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

Trial Status: Active

This purpose of this phase Ib trial is to develop a new drug treatment to reverse resistance to radioiodine therapy in treating patients with BRAF gene mutated thyroid cancer that does not respond to radioiodine therapy alone (radioiodine-refractory), so that radioiodine can be given to shrink these tumors. BRAF gene mutation in thyroid cancer makes it unlikely to respond to radioiodine therapy. This trial investigates 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. Iodine-124 (I-124) is used only to detect thyroid cancers on imaging studies called positron emission tomography / computed tomography (PET / CT) scans. Iodine-131 (I-131) is used to detect thyroid cancers on scans and to shrink thyroid tumors. Some tumors do not absorb enough (I-131) to cause them to shrink. In some tumors, mutation of the BRAF gene is the primary reason I-131 cannot be absorbed and why it does not shrink those tumors. Vemurafenib inhibits BRAF, and in some patients this drug can increase the amount of radioiodine taken up by tumors with BRAF mutations. Copanlisib blocks PI3K, which is a protein that causes radioiodine resistance by forcing thyroid cancer cells to eliminate radioiodine before it can deliver radiation to kill the tumor. Giving copanlisib and vemurafenib may cause radioiodine to be better absorbed and held longer in thyroid cancer cells, making radioiodine treatment more effective in treating 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 Clinical Laboratory Improvement Act (CLIA)-certified laboratory or using an Food and Drug Administration (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 fludeoxyglucose F-18 (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 6 months of initiating the protocol * No external beam radiation therapy < 4 weeks before initiation of the protocol * No chemotherapy or targeted therapy including tyrosine kinase inhibitors (TKIs) < 4 weeks (or < 5 half-lives of the drug) before the initiation of this protocol
  • Eastern Cooperative Oncology Group (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
  • White blood count (WBC) >= 2000/uL
  • Neutrophils >= 1500/uL
  • Platelets >= 100 x 10^3/uL
  • Hemoglobin > 9.0 g/dL
  • Lipase =< 1.5 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x 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)

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 glycosylated hemoglobin (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
  • Non-healing wound, ulcer, or bone fracture (tumor-related non-healing wounds are allowed)
  • Active, clinically serious infections Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 grade > 2
  • History of concurrent condition of interstitial lung disease and/or severely impaired lung function
  • Known history of human immunodeficiency virus (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 non-prohibited 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) polymerase chain reaction (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
  • Hepatitis B virus (HBV) or hepatitis C virus (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 hepatitis B surface antigen (HBsAg) or hepatitis B surface antibody (HBcAb) will be eligible if they are negative for HBV-deoxyribonucleic acid (DNA) (these patients should receive prophylactic HBV antiviral therapy). Patients positive for anti-HCV antibody will be eligible if they are negative for HCV-ribonucleic acid (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, post ovulation 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 (follicle-stimulating hormone [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

New Jersey

Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: ACTIVE
Contact: Alan Loh Ho
Phone: 646-888-4235
Email: hoa@mskcc.org
Middletown
Memorial Sloan Kettering Monmouth
Status: ACTIVE
Contact: Alan Loh Ho
Phone: 646-888-4235
Email: hoa@mskcc.org
Montvale
Memorial Sloan Kettering Bergen
Status: ACTIVE
Contact: Alan Loh Ho
Phone: 646-888-4235
Email: hoa@mskcc.org

New York

Commack
Memorial Sloan Kettering Commack
Status: ACTIVE
Contact: Alan Loh Ho
Phone: 646-888-4235
Email: hoa@mskcc.org
New York
Memorial Sloan Kettering Cancer Center
Status: ACTIVE
Contact: Alan Loh Ho
Phone: 646-888-4235
Email: hoa@mskcc.org
Uniondale
Memorial Sloan Kettering Nassau
Status: ACTIVE
Contact: Alan Loh Ho
Phone: 646-888-4235
Email: hoa@mskcc.org
West Harrison
Memorial Sloan Kettering Westchester
Status: ACTIVE
Contact: Alan Loh Ho
Phone: 646-888-4235
Email: hoa@mskcc.org

PRIMARY OBJECTIVE:

I. To identify the maximum tolerated dose (MTD) of vemurafenib plus copanlisib for patients with BRAF mutant radioiodine-refractory (RAIR) thyroid cancer.

SECONDARY OBJECTIVES:

I. To determine the proportion of patients with BRAF mutant RAIR thyroid cancer treated with vemurafenib and copanlisib at the MTD who meet the criteria for I-131 treatment as determined by I-124 PET/CT lesional dosimetry.

II. To determine the proportion of patients with BRAF mutant RAIR thyroid cancer treated with vemurafenib and copanlisib (all dose levels) who meet the criteria for I-131 treatment as determined by I-124 PET/CT lesional dosimetry.

III. To quantify the effect of vemurafenib and copanlisib on RAI uptake and retention using serial I-124 PET/CT scans.

IV. To evaluate whether the combination of vemurafenib and copanlisib enhances I-131 activity, by determining the overall response rate (ORR) (per Response Evaluation Criteria in Solid Tumors [RECIST] version [v]1.1) at 6 months after treatment with vemurafenib plus copanlisib and I-131.

V. To evaluate whether the combination of vemurafenib and copanlisib enhances I-131 activity, by determining progression-free survival (PFS) at 6 months (per RECIST v1.1) after treatment with vemurafenib plus copanlisib and I-131.

EXPLORATORY OBJECTIVES:

I. To evaluate tumoral gene expression changes associated with vemurafenib plus copanlisib in serial research biopsy specimens.

II. To examine genomic alterations in tumors from patients in whom vemurafenib plus copanlisib does and does not enhance RAI uptake and retention, by use of research biopsy specimens or archival tissue.

OUTLINE: This is a dose-escalation study.

Patients receive thyrotropin-alpha intramuscularly (IM), I-124 orally (PO), and undergo thyrogen-stimulated I-124 PET/CT lesional dosimetry scan at baseline. Patients then receive vemurafenib PO twice daily (BID) on days 1-20 and copanlisib intravenously (IV) over 1 hour on days 8 and 15 in the absence of disease progression or unacceptable toxicity. Patients receive additional doses of thyrotropin-alpha IM on days 8, 9, 16 and 17, and I-124 PO on day 10. Patients also undergo a second series of PET/CT scans on days 11, 12, 13, and 15. Patients benefiting from treatment with vemurafenib and copanlisib after the day 10 PET/CT scan receive I-131 PO on day 18.

After completion of study treatment, patients are followed up at 7 and 14 days, 1 month, 3-4 months, and 6 months.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Alan Loh Ho

  • Primary ID 20-053
  • Secondary IDs NCI-2020-05188
  • Clinicaltrials.gov ID NCT04462471