Vemurafenib Plus Copanlisib in Radioiodine-Refractory (RAIR) Thyroid Cancers

Inclusion Criteria

• Histologically or cytologically confirmed thyroid carcinoma of follicular origin (including papillary, follicular, and poorly differentiated subtypes and their respective variants).
• A tumor sample (primary, recurrent, or metastatic tumors) possessing a BRAF V600 mutation, as confirmed in a CLIA-certified laboratory or using an FDA-approved assay
• Measurable disease by RECIST v1.1 (tumors in previously irradiated fields may be considered measurable if there is evidence of tumor progression after radiation treatment)
• RAIR disease, as defined by any one of the following:
• A metastatic lesion that is not RAI-avid on a diagnostic radioiodine scan
• An RAI-avid lesion that remained stable in size or progressed despite RAI treatment before entry in this study (there are no size limitations for the index lesion used to satisfy this entry criterion)
• The presence of at least 1 FDG-avid lesion
• No receipt of treatment for thyroid cancer, defined as:
• No I-131 therapy 9.0 g/dL
• Lipase ≤ 1.5 × ULN
• AST/ALT ≤ 3 × ULN
• Total bilirubin ≤ 1.5 x ULN (except subjects with Gilbert syndrome, who can have total bilirubin 2 years before drug initiation and currently have no evidence of disease
• Inability to follow a low-iodine diet or requiring a medication with a high content of iodide (amiodarone)
• Current congestive heart failure class >2, as defined by the New York Heart Association functional classification system
• Myocardial infarction 150/90, despite optimal medical management)
• Uncontrolled type I or II diabetes mellitus, as judged by the investigator, or Hgb A1C of >8.5
• Arterial or venous thrombotic event or embolic event, such as a cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism, within 3 months before the start of study medication
• Nonhealing wound, ulcer, or bone fracture (tumor-related nonhealing wounds are allowed)
• Active, clinically serious infections CTCAE v5.0 grade >2
• History of concurrent condition of interstitial lung disease and/or severely impaired lung function
• Known history of HIV infection (all patients must be screened for HIV up to 28 days before start of study)
• Seizure disorder requiring medication
• Therapy with a prohibited concomitant medication that cannot be temporarily held (at least 2 weeks before initiation of vemurafenib plus copanlisib until 1 week after the last dose) or replaced with a nonprohibited concomitant medication
• Systemic corticosteroid therapy at a daily dose >15 mg prednisone or equivalent (previous corticosteroid therapy must be stopped or reduced to the allowed dose at least 7 days before study registration)
• Cytomegalovirus (CMV) PCR-positive at baseline
• Evidence or history of a bleeding diathesis or any hemorrhage or bleeding CTCAE v5.0 grade ≥ 3 within 4 weeks before the start of study protocol
• HBV or HCV infection. All patients must be screened for HBV and HCV up to 28 days before the start of study medication using the routine hepatitis virus laboratorial panel. Patients positive for HBsAg or HBcAb will be eligible if they are negative for HBV-DNA (these patients should receive prophylactic HBV antiviral therapy). Patients positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA
• Known hypersensitivity to any of the test drugs, test drug classes, or excipients in the formulation
• Substance abuse or medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
• Patients who are pregnant
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 6 months after the last administration of study treatment. Highly effective contraception methods include:
• Total abstinence (when this is in line with the preferred and usual lifestyle of the pat