Clinical Trials /

Testing the Combination of Cabozantinib, Nivolumab, and Ipilimumab (CaboNivoIpi) for Advanced Differentiated Thyroid Cancer

NCT03914300

Description:

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.

Related Conditions:
  • Well-Differentiated Thyroid Gland Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing the Combination of Cabozantinib, Nivolumab, and Ipilimumab (CaboNivoIpi) for Advanced Differentiated Thyroid Cancer
  • Official 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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-02220
  • SECONDARY ID: NCI-2019-02220
  • SECONDARY ID: 10240
  • SECONDARY ID: 10240
  • SECONDARY ID: UM1CA186712
  • NCT ID: NCT03914300

Conditions

  • Differentiated Thyroid Gland Carcinoma
  • Follicular Variant Thyroid Gland Papillary Carcinoma
  • Poorly Differentiated Thyroid Gland Carcinoma
  • Progressive Thyroid Carcinoma
  • Refractory Thyroid Gland Carcinoma
  • Tall Cell Variant Thyroid Gland Papillary Carcinoma
  • Thyroid Gland Follicular Carcinoma
  • Thyroid Gland Hurthle Cell Carcinoma
  • Thyroid Gland Papillary Carcinoma

Interventions

DrugSynonymsArms
CabozantinibTreatment (cabozantinib S-malate, nivolumab, ipilimumab)
Cabozantinib S-malateBMS-907351, Cabometyx, Cometriq, XL-184, XL184Treatment (cabozantinib S-malate, nivolumab, ipilimumab)
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyTreatment (cabozantinib S-malate, nivolumab, ipilimumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (cabozantinib S-malate, nivolumab, ipilimumab)

Purpose

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.

Detailed Description

      PRIMARY OBJECTIVE:

      I. 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 cabozantinib S-malate (XL184 [cabozantinib]), nivolumab, and ipilimumab
      (CaboNivoIpi).

      SECONDARY OBJECTIVES:

      I. To assess duration of objective response (DOR), progression-free survival (PFS), and
      overall survival (OS).

      II. To assess tolerability and adverse events of CaboNivoIpi in patients with differentiated
      thyroid cancer (DTC).

      EXPLORATORY OBJECTIVES:

      I. To correlate treatment response (Response Evaluation Criteria in Solid Tumors [RECIST]
      version [v]1.1) with tumor mutation status.

      II. 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.

      III. 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.

      IV. 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).

      V. 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).

      VI. 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.

      OUTLINE:

      Patients receive cabozantinib S-malate orally (PO) once daily (QD) on days -14 to -1 prior to
      cycle 1, days 1-42 of cycles 1-4 and days 1-28 of subsequent cycles. Patients also receive
      nivolumab intravenously (IV) over 30 minutes on days 1, 15, and 29 of cycles 1-4 and day 1 of
      subsequent cycles and ipilimumab IV over 90 minutes on day 1 of cycles 1-4. Treatment repeats
      every 42 days for cycles 1-4 and every 28 days for subsequent cycles in the absence of
      disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 6 weeks, and then every 12
      weeks for up to 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (cabozantinib S-malate, nivolumab, ipilimumab)ExperimentalPatients receive cabozantinib S-malate PO QD on days -14 to -1 prior to cycle 1, days 1-42 of cycles 1-4 and days 1-28 of subsequent cycles. Patients also receive nivolumab IV over 30 minutes on days 1, 15, and 29 of cycles 1-4 and day 1 of subsequent cycles and ipilimumab IV over 90 minutes on day 1 of cycles 1-4. Treatment repeats every 42 days for cycles 1-4 and every 28 days for subsequent cycles in the absence of disease progression or unacceptable toxicity.
  • Cabozantinib
  • Cabozantinib S-malate
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically or cytologically confirmed papillary thyroid cancer
             (PTC), follicular thyroid cancer (FTC), or Hurthle cell thyroid cancer (HTC).
             Follicular variant of PTC or any of the above mixed histology will be allowed, as well
             as tall cell, insular, or poorly-differentiated thyroid cancers. Patients with
             anaplastic thyroid cancers (ATC) or medullary thyroid cancers (MTC) are not eligible

          -  Patients must have measurable disease as defined by Response Evaluation Criteria in
             Solid Tumors (RECIST) v1.1

          -  Patients must have radioactive iodine (RAI)-refractory/resistant disease as defined by
             one or more of the following criteria:

               -  One or more measurable lesions that do not demonstrate RAI uptake,

               -  Progressive disease (PD) (new lesion or progression of previously known lesions),
                  as defined by RECIST v1.1, within 12 months of prior RAI therapy,

               -  One or more measurable lesion present after cumulative RAI dose of > 600 mCi, or

               -  Fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan-positive disease
                  (SUV >= 5 in tumor lesion)

          -  The patient'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. Patients 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

          -  Patients must have Eastern Cooperative Oncology Group (ECOG) performance status =< 2
             (Karnofsky >= 60%)

