A Phase 2 Trial of Ponatinib in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumor

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Ariad Pharmaceuticals
Sponsor:
Information provided by (Responsible Party):
Ariad Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT01874665
First received: May 29, 2013
Last updated: May 23, 2014
Last verified: May 2014

May 29, 2013
May 23, 2014
May 2013
June 2016   (final data collection date for primary outcome measure)
Clinical Benefit Rate (CBR) [ Time Frame: 16 weeks after first dose ] [ Designated as safety issue: No ]
To assess clinical benefit rate in patients with KIT exon 11-mutant GIST. Defined as the composite of complete response (CR), partial response (PR), and stable disease (SD) lasting ≥16 weeks per modified RECIST 1.1 as a measure of disease control
Same as current
Complete list of historical versions of study NCT01874665 on ClinicalTrials.gov Archive Site
  • Clinical Benefit Rate (CBR) [ Time Frame: 16 weeks after first dose ] [ Designated as safety issue: No ]
    To assess clinical benefit rate in patients with GIST that lacks KIT exon 11 mutations (Cohort B) and in the total patient population
  • Progression-free survival (PFS) [ Time Frame: From date of enrollment until the end of the study or disease progression or death due to any cause, whichever came first, assessed up to 3 years ] [ Designated as safety issue: No ]
    Defined as the duration of time from start of study drug administration to time of objective disease progression or death due to any cause, whichever may come first. To assess PFS in each cohort and in the total patient population
  • Objective Response Rate (ORR) [ Time Frame: From date of enrollment until discontinuation or the end of the study, whichever came first, assessed up to 3 years ] [ Designated as safety issue: No ]
    Defined as the composite of CR and PR. To assess objective response rate (ORR) in each cohort and in the total patient population
  • Overall survival (OS) [ Time Frame: From date of enrollment until the end of the study or death, whichever came first, assessed up to 3 years ] [ Designated as safety issue: No ]
    Defined as the interval between enrollment and death due to any cause, censored at the last contact date. To assess OS in each cohort and in the total patient population
  • Safety [ Time Frame: From date of enrollment until the End-of-Treatment, assessed up to 3 years ] [ Designated as safety issue: Yes ]
    Measured by routine physical and laboratory evaluations, ECG, ECHO, and AE monitoring. To evaluate the safety and tolerability of ponatinib in the total patient population
  • Pharmacokinetic (PK) parameters of steady-state plasma concentration [ Time Frame: Up to 1 month after the start of treatment ] [ Designated as safety issue: No ]
    PK samples will be taken to assess limited elements of PK in the total patient population
Same as current
Not Provided
Not Provided
 
A Phase 2 Trial of Ponatinib in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumor
Phase 2 Trial of Ponatinib in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumor Following Failure of Prior Tyrosine Kinase Inhibitor Therapy

The purpose of this study is to evaluate the efficacy and safety of ponatinib in patients with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) following failure of prior tyrosine kinase inhibitor (TKI) therapy.

This is a non-randomized, open label, multi-center phase 2 study to evaluate the efficacy and safety of ponatinib in patients with metastatic and/or unresectable GIST after failure of prior TKI therapy. Patients whose tumors have an activating mutation in exon 11 of cellular KIT (KIT) will be enrolled into Cohort A. Patients whose tumors have other activating mutations will be enrolled into in Cohort B.

The primary objective is to assess clinical benefit in patients with KIT exon 11-mutant GIST (Cohort A) defined as clinical benefit rate (CBR), which is the composite of complete response (CR), partial response (PR) and stable disease (SD) lasting ≥16 weeks per modified response evaluation criteria in solid tumors (RECIST 1.1 [Demetri et al., 2012]) as a measure of disease control. The secondary objective is to assess clinical benefit in patients with GIST that lacks an activating KIT exon 11 mutation (Cohort B) and in the total patient population. The efficacy assessments are tumor response using Response Criteria in Solid Tumors (RECIST) Version 1.1, modified for GIST and assessment of progression-free survival (PFS) and overall survival (OS). The safety assessments include routine physical and laboratory evaluations, electrocardiograms (ECGs), echocardiograms (ECHOs), and adverse event (AE) monitoring. Other assessments include optional 18F fluorodeoxyglucose positron emission tomography (FDG-PET); optional pre- and post-treatment tumor biopsy for pharmacodynamic studies; and pharmacokinetics (PK). It is estimated that accrual will be complete within 1 year; the total estimated duration of the study is 3 years.

