Clinical trial NCT01271712: Study of Regorafenib as a 3rd-line or Beyond Treatment for Gastrointestinal Stromal Tumors (GIST)
Official title: A Randomized, Double-blind, Placebo-controlled Phase III Study of Regorafenib Plus Best Supportive Care Versus Placebo Plus Best Supportive Care for Subjects With Metastatic and/or Unresectable Gastrointestinal Stromal Tumors (GIST) Whose Disease Has Progressed Despite Prior Treatment With at Least Imatinib and Sunitinib
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Gastrointestinal Stromal Tumors
Keywords: Gastrointestinal stromal cancer
GIST
multikinase inhibitor
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2011-01-07
Enrollment: 199
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: A randomized, double-blind, placebo-controlled phase III study of regorafenib plus best supportive care versus placebo plus best supportive care for subjects with metastatic and/or unresectable gastrointestinal stromal tumors (GIST) whose disease has progressed despite prior treatment with at least imatinib and sunitinib.

The study is composed of 3 periods: A Screening Period, a Treatment Period, and a Survival Follow up Period.

Subjects randomized to be treated with regorafenib will receive 160 mg po od for 3 weeks of every 4 week (28 day) cycle (ie, 3 weeks on/1 week off). In addition subjects will receive best supportive care which excludes any disease specific anti cancer therapy such as any kinase inhibitor, chemotherapy, radiation therapy, or surgery.

Tumor assessment will be every 4 weeks for the first 3 months, every 6 weeks for the next 3 months (through month 6), and every 8 weeks until the end of treatment, or more frequently if clinically indicated. Tumor assessments include CT or MRI and will be performed until tumor progression is seen in a central radiology review.

Subjects receiving placebo who experience disease progression may be offered active treatment.

Subjects who experience progression during regorafenib treatment may continue open label treatment.

All subjects will enter the Survival Follow-up Period upon discontinuation of randomized study treatment.


Eligibility criteria: Inclusion Criteria:

* Male or female subjects 18 years of age.
* Subjects with histologically confirmed metastatic and/or unresectable GIST.
* At least imatinib and sunitinib as prior treatment regimens, with objective disease progression or intolerance to imatinib, as well as disease progression while on sunitinib therapy. Additionally, disease progression or intolerance to other systemic therapies, as well as investigational new agents, is allowed, except prior treatment with any other vascular endothelial growth factor receptor (VEGFR) inhibitor.
* Subjects must have at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST), version 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.

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

* Adequate bone marrow, liver, and renal function as assessed by laboratory parameters.

Recovery to NCI-CTCAE v4.0 Grade 0 or 1 level or recovery to baseline preceding the prior treatment from any previous drug/procedure-related toxicity (except alopecia and anemia).

Exclusion Criteria:

* Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication.
* Congestive heart failure New York Heart Association (NYHA) class 2.
* Unstable angina (angina symptoms at rest, new-onset angina, ie, within the last 3 months) or myocardial infarction (MI) within the past 6 months before start of study medication.
* Uncontrolled hypertension (systolic blood pressure 140 mmHg or diastolic pressure 90 mmHg despite optimal medical management).

Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or pulmonary embolism within the 6 months before start of study drug or venous thrombotic events such as deep vein thrombosis within the 3 months before start of study drug.

* Ongoing infection grade 2 National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.

Symptomatic metastatic brain or meningeal tumors.

* Subjects with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event NCI-CTCAE version 4.0 grade 3 or higher within 4 weeks prior to the start of study drug.

Non-healing wound, ulcer, or bone fracture.

* Persistent proteinuria of NCI-CTCAE version 4.0 grade 3 or higher (3.5 g/24 hrs, measured by urine protein:creatinine ratio on a random urine sample).

Primary outcomes:
measure: Progression-free Survival
timeFrame: From randomization of the first subject until approximately 144 progression-free survival events had occurred (study duration approximately one year)
Secondary outcomes:
measure: Overall Survival
timeFrame: From randomization of the first subject until date of database cutoff (08 Jun 2015)
measure: Time to Progression (TTP)
timeFrame: From randomization of the first subject until until date of database cutoff (26 Jan 2012); study duration approximately 1 year
measure: Tumor Response
timeFrame: From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year
measure: Objective Response Rate
timeFrame: From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year.
measure: Disease Control Rate (DCR)
timeFrame: From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year
measure: Duration of Response (DOR)
timeFrame: From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year
Other outcomes:
Locations:
city: Scottsdale
country: United States
state: Arizona
city: Evanston
country: United States
state: Illinois
city: Skokie
country: United States
state: Illinois
city: Boston
country: United States
state: Massachusetts
city: Minneapolis
country: United States
state: Minnesota
city: New York
country: United States
state: New York
city: Portland
country: United States
state: Oregon
city: Philadelphia
country: United States
state: Pennsylvania
city: Seattle
country: United States
state: Washington
city: Graz
country: Austria
state: Steiermark
city: Innsbruck
country: Austria
city: Wien
country: Austria
city: Leuven
country: Belgium
city: Edmonton
country: Canada
state: Alberta
city: London
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Guangzhou
country: China
state: Guangdong
city: Nanjing
country: China
state: Jiangsu
city: Beijing
country: China
city: Shanghai
country: China
city: Helsinki
country: Finland
city: Bordeaux Cedex
country: France
city: Lille Cedex
country: France
city: Lyon Cedex 08
country: France
city: Villejuif
country: France
city: Mannheim
country: Germany
state: Baden-Württemberg
city: Tübingen
country: Germany
state: Baden-Württemberg
city: Bad Saarow
country: Germany
state: Brandenburg
city: Hannover
country: Germany
state: Niedersachsen
city: Düsseldorf
country: Germany
state: Nordrhein-Westfalen
city: Essen
country: Germany
state: Nordrhein-Westfalen
city: Köln
country: Germany
state: Nordrhein-Westfalen
city: Tel Aviv
country: Israel
city: Bologna
country: Italy
state: Emilia-Romagna
city: Milano
country: Italy
state: Lombardia
city: Torino
country: Italy
state: Piemonte
city: Palermo
country: Italy
state: Sicilia
city: Nagoya
country: Japan
state: Aichi
city: Kashiwa
country: Japan
state: Chiba
city: Sapporo
country: Japan
state: Hokkaido
city: Chuo-ku
country: Japan
state: Tokyo
city: Niigata
country: Japan
city: Osaka
country: Japan
city: Goyang-si
country: Korea, Republic of
state: Gyeonggido
city: Busan
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Leiden
country: Netherlands
city: Nijmegen
country: Netherlands
city: Warszawa
country: Poland
city: Singapore
country: Singapore
city: L'Hospitalet de Llobregat
country: Spain
state: Barcelona
city: Barcelona
country: Spain
city: Leicester
country: United Kingdom
state: Leicestershire
city: London
country: United Kingdom
city: Manchester
country: United Kingdom
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References:
citation: 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, Schoffski 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.
citation: Poole CD, Connolly MP, Chang J, Currie CJ. Health utility of patients with advanced gastrointestinal stromal tumors (GIST) after failure of imatinib and sunitinib: findings from GRID, a randomized, double-blind, placebo-controlled phase III study of regorafenib versus placebo. Gastric Cancer. 2015 Jul;18(3):627-34. doi: 10.1007/s10120-014-0391-x. Epub 2014 Jun 24.
citation: Komatsu Y, Doi T, Sawaki A, Kanda T, Yamada Y, Kuss I, Demetri GD, Nishida T. Regorafenib for advanced gastrointestinal stromal tumors following imatinib and sunitinib treatment: a subgroup analysis evaluating Japanese patients in the phase III GRID trial. Int J Clin Oncol. 2015 Oct;20(5):905-12. doi: 10.1007/s10147-015-0790-y. Epub 2015 Feb 6.
citation: Mross K, Frost A, Steinbild S, Hedbom S, Buchert M, Fasol U, Unger C, Kratzschmar J, Heinig R, Boix O, Christensen O. A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin Cancer Res. 2012 May 1;18(9):2658-67. doi: 10.1158/1078-0432.CCR-11-1900. Epub 2012 Mar 15.