The standard Gleevec dosage is 400 mg per day. This can be taken as one 400 mg tablet or four 100 mg tablets. For patients that are resistant to standard dose, the recommended dose is 800 mg per day, if tolerated. For patients with KIT exon 9 mutations, NCCN guidelines note, “Patients with documented mutations in KIT exon 9 may benefit from dose escalation up to 800 m daily (given as 400 mg twice daily), depending upon tolerance.”
The optimal dose of Gleevec is still the subject of some debate; however, data from two large phase III trials helps shed some light on which patients are most likely to benefit from higher doses. Researchers have found that patients with a particular type of mutation, an exon 9 mutation in the c-kit gene, are much more likely to benefit from higher doses of Gleevec. Testing to determine which type of mutation a GIST patient has, is clinically available.
At the 2005 annual American Society of Clinical Oncologists (ASCO) meeting, Dr. Michael Heinrich reported on results of the U.S./Canadian phase III trial. In this trial, GIST patients with mutations in exon 9 of the c-kit gene were 8 times as likely to have a response (significant shrinkage) if they were randomized to the high-dose arm of the trial as compared to the low-dose arm (you must view the ASCO presentation, not the abstract, to get the details of response). In the European Organization for Research and Treatment of Cancer (EORTC) phase III trial, this same patient group (exon 9) had a much longer time-to-progression (TTP) in the high dose arm as well. The median TTP was approximately 20 months in the high-dose arm vs. about 4 months in the low-dose arm; a five-fold increase in TTP for the high-dose arm. These results suggest that imatinib should be dosed at 400 mg twice a day in patients with tumors bearing KIT exon 9 mutations according to the authors of the EORTC study.
Information about Gleevec Blood Levels
At the 2008 GI ASCO (American Society of Clinical Oncologists), Dr. George Demetri presented new information that higher concentrations of imatinib in GIST patients
|The impact of the randomly allocated initial dose of imatinib on time-to-progression: (A) Kaplan–Meier estimate of the probability of progression-free survival for all 377 patients in the study, (B) for patients with tumors bearing KIT exon 9 mutations, (C) for patients with tumors carrying KIT exon 11 mutations, (D) and for patients with tumors with wild-type genotype.
Reprinted from European Journal of Cancer, 42, Maria Debiec-Rychter et al., KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumors, 1090-1103, 2006, with permission from Elsevier.
In both phase III trials, patients in the high-dose arm started Gleevec at 800 mg/day. Patients in the low-dose arm initially received 400 mg/day. In the EORTC study, patients starting at 800 mg. interrupted treatment 64 percent of the time and reduced their dose 60 percent of the time, compared to 40 percent and 16 percent, respectively, for patients starting at 400 mg. The side effects were mostly fatigue and edema, with few effects on blood counts.
Data from the U.S. phase III trial showed that patients starting at 800 mg required a dose reduction 58 percent of the time. Only 10 percent of patients on 400 mg. needed to reduce their dose. For patients starting at 400 mg. and then crossing over to 800 mg. due to disease progression, only 16 percent required a dose reduction). According to Dr. Jonathan Trent, a GIST expert from M.D. Anderson Cancer Center, “toxicity doesn’t markedly increase after a patient has been on 400 mg. for a while and then increases the dose to 800 mg. In patients who require a higher dose of Gleevec, I slowly titrate to the target dose over several weeks or even months.”
In phase I clinical trials, the maximum tolerated dose (MTD) of Gleevec was found to be 800 mg/day.
In the U.S., the FDA recommended starting Gleevec dosage at this time (as of December, 2008) is 400 mg/day for patients with unresectable and/or metastatic, malignant GIST and for patients receiving adjuvant Gleevec. Dose increase up to 800 mg daily (given as 400 mg twice daily) may be considered, as clinically indicated, in patients showing clear signs or symptoms of disease progression at a lower dose and in the absence of severe adverse drug reactions. It is possible that this may change as the new data on exon 9 response is reviewed.
The prescribed dose should be administered orally, with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day.
The following link goes to the full FDA patient prescribing information at the Novartis website.
Phase I clinical trial results
In August 2000, the European Organization for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group initiated a multi-national, phase I, dose-escalation study of Gleevec for patients with advanced soft tissue sarcoma (STS), including patients with GIST. Patients were required to have a measurable tumor lesion with recent progression (<6 weeks prior to initiating therapy).
