Cabozantinib-S-Malate in Treating Patients With Refractory Thyroid Cancer

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Brief Title

Cabozantinib-S-Malate in Treating Patients With Refractory Thyroid Cancer

Official Title

Phase II Study of Cabozantinib in Patients With Radioiodine-Refractory Differentiated Thyroid Cancer Who Progressed on Prior VEGFR-Targeted Therapy

Brief Summary

      This phase II trial studies how well cabozantinib-s-malate works in treating patients with
      thyroid cancer that does not respond to treatment. Cabozantinib-s-malate may stop the growth
      of thyroid cancer by blocking some of the enzymes needed for cell growth.
      Cabozantinib-s-malate may also stop the growth of thyroid cancer by blocking blood flow to
      the tumor.
    

Detailed Description

      PRIMARY OBJECTIVES:

      I. 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 (cabozantinib-s-malate).

      SECONDARY OBJECTIVES:

      I. To assess duration of objective response, progression-free survival and overall survival.

      II. To assess tolerability and adverse events of cabozantinib as a 2nd line therapy in
      patients with differentiated thyroid cancer (DTC).

      TERTIARY OBJECTIVES:

      I. To assess effect of cabozantinib on serum tumor marker thyroglobulin and its correlation
      with overall response rate.

      II. To assess response of cabozantinib in bone metastasis (bone metastasis-specific
      progression free survival) as evaluated by pre- and on-study functional imaging such as bone
      scan, fludeoxyglucose F 18 (18F-FDG) positron emission tomography (PET) scan and/or 18F
      sodium fluoride (NaF) PET scan.

      III. To assess effect of cabozantinib on serum and urinary markers of bone turnover and its
      correlation with response to bone metastasis.

      IV. To assess predictors of response by performing tumor genotype studies (e.g. v-raf murine
      sarcoma viral oncogene homolog B [BRAF], rat sarcoma [RAS],
      phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha [PIK3CA],
      mitogen-activated protein kinase 1 [MAP2K1], v-akt murine thymoma viral oncogene homolog 1
      [AKT1], mesenchymal-epithelial transition [MET], rearranged in transformation [RET]/papillary
      thyroid carcinoma [PTC] rearrangement) in archived tumor tissue.

      V. To assess predictors of response by assessing baseline expression levels of vascular
      endothelial growth factor (VEGF), phosphorylated vascular endothelial growth factor receptor
      (pVEGFR), phosphorylated mitogen-activated protein kinase 1 (pERK), phosphorylated AKT1
      (pAKT) and/or total met proto-oncogene (MET) by immunohistochemistry in archived tumor
      tissue.

      OUTLINE:

      Patients receive cabozantinib-s-malate orally (PO) daily on days 1-28. Courses repeat every
      28 days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 4 weeks and then every 3
      months for 1 year.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Objective Response Rate, Defined as the Proportion of Patients Who Have Had a PR or CR as Assessed by the RECIST Version (v)1.1

Secondary Outcome

 Bone Turnover, as Measured by Serum and Urinary Markers of Bone Turnover

Condition

Poorly Differentiated Thyroid Gland Carcinoma

Intervention

Cabozantinib S-malate

Study Arms / Comparison Groups

 Treatment (cabozantinib-s-malate)
Description:  Patients receive cabozantinib-s-malate PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

25

Start Date

May 8, 2013

Completion Date

October 9, 2017

Primary Completion Date

July 13, 2015

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically or cytologically confirmed papillary thyroid cancer,
             follicular thyroid cancer or hurthle cell thyroid cancer (cancer, follicular variant
             of papillary thyroid cancers or any of the above mixed histology will be allowed;
             these patients will be enrolled on Arm A of the trial); patients with the following
             aggressive histologies will be enrolled on Arm B of the trial; tall cell, insular or
             poorly differentiated thyroid cancer

          -  Patients must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension (longest diameter to be recorded for
             non-nodal lesions and short axis for nodal lesions) as >= 2.0 cm with conventional
             techniques or as >= 1.0 cm (or >= 1.5 cm in short axis for lymph node) with spiral
             computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by
             clinical exam

          -  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

               -  One or more measurable lesions progressive by Response Evaluation Criteria in
                  Solid Tumors (RECIST) 1.1 within 12 months of prior RAI therapy

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

          -  Patients must have "progressed on" up to 2 lines of prior vascular endothelial growth
             factor receptor (VEGFR)-targeted therapy (including but not limited to sorafenib,
             sunitinib, vandetanib, pazopanib, or lenvatinib) as defined by progressive disease per
             RECIST while receiving VEGFR-targeted therapy; Note: patients who progressed on kinase
             inhibitor that target VEGFR and MET will not be eligible

