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Poorly Differentiated Thyroid Gland CarcinomaPhase 2NCT01811212

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

A Phase 2 study testing Cabozantinib S-malate and Laboratory Biomarker Analysis in people with Poorly Differentiated Thyroid Gland Carcinoma and Recurrent Thyroid Gland Carcinoma, run by National Cancer Institute (NCI) at 7 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Cabozantinib S-malate and Laboratory Biomarker Analysis
Could I receive a placebo?
No, everyone receives an active treatment
How many people
25 participants
Where
7 sitesUnited States
Study dates
8 May 2013to 9 Oct 2017
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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
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  • 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

Trial locations and contacts

7 sites in 1 country.

7 sites in 1 country

United States7 sites

  • Massachusetts General Hospital Cancer Center

    Boston, Massachusetts, 02114

  • University of Chicago Comprehensive Cancer Center

    Chicago, Illinois, 60637

  • Ohio State University Comprehensive Cancer Center

    Columbus, Ohio, 43210

  • M D Anderson Cancer Center

    Houston, Texas, 77030

  • Mayo Clinic in Florida

    Jacksonville, Florida, 32224-9980

  • Mayo Clinic

    Rochester, Minnesota, 55905

  • MedStar Georgetown University Hospital

    Washington D.C., District of Columbia, 20007

Other trials in United States

About this study

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

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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:

  1. 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:

  1. 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.

  1. 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.

Being tested
Cabozantinib S-malate, Laboratory Biomarker Analysis
Medical subject headings
Thyroid Neoplasms, Adenocarcinoma, Follicular, Thyroid Cancer, Papillary, Thyroid cancer, Hurthle cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Cabozantinib S-malateDrug

    Given PO

  • Laboratory Biomarker AnalysisOther

    Correlative studies

Study groups in NCT01811212
Study groupRoleWhat they receive
Treatment (cabozantinib-s-malate)ExperimentalPatients receive cabozantinib-s-malate PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Receives: Drug: Cabozantinib S-malate; Other: Laboratory Biomarker Analysis

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

    Measured: Up to 6 months

Secondary outcomes (9)

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

    Measured: Up to 2 months

  2. Duration of Objective Response as Assessed by the RECIST v1.1

    Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

    Measured: From date of documentation of response to the date of progression or death, assessed up to 1 year

  3. Expression Levels of Predictive Biomarkers of Response by Immunohistochemistry in Archived Tumor Tissue

    These baseline levels will be quantitatively summarized and graphically explored, in particular in terms of how they relate to clinical outcomes of interest. Analyses exploring differences in these angiogenic and correlative markers in relation to clinical outcomes will be largely hypothesis-generating. With limited numbers of patients patterns of difference will primarily be looked for using graphical analyses; these can include plots of these marker levels in relation to clinical outcomes to identify potential patterns of interest.

    Measured: Baseline

  4. Genotype of Biomarkers Potentially Predictive of Response

    These baseline levels will be quantitatively summarized and graphically explored, in particular in terms of how they relate to clinical outcomes of interest. Analyses exploring differences in these angiogenic and correlative markers in relation to clinical outcomes will be largely hypothesis-generating. With limited numbers of patients patterns of difference will primarily be looked for using graphical analyses; these can include plots of these marker levels in relation to clinical outcomes to identify potential patterns of interest.

    Measured: Baseline

  5. Incidence of Severe (Grade 3+) Adverse Events, Graded According to the National Cancer Institute CTCAE v4.0

    The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. Tolerability of the regimens will be assessed through assessing the number of patients who required dose modifications and/or dose delays. In addition, the proportion of patients who go off treatment due to adverse reactions or even those who refuse further treatment for lesser toxicities that inhibit their willingness to continue participation on the trial will be captured.

    Measured: Up to 1 year

  6. Overall Survival

    The Kaplan-Meier method will be used.

    Measured: Time from start of treatment to time of death, assessed up to 1 year

  7. Percent Change in Serum Tumor Marker Thyroglobulin Levels

    Side-by-side boxplots will be used to assess possible differences in this change between responders and non-responders, and scatterplots can assess the influence of baseline thyroglobulin levels on these measures of change.

    Measured: Baseline to 6 months

  8. Progression-free Survival

    The Kaplan-Meier method will be used.

    Measured: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year

  9. Response of Cabozantinib-s-malate in Bone Metastasis (Bone Metastasis-specific Progression Free Survival) as Evaluated by Functional Imaging

    Measured: Up to 2 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Mar 2013 (estimated)
  2. Study start8 May 2013
  3. Primary completion13 Jul 2015
  4. Study completion9 Oct 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
25 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01811212
Sponsor's protocol ID
NCI-2013-00554
Other IDs
NCI-2013-00554, 2012C0101, RU241210I, OSU 12154, 9312, 9312, N01CM00039, N01CM00070
Status last verified
Mar 2018
First submitted
12 Mar 2013
Last updated
3 Apr 2018
Data monitoring committee
Yes

Publications

  • Cabanillas ME, de Souza JA, Geyer S, Wirth LJ, Menefee ME, Liu SV, Shah K, Wright J, Shah MH. Cabozantinib As Salvage Therapy for Patients With Tyrosine Kinase Inhibitor-Refractory Differentiated Thyroid Cancer: Results of a Multicenter Phase II International Thyroid Oncology Group Trial. J Clin Oncol. 2017 Oct 10;35(29):3315-3321. doi: 10.1200/JCO.2017.73.0226. Epub 2017 Aug 17.

    PubMed 28817373

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Cabozantinib S-malate and Laboratory Biomarker Analysis in people with Poorly Differentiated Thyroid Gland Carcinoma and Recurrent Thyroid Gland Carcinoma, run by National Cancer Institute (NCI) at 7 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 26 inclusion and 56 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 3 Apr 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 3 Apr 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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 (time frame: Up to 6 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01811212, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Apr 2018.

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