Enhancing Radioiodine Incorporation Into BRAF Mutant Thyroid Cancers With the Combination of Vemurafenib and KTN3379

Enhancing Radioiodine (RAI) Incorporation Into BRAF Mutant, RAI Refractory Thyroid Cancers With the Combination of BRAF Inhibitor Vemurafenib and Anti-ErbB3 Antibody KTN3379: A Pilot Study With a Phase 1 Run-in

This is a patient pilot study testing the hypothesis that vemurafenib with the addition of KTN3379 can restore iodine incorporation in BRAF mutant (MUT), radioiodine-refractory (RAIR) thyroid cancer patients.

Study Overview

• Status: Completed
• Conditions: Thyroid Cancer
• Intervention / Treatment: Biological: KTN3379; Drug: vemurafenib

Detailed Description

This is a patient pilot study testing the hypothesis that vemurafenib with the addition of KTN3379 can restore iodine incorporation in BRAF mutant (MUT), radioiodine-refractory (RAIR) thyroid cancer patients. Eligible patients with BRAF MUT, RAIR thyroid cancer will undergo human recombinant TSH (rhTSH or Thyrogen)-stimulated 124I PET/CT lesional dosimetry to quantify the baseline RAI avidity of index metastatic lesion(s). Patients will then receive vemurafenib followed by the addition of KTN3379 after which a second Thyrogen-stimulated 124I PET/CT lesional dosimetry will be performed. For patients whose tumor(s) demonstrate sufficient iodine incorporation warranting 131I therapy, Thyrogen-stimulated standard dosimetry will be performed and therapeutic 131I will be administered concurrently with vemurafenib and KTN3379. Subsequent to discontinuation of vemurafenib, tumor assessments will be conducted with serial radiologic scan(s) and thyroglobulins (scans will be performed at baseline, before 131I, 3 months (+/- 1 month) following 131I, and 6 months after 131I).

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed thyroid carcinoma of follicular origin (including papillary, follicular, or poorly differentiated subtypes and their respective variants).
• Confirmation in a CLIA certified laboratory or in an FDA-approved assay that one of the patient's thyroid tumors (primary tumor, recurrent tumor, or metastasis) possesses a BRAF mutation at V600.
• Patients must have measurable disease defined by RECIST criteria 1.1.
• Tumors in previously irradiated fields may be considered measureable if there is evidence of tumor progression after radiation treatment.
• RAI-refractory disease on structural imaging
• Age ≥ 18 years.
• ECOG performance status ≤ 2

• Patients must have normal organ and marrow function as defined below:

  • Absolute neutrophil count (ANC) > 1500/mcl
  • Hemoglobin ≥ 9 g/dL
  • Platelets ≥ 100,000/mcl
  • Albumin ≥ 2.5 g/dL
  • Total bilirubin ≤ 1.5x institutional ULN
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2x institutional ULN unless it is related to the primary disease
  • Creatinine ≤ 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) ≥ 50 mL/min OR 24-hour urine creatinine clearance ≥ 50 mL/min

Exclusion Criteria:

• Concomitant malignancies or previous malignancies treated within the past 3 years. Exception: Patients who have been disease-free for 3 years, patients with a history of completely resected non-melanoma skin cancer, and/or patients with indolent secondary malignancies, are eligible.
• Use of other investigational drugs within 28 days preceding the first dose of vemurafenib on this study.
• Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression.

• History or evidence of cardiovascular risk including any of the following:

  • Corrected QT (QTc) interval ≥ 450 msec at baseline or history of congenital long QT syndrome or uncorrectable electrolyte abnormalities. (Patients with well controlled atrial fibrillation are exempt from this criteria.)
  • History of cerebrovascular attack or transient ischemic attack within 6 months prior to the initiation of therapy on this protocol.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Combination of Vemurafenib and KTN3379; Vemurafenib 960 mg po bid KTN3379 1000 mg IV q2weeks	Biological: KTN3379; IV every 2 weeks; Drug: vemurafenib; 960 mg po bid; Other Names: Zelboraf

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The number of patients with BRAF MUT, radioiodine-refractory thyroid cancer in which the combination of vemurafenib and KTN3379 can increase tumoral iodine incorporation to warrant 131I treatment	4 to 6 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Safety and tolerability of the combination of vemurafenib and KTN3379 by assessing adverse events	6 to 8 weeks

Other Outcome Measures

Outcome Measure	Time Frame
The ORR by RECIST v1.1 criteria at 6 months following treatment with vemurafenib and KTN3379 plus 131I	6 months
The proportion of patients alive at 6 months without disease progression by RECIST v1.1 criteria following treatment with vemurafenib and KTN3379 plus 131I	6 months
Changes in thyroglobulin levels in patients treated with 131I	6 months

Collaborators and Investigators

• Sponsor: Celldex Therapeutics
• Collaborators: Memorial Sloan Kettering Cancer Center

Publications and helpful links

General Publications

• Tchekmedyian V, Dunn L, Sherman E, Baxi SS, Grewal RK, Larson SM, Pentlow KS, Haque S, Tuttle RM, Sabra MM, Fish S, Boucai L, Walters J, Ghossein RA, Seshan VE, Knauf JA, Pfister DG, Fagin JA, Ho AL. Enhancing Radioiodine Incorporation in BRAF-Mutant, Radioiodine-Refractory Thyroid Cancers with Vemurafenib and the Anti-ErbB3 Monoclonal Antibody CDX-3379: Results of a Pilot Clinical Trial. Thyroid. 2022 Mar;32(3):273-282. doi: 10.1089/thy.2021.0565.

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (Actual): October 13, 2016
• Study Completion (Actual): October 13, 2016

Study Registration Dates

• First Submitted: May 20, 2015
• First Submitted That Met QC Criteria: May 26, 2015
• First Posted (Estimate): May 28, 2015

Study Record Updates

• Last Update Posted (Actual): September 5, 2017
• Last Update Submitted That Met QC Criteria: August 31, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: CDX3379
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Endocrine System Diseases; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Thyroid Diseases; Thyroid Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Vemurafenib
• Other Study ID Numbers: KTN3379-CL-003