Ponatinib for Advanced Medullary Thyroid Cancer

NCT01838642 | Terminated Phase 2 Results

• 2 other identifiers: 13010813-C-0108
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief Summary

Background:

• Medullary thyroid cancer (MTC) represents 5% of thyroid cancers and presents as a hereditary (25% of cases) or sporadic (75% of cases) neuroendocrine malignancy.
• MTC arises from the parafollicular C-cells of the thyroid.
• Germline mutations in the rearranged during transfection (RET) proto-oncogene occur in virtually all of hereditary MTC cases, and somatic RET mutations occur in 50% of sporadic cases.
• Drugs targeting RET kinase such as vandetanib and cabozantinib have shown efficacy in the treatment of advanced or metastatic MTC, however, more effective RET inhibitors are needed for previously untreated patients as well as patients who have become refractory to other molecular targeted therapeutics (MTTs).
• Ponatinib, a drug that is Food and Drug Administration (FDA) approved as a therapy for chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), is a potent inhibitor of RET kinase. Primary Objective:
• To determine the objective overall response rate (complete response \[CR\] + partial response \[PR\] by Response Evaluation Criteria in Solid Tumors (RECIST) to ponatinib in the treatment of patients with advanced or metastatic MTC previously treated with cabozantinib and vandetanib who: 1) have tumors with RET mutations and 2) have tumors without RET mutations. Eligibility:
• Patients must have histologically confirmed, unresectable, locally advanced or metastatic MTC, with measurable disease by RECIST criteria.
• Patients must have disease amenable to biopsy and be willing to undergo biopsy for molecular analysis, and also have adequate archival material from their thyroidectomy or from a tumor biopsy obtained prior to beginning any systemic therapy.
• Patients must have failed or been intolerant to prior treatment with both cabozantinib and vandetanib.
• The last dose of prior systemic therapy must be more than 28 days prior to the first dose of ponatinib
• Radiation therapy is permitted if the last treatment was received more than 28 days prior to the first dose of ponatinib. Design:
• Open label phase II trial with 2 treatment groups:
• RET mutation positive MTC, previously treated with vandetanib and cabozantinib
• RET mutation negative MTC, previously treated with vandetanib and cabozantinib
• Patients will receive ponatinib 30 mg orally daily until disease progression or until the development of intolerable side effects.
• Tumor response will be assessed by RECIST 1.1 criteria at 8 weeks and then every 12 weeks thereafter. After one year on study, tumor response will be assessed every 16 weeks.
• Patients will have a biopsy of their MTC for molecular analysis prior to initiating treatment with ponatinib. Patients will also have a biopsy of their MTC at the time of tumor progression, should that occur.

Conditions

Thyroid Neoplasms

Keywords

Monoclonal Antibody; AP24534; RET Mutation Positive; RET Mutation Negative; RET Inhibitor

Outcome Measures

Primary Outcomes (1)

• Overall Response Rate.

  Defined as the percentage of participants with a best response (complete response (CR) + partial response (PR)) recorded from the start of the treatment until disease progression/recurrence assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is the disappearance of all target lesions. Any pathological lymph nodes (Whether target or non-target) must have reduction in short axis to \<10 mm. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.

  2-4 months

Secondary Outcomes (7)

• Progression Free Survival

  2-4 months

• Number of Participants With Adverse Events

  17 months and 19 days

• Molecular Differences in Advanced Medullary Thyroid Cancer (MTC)

  Prior to the first dose of ponatinib

• Changes in Serum Levels of MTC Tumor Markers Calcitonin (CTN) and Its Relation With Clinical Response

  Baseline to 4 weeks

• Objective Response to Ponatinib

  up to 4 cycles of treatment with ponatinib

Study Arms (2)

RET mutation positive participants

ACTIVE COMPARATOR

Rearranged during transfection (RET) mutation positive

Drug: Ponatinib

RET mutation negative participants

ACTIVE COMPARATOR

Rearranged during transfection (RET) mutation negative

Drug: Ponatinib

Interventions

Ponatinib DRUG

Ponatinib tablets will be administered orally, continually, once daily at a dose of 30 mg. A cycle of ponatinib is defined as 28 consecutive days starting with the first day of the treatment cycle. Treatment will be administered primarily in an outpatient setting.