          -  Prior external beam radiation, systemic cytotoxic chemotherapy or BRAF- or
             non-VEGFR-targeted therapies will be allowed, provided that >= 4 weeks has elapsed
             since receiving prior treatment and they have recovered to =< grade 1
             treatment-related toxicities

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Absolute neutrophil count >= 1,500/mcL

          -  Platelet count >= 100,000/mcL

          -  Hemoglobin >= 9 g/dL

          -  Thyroid stimulating hormone (TSH) < lower limit of normal (LLN) (patients not able to
             tolerate TSH suppression can be granted an exception)

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients [Pts] with Gilbert's
             syndrome are excluded from this requirement)

          -  Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and
             serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3.0 x
             institutional upper limit of normal

          -  Creatinine =< 1.5 x ULN

          -  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

          -  Serum phosphorus, calcium, magnesium and potassium >= LLN

          -  Prothrombin time (PT) < 1.3 x ULN

          -  International normalized ratio (INR) < 1.3 x ULN

          -  Partial thromboplastin time (PTT) test < 1.3 x ULN

          -  Women of childbearing potential must have a negative pregnancy test at screening;
             women of childbearing potential include women who have experienced menarche and who
             have not undergone successful surgical sterilization (hysterectomy, bilateral tubal
             ligation, or bilateral oophorectomy) or are not postmenopausal; postmenopause is
             defined as amenorrhea >= 12 consecutive months; Note: women who have been amenorrheic
             for 12 or more months are still considered to be of childbearing potential if the
             amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression
             or any other reversible reason

          -  Women of child-bearing potential and men must agree to use adequate contraception;
             women of child-bearing potential and men must agree to use adequate contraception
             prior to study entry and for the duration of study participation; should a woman
             become pregnant or suspect she is pregnant while she or her partner is participating
             in this study, she should inform her treating physician immediately; men treated or
             enrolled on this protocol must also agree to use adequate contraception prior to the
             study, for the duration of study participation, and 4 months after completion of
             cabozantinib administration; sexually active subjects (men and women) must agree to
             use medically accepted barrier methods of contraception (e.g., male or female condom)
             during the course of the study and for 4 months after the last dose of study drug(s),
             even if oral contraceptives are also used; all subjects of reproductive potential must
             agree to use both a barrier method and a second method of birth control during the
             course of the study and for 4 months after the last dose of study drug(s)

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Prior treatment with cabozantinib or any tyrosine kinase inhibitor that targets MET or
             monoclonal antibody (mAb) targeting MET (such as onartuzumab [MetMAb])

          -  The subject has received radionuclide treatment =< 6 weeks of the first dose of study
             treatment

          -  The subject has received any other type of investigational agent =< 28 days before the
             first dose of study treatment

          -  The subject has not recovered to baseline or Common Terminology Criteria for Adverse
             Events (CTCAE) =< grade 1 from toxicity due to all prior therapies except alopecia and
             other non-clinically significant adverse events (AEs)

          -  The subject has active brain metastases or epidural disease; subjects with brain
             metastases previously treated with whole brain radiation or radiosurgery or subjects
             with epidural disease previously treated with radiation or surgery who are
             asymptomatic and do not require steroid treatment for at least 2 weeks before starting
             study treatment are eligible; baseline brain imaging with contrast-enhanced CT or MRI
             scans for subjects with known brain metastases is required to confirm eligibility;
             eligible patients with brain metastases can be taking anti-convulsant medications but
             only non-enzyme inducing anti-epileptic agents (NEIAED) will be allowed

          -  The subject requires concomitant treatment, in therapeutic doses, with anticoagulants
             such as warfarin or warfarin-related agents, heparin, thrombin or factor xabans (Xa)
             inhibitors, or antiplatelet agents (e.g., clopidogrel); low dose aspirin (=< 81
             mg/day), low-dose warfarin (=< 1 mg/day), and prophylactic low molecular weight
             heparin (LMWH) are permitted

          -  The subject requires chronic concomitant treatment of strong cytochrome P450, family
             3, subfamily A, polypeptide 4 (CYP3A4) inducers (e.g., dexamethasone, phenytoin,
             carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John's Wort) or
             strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, indinavir,
             nefazodone, nelfinavir, ritonavir, voriconazole, and posaconazole); Note: because the
             lists of these agents are constantly changing, it is important to regularly consult a
             frequently-updated lists; medical reference texts such as the Physicians' Desk
             Reference may also provide this information; as part of the enrollment/informed
             consent procedures, the patient 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

          -  The subject has experienced any of the following:

               -  Clinically-significant gastrointestinal bleeding =< 6 months before the first
                  dose of study treatment

               -  Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood =< 3 months before the first
                  dose of study treatment

               -  Any other signs indicative of pulmonary hemorrhage =< 3 months before the first
                  dose of study treatment