          -  Patients must have recovered to baseline or =< Common Terminology Criteria for Adverse
             Events (CTCAE) v5.0 grade 1 from toxicities related to any prior treatments, unless
             adverse event (AE)(s) are clinically nonsignificant and/or stable on supportive
             therapy

          -  Absolute neutrophils >= 1,500/mcL

          -  Platelets >= 100,000/mcL

          -  Hemoglobin >= 9 g/dL

          -  Serum thyroid-stimulating hormone (TSH) within institutional normal limits

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN); =< 3.0 x ULN for
             patients with Gilbert's syndrome

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 3.0 x institutional ULN

          -  Alkaline phosphatase =< 3.0 x institutional ULN; =< 5.0 x ULN with documented bone
             metastases

          -  Creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using the
             Cockcroft-Gault formula)

          -  Serum albumin >= 2.8 g/dL

          -  Lipase < 2.0 x ULN and no radiologic or clinical evidence of pancreatitis

          -  Urine protein/creatinine ratio (UPCR) =< 1 mg/mg

          -  Serum phosphorus, calcium, magnesium, and potassium within institutional normal limits

          -  Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin
             time (PTT) test < 1.3 x ULN

          -  Patients 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

          -  Patients with evidence of chronic hepatitis B virus (HBV) infection must have
             undetectable HBV viral load on suppressive therapy, if indicated

          -  Patients with a history of hepatitis C virus (HCV) infection must have been treated
             and cured. Patients with HCV infection who are currently on treatment are eligible if
             they have an undetectable HCV viral load

          -  The effects of XL184 (cabozantinib), nivolumab, and ipilimumab on the developing human
             fetus are unknown. For this reason, women of child-bearing potential (WOCBP) 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. WOCBP
             should use an adequate method to avoid pregnancy for 5 months after the last dose of
             study therapy. Women of childbearing potential must have a negative serum or urine
             pregnancy test (minimum sensitivity: 25 IU/L or equivalent units of human chorionic
             gonadotropin [hCG]) within 24 hours prior to the start of study therapy. Women must
             not be breastfeeding. Men who are sexually active with WOCBP must use any
             contraceptive method with a failure rate of < 1% per year. Men who receive study
             therapy and who are sexually active with WOCBP will be instructed to adhere to
             contraception for a period of 7 months after the last dose of study therapy. Women who
             are not of childbearing potential (i.e., who are postmenopausal or surgically sterile)
             as well as azoospermic men do not require contraception

          -  WOCBP is defined as any female who has experienced menarche and who has not undergone
             surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not
             postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman
             over 45 in the absence of other biological or physiological causes. In addition, women
             under the age of 55 must have a documented serum follicle stimulating hormone (FSH)
             level < 40 mIU/mL

          -  WOCBP and men who are sexually active with WOCBP will be instructed to adhere to
             contraception for a period of 5 and 7 months, respectively, after the last dose of
             study therapy. These durations have been calculated using the upper limit of the
             half-life for nivolumab (25 days) and are based on the protocol requirement that WOCBP
             use contraception for 5 half-lives plus 30 days and men who are sexually active with
             WOCBP use contraception for 5 half-lives plus 90 days

          -  Should a woman become pregnant or suspect she is pregnant while she or her partner is
             participating in this study, she (or the participating partner) must inform the
             treating physician immediately

          -  Patients must be able to swallow tablets

          -  Patients must be able to understand be willing to sign a written informed consent
             document

          -  Patients with impaired decision-making capacity (IDMC) will be eligible if they have a
             legally authorized representative (LAR) or caregiver available to assist them

        Exclusion Criteria:

          -  Patients 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

          -  Patients 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

          -  Patients 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)

          -  Patients 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

          -  Patients 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. Patients may continue on bone-modifying agents (denosumab or
             bisphosphonates) with caution

          -  Patients must not have received radiation therapy:

               -  To the thoracic cavity, abdomen, or pelvis within 4 weeks before the first dose
                  of study treatment;

               -  To bone metastases within 14 days before the first dose of study treatment;

               -  To any other sites within 4 weeks before the first dose of study treatment

          -  Patients must not have clinically relevant, ongoing complications from prior radiation
             therapy. Palliative (limited-field) radiation therapy is permitted as long as the
             patient does not have disease progression according to RECIST v 1.1

          -  Patients 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

          -  Patients must not have received any other type of investigational agent within 4 weeks
             before the first dose of study treatment

          -  Patients 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

               -  Note: if a single EKG shows a QTcF with an absolute value > 500 msec, two
                  additional EKGs at intervals of approximately 3 min must be performed within 30
                  min after the initial EKG, and the average of these three consecutive results for
                  QTcF will be used to determine eligibility

          -  Patients 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, patients 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

