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Clinical Trial 20315

Cancer Type: Head & Neck
Study Type: Treatment
NCT#: NCT03914300

Phase: Phase II
Prinicipal Investigator:

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Overview

Study Title

Phase II Study of XL184 (cabozantinib) in combination with Nivolumab and Ipilimumab (CaboNivoIpi) in Patients with Radioiodine-refractory Differentiated Thyroid Cancer whose Cancer Progressed after One Prior VEGFR-Targeted Therapy

Summary

This phase II trial studies how well cabozantinib, nivolumab, and ipilimumab work in treating patients with differentiated thyroid cancer that does not respond to radioactive iodine and that worsened after treatment with a drug targeting the vascular endothelial growth factor receptor (VEGFR), a protein needed to form blood vessels. Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving cabozantinib, nivolumab and ipilimumab may work better than the usual approach consisting of chemotherapy with drugs such as doxorubicin, sorafenib, and lenvatinib for this type of thyroid cancer.

Objective

Primary Objective: To assess the objective response rate, defined as the proportion of patients who have had a partial response (PR) or complete response (CR) within the first 6 months after initiation of therapy with XL184 (cabozantinib), nivolumab, and ipilimumab(CaboNivoIpi). Secondary Objectives: To assess duration of objective response (DOR), progression-free survival (PFS), and overall survival (OS). To assess tolerability and adverse events of CaboNivoIpi in patients with differentiated thyroid cancer (DTC). Exploratory Objectives: To correlate treatment response (Response Evaluation Criteria in Solid Tumors[RECIST] v1.1) with tumor mutation status. To correlate treatment response (RECIST v1.1) with frequency of tumor infiltrating lymphocytes in biopsies taken pre-treatment and after 12 weeks of CaboNivoIpi therapy. To evaluate the effect of CaboNivoIpi on T cell receptor (TCR) repertoire and to identify the frequency of shared T cell clones between tumor and peripheral blood. To evaluate the effect of XL184 (cabozantinib) alone and of the CaboNivoIpi combination on peripheral blood mononuclear cells (PBMCs) and to correlate their frequency with treatment response (RECIST v1.1). To evaluate the effect of XL184 (cabozantinib) alone and of the CaboNivoIpi combination on myeloid-derived suppressor cells (MDSCs) and to correlate their frequency with treatment response (RECIST v1.1). To correlate treatment response (RECIST v1.1) with programmed cell death protein 1 (PD-1) / programmed cell death-ligand 1 (PD-L1) expression in the primary/metastatic tumor.

Treatments

Therapies

Medications

BMS-936558 (Nivolumab); Cabozantinib (XL 184); Ipilimumab (); Nivolumab (); Yervoy (Ipilimumab)

Inclusion Criteria

  • Participants must have histologically or cytologically confirmed papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), or Hurthle cell thyroid cancer (HTC). Participants with anaplastic thyroid cancers (ATC) or medullary thyroid cancers (MTC) are not eligible
  • Participants must have measurable disease as defined by RECIST v1.1
  • Participants must have radioactive iodine refractory/resistant disease
  • The participant's disease must have progressed on one line of VEGFR-targeted therapy (including, but not limited to, sorafenib, sunitinib, vandetanib, pazopanib, or lenvatinib, etc.) as defined by PD per RECIST v1.1 while receiving VEGFR-targeted therapy. Participants who have received more than one line of prior VEGFR-targeted therapy will not be eligible
  • Prior external beam radiation to extra-osseous disease, systemic cytotoxic chemotherapy or BRAF- or non-VEGFR-targeted therapies will be allowed, provided that > 4 weeks has elapsed since receiving prior treatment. Radiation to bone metastases is allowed up to 2 weeks prior to initiation of study treatment
  • Participants must have ECOG performance status == 60%)
  • Participants must have recovered to baseline or => Participants with a history of human immunodeficiency virus (HIV) infection must be on an effective anti-retroviral regimen utilizing agents that do not strongly induce or inhibit cytochrome P450 (CYP) 3A4, and must have an undetectable viral load measured within 6 months prior to study registration
  • Participants with evidence of chronic HBV infection must have undetectable HBV viral load on suppressive therapy, if indicated
  • Participants with a history of HCV infection must have been treated and cured. Participants with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation.
  • Participants must be able to swallow tablets

  • Exclusion Criteria

  • Participants must not have had prior treatment with XL184 (cabozantinib), any MET-targeting tyrosine kinase inhibitor (TKI), or any MET-targeting monoclonal antibody (MetMAb), such as onartuzumab
  • Participants must not have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T cell co-stimulation or immune checkpoint pathways
  • Participants must not have a tumor invading or encasing any major blood vessels, and must not have evidence of tumor invading the gastrointestinal (GI) tract (esophagus, stomach, small or large bowel, rectum, or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of XL184 (cabozantinib)
  • Participants must not have a diagnosis of another malignancy within 2 years before the first dose of study treatment, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy. Adjuvant hormonal therapy for history of prostate or breast cancer is allowed
  • Participants must not have received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 4 weeks, or nitrosoureas/ mitomycin C within 6 weeks, before the first dose of study treatment. Participants may continue on bone-modifying agents (denosumab or bisphosphonates) with caution
  • Participants must not have received radiation therapy
  • Participants must not have clinically relevant, ongoing complications from prior radiation therapy. Palliative (limited-field) radiation therapy is permitted as long as the participant does not have disease progression according to RECIST v 1.1
  • Participants must not have received any type of small molecule kinase inhibitor (including investigational kinase inhibitors) within 4 weeks before the first dose of study treatment
  • Participants must not have received any other type of investigational agent within 4 weeks before the first dose of study treatment
  • Participants must not have a corrected QT interval calculated by the Fridericia formula (QTcF) > 500 msec by electrocardiogram (EKG) within 28 days before the first dose of study treatment
  • Participants should not have known, untreated brain metastases or leptomeningeal metastases because of poor prognosis and concerns that progressive neurologic dysfunction could confound the evaluation of neurologic and other adverse events. However, participants will be eligible if metastases have been treated, and there is no magnetic resonance imaging (MRI) evidence of progression for at least 4 weeks after treatment for metastases is complete and within 28 days prior to the first dose of study treatment
  • Participants must not require systemic corticosteroids treatment (>= 10 mg/day prednisone equivalents) or other immunosuppressive medications within 14 days prior to study drug administration. Inhaled or topical steroids and adrenal replacement doses = 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted, as is steroid pre-medication for contrast allergy
  • Participants must not have a history of severe hypersensitivity reactions to any monoclonal antibodies
  • Participants must not require concomitant treatment with strong CYP3A4 inducers

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