Dovitinib for Imatinib/Sumitinib-failed Gastrointestinal Stromal Tumors (GIST): TKI258

NCT01440959 | Completed Phase 2 Results

• 1 other identifier: AMC1403
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

With discovery of KIT mutations and the advent of KIT tyrosine kinase inhibitor imatinib (GlivecTM, Novartis), there has been substantial improvement in overall survival in patients with advanced and/or metastatic gastrointestinal tumors (GIST). Recently, sunitinib (SuteneTM, Pfizer) showed activity as second-line therapy in GIST patients after failure with imatinib. However, virtually all patients will eventually progress or become intolerable after the first-line imatinib and the second-line sunitinib. Dovitinib (TKI258, Novartis) is a multi-kinase inhibitor. TKI258 is a potent inhibitor of the VEGFR 1, 2, and 3, FGFR1, 2 and 3, PDGFRβ, Kit, RET, TrkA, CSF 1R, and FLT3 with inhibitory concentration 50% (IC50s) of less than 40nM. Stem cell factor (SCF) also termed KIT ligand, or steel factor has been shown to modulate tumor angiogenesis. In cultured human endothelial cells and Kit expressing cancer cells, TKI258 inhibits VEGF- and SCF-stimulated mitogenesis. .

Conditions

Gastrointestinal Stromal Tumors

Keywords

This is a single-center; prospective; single-arm; open-label phase II study

Outcome Measures

Primary Outcomes (1)

• Disease Control Rate (DCR; OR + Stable Disease)

  Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR; Progressive disease (PD), \>20% increase in the sum of the longest diameter of target lesions; Stable Disease (SD), Insufficient change to qualify for PR or PD This was evaluated with abdominal and pelvic dynamic CT scan every 4 weeks for the initial 8 weeks, and then every 8 weeks.

  Up to 24 weeks

Secondary Outcomes (6)

• Overall Response Rate Using Both CT and PET Scans

  Up to 24 weeks

• Efficacy According to the Primary Mutation Type

  Up to 24weeks

• Efficacy According to the Concentrations of Circulating Growth Factors

  Up to 24weeks

• Number of Participants With Adverse Events

  Monitoring of adverse events will be continued for at least 28 days following the last dose of study treatment, up to 3 year.

• Progression-free Survival

  Up to 3 years

Study Arms (1)

TKI258

EXPERIMENTAL

Drug: dovitinib

Interventions

dovitinib DRUG

TKI258 at 500 mg/day on a 5 days on/2 days off dosing schedule

Also known as: A phase II study of TKI258

TKI258

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 20 years or older
• Histologically confirmed metastatic and/or advanced GIST with CD117(+), DOG-1(+), or mutation in KIT or PDGFRα gene
• Failed (progressed and/or intolerable) after prior treatments for GIST, including at least both imatinib and sunitinib .
• ECOG performance status of 0\~2
• Resolution of all toxic effects of prior treatments to grade 0 or 1 by NCI-CTCAE version 3.0
• At least one measurable lesion as defined by RECIST version 1.0.
• Adequate bone marrow, hepatic, renal, and other organ functions
• Neutrophil \> 1,500/mm3
• Platelet \> 75,000/mm3
• Hemoglobin \> 8.0 g/dL
• Total bilirubin \< 1.5 x upper limit of normal (ULN)
• AST/ALT \< 2.5 x ULN (or \< 5 x ULM in case of liver metastases)
• Creatinine \< 1.5 x ULN
• Amylase, lipase \< ULN
• Electrolytes should be within normal limits.

You may not qualify if:

• Women of child-bearing potential who are pregnant or breast feeding or adults of reproductive potential not employing an effective method of birth control.
• Clinically significant cardiac disease (New York Heart Association, Class III or IV) or impaired cardiac function or clinically significant cardiac diseases,
• Uncontrolled infection.
• Diabetes mellitus (insulin dependent or independent disease, requiring chronic medication) with signs of clinically significant peripheral vascular disease.
• Previous pericarditis; clinically significant pleural effusion in the previous months or current ascites requiring two or more interventions/month.
• Known pre-existing clinically significant disorder of the hypothalamic-pituitary axis, adrenal or thyroid glands.
• Prior acute or chronic pancreatitis of any etiology.
• Acute and chronic liver disease and all chronic liver impairment.
• Malabsorption syndrome or uncontrolled gastrointestinal toxicities with toxicity greater than NCI CTCAE grade 2.
• Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality.
• Treatment with any of the medications that have a potential risk of prolonging the QT interval or inducing Torsades de Points and the treatment cannot be discontinued or switched to a different medication prior to starting study drug.
• Use of ketoconazole, erythromycin, carbamazepine, phenobarbital, rifampin, phenytoin and quinidine 2 weeks prior baseline.
• Major surgery ≤ 28 days prior to starting study drug or who have not recovered from side effects of such therapy.
• Known diagnosis of HIV infection .
• History of another primary malignancy that is currently clinically significant or currently requires active intervention.

Sponsors & Collaborators

• Asan Medical Center: lead

Study Sites (1)

Asan Medical Center, University of Ulsan College of Medicine

Seoul, 138-736, South Korea

Location

MeSH Terms

Conditions

Gastrointestinal Stromal Tumors

Interventions

4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one

Condition Hierarchy (Ancestors)

Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases

Results Point of Contact

• Title: Dr. Yoon-Koo Kang
• Organization: Asan Medical Center

ykkang@amc.seoul.kr

+82-2-3010-3210

Study Officials

• Yoon-Koo Kang, MD, PhD

  Asan Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Study Principal Investigator

Study Record Dates

• First Submitted: September 8, 2011
• First Posted: September 27, 2011
• Study Start: September 1, 2011
• Primary Completion: March 1, 2013
• Study Completion: March 1, 2013
• Last Updated: January 18, 2020
• Results First Posted: March 3, 2014

Record last verified: 2020-01

Locations

KR (1)