GIST Support Wiki

GIST Drug Trials outside the US

TRIAL FOR LIVER METS: SEPT 2011 The only location is in Toronto.

Intervention Details:

Drug: Sorafenib

Sorafenib doses will be 200mg twice daily orally for 28 days in level I, 400 mg in the morning and 200mg in the evening in level II, and 400mg twice daily orally for 28 days in level III . Radiotherapy will be started at day 8, patients will receive a total of 6 fractions over 2 weeks. Patients will be assessed weekly during treatment, 1 month post-tx, then at 3-month intervals for up to a year after tx, and then followed-up at 6-month intervals up to 3 years. Detailed Description: In this study, Stereotactic Body Radiation Therapy(SBRT) and Whole Liver Radiotherapy (WLRT) will be used concurrently with sorafenib at 3 different dosages to determine the tolerability and efficacy of this combined treatment. Sorafenib doses will be 200mg twice daily orally for 28 days in level I, 400 mg in the morning and 200mg in the evening in level II, and 400mg twice daily orally for 28 days in level III . Radiotherapy will be started at day 8, patients will receive a total of 6 fractions over 2 weeks. Patients will be assessed weekly during treatment, 1 month post-tx, then at 3-month intervals for up to a year after tx, and then followed-up at 6-month intervals up to 3 years. Once the Maximum Tolerated Dose (MTD) is established, an expanded cohort for each stratum will accrue such that a total of 10 patients per strata. This will allow us to gain further experience with this regimen and consolidate the safety and efficacy data. Quality of Life (QOL) assessment will be carried out at baseline and 1/3/6/9 mos post-tx. Patients will also be offered correlative studies looking at biomarkers through tissue, blood, and urine samples, and an imaging study looking at tissue perfusion.


A new trial protocol listed at NOV 1, 2011

""The current trial aims to evaluate whether tumor DNA carrying mutations for CKIT and PDGFRA can be detected and quantified in the plasma of patients with active GIST, and whether detection can be correlated with the clinical course of disease either under therapy or in progressive disease irrespective of current therapy.""


The question is whether fragments of the mutant DNA from that was shed from GIST cells anddiscarded into blood plasma when the GIST cells broke open or died can be detected from a mutational analysis of the blood plasma.

This is called Circulating Free DNA: "CF DNA".

If the procedure works, then it has some advantages for patients.

First, it might eliminate the need for certain tumor biopsies along the way. Second, it might resolve the problem that resistance causing mutations can only be detected if the biopsy needle happened to probe their part of the tumor mass. We know that a single patient can have many different resistance causing mutations in his tumor load, depending on which tumor and even which subregion of a single tumor. In principle, the blood stream could be a "soup" of many if not all of the resistance causing mutations within a patient's entire tumor load. And maybe the test would pick them up.

I hope this test works! I think it could be a diagnostic boost to deciding what is the next best treatment after resistance has occurred.

phase II trial for second line defense against resistant GIST

""Phase II Trial to Evaluate the Efficacy and Safety of Dovitinib (TKI258) in Patients With Gastrointestinal Stromal Tumors Refractory and/or Intolerant to Imatinib""

A new listing for Dovitinib (Novartis) for Gleevec resistant GIST. Eligible patients are not allowed to have received other tyrosine-kinase inhibitors beyond the first line of defense treatments with imatinib. Hence, this trial is addressing second line of defense, for which Sutent is currently the standard.

The trial is not yet recruiting. Listed countries are France, Finland, Italy, Belgium, Germany, Spain.

Estimated Enrollment: 36 Study Start Date: January 2012 Estimated Study Completion Date: December 2013 Estimated Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)

Dovitinib (also known as TKI258) has been around for a while. It was originally named CHIR258 by Chiron, which was acquired by Novartis. Dovitinib is a mulitkinase inhibitor, targeting KIT, VEGF receptors, PDGF receptors, fibroblast growth factor receptors, FLT3.

JUNE 2012

A Dose-finding Study of a Combination of Imatinib and BKM120 in the Treatment of 3rd Line GIST Patients identifier: NCT01468688

A new phase 1b clinical trial opening in Europe and the USA aims to study the effectiveness of combinations of two of Novartis’ drugs; imatinib and a PI3k pathway inhibitor, BKM120. The purpose of this study is to determine a maximum tolerated dose and/or recommended dose for a phase II trial of a combination of imatinib and BKM120 as 3rd line treatment of GIST patients.

