Vemurafenib Plus Copanlisib in Radioiodine-Refractory (RAIR) Thyroid Cancers
Vemurafenib Plus Copanlisib in Radioiodine-Refractory (RAIR) Thyroid Cancers
The purpose of this study is to develop a new drug treatment to reverse tumor resistance to
 radioiodine in BRAF mutant tumors so that radioiodine can be given to shrink tumors. This
 study is also being done to find out the highest doses of copanlisib and vemurafenib that,
 when given in combination, do not cause serious side effects, and whether the study treatment
 will make radioiodine therapy work better in patients with BRAF-mutant 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 < 6 months before initiation of the protocol (time of initiation
 of the protocol is defined as the first day of drug therapy with vemurafenib and
 copanlisib); diagnostic activities of I-131 (0-10m Ci) are allowed within 6months
 of initiating the protocol

 -  No external beam radiation therapy <4 weeks before initiation of the protocol

 -  No chemotherapy or targeted therapy including TKIs <4 weeks (or <5 half lives of
 the drug) before the initiation of this protocol

 -  Age of ≥ 18 years

 -  ECOG performance status ≤ 2 or Karnofsky Performance Score (KPS) ≥ 70%

 -  Tissue from the primary tumor or metastases available for correlative studies. Either
 a paraffin block or at least 20 unstained slides are acceptable (30 unstained slides
 is ideal); if <20 unstained slides are available, and a paraffin block is not
 available, the patient may be able to participate at the discretion of the
 investigator

 -  Able to swallow and retain an orally administered pill without any clinically
 significant gastrointestinal abnormalities that may alter absorption, such as
 malabsorption syndrome or major resection of the stomach or bowels

 -  Agree to undergo 2 research biopsies of (a) malignant lesion(s). Tumor tissue obtained
 before study consent or treatment can also be submitted in lieu of performance of the
 first pretreatment biopsy if the Principal Investigator deems it to be of sufficient
 quantity/quality/timeliness (tumor tissue obtained more than 3 years from time of
 study consent would not be eligible). Patients may be exempt from biopsy if (1) the
 investigator or person performing the biopsy judges that no tumor is accessible for
 biopsy, (2) the investigator or person performing the biopsy feels that the biopsy
 poses too great of a risk to the patient, or (3) the patient's platelet count is
 <100,000/mcL or the patient cannot be safely removed from anticoagulation therapy (if
 the anticoagulation therapy needs to be temporarily held for the biopsy procedure). If
 the investigator deems a second research biopsy to be high risk, the patient may be
 exempt from the second biopsy.

 -  Screening laboratory values meeting the following criteria:

 -  WBC ≥ 2000/µL

 -  Neutrophils ≥ 1500/µL

 -  Platelets ≥ 100 × 10^3/µL

 -  Hemoglobin >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 <3.0 mg/dL)

 -  Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using
 the Cockcroft-Gault formula below):

 Female CrCl = (140 - age in years) x weight in kg x 0.85 / 82 x serum creatinine in mg/dL

 Male CrCl = (140 - age in years) x weight in kg x 1.00 / 72 x serum creatinine in mg/dL

 Exclusion Criteria:

 -  Untreated metastatic brain or leptomeningeal tumors (metastatic brain or
 leptomeningeal tumors treated with radiation and/or surgery are allowed)

 -  Prior malignancy if diagnosed and treated within 2 years of trial drug initiation
 (with the exception of nonmelanoma skin cancers or Stage I cancers treated with
 curative intent).Patients may be included if they have completed therapy for a prior
 malignancy >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 < 6 months before the initiation of protocol

 -  Unstable angina (angina symptoms at rest) or new-onset angina (begun within the last 3
 months)

 -  Uncontrolled hypertension (blood pressure >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 patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal,
 postovulation methods) and withdrawal are not acceptable methods of contraception

 -  Female sterilization (have had surgical bilateral oophorectomy with or without
 hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before
 taking study treatment. In cases of oophorectomy alone, only when the
 reproductive status of the woman has been confirmed by follow-up hormone-level
 assessment (FSH level in the postmenopausal range) is this acceptable

 -  Male sterilization (at least 6 months before screening). The vasectomized male
 partner should be the sole partner for that patient

 -  Use of oral, injected, or implanted hormonal methods of contraception or
 placement of an intrauterine device or intrauterine system or other forms of
 hormonal contraception that have comparable efficacy (failure rate <1%)-for
 example, hormone vaginal ring or transdermal hormone contraception. Note: In
 cases of use of oral contraception, women should have been stable, on the same
 pill for a minimum of 3 months before taking study treatment

 -  Women are considered postmenopausal and not of child-bearing potential if they
 have had 12 months of natural (spontaneous) amenorrhea with an appropriate
 clinical profile (i.e., age appropriate, history of vasomotor symptoms) or have
 had surgical bilateral oophorectomy (with or without hysterectomy), total
 hysterectomy, or tubal ligation at least 6 weeks ago. In cases of oophorectomy
 alone, only when the reproductive status of the woman has been confirmed by
 follow-up hormone-level assessment is she considered not of child-bearing
 potential.

 -  Sexually active men, unless they use a condom during intercourse while on treatment
 and for 6 months after stopping treatment with study drugs (men should not father a
 child in this period). A condom is required to be used by vasectomized men as well
 during intercourse to prevent delivery of the drug via semen.