          -  The subject has radiographic evidence of cavitating pulmonary lesion(s)

          -  The subject has tumor that is invading or encasing any major blood vessels

          -  The subject has 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 =< 28 days before the first dose of cabozantinib

          -  The subject has uncontrolled, significant intercurrent or recent illness including,
             but not limited to, the following conditions:

               -  Cardiovascular disorders including:

                    -  Congestive heart failure (CHF): New York Heart Association (NYHA) class III
                       (moderate) or class IV (severe) at the time of screening

                    -  Concurrent uncontrolled hypertension defined as sustained blood pressure
                       (BP) > 140 mmHg systolic, or > 90 mmHg diastolic despite optimal
                       antihypertensive treatment =< 7 days of the first dose of study treatment

                    -  Any history of congenital long QT syndrome

                    -  Any of the following =< 6 months before the first dose of study treatment:

                         -  Unstable angina pectoris

                         -  Clinically-significant cardiac arrhythmias

                         -  Stroke (including transient ischemic attack [TIA], or other ischemic
                            event)

                         -  Myocardial infarction

                         -  Thromboembolic event requiring therapeutic anticoagulation (Note:
                            subjects with a venous filter [e.g. vena cava filter] are not eligible
                            for this study)

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

                    -  Any of the following =< 28 days before the first dose of study treatment

                         -  Intra-abdominal tumor/metastases invading GI mucosa

                         -  Active peptic ulcer disease as evidenced by esophagogastroduodenoscopy
                            (EGD)

                         -  Inflammatory bowel disease (including ulcerative colitis and Crohn's
                            disease), diverticulitis, cholecystitis, symptomatic cholangitis or
                            appendicitis

                         -  Malabsorption syndrome

                    -  Any of the following =< 6 months before the first dose of study treatment:

                         -  Abdominal fistula

                         -  Gastrointestinal perforation

                         -  Bowel obstruction or gastric outlet obstruction

                         -  Intra-abdominal abscess; Note: complete resolution of an
                            intra-abdominal abscess must be confirmed prior to initiating treatment
                            with cabozantinib even if the abscess occurred more than 6 months
                            before the first dose of study treatment

               -  Other disorders associated with a high risk of fistula formation including
                  percutaneous endoscopic gastrostomy (PEG) tube placement =< 3 months before the
                  first dose of study therapy

               -  Other clinically significant disorders such as:

                    -  Active infection requiring systemic treatment =< 28 days before the first
                       dose of study treatment

                    -  Serious non-healing wound/ulcer/bone fracture =< 28 days before the first
                       dose of study treatment

                    -  History of organ transplant

                    -  History of major surgery as follows:

                         -  Major surgery =< 3 months of the first dose of cabozantinib if there
                            were no wound healing complications or =< 6 months of the first dose of
                            cabozantinib if there were wound complications

                         -  Minor surgery =< 1 months of the first dose of cabozantinib if there
                            were no wound healing complications or =< 3 months of the first dose of
                            cabozantinib if there were wound complications

                         -  In addition, complete wound healing from prior surgery must be
                            confirmed at least 28 days before the first dose of cabozantinib
                            irrespective of the time from surgery

          -  The subject is unable to swallow tablets

          -  The subject has a corrected QT interval calculated by the Fridericia or Bazett's
             formula (QTcF) > 480 ms within 28 days before registration; Note: if initial QTcF or
             QTcB is found to be > 480 ms, two additional electrocardiograms (EKGs) separated by at
             least 3 minutes should be performed; if the average of these three consecutive results
             for QTcF or QTcB is =< 480 ms, the subject meets eligibility in this regard

          -  The subject is unable or unwilling to abide by the study protocol or cooperate fully
             with the investigator or designee

          -  The subject has had evidence within 2 years of the start of study treatment of another
             malignancy which required systemic treatment

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to cabozantinib

          -  Any of the following:

               -  Pregnant women

               -  Nursing women

               -  Men or women of childbearing potential who are unwilling to employ adequate
                  contraception

          -  Immunocompromised patients and patients known to be human immunodeficiency virus (HIV)
             positive and currently receiving antiretroviral therapy; Note: patients known to be
             HIV positive, but without clinical evidence of an immunocompromised state, are
             eligible for this trial

          -  The subject has received prior treatment with a small molecule kinase inhibitor or a
             hormonal therapy (including investigation kinase inhibitors or hormones) within 14
             days or five half-lives of the compound or active metabolites, whichever is longer,
             before the first dose of the treatment
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Manisha Shah, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01811212

Organization ID

NCI-2013-00554

Secondary IDs

NCI-2013-00554

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)

Collaborators

 Exelixis

Study Sponsor

Manisha Shah, Principal Investigator, Ohio State University Comprehensive Cancer Center


Verification Date

March 2018