Interventional
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
GIST
Drug: ponatinib
45 mg tablet, taken orally once-daily
Other Name: AP24534
Experimental: ponatinib
Patients with KIT exon 11-mutant GIST (Cohort A) and patients with GIST that lack KIT exon 11 mutations (Cohort B)
Intervention: Drug: ponatinib
Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, Hohenberger P, Leahy M, von Mehren M, Joensuu H, Badalamenti G, Blackstein M, Le Cesne A, Schöffski P, Maki RG, Bauer S, Nguyen BB, Xu J, Nishida T, Chung J, Kappeler C, Kuss I, Laurent D, Casali PG; GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):295-302. doi: 10.1016/S0140-6736(12)61857-1. Epub 2012 Nov 22.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
45
Not Provided
June 2016   (final data collection date for primary outcome measure)

Inclusion Criteria:

  1. GIST with failure of prior TKI therapy defined as:

    1. Histologically confirmed metastatic and/or unresectable GIST after experiencing failure of prior treatment with imatinib, sunitinib, and regorafenib. If prior TKI treatment was neoadjuvant therapy, then relapse must have occurred during the neoadjuvant therapy in order to consider it failed therapy
    2. Patients in Cohort A must have evidence of activation mutations of exon 11 of KIT in their tumors. Demonstration of an exon 11 mutation may be based on prior assessment or on evaluation of a tumor sample after enrollment in this study. Patients in Cohort B must have GIST that lacks activating mutations in KIT exon 11, but may have evidence of another activating mutation such as in KIT exon 9 or PDGFR-α. Patients may be enrolled in the study prior to determination of appropriate cohort (as long as both cohorts are open for enrollment).
  2. Measurable disease per modified RECIST 1.1. A lesion in a previously irradiated area is eligible to be considered as measurable disease as long as there is objective evidence of progression of the lesion prior to study enrollment
  3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
  4. Adequate hepatic function as defined by the following criteria:

    1. Total serum bilirubin ≤1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome
    2. ALT ≤2.5×ULN or ≤5.0xULN if liver metastases are present
    3. AST ≤2.5×ULN or ≤5.0xULN if liver metastases are present
  5. Adequate renal function as defined by the following criterion:

    a. Serum creatinine <1.5×ULN

  6. Adequate pancreatic function as defined by the following criterion:

    a. Serum lipase and amylase ≤1.5×ULN

  7. Fully recovered (≤Grade 1 or returned to baseline or deemed irreversible) from the acute effects of prior cancer therapy before initiation of study drug

Exclusion Criteria:

  1. Major surgery within 28 days prior to initiating therapy
  2. History of bleeding disorder
  3. History of acute pancreatitis within 1 year of study or history of chronic pancreatitis
  4. History of alcohol abuse
  5. Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL)
  6. Clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:

    1. Any history of myocardial infarction (MI)
    2. Any history of unstable angina
    3. Congestive heart failure within 6 months prior to enrollment, or LVEF less than lower limit of normal per local institutional standards within 6 months prior enrollment
    4. History of clinically significant (as determined by the treating physician) atrial arrhythmia
    5. Any history of ventricular arrhythmia
    6. Any history of cerebrovascular accident or transient ischemic attack (TIA)
    7. Any history of peripheral vascular infarction, including visceral infarction; or any revascularization procedure of any vasculature, including the placement of a stent
    8. Venous thromboembolism including deep venous thrombosis (DVT) or pulmonary embolism within 6 months prior to enrollment
  7. Uncontrolled hypertension (diastolic blood pressure >90 mm Hg; systolic >140 mm Hg). Patients with hypertension should be under treatment on study entry to effect blood pressure control
  8. Taking medications with a known risk of Torsades de Pointes
  9. Taking any medications or herbal supplements that are known to be strong inhibitors of CYP3A4 within at least 14 days before the first dose of ponatinib
  10. Ongoing or active infection. This includes, but is not limited to, the requirement for intravenous antibiotics
  11. Known history of human immunodeficiency virus. Testing is not required in the absence of prior documentation or known history
  12. Pregnant or breastfeeding
  13. Malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drugs
  14. Individuals with a history of a different malignancy, other than cervical cancer in situ, basal cell or squamous cell carcinoma of the skin, are ineligible, except if they have been disease-free for at least 5 years, and are deemed by the investigator to be at low risk for recurrence of that malignancy OR if the other primary malignancy is neither currently clinically significant nor requiring active intervention.
  15. Use of any approved TKIs or investigational agents within 2 weeks or 6 half-lives of the agent, whichever is longer, prior to receiving study drug
  16. Any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of the drug
Both
18 Years and older
No
Contact: Frank G. Haluska, MD, PhD 617-494-0400 frank.haluska@ariad.com
Contact: Christopher D. Turner, MD 617-494-0400 christopher.turner@ariad.com
United States
 
NCT01874665
AP24534-12-202
No
Ariad Pharmaceuticals
Ariad Pharmaceuticals
Not Provided
Not Provided
Ariad Pharmaceuticals
May 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP