E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Unresectable, metastatic or recurrent gastrointestinal stromal tumor (GIST) |
|
E.1.1.1 | Medical condition in easily understood language |
A specific type of cancer arising along the gastrointestinal tract |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10062427 |
E.1.2 | Term | Gastrointestinal stromal tumor |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the antitumor activity of Dovitinib (TKI258) in terms of disease control rate (DCR):
CR+PR+SD, at 12 weeks in adult patients with documented disease progression while on
therapy with imatinib for unresectable and/or metastatic GIST, recurrent GIST on adjuvant
imatinib or within the first 3 months after discontinuation of adjuvant imatinib or, unresectable
and/or metastatic GIST intolerant to imatinib |
|
E.2.2 | Secondary objectives of the trial |
Secondary objectives: to assess
- Progression-free survival (PFS)
- Time to treatment failure (TTF)
- Duration of response or stable disease
- Time to progression (TTP)
- Overall response rate (ORR)
- Overall survival (OS)
- Safety and tolerability of Dovitinib (TKI258) |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this study have to meet all of the following criteria
- Male or female patients ≥ 18 years of age
- 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 on KIT or PDGFRA genes
- 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).
- A performance status of 0, 1 or 2 according to ECOG
- Recovery from Grade 2 to 4 toxicity related to prior imatinib assessed according to NCI-CTCAE v.4.0
- Adequate bone marrow function
- Adequate liver function
- Adequate renal function
Other protocol-defined inclusion criteria may apply
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E.4 | Principal exclusion criteria |
- Patients who have received any other tyrosine-kinase inhibitor but imatinib for GIST
- Use of any investigational agent within 28 days prior to starting Dovitinib (TKI258) or foreseen use of an investigational agent during the study
- Imatinib must be discontinued at least 5 days before first dose of Dovitinib (TKI258)
- 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
- Patients with another primary malignancy within 3 years prior to starting the study drug, with the exception of adequately treated in-situ carcinoma of the uterine cervix, or completely excised (R0 resection) basal or squamous cell carcinoma of the skin
- Patients who have undergone major surgery 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 certain QT-related medicinal conditions
- Patients with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of Dovitinib
- Uncontrolled hypertension
- Patients with any clinically significant medical or surgical condition which should preclude participation
- Known diagnosis of human immunodeficiency virus (HIV) infection. HIV testing is not mandatory
- Patients who are currently receiving anticoagulation treatment with therapeutic doses of warfarin or equivalent anticoagulant
- Pregnant or breast-feeding women
- Women of child-bearing potential not employing two highly effective methods of birth control having at least onefailure ratio < 1%.
- Fertile males not willing to use contraception
Other protocol-defined exclusion criteria may apply
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E.5 End points |
E.5.1 | Primary end point(s) |
Disease control rate defined as the proportion of patients with a best overall response of CR, PR and SD at 12 weeks according to RECIST. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
12 weeks after the first dose of study drug. |
|
E.5.2 | Secondary end point(s) |
- Progression Free Survival (PFS): time from entry into the study to the date of the first documented progression or death due to any cause.
- Time to treatment failure (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’.
- Duration of response or stable disease: time from the date of entry into the study to the earliest date of the first objective tumor progression or death.
- TTP: time from the date of entry into the study to first documentation of tumor progression or death
due to the underlying cancer.
- ORR: proportion of patients whose best overall response is either complete response (CR) or partial
response (PR) according to RECIST (version 1.1).
- OS: 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.
- Incidence of adverse events (AEs), serious adverse events (SAEs) and abnormal laboratory results (hematology, blood chemistry) will be assessed by the Common Terminology Criteria for Adverse Events (CTCAE), v4.0. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy: at day 28 of Cycle 1 then every 8 weeks until month six and then every 12 weeks until disease progression or starting other treatment. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 9 |