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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04462471
Recruitment Status : Recruiting
First Posted : July 8, 2020
Last Update Posted : July 8, 2020
Sponsor:
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Thyroid Carcinoma Thyroid Cancer Thyroid Cancer, Follicular Thyroid Cancer (Follicular Cell) Thyroid Cancer, Papillary BRAF V600E Mutation Positive Diagnostic Test: I-124 PET/CT lesion dosimetry Drug: Vemurafenib Drug: Copanlisib Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 22 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib Trial of Vemurafenib Plus Copanlisib to Enhance Radioiodine Avidity in Radioiodine-Refractory Thyroid Cancers
Actual Study Start Date : June 26, 2020
Estimated Primary Completion Date : June 2022
Estimated Study Completion Date : June 2022


Arm Intervention/treatment
Experimental: Participants with thyroid cancer
Eligible participants will have a diagnosis of BRAF mutant RAIR thyroid cancer
Diagnostic Test: I-124 PET/CT lesion dosimetry
I-124 PET/CT scans will be performed during this process to quantify baseline RAI avidity in index metastatic lesion(s)

Drug: Vemurafenib
Dose level 1 & 2: 960 mg PO bid Dose level -1: 720 mg PO bid Dose level -2: 480 mg PO bid

Drug: Copanlisib
Dose level 2: 60 mg IV weekly Dose level 1, -1, -2: 45 mg IV weekly




Primary Outcome Measures :
  1. Maximum tolerated dose of vemurafenib plus copanlisib [ Time Frame: 6 months ]
    The primary objective of this study is to determine the MTD of vemurafenib plus copanlisib inpatients with advanced BRAF mutant RAIR thyroid cancer. The MTD is defined as the highest dose at which no more than 1 of 6 patients treated at that dose experience a DLT.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 medication)
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04462471


Contacts
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Contact: Alan L Ho, MD, PhD 646-608-3774 hoa@mskcc.org
Contact: James A Fagin, MD 646-888-2136 faginj@mskcc.org

Locations
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United States, New Jersey
Memoral Sloan Kettering Basking Ridge (Limited Protocol Activities) Recruiting
Basking Ridge, New Jersey, United States, 07920
Contact: Alan Ho, MD. PhD    646-608-3774      
Memoral Sloan Kettering Monmouth (Limited protocol activities) Recruiting
Middletown, New Jersey, United States, 07748
Contact: Alan Ho, MD, PhD    646-608-3774      
Memorial Sloan Kettering Bergen (Limited Protocol Activities) Recruiting
Montvale, New Jersey, United States, 07645
Contact: Alan Ho, MD, PhD    646-608-3774      
United States, New York
Memorial Sloan Kettering Cancer Center @ Commack (Limited Protocol Activities) Recruiting
Commack, New York, United States, 11725
Contact: Alan Ho, MD, PhD    646-608-3774      
Memoral Sloan Kettering Westchester (Limited protocol activities) Recruiting
Harrison, New York, United States, 10604
Contact: Alan Ho, MD, PhD    646-608-3774      
Memorial Sloan-Kettering Cancer Center (All protocol activities) Recruiting
New York, New York, United States, 10065
Contact: Alan Ho, MD. PhD    646-608-3774      
Memorial Sloan Kettering Nassau (Limited protocol activities) Recruiting
Rockville Centre, New York, United States, 11553
Contact: Alan Ho, MD, PhD    646-608-3774      
Sponsors and Collaborators
Memorial Sloan Kettering Cancer Center
Investigators
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Principal Investigator: Alan L Ho, MD, PhD Memorial Sloan Kettering Cancer Center
Additional Information:
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Responsible Party: Memorial Sloan Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT04462471    
Other Study ID Numbers: 20-053
First Posted: July 8, 2020    Key Record Dates
Last Update Posted: July 8, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Memorial Sloan Kettering Cancer Center:
thyroid carcinoma of follicular origin
thyroid cancer
thyroid cancer, follicular
thyroid cancer, papillary
thyroid cancer, poorly differentiated
BRAF V600
RAIR disease
Memorial Sloan Kettering Cancer Center
20-053
Additional relevant MeSH terms:
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Thyroid Neoplasms
Thyroid Cancer, Papillary
Thyroid Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Endocrine System Diseases
Endocrine Gland Neoplasms
Neoplasms by Site
Head and Neck Neoplasms
Adenocarcinoma, Papillary
Adenocarcinoma
Vemurafenib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action