Ponatinib in Advanced or Metastatic Medullary Thyroid Cancer

A Study of Ponatinib in Advanced or Metastatic Medullary Thyroid Cancer (MTC)

The primary objective of this study is to determine in an exploratory manner the objective overall response rate to ponatinib in the treatment of patients with advanced or metastatic MTC previously treated with cabozantinib or vandetanib who have tumors with rearranged-during-transfection (RET) mutations and have tumors without RET mutations.

Study Overview

• Status: Withdrawn
• Conditions: Medullary Thyroid Cancer
• Intervention / Treatment: Drug: Ponatinib

Detailed Description

Ponatinib is an investigational agent that blocks abnormal cancer proteins and therefore harms cancer cells. It was recently approved by the Food and Drug Administration for leukemia treatment, but is not approved for medullary thyroid cancer treatment. Early studies, however, have shown that medullary thyroid tumors respond to ponatinib. These studies were done in the laboratory and not performed on humans. This is a study designed for patients with medullary thyroid cancer. Treatment will consist of a drug called ponatinib which is a pill that taken once each day and continue throughout the duration of the study. The purpose of the study is to:

1. Determine if this treatment will be effective in decreasing the amount of cancer and, if it does, to determine how long the response will last.
2. Determine the side effects that may occur with this treatment.
3. To analyze genetic mutations in tumors to help us understand how tumors grow and how these drugs interact with the mechanisms within the tumor.

Ponatinib has been given to many patients with leukemia and is now approved by the United States Food and Drug Administration for treatment of certain types of leukemia. This study will seek to determine if ponatinib can bring benefit to patients with medullary thyroid cancer.

• Study Type: Interventional
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of localized or metastatic unresectable MTC.
• 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 ≥20 mm with conventional techniques or as ≥10 mm with spiral computerized tomography (CT) scan.
• The last dose of previous therapy targeting RET kinase must be given at least 4 weeks - 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 or vandetanib.
• Age ≥18 years old
• Eastern Cooperative Oncology Group (ECOG) performance status ≤2
• Normal organ and marrow function as defined below:

• Negative pregnancy test for women of childbearing potential or male patients, even if surgically sterilized (i.e., status post-vasectomy), who:

  • Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or
  • Agree to completely abstain from heterosexual intercourse
• Normal QT interval corrected on screening electrocardiogram (ECG) evaluation, defined as the corrected QT interval by Fredericia (QTcF) of ≤450 ms.
• Ability to understand and the willingness to sign a written informed consent document and follow the guidelines of the clinical protocol including visits for treatment and follow up
• Life expectancy of greater than 12 weeks
• Available archival tissue or willingness to undergo fresh biopsy if no archival tissue is available.

Exclusion Criteria:

• Patients who are receiving any other investigational agent.
• Patients with brain metastases or spinal cord compression unless they completed radiation therapy ≥4 weeks prior to the first dose of ponatinib and are stable without steroids or anti-convulsant therapy for ≥10 days.
• Patients who cannot discontinue medications that are known to be associated with Torsades de Pointes. These medications are listed in Attachment 3
• Uncontrolled hypertension (systolic blood pressure >150 or diastolic blood pressure >100
• Significant or active cardiovascular disease within 6 months prior to enrollment
• A history of pancreatitis or alcohol abuse
• Uncontrolled hypertriglyceridemia (>450 mg/dL)
• Major surgery (with the exception of minor surgical procedures, such as catheter placement or tumor biopsy) within 28 days prior to the first dose of ponatinib
• Ongoing or active infection including known history of human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C (HCV). Testing for these viruses is not required in the absence of a history of infection.
• Suffer from any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of the safety of the study drug
• Evidence of a bleeding diathesis that cannot be corrected with standard therapy or factor replacement
• Presence of another primary malignancy within the past 2 years (except for non-melanoma skin cancer or cervical cancer in situ. Prior prostate cancer is also permitted if prostate-specific antigen (PSA) is now undetectable)
• Pregnant or lactating
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to investigational agent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ponatinib Arm; Ponatinib tablets will be taken by mouth, continuously, 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 can be taken with water, with or without food, at approximately the same time each day.	Drug: Ponatinib; A daily oral dose at 30 mg.; Other Names: ICLUSIG

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	ORR is defined as the proportion of the subjects in the analysis population who have a complete response (CR) or partial response (PR). Responses are based on assessments per RECIST.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	PFS is defined as the time from the first day of trial treatment to the first documented disease progression per the Kaplan-Meier curve.	24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Number of Adverse Reactions	Testing safety and toxicity assessed using CTCAE criteria	24 months

Collaborators and Investigators

• Sponsor: Antonio Fojo
• Collaborators: Millennium Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): July 26, 2019
• Primary Completion (Actual): June 14, 2021
• Study Completion (Actual): June 14, 2021

Study Registration Dates

• First Submitted: February 11, 2019
• First Submitted That Met QC Criteria: February 11, 2019
• First Posted (Actual): February 12, 2019

Study Record Updates

• Last Update Posted (Actual): October 13, 2021
• Last Update Submitted That Met QC Criteria: October 6, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Ponatinib; Metastatic Medullary; Advanced Medullary
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Thyroid Diseases; Thyroid Neoplasms; Carcinoma, Neuroendocrine; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Ponatinib
• Other Study ID Numbers: AAAR5196

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No