Breast Cancer Stage IIBPhase 2NCT03032406
CLEVER Pilot Trial: A Phase II Pilot Trial of HydroxyChLoroquine, EVErolimus or the Combination for Prevention of Recurrent Breast Cancer
A Phase 2 study testing Hydroxychloroquine and Everolimus in people with Breast Cancer Stage IIB, run by Abramson Cancer Center at Penn Medicine at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Breast Cancer Stage IIB
- What is being tested?
- Hydroxychloroquine and Everolimus
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 53 participants
- Where
- 1 siteUnited States
- Study dates
- 23 Jan 2017to 1 Jan 2027
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 19Show fewer
- 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
Who cannot join
- 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.)
Trial locations and contacts
1 site in 1 country.
United States1 site
Abramson Cancer Center of the University of Pennsylvania
Philadelphia, Pennsylvania, 19104
About this study
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
- Being tested
- Hydroxychloroquine, Everolimus
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Hydroxychloroquine
EverolimusDrug
Everolimus
| Study group | Role | What they receive |
|---|---|---|
| HCQ alone (Arm A) | Experimental | Not described Receives: Drug: Hydroxychloroquine |
| EVE alone (Arm B) | Experimental | Not described Receives: Drug: Everolimus |
| combination HCQ and EVE (Arm C+D) | Experimental | Not described Receives: Drug: Hydroxychloroquine; Drug: Everolimus |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Jan 2017 (estimated)
- Study start23 Jan 2017
- Primary completion17 May 2022
- Study completion1 Jan 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Breast Cancer Stage IIBStudies of the same condition, open and under way.
- More trials run by Abramson Cancer Center at Penn MedicineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 53 participants (actual)
Sponsor and investigators
- Lead sponsor
- Abramson Cancer Center at Penn Medicine
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Angela DeMichele, MD, Principal investigator, Abramson Cancer Center at Penn Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03032406
- Sponsor's protocol ID
- UPCC 24116
- Status last verified
- Jun 2026
- First submitted
- 24 Jan 2017
- Last updated
- 29 Jun 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
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.
PubMed 40897974
Study at a glance
From the registry record, last updated by the sponsor on 29 Jun 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- CLEVER Pilot Trial: A Phase II Pilot Trial of HydroxyChLoroquine, EVErolimus or the Combination for Prevention of Recurrent Breast Cancer
- ClinicalTrials.gov ID
- NCT03032406
- Acronym / sponsor ID
- UPCC 24116
- Conditions
- Breast Cancer Stage IIB
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 53 participants (actual)
- Lead sponsor
- Abramson Cancer Center at Penn MedicineUniversity, hospital or other
- Study start
- 23 Jan 2017 (actual)
- Primary completion
- 17 May 2022 (actual)
- Study completion
- 1 Jan 2027 (estimated)
- First posted
- 26 Jan 2017 (estimated)
- Results
- Posted 5 Mar 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| 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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (19 listed)
- Histologically-confirmed, primary, invasive breast cancer diagnosed within 5 years of study entry.
- Qualifying risk status, at diagnosis utilizing receptor testing by
- 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
Key exclusion criteria (7 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| HydroxychloroquineHydroxychloroquine | Drug | HCQ alone (Arm A), combination HCQ and EVE (Arm C+D) |
| EverolimusEverolimus | Drug | EVE alone (Arm B), combination HCQ and EVE (Arm C+D) |
Primary outcome
Feasibility: Number of Participants Who Completed 6 Cycles of Protocol Treatment Without Grade 3 or 4 Toxicity
Time frame: 3 years
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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Jun 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 40897974DeMichele 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Angela DeMichele, MD principal investigator
Abramson Cancer Center at Penn Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Hydroxychloroquine and Everolimus in people with Breast Cancer Stage IIB, run by Abramson Cancer Center at Penn Medicine at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 19 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 29 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 5 Mar 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Feasibility: Number of Participants Who Completed 6 Cycles of Protocol Treatment Without Grade 3 or 4 Toxicity (time frame: 3 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03032406, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Jun 2026.