RET mutation negative participants; RET mutation positive participants

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of localized or metastatic unresectable medullary thyroid cancer (MTC). The histological diagnosis of MTC must be confirmed on review of submitted tumor tissue by the Laboratory of Pathology in the National Cancer Institute
• 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 greater than or equal to 20 mm with conventional techniques or as greater than or equal to 10 mm with spiral computed tomography (CT) scan.
• Disease amenable to biopsy and agree to undergo biopsy for molecular analysis
• The last dose of previous therapy targeting rearranged during transfection (RET) kinase must be given at least 4 weeks prior to the first dose of ponatinib.
• Previous treatment with cytotoxic chemotherapy, immunotherapy, or radiotherapy are permitted, if the last dose was given at least 4 weeks prior to the first dose of ponatinib
• Patient must have failed (progressed on or been intolerant of) prior treatment with cabozantinib and vandetanib.
• Age greater than or equal to 18 years old
• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
• Normal organ and marrow function as defined below:
• Leukocytes greater than or equal to microL
• Absolute neutrophil count 1,500/microL
• Platelet count greater than or equal to 100,000 microL
• Total bilirubin \< 1.5 times upper limit of normal (ULN)
• Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase(SGOT)/alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) \< 2.5 times institutional ULN or \< 5 times ULN if liver involvement
• Prothrombin Time \< 1.5 times ULN

You may not qualify if:

• Patients who are receiving any other investigational agent.
• Patients with brain metastases or spinal cord compression unless they completed radiation therapy greater than or equal to 4 weeks prior to the first dose of ponatinib and are stable without steroids or anti-convulsant therapy for greater than or equal to 10 days.
• Medications that are known to be associated with Torsades de Pointes.
• Uncontrolled hypertension (systolic blood pressure \> 150 or diastolic blood pressure \> 100
• Significant or active cardiovascular disease, specifically including but not restricted to:
• History of myocardial infarction
• History of atrial or ventricular arrhythmia
• Unstable angina within 6 months prior to first dose of ponatinib
• History of congestive heart failure
• Left ventricular ejection fraction fraction (LVEF) less than lower limit of normal
• History of peripheral arterial occlusive disease
• History of cerebrovascular accident or transient ischemic attack
• Venous thromboembolism including deep venous thrombosis or pulmonary embolism within 6 months prior to enrollment
• A history of pancreatitis or alcohol abuse
• Uncontrolled hypertriglyceridemia (\> 450 mg/dL)

Sponsors & Collaborators

• National Institutes of Health Clinical Center (CC): lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Lakhani VT, You YN, Wells SA. The multiple endocrine neoplasia syndromes. Annu Rev Med. 2007;58:253-65. doi: 10.1146/annurev.med.58.100305.115303.

  PMID: 17037976 BACKGROUND

• Modigliani E, Cohen R, Campos JM, Conte-Devolx B, Maes B, Boneu A, Schlumberger M, Bigorgne JC, Dumontier P, Leclerc L, Corcuff B, Guilhem I. Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d'etude des tumeurs a calcitonine. Clin Endocrinol (Oxf). 1998 Mar;48(3):265-73. doi: 10.1046/j.1365-2265.1998.00392.x.

  PMID: 9578814 BACKGROUND

• Moley JF, DeBenedetti MK. Patterns of nodal metastases in palpable medullary thyroid carcinoma: recommendations for extent of node dissection. Ann Surg. 1999 Jun;229(6):880-7; discussion 887-8. doi: 10.1097/00000658-199906000-00016.

  PMID: 10363903 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Thyroid Neoplasms

Interventions

ponatinib

Condition Hierarchy (Ancestors)

Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Head and Neck Neoplasms; Endocrine System Diseases; Thyroid Diseases

Results Point of Contact

• Title: Dr. James Gulley
• Organization: National Cancer Institute

gulleyj@mail.nih.gov

301-496-4916

Study Officials

• James Gulley, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: April 20, 2013
• First Posted: April 24, 2013
• Study Start: March 1, 2013
• Primary Completion: December 1, 2015
• Study Completion: January 1, 2016
• Last Updated: February 15, 2017
• Results First Posted: March 17, 2016

Record last verified: 2016-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)