Avelumab or Hydroxychloroquine With or Without Palbociclib to Eliminate Dormant Breast Cancer (PALAVY)
K
Kathy Miller, MD
Primary Investigator
Enrolling By Invitation
18 years and older
All
Phase
2
96 participants needed
3 Locations
Overview
This clinical trial will assess the safety and early efficacy of Hydroxychloroquine or
Avelumab, with or without Palbociclib, in early-stage ER+ breast cancer patients who areund to harbor disseminated tumor cells (DTCs) in the bone marrow after definitive surgeryd standard adjuvant therapy.
Description
The overarching goal of this clinical trial is to reduce the incidence of incurable recurrentbreast cancer by targeting the precursors of these recurrences, bone marrow
disseminated tumor cells (DTCs) present after definitive treatment. This trial targets uniquehanisms by which DTCs maintain a dormant phenotype (autophagy) and by which they escape
dormancy (upregulation of the cyclin-dependent kinase4/6 (CDK4/6) pathway andvironmental 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 mechanismsular 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 additionalght into the relationship between the primary tumor and both the biology of DTCs and hostune surveillance for target validation and development, as well as evaluate the role ofdditional biomarkers both in the bone marrow (with a novel flow-based assay), and in theheral circulation (including both circulating tumor cells and cell-free DNA), todentify patients with minimal residual disease (MRD) and targets for intervention andurement of DTC response.
Eligibility
You may be eligible for this study if you meet the following criteria:
-
Conditions:
Breast Cancer
-
Age: 18 Years
-
Gender: All
Inclusion Criteria:
- Bone marrow aspirate after completion of all definitive therapy demonstratesdetectable DTCs (via IHC) as performed by central laboratory assessment at UniversityPennsylvania.
- History of stage II-III histologically-confirmed ER+/Her2 neg invasive breast cancerwith no evidence of recurrent local or distant disease (by American Joint Committee onCancer 7th edition). Patients with bilateral breast cancer are eligible, so long asboth cancers are ER+/Her2 neg, at least one meets other eligibility criteria andd with curative intent. For patients who undergo neoadjuvant therapy,gibility is based upon pathologic stage of residual disease at surgery.
- ER+/Her2 neg receptor status on breast primary tumor (by American Society of Clinicalgy/College of American Pathologists guidelines). Any partial response (PR)us is allowed. Tumors that are ER negative and PR positive are not eligible.Patients who undergo neoadjuvant therapy are eligible if either the pre-treatmentbiopsy or residual disease at surgery is ER+/Her2 neg.
- Patients must have completed all primary and adjuvant therapy (including surgery,hemotherapy, and radiation) with the exception of adjuvant endocrine therapy. Priord toxicity must be resolved to ≤ Grade 1 with the exception ofd peripheral neuropathy, prior to study enrollment.
- Patients may have received prior CDK4/6 inhibitor therapy with an agent other thanPalbociclib. Patients must have discontinued CDK4/6 inhibitor at least 6 months priorg.
- Patients must be receiving adjuvant endocrine therapy at the time of enrollment.Patients are eligible to enroll within 2-7 years after initiation of adjuvantdocrine therapy. Use of tamoxifen as adjuvant endocrine therapy during studywed on hydroxychloroquine arms due to the potential drug-drugwith hydroxychloroquine. However, patients on tamoxifen at the time ofg may enroll on the treatment trial if switched to an aromatase inhibitor at21 days prior to starting study therapy in the event patient is randomized to ahydroxychloroquine containing arm. Premenopausal patients on concurrent ovarianuppression are eligible. Patients on any other adjuvant endocrine therapy, includingy investigational therapy, are ineligible.
- Patients receiving bone modifying agents (bisphosphonates or rank-ligand inhibitors)he time of screening may continue this therapy. Bone modifying agents may not bed 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 uncontrolleddical 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 thiswas diagnosed > 5 years prior to enrollment. Patients with prior invasive malignancyher than breast cancer are eligible if they have been disease-free for at least 5years prior to enrollment.
- Patients receiving chronic, high dose systemic treatment with corticosteroids defined: chronic use of cortisone >50mg; hydrocortisone >40mg, prednisone >10mg,hylprednisone >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 couldubject participation in the study including:
- Chronic autoimmune disease
- History or evidence of increased cardiovascular risk including any of thewing
- Current clinical significant uncontrolled arrhythmias. Exception: Subjectswith controlled atrial fibrillation
- History of acute coronary syndromes (including myocardial infarction andunstable angina), coronary angioplasty, or stenting within 6 months prior to
- Current ≥ Class II congestive heart failure as defined by New York HeartAssociation
- History of pneumonitis/interstitial lung disease or severely impaired lung
function with a previously documented spirometry and Diffusing Capacity of LungCarbon Monoxide (DLCO) that is 50% of the normal predicted value (these testsquired at screening; prior results, if performed for standard of carehould be referenced) and/or O2 saturation that is 88% or less at rest on room
- Uncontrolled diabetes
- Active (acute or chronic) or uncontrolled severe infections
- Liver disease such as cirrhosis, chronic active hepatitis or chronic persistenthepatitis
- HIV positive patient who are receiving combination anti-retroviral therapy aregible because of the potential for pharmacokinetic interactions or increasedunosuppression with Palbociclib. However, HIV per se is not a contraindicationudy participation and HIV testing is not required.
- Impairment of gastrointestinal function or gastrointestinal disease that maygnificantly alter the absorption of hydroxychloroquine (e.g., ulcerativedisease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or smallbowel resection)
- Patients with an active, bleeding diathesis. Patients receiving therapeuticgulation 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.
Updated on
15 May 2024.
Study ID: UPCC 01121
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