Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial of SU11248 in Patients Following Failure of Imatinib for Metastatic GIST

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View the ASCO presentation by Dr. George Demetri

Trial results presented at the 2005 ASCO meeting: Abstract 4000

Trial Design:

A phase 3, multicenter, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of SU11248 in patients with GIST following failure of Imatinib (due to objective disease progression or intolerable adverse effects of prior imatinib). SU11248 was administered at 50 mg/day for 4 weeks, followed by a 2-week break in each 6-week cycle, and was compared with placebo (randomization ratio of 2:1, SU112348 to placebo). Patients who progressed had their treatment unblinded and were offered crossover to receive SU11248 therapy.

Objective:

To determine the efficacy of SU11248 in patients with imatinib-resistant GIST, or those intolerant to imatinib therapy

Number of Patients:

Intent-to-treat population: 312 (efficacy analysis)
- SU11248: 207
- Placebo: 105
As-treated population: 304 (safety analysis)
- SU11248: 202
- Placebo: 102

Key Inclusion Criteria:

Histologically-proven diagnosis of malignant GIST
Measurable disease
Demonstrated failure of prior treatment with imatinib (disease progression or significant toxicity)
Resolution of prior imatinib toxicity
ECOG performance score of 0 or 1
Adequate organ function
Age ≥ 18 years

Key Exclusion Criteria:

Other concurrent treatments for GIST
Diagnosis of other malignancy within the last 5 years
Significant cardiovascular disease
Positive for human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness

Results:

All efficacy endpoints were achieved at the first interim analysis and treatment was unblinded following discussion between the Independent Data and Safety Monitoring Board and Study Sponsor (Pfizer)

Blinded Phase

During the blinded phase, SU11248 was associated with a >4-fold increase in median time-to-progression (the primary endpoint of the trial) compared with placebo (6.3 vs 1.5 months; P<0.00001; hazard ratio [HR]=0.335
SU11248 significantly improved survival compared with placebo (P-0.00674; HR=0.491)
Non-hematologic adverse events that were more common in the SU11248 treated arm included low-grade fatigue, diarrhea, nausea, sore mouth, skin discoloration, and hand-foot effects and higher grade hypertension.
Hematologic adverse events that were more common in the SU11248 arm were neutropenia and thrombocytopenia, primarily low grade.

Efficacy-cross-over

59 placebo-treated patients opted to receive SU11248; patients in the SU11248 arm could continue if clinical benefit was perceived
10% of placebo cross-over patients subsequently experienced a partial response

Overall response (Central Review Assessment)

	SU11248 (n=207)	Placebo (n=105)
Partial response	8	0
Stable disease	58	50
Progressive disease	20	39
Not evaluable (too early or missing)	14	11

Principal Investigator:

George D. Demetri, MD
Dana-Farber Cancer Institute

SU11248 Product Information:

SU11248 is now approved in many countries and is available as Sutent®.

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