The overarching goal of this clinical trial is to reduce the incidence of incurable recurrent
metastatic breast cancer by targeting the precursors of these recurrences, bone marrow
disseminated tumor cells (DTCs) present after definitive treatment. This trial targets unique
mechanisms by which DTCs maintain a dormant phenotype (autophagy) and by which they escape
dormancy (upregulation of the cyclin-dependent kinase4/6 (CDK4/6) pathway and
microenvironmental factors such as immune evasion). The selection of these agents is based
upon strong preclinical data demonstrating the relevance of autophagy (inhibited by HCQ), the
CDK4/6 pathway (inhibited by palbociclib) and the programmed cell death-1 (PD-1)/Programmed
death-ligand 1 (PD-L1) immune checkpoint pathway (blocked by avelumab) as critical mechanisms
of cellular and immunological tumor dormancy.
The phase II trial is designed to provide "proof of concept" and estimates of effect of
various combinations and durations of these therapies on bone marrow DTCs as a surrogate for
ultimate reduction in recurrence. The correlative science aims will provide additional
insight into the relationship between the primary tumor and both the biology of DTCs and host
immune surveillance for target validation and development, as well as evaluate the role of
additional biomarkers both in the bone marrow (with a novel flow-based assay), and in the
peripheral circulation (including both circulating tumor cells and cell-free DNA), to
identify patients with minimal residual disease (MRD) and targets for intervention and
measurement of DTC response.
Inclusion Criteria:
- Bone marrow aspirate after completion of all definitive therapy demonstrates
detectable DTCs (via IHC) as performed by central laboratory assessment at University
of Pennsylvania.
- History of stage II-III histologically-confirmed ER+/Her2 neg invasive breast cancer
with no evidence of recurrent local or distant disease (by American Joint Committee on
Cancer 7th edition). Patients with bilateral breast cancer are eligible, so long as
both cancers are ER+/Her2 neg, at least one meets other eligibility criteria and
patient is treated with curative intent. For patients who undergo neoadjuvant therapy,
eligibility is based upon pathologic stage of residual disease at surgery.
- ER+/Her2 neg receptor status on breast primary tumor (by American Society of Clinical
Oncology/College of American Pathologists guidelines). Any partial response (PR)
status is allowed. Tumors that are ER negative and PR positive are not eligible.
Patients who undergo neoadjuvant therapy are eligible if either the pre-treatment
biopsy or residual disease at surgery is ER+/Her2 neg.
- Patients must have completed all primary and adjuvant therapy (including surgery,
chemotherapy, and radiation) with the exception of adjuvant endocrine therapy. Prior
treatment-related toxicity must be resolved to ≤ Grade 1 with the exception of
alopecia and peripheral neuropathy, prior to study enrollment.
- Patients may have received prior CDK4/6 inhibitor therapy with an agent other than
Palbociclib. Patients must have discontinued CDK4/6 inhibitor at least 6 months prior
to screening.
- Patients must be receiving adjuvant endocrine therapy at the time of enrollment.
Patients are eligible to enroll within 2-7 years after initiation of adjuvant
endocrine therapy. Use of tamoxifen as adjuvant endocrine therapy during study
treatment is not allowed on hydroxychloroquine arms due to the potential drug-drug
interaction with hydroxychloroquine. However, patients on tamoxifen at the time of
screening may enroll on the treatment trial if switched to an aromatase inhibitor at
least 21 days prior to starting study therapy in the event patient is randomized to a
hydroxychloroquine containing arm. Premenopausal patients on concurrent ovarian
suppression are eligible. Patients on any other adjuvant endocrine therapy, including
any investigational therapy, are ineligible.
- Patients receiving bone modifying agents (bisphosphonates or rank-ligand inhibitors)
at the time of screening may continue this therapy. Bone modifying agents may not be
initiated while receiving study treatment.
- No concurrent enrollment on another investigational therapy clinical trial.
- Men and women, age ≥ 18 years.
- No contraindications to the study medications (refer to Section 7.2) or uncontrolled
medical illness.
- Adequate bone marrow, liver, and renal function and other parameters.
- Ability to speak and understand English
Exclusion Criteria:
- Patients with a history of another prior invasive breast cancer are ineligible.
Patients with prior Ductal carcinoma in situ (DCIS) of the breast are eligible if this
was diagnosed > 5 years prior to enrollment. Patients with prior invasive malignancy
other than breast cancer are eligible if they have been disease-free for at least 5
years prior to enrollment.
- 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.
- EKG demonstrating QT interval corrected (QTC) > 480 ms
- Any severe and/or uncontrolled medical conditions or other conditions that could
affect subject participation in the study including:
- Chronic autoimmune disease
- History or evidence of increased cardiovascular risk including any of the
following:
- Current clinical significant uncontrolled arrhythmias. Exception: Subjects
with controlled atrial fibrillation
- History of acute coronary syndromes (including myocardial infarction and
unstable angina), coronary angioplasty, or stenting within 6 months prior to
enrollment
- Current ≥ Class II congestive heart failure as defined by New York Heart
Association
- History of pneumonitis/interstitial lung disease or severely impaired lung
function with a previously documented spirometry and Diffusing Capacity of Lung
for Carbon Monoxide (DLCO) that is 50% of the normal predicted value (these tests
not required at screening; prior results, if performed for standard of care
should be referenced) and/or O2 saturation that is 88% or less at rest on room
air
- Uncontrolled diabetes
- Active (acute or chronic) or uncontrolled severe infections
- Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent
hepatitis
- HIV positive patient who are receiving combination anti-retroviral therapy are
ineligible because of the potential for pharmacokinetic interactions or increased
immunosuppression with Palbociclib. However, HIV per se is not a contraindication
to study participation and HIV testing is not required.
- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of hydroxychloroquine (e.g., ulcerative
disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small
bowel resection)
- Patients with an active, bleeding diathesis. Patients receiving therapeutic
anticoagulation are not eligible for study participation.
- History of retinopathy or retinal vein occlusion
- Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods.
