Efficacy and Safety of Dovitinib in Patients With Gastrointestinal Stromal Tumors Refractory and/or Intolerant to Imatinib

Phase 2

Completed

Conditions: Gastrointestinal Stromal Tumors

Interventions: Drug: Dovitinib (TKI258)

Registration Number: NCT01478373

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: The purpose of this study is to evaluate the efficacy and safety of Dovitinib in patients with gastrointestinal stromal tumors refractory and/or intolerant to Imatinib

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 39

Inclusion Criteria

Histologically confirmed GIST of any anatomical location, which is 1) unresectable and/ or metastatic with documented disease progression while on therapy with imatinib or 2) surgically removed localized GIST, recurrent on adjuvant imatinib or recurrent within the first 3 months after discontinuation of adjuvant imatinib or 3) patients with unresectable and/or metastatic GIST intolerant to imatinib
Positive immunohistochemical staining for c-KIT (CD117); or negative staining for KIT, but with either positive staining for DOG1 or an identified mutation of KIT or PDGFRA gene
Documented disease progression according to RECIST (version 1.1) on prior therapy with imatinib at a dose of at least 400mg/day or patients with unresectable and/or metastatic GIST who are intolerant to imatinib
At least one measurable GIST lesion according to RECIST (version 1.1).
Adequate bone marrow, liver and renal function

Exclusion Criteria

Patients who have received any other tyrosine-kinase inhibitor but imatinib for GIST
Patients who received cytotoxic drugs ≤ 4 weeks prior to starting Dovitinib (TKI258)
Patients who are treated or planned to be treated concomitantly with other cytotoxic or antineoplastic treatments, such as chemotherapy, immunotherapy, biological response modifiers, or radiotherapy
Patients with another primary malignancy within 3 years prior to starting the study drug
Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic) ≤ 4 weeks prior to starting Dovitinib (TKI258) or who have not recovered from the adverse effects of such therapy
Patients with a history of pulmonary embolism (PE), or untreated deep venous thrombosis (DVT) within the past 6 months
Patients with impaired cardiac function or clinically significant cardiac diseases
Patients with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of Dovitinib
Patients with prior complete gastrectomy
Patients with brain metastasis or history of brain metastasis
Patients who are currently receiving anticoagulation treatment with therapeutic doses of warfarin or equivalent anticoagulant
Pregnant or breast-feeding women

Other protocol-defined inclusion/exclusion criteria may apply.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Dovitinib (TKI258)	Dovitinib (TKI258)	Patients will receive Dovitinib (TKI258) on an outpatient basis at the dose of 500 mg qd for 5 days followed by 2 days off, every week for cycle of 4 weeks (28d) until disease progression, unacceptable toxicity, or consent withdrawal.

Primary Outcome Measures

Name	Time	Method
Antitumor Activity of Dovitinib in Terms of Disease Control Rate (DCR): Complete Response+Partial Response +Stable Disease	12 Weeks	DCR is defined as the proportion of patients with a best overall response of Complete Responses (CR), Partial Response (PR) and Stable Disease (SD) at 12 weeks according to RECIST (version 1.1). Complete Response (CR): Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm 1;Partial Response (PR): At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm2. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD.

Secondary Outcome Measures

Name	Time	Method
Time to Treatment Failure (TTF)of Patients Treated With Dovitinib	9 months	TTF: the date of entry into the study to the earliest date of the first objective tumor progression, date of death due to any cause, or date of discontinuation due to reasons other than 'Protocol deviation' or 'Administrative problems'.
Progression-free Survival (PFS) of Patients Treated With Dovitinib	9 months	The PFS duration: time from entry into the study to the date of the first documented progression (assessed using conventional RECIST (version 1.1) or death due to any cause. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Overall Response Rate (ORR) of Patients Treated With Dovitinib	Baseline, 12 weeks	Outcome Measure Description: ORR: proportion of patients whose best overall response is either complete response (CR) or partial response (PR) according to RECIST (version 1.1). Complete Response (CR): Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm 1;Partial Response (PR): At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm2. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD.
Overall Survival (OS) of Patients Treated With Dovitinib	21 months (9 months of estimated treatment plus 12 months of survival follow up)	Outcome Measure Description: OS: time from the date of entry into the study to the date of death due to any cause. A patient who has not died by the date of the analysis cut-off would have the OS censored at the time of the last contact before the cut-off date.
Time to Tumor Progression (TTP)of Patients Treated With Dovitinib	9 months	TTP: time from the date of entry into the study to first documentation of tumor progression or death due to the underlying cancer. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
DCR (CR+PR+SD) at the End of Treatment	Up to 9 months of estimated treatment	DCR is defined as the proportion of patients with a best overall response of CR, PR and SD at the end of dovitinib treatment according to RECIST (version 1.1). Complete Response (CR): Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm 1;Partial Response (PR): At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm2. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD.
Duration of Response or Stable Disease (SD)	9 months	Duration of response or SD: time from date of entry into study to earliest date of first objective tumor progression or death. DCR is defined as proportion of patients with best overall response of CR, PR and SD at 12 weeks according to RECIST (version 1.1). CR: Disappearance of all non-nodal target lesions. Any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm 1; PR: At least a 30% decrease in sum of diameter of all target lesions, taking as reference the baseline sum of diameters. PD: At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm2. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD.