Avelumab or Hydroxychloroquine with or without Palbociclib for the Treatment of Stage II-III Breast Cancer, PALAVY Study
Avelumab or Hydroxychloroquine with or without Palbociclib for the Treatment of Stage II-III Breast Cancer, PALAVY Study
This phase II trial investigates the effect of avelumab or hydroxychloroquine sulfate with or without palbociclib in treating patients with stage II-III breast cancer that is positive for disseminated tumor cells (DTCs) after curative therapy. DTCs are breast cancer cells that are asleep (dormant) in the bone marrow. There are multiple ways in which these cells stay alive, and three of these mechanisms are inhibited by the drugs in this trial. First, dormant cancer cells need a protein signal pathway involving CDK 4/6 to start dividing once they wake up in order to survive as an active cancer cell. Palbociclib works by blocking the CDK 4/6 protein and by doing so may limit the dormant cancer cell from being able to survive. In addition, palbociclib may also help both of the other drugs in the trial to work better. Second, dormant cancer cells also use a process called autophagy to generate their own nutrition, which can allow them to stay asleep. Hydroxychloroquine has been shown to block autophagy, which leads to starvation of the cells. Third, dormant cancer cells are able to hide from the bodys immune system. The immune system sends a type of cell called T cells throughout the body to detect and fight infections and diseasesincluding cancers. One way the immune system controls the activity of T cells is through the PD-1/PD-L1 (programmed cell death protein-1) pathway. However, some cancer cells hide from T-cell attack by taking control of the PD-1/PD-L1 interaction and this stops T cells from attacking cancer cells. Avelumab is an antibody designed to block the PD-1/PD-L1 pathway and helps the immune system in detecting and fighting dormant cancer cells. Because palbociclib, hydroxychloroquine, and avelumab work on the mechanisms that keep the dormant cells alive, taking one or a combination of these drugs may be able to eliminate DTCs.
Breast
Phase II
Adults
Not Available
Not Available
Reid, Sonya
National
Vanderbilt University
06-23-2022
Eligibility
18 Years
BOTH
NO
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 * NOTE: This criterion will be assessed AFTER confirmation of the eligibility criteria below with the exception of screening scans for metastatic disease, which will only be done should the bone marrow aspirate be positive for DTCs. Patients must be pre-registered for screening of DTCs
History of stage II-III histologically-confirmed estrogen receptor (ER)+/Her2 negative (neg) invasive breast cancer with no evidence of recurrent local or distant disease (by American Joint Committee on Cancer [AJCC] 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 [ASCO]/College of American Pathologists [CAP] guidelines). Any progesterone receptor (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 or uncontrolled medical illness
Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
Platelets >= 100 x 10^9/L
Hemoglobin > 9 g/dL
Serum bilirubin = 1.5 x upper limit of normal (ULN)
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 2.5 x ULN
Serum creatinine = 2.0 x ULN or creatinine clearance (CrCl) >= 30 mL/min obtained within 30 days prior to registration. A calculated creatinine clearance by Cockcroft-Gault Formula is acceptable in lieu of a measured value
Normal coagulation studies: Prothrombin time (PT) and partial thromboplastin time (PTT) = 1.5 x upper limit of normal per institutional laboratory range
Ability to provide informed consent
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 > 50 mg; hydrocortisone > 40 mg, prednisone > 10 mg, methylprednisone > 8 mg or dexamethasone > 1.5 mg; or another immunosuppressive agent. Topical or inhaled corticosteroids are allowed
Electrocardiogram (EKG) demonstrating corrected QT interval (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 carbon monoxide diffusing capability (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 oxygen (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 * Human immunodeficiency virus (HIV) positive patients who are receiving combination anti-retroviral therapy are ineligible because of the potential for pharmacokinetic interactions or increased immunosuppression with palbociclib. However, HIV infection 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
Use of a prohibited concomitant medication that cannot be discontinued or changed to an alternate therapy
Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. Male participants and female participants of childbearing potential must agree to employ adequate contraceptive methods throughout treatment and for at least 30 days after the last dose of study medication. (Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to administration of therapy)
Bone marrow aspirate after completion of all definitive therapy demonstrates detectable DTCs (via IHC) as performed by central laboratory assessment at University of Pennsylvania * NOTE: This criterion will be assessed AFTER confirmation of the eligibility criteria below with the exception of screening scans for metastatic disease, which will only be done should the bone marrow aspirate be positive for DTCs. Patients must be pre-registered for screening of DTCs
History of stage II-III histologically-confirmed estrogen receptor (ER)+/Her2 negative (neg) invasive breast cancer with no evidence of recurrent local or distant disease (by American Joint Committee on Cancer [AJCC] 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 [ASCO]/College of American Pathologists [CAP] guidelines). Any progesterone receptor (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 or uncontrolled medical illness
Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
Platelets >= 100 x 10^9/L
Hemoglobin > 9 g/dL
Serum bilirubin = 1.5 x upper limit of normal (ULN)
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 2.5 x ULN
Serum creatinine = 2.0 x ULN or creatinine clearance (CrCl) >= 30 mL/min obtained within 30 days prior to registration. A calculated creatinine clearance by Cockcroft-Gault Formula is acceptable in lieu of a measured value
Normal coagulation studies: Prothrombin time (PT) and partial thromboplastin time (PTT) = 1.5 x upper limit of normal per institutional laboratory range
Ability to provide informed consent
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 > 50 mg; hydrocortisone > 40 mg, prednisone > 10 mg, methylprednisone > 8 mg or dexamethasone > 1.5 mg; or another immunosuppressive agent. Topical or inhaled corticosteroids are allowed
Electrocardiogram (EKG) demonstrating corrected QT interval (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 carbon monoxide diffusing capability (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 oxygen (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 * Human immunodeficiency virus (HIV) positive patients who are receiving combination anti-retroviral therapy are ineligible because of the potential for pharmacokinetic interactions or increased immunosuppression with palbociclib. However, HIV infection 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
Use of a prohibited concomitant medication that cannot be discontinued or changed to an alternate therapy
Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. Male participants and female participants of childbearing potential must agree to employ adequate contraceptive methods throughout treatment and for at least 30 days after the last dose of study medication. (Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to administration of therapy)
