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Phase 2 Trial of Ponatinib in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumor Following Failure of Prior Therapy With at Least 1 Tyrosine Kinase Inhibitor


Phase 2
18 Years
N/A
Open (Enrolling)
Both
GIST

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Trial Information

Phase 2 Trial of Ponatinib in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumor Following Failure of Prior Therapy With at Least 1 Tyrosine Kinase Inhibitor


This is a non-randomized, open label, multicenter phase 2 study to evaluate the efficacy and
safety of ponatinib in patients with metastatic and/or unresectable GIST after prior failure
of at least 1 TKI. 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, electrocardiogram (ECG), echocardiograms (ECHO), 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.


Inclusion Criteria:



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

1. Histologically confirmed metastatic and/or unresectable GIST after at least 1
failure of any prior treatment with a TKI. 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. Myocardial infarction (MI) within 6 months prior to enrollment

2. Unstable angina within 6 months prior to enrollment

3. Congestive heart failure within 6 months prior to enrollment, or LVEF less than
lower limit of normal per local institutional standards

4. History of clinically significant (as determined by the treating physician)
atrial arrhythmia

5. Any history of ventricular arrhythmia

6. Cerebrovascular accident or transient ischemic attack (TIA) within 6 months
prior to enrollment

7. Any history of peripheral arterial occlusive disease requiring revascularization

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 that are known to be associated with 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

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Clinical Benefit Rate (CBR)

Outcome Description:

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

Outcome Time Frame:

16 weeks after first dose

Safety Issue:

No

Authority:

United States: Food and Drug Administration

Study ID:

AP24534-12-202

NCT ID:

NCT01874665

Start Date:

May 2013

Completion Date:

Related Keywords:

  • GIST
  • Gastrointestinal Neoplasms
  • Gastrointestinal stromal tumor
  • mesenchymal tumor
  • Gastrointestinal Stromal Tumors

Name

Location

Oregon Health & Sciences UniversityPortland, Oregon  97201