          -  Patients must not require concomitant treatment with oral anticoagulants (e.g.,
             warfarin, direct thrombin, and factor Xa inhibitors) or platelet inhibitors (e.g.,
             clopidogrel). The following anticoagulants are allowed:

               -  Low-dose aspirin for cardioprotection (per local applicable guidelines),

               -  Low-dose low molecular weight heparins (LMWH),

               -  Therapeutic doses of LMWH are allowed in patients without known brain metastases
                  who are on a stable dose of LMWH for at least 6 weeks before the first dose of
                  study treatment, and who have had no clinically significant hemorrhagic
                  complications from the anticoagulation regimen or the tumor

          -  Patients 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 are permitted in the absence of active autoimmune disease.
             Patients are permitted to use topical, ocular, intra-articular, intranasal, and
             inhalational corticosteroids (with minimal systemic absorption). Physiologic
             replacement doses of systemic corticosteroids are permitted, even if >= 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

          -  Patients must not have a history of severe hypersensitivity reactions to any
             monoclonal antibodies

          -  Patients must not have a history of allergic reactions attributed to compounds of
             similar chemical or biologic composition to agents used in study

          -  Patients must not require concomitant treatment with strong CYP3A4 inducers (e.g.,
             dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin,
             phenobarbital, or St. John's wort). Because lists of these agents are constantly
             changing, it is important to regularly consult a frequently-updated list. Medical
             reference texts such as the Physicians' Desk Reference may also provide this
             information. As part of the enrollment/informed consent procedures, patients will be
             counseled on the risk of interactions with other agents, and what to do if new
             medications need to be prescribed or if the patient is considering a new
             over-the-counter medicine or herbal product

          -  Patients must not have uncontrolled, significant intercurrent or recent illness
             including, but not limited to, the following conditions:

               -  Cardiovascular disorders:

                    -  Congestive heart failure New York Heart Association (NYHA) class 3 or 4,
                       unstable angina pectoris, serious cardiac arrhythmias

                    -  Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm
                       Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive
                       treatment within seven days prior to the first dose of study treatment

                    -  Stroke (including transient ischemic attack [TIA]), myocardial infarction
                       (MI), or other ischemic event, or thromboembolic event (e.g., deep venous
                       thrombosis [DVT], pulmonary embolism [PE]) within 6 months before first dose

               -  GI disorders including those associated with a high risk of perforation or
                  fistula formation:

                    -  The patient has evidence of tumor invading the GI tract, active peptic ulcer
                       disease, inflammatory bowel disease (e.g., Crohn's disease), diverticulitis,
                       cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis,
                       acute obstruction of the pancreatic duct or common bile duct, or gastric
                       outlet obstruction

                    -  Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal
                       abscess within 6 months before first dose. Complete healing of an
                       intra-abdominal abscess must be confirmed before first dose

               -  Clinically significant hematuria, hematemesis, or hemoptysis or other history of
                  significant bleeding (e.g., pulmonary hemorrhage) within 12 weeks before first
                  dose

               -  Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
                  manifestation

               -  Lesions invading or encasing any major blood vessels

               -  Other clinically significant disorders that would preclude safe study
                  participation

                    -  Serious non-healing wound/ulcer/bone fracture

                    -  Uncompensated/symptomatic hypothyroidism

                    -  Moderate to severe hepatic impairment (Child-Pugh B or C)

          -  Patients must not have had major surgery (e.g., GI surgery or removal or biopsy of
             brain metastasis) within 8 weeks before first dose of study treatment. Complete wound
             healing from major surgery must have occurred 1 month before the first dose of study
             treatment and from minor surgery (e.g., simple excision or tooth extraction) at least
             10 days before the first dose. Patients with clinically relevant ongoing complications
             from prior surgery are not eligible

          -  Pregnant women are excluded from this study because XL184 (cabozantinib) has the
             potential for teratogenic or abortifacient effects, and the effects of nivolumab and
             ipilimumab on the developing fetus are not well known. Because there is an unknown but
             potential risk for AEs in nursing infants secondary to treatment of the mother,
             breastfeeding must be discontinued if the mother is t
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate
Time Frame:Up to 6 months after initiation of therapy
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Incidence of adverse events (AEs)
Time Frame:Up to 2 years
Safety Issue:
Description:Assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. Frequency and severity of AEs and tolerability of the regimen will be collected and summarized by descriptive statistics. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.
Measure:Duration of response
Time Frame:From response (PR or CR) to documented progression, assessed up to 2 years
Safety Issue:
Description:
Measure:Progression-free survival
Time Frame:From initiation of therapy to documented progression or death, whichever occurs first, assessed up to 2 years
Safety Issue:
Description:Will be analyzed using Kaplan-Meier methods, resulting in median survival times with 95% confidence interval (CI).
Measure:Overall survival
Time Frame:From initiation of therapy to death from any cause, assessed up to 2 years
Safety Issue:
Description:Will be analyzed using Kaplan-Meier methods, resulting in median survival times with 95% CI.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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