identifier: UPCC 24116
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Breast Cancer Stage IIB

Outcome Measures

Primary Outcomes (1)

• 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

Study Arms (3)

HCQ alone (Arm A)

EXPERIMENTAL

Drug: Hydroxychloroquine

EVE alone (Arm B)

EXPERIMENTAL

Drug: Everolimus

combination HCQ and EVE (Arm C+D)

EXPERIMENTAL

Drug: Hydroxychloroquine; Drug: Everolimus

Interventions

Hydroxychloroquine DRUG

Hydroxychloroquine

HCQ alone (Arm A); combination HCQ and EVE (Arm C+D)

Everolimus DRUG

Everolimus

EVE alone (Arm B); combination HCQ and EVE (Arm C+D)

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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.)

Sponsors & Collaborators

• Abramson Cancer Center at Penn Medicine: lead

Study Sites (1)

Abramson Cancer Center of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (1)

• DeMichele A, Clark AS, Shea E, Bayne LJ, Sterner CJ, Rohn K, Dwyer S, Pan TC, Nivar I, Chen Y, Wileyto P, Berry LR, Deluca S, Savage J, Makhlin I, Pant DK, Martin H, Egunsola A, Mears N, Goodspeed BL, Chislock EM, Graves J, Wang J, Shih N, Belka GK, Berry D, Nayak A, Feldman M, Chodosh LA. Targeting dormant tumor cells to prevent recurrent breast cancer: a randomized phase 2 trial. Nat Med. 2025 Oct;31(10):3464-3474. doi: 10.1038/s41591-025-03877-3. Epub 2025 Sep 2.

  PMID: 40897974 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Hydroxychloroquine; Everolimus

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Sirolimus; Macrolides; Lactones; Organic Chemicals

Limitations and Caveats

The results are limited by the small study sample size, low event rates, and lack of a placebo control.

Results Point of Contact

• Title: Dr Angela DeMichele
• Organization: University of Pennsylvania

angela.demichele@pennmedicine.upenn.edu

2156624000

Study Officials

• Angela DeMichele, MD

  Abramson Cancer Center at Penn Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 24, 2017
• First Posted: January 26, 2017
• Study Start: January 23, 2017
• Primary Completion: May 17, 2022
• Study Completion: January 1, 2026
• Last Updated: July 22, 2025
• Results First Posted: March 5, 2025

Record last verified: 2025-07

Locations

US (1)