A Study of Hydroxychloroquine vs Placebo to Prevent COVID-19 Infection in Patients Receiving Radiotherapy

Inclusion Criteria: * Age ≥ 18 * ECOG 0-3 * For patients who have not started radiation at the time of screening: patients are required to have a plan in place for a minimum of 10 radiation treatments with or without concurrent systemic therapy * For patients who have already started radiation at the time of screening: patients must complete enrollment such that they are able to receive at least 10 radiation treatments with hydroxychloroquine. * Disease Site * Mandatory inclusion criteria: * No COVID-19 symptoms within 14 days of enrollment: * (Temp \>38C in addition to sore throat, cough, wheezing, chest tightness, shortness of breath, body aches, chills, diarrhea, and anosmia) * If symptoms are present within 14 days of enrollment, patients with a negative COVID-19 PCR or COVID-19 serology assay are eligible for inclusion. * No close contact with confirmed COVID-19 person * Close contact defined as: * Within 6 feet for prolonged period * Cohabitating * Optional laboratory criteria (Recommended if available) * Negative pre-treatment SARS-CoV-2 rapid antigen test result (within 1 week of enrollment) * Negative pre-treatment SARS-CoV-2 PCR test result (within 1 week of enrollment) using MSKCC laboratory or outside laboratory assay * Negative pre-treatment Standard Q COVID-19 IgM/IgG rapid serology result (within 1 week of enrollment) * Blood serum for SARS-CoV-2 serology tests (being validated by MSKCC) * Disease site meets following criteria: * Head and Neck / High-Risk Skin Cancer * Lung Cancer * Breast Cancer * Prostate Cancer * Central Nervous System Tumors * Gastrointestinal System Cancer * Gynecologic cancer * Other disease sites permitted at PI discretion Exclusion Criteria: * Previous positive test for SARS-CoV-2 * Previous positive serology test for SARS-CoV-2 * Recent Chest CT meeting CT exclusion criteria * Live in a skilled nursing facility with COVID-19 symptoms (Temp \>38 C in addition to sore throat, cough, wheezing, chest tightness, shortness of breath, body aches or chills, diarrhea, anosmia) * Known hypersensitivity to hydroxychloroquine or 4-aminoquinoline derivatives * Pre-existing retinopathy * Known chronic kidney disease, stage 4 or 5, or receiving dialysis * Breast Feeding * Tamoxifen * Absolute neutrophil Count \<1,000/ml at registration * Concurrent use of any other quinine derivative * Antiarrhythmic medications: amiodarone, sotalol, dofetilide, procainamide, quinidine, flecainide * Glucose-6-phosphate dehydrogenase deficiency * Pre-treatment corrected QT interval (QTc) ≥470 milliseconds\*\* * Prisoners * Inability to participate * Psoriasis * History of suicidal ideation * CT Criteria for Enrollment Exclusion (Optional - only for patients who received a diagnostic CT as part of standard of care or a thoracic CT as part of radiation simulation): All patients with COVID-19 typical radiographic findings on CT Chest as defined by the RSNA will be excluded. Patients with any NEW COVID-19 indeterminate radiographic findings on CT Chest that are concerning for COVID-19 will be excluded. COVID-19 indeterminate features are permitted if they can be demonstrated as STABLE on prior (\>14 calendar days) CT Chest or PET/CT. If no prior comparison is available AND any intermediate or typical feature is present, the patient is not eligible. * COVID-19 Atypical Features * Isolated lobar or segmental consolidation without GGO * Discrete small nodules (centrilobular, "tree-in-bud") * Lung cavitation * Smooth interlobular septal thickening with pleural effusion * COVID-19 Indeterminate Features * Multifocal, diffuse, perihilar, or unilateral GGO with or without consolidation lacking a specific distribution and are non-rounded or non-peripheral * Few very small GGO with a non-rounded and non-peripheral distribution * COVID-19 Typical Features * Peripheral, bilateral GGO with or without consolidation or visible intralobular lines ("crazy paving") * Multifocal GGO of rounded morphology with or without consolidation or visible intralobular lines ("crazy paving") * Reverse Halo sign or other findings of organizing pneumonia \*\* If pre-treatment QTC can be decreased to \<470, the patient can be re-considered for trial.