BKM120 is currently being investigated in Phase I and II clinical trials in advanced solid tumour patients as a single agent as well as in combination with other agents.

The PI3K pathway is the most frequently hyperactivated pathway in cancer. Abnormal activation of the PI3K-AKT-mTOR pathway is an important step towards the initiation and maintenance of human tumours. The PI3K-AKT-mTOR pathway regulates cellular metabolism, proliferation, and survival. This signaling cascade is also a key regulator of angiogenesis and upregulated metabolic activities in tumour cells.

Targeting the PI3K-AKT-mTOR pathway could arrest tumour growth and induce cell death in cancers that are resistant to currently available therapies. BKM120 is a potent and highly specific oral pan-class I PI3K inhibitor. Unlike other inhibitors, it does not inhibit the related kinases—mTOR and Vps34.

Enrolment for the new phase Ib study is estimated to be of 50 patients who have had progression on imatinib and sunitinib. Accrual of patients has already commenced in two sites (Netherlands and Belgium), and will also open in 7 furhte countries in Europe and North America.. The primary completion date is estimated to be January 2014.

Patients will be given varying doses of BKM120 in combination with imatinib until maximum tolerated dose is established. The study will comprise of 2 parts: a) Dose escalation phase: Patients will receive increasing doses of BKM120 in combination with 400mg imatinib daily until maximum tolerated dose (MTD) is determined, and b) Expansion phase: 35 patients will enter the expansion phase with 18 patients having a pharmacokintic (PK) run-in period of 8 days receiving imatinib monotherapy or BKM120 monotherapy.followed a combination of both.

Previous Phase 1 data ASCO 2010 report:

BKM120 was evaluated from 12.5-150 mg. Daily oral dosing at 100 mg (MTD) showed a favourable PK profile, consistent PD changes, and clear signs of clinical activity.

Side effects: Treatment-related adverse events in more than 10% of patients: rash, hyperglycemia, diarrhoea, nausea, anorexia, pruritus, fatigue, mood alteration, malaise, vomiting, and mucositis.


Patients (18 years plus) must meet the minimum treatment and safety evaluation requirements of the study. Patients will be treated until they experience progression of disease, withdraw consent, or experience unacceptable toxicity. One study cycle equals 28 days.

Inclusion criteria:

Histologically confirmed diagnosis of GIST that is unresectable or metastatic Available tissue specimen: Dose-escalation cohorts: archival tumour tissue must be available Dose-expansion cohort: archival tumour tissue must be available and patients must agree to a fresh pre-treatment biopsy. Failed prior therapy with imatinib followed by sunitinib for the treatment of unresectable or metastatic GIST. Note the following specific criteria for the two phases of the trial: Dose-escalation cohorts: patients who failed prior therapy with imatinib and then have failed therapy with sunitinib, failure could either be due to progression on therapy (both imatinib and sunitinib) or intolerance to therapy (sunitinib). Dose-escalation cohort patients may have had additional lines of therapy not limited to imatinib and sunitinib. Dose-expansion cohort: patients must have documented disease progression on both imatinib and sunitinib. In addition, patients may have had no more than two lines of prior therapy (i.e. treatment with imatinib followed by treatment with sunitinib). Adjuvant imatinib will not count as a prior course of imatinib for the purposes of this criterion

Exclusion Criteria:

1. Previous treatment with PI3-K inhibitors

2. A medical history of one of various mood disorders

3. Poorly controlled diabetes mellitus (defined as HbA1c > 8%)

'Trial sites

USA - Boston, NY, Washington, Canada - Vancouver Europe Belgium - Leuven - Recruiting France – Lyon and Villejuif Germany – Munich and Berlin Italy - Milan Netherlands - Leiden - Recruiting Spain - Barcelona UK - London and Manchester

ASCO 2012 poster: Efficacy of a phosphoinositol 3 kinase (PI3K) inhibitor in gastrointestinal stromal tumor (GIST) models. Thomas Van Looy, Agnieszka Wozniak et al

AACR 2012 Novartis report on “The effect combining the KIT inhibitor Imatinib with the PI3K inhibitor BKM120 or the dual PI3K/mTOR inhibitor BEZ235 on the proliferation of gastrointestinal stromal tumor cell lines”

For a free-access medical paper about this drug strategy, see "Practicalities of Drugging the Phosphatidylinositol-3-Kinase/Akt Cell Survival Signaling Pathway"