- Forty patients were enrolled in the study, including 36 patients with documented c-Kit–positive GIST and 4 patients with non-GIST STS.
- Patients initially received a once-daily dose of 400 mg of Gleevec.
- Dose was increased by 200 mg increments in subsequent cohorts of patients and the 4 dosing schedules used were:
400 mg daily (n=8)
300 mg twice daily (n=8)
400 mg twice daily (n=16)
500 mg twice daily (n=8)
- The primary objective of this trial was to establish the maximum tolerated dose of Gleevec, according to the NCI CTC. A secondary objective was to assess the effectiveness of Gleevec for treating patients with GIST.
- Dose-limiting toxic effects (grade 3) were observed in 5 patients who received 1000 mg, and included nausea, vomiting, edema, and dyspnea.
- A daily dose of 800 mg was thus determined to be safe and tolerable for patients with GIST. For patients who received lower doses of Gleevec, the side-effects were mild or moderate and manageable based upon the NCI toxicity standards (See the side effects survey). The overall incidence of myelosuppression was low and this side effect was not dose-dependent.
Phase II clinical trial results
An open-label, randomized, multicenter phase II clinical trial was conducted to evaluate the antitumor response, safety, and tolerability of Gleevec in 147 patients with advanced GIST. Patients were randomly assigned to receive either 400 mg or 600 mg of Gleevec daily.
This trial originally enrolled 10 patients at each of 3 U.S. centers, and an additional small number of patients in Finland, but because of the excellent early activity of Gleevec, it was quickly expanded to 147 patients. This trial started in July, 2000 and was scheduled for 2 years. The trial has been extended in length to provide long term follow-up of these patients.
The phase II trial was not adequately powered to distinguish between the efficacy of the 400 mg and 600 mg doses. Although there was no statistically significant difference between the dose levels, three of the nine patients who received the higher dose after evidence of disease progression was uncovered had a sustained partial response or stable disease after the crossover (to a higher dose).
Phase III clinical trial results
Two large phase III trials have been conducted to compare 400 mg to 800 mg. The United States & Canada group data is still preliminary. The European & Austral-Asia group data is complete (final, and peer reviewed).
You may view either the abstracts or slide presentations given at the 2003 American Society of Clinical Oncology (ASCO) meeting. Audiocassettes are also available for purchase at this site.
Early efficacy comparison of two doses of imatinib for the treatment of advanced Gastro-Intestinal Stromal Tumors (GIST): Interim results of a randomized phase III trial from the EORTC-STBSG, ISG and AGITG
The larger phase III trial was conducted by the EORTC Soft Tissue and Bone Sarcoma Group, the Italian Sarcoma Group, and the Australasian Gastrointestinal Trials Group. This trial is now complete. Results were reported in the September 25, 2004 issue of The Lancet. The title of the study was “Progression-free survival in gastrointestinal stromal tumors with high-dose imatinib: randomised trial.”
The results show that, in both groups, the trials do not show any difference in response rates between the two doses, but the two groups do not agree on whether the results show a difference in progression-free survival. The preliminary data from the United States & Canada group reported no difference in progression-free survival, while final data from the Europe & Austral-Asia group reported that progression-free survival was significantly better at the 800 mg/day dose. It should be noted that the progression-free survival curves in both studies are similar, but they are non-significant in the US/Canada study, which may be attributable to the fact that is was a smaller study.
The phase III report concluded, “…if the aim of treatment is response induction, a daily dose of 400 mg given for 4–6 months seems to be sufficient. However, in patients with widespread metastatic disease, the prolonged progression-free survival achieved with 400 mg twice daily might lead one to favor this regimen. Whether a similar outcome could be achieved with fewer side effects by making use of the reduction in drug clearance over time — e.g., with a starting dose of 400 mg daily followed by stepwise dose escalation to 400 mg twice a day — is still a matter for further clinical investigations.
Dose and drug concentrations
Patients metabolize drugs at different rates. This means that 2 patients taking the same dose can have different concentrations of the drug in their body.
Documentation supplied to the FDA shows that drug concentrations can vary up to 40% between patients taking the same dose.
Other drugs can affect Gleevec drug concentrations. Gleevec is primarily metabolized by an enzyme in the liver known as P450 3A4, also known as CYP 3A4.
Drugs that INDUCE CYP 3A4 can LOWER Gleevec drug concentrations. In extreme cases, this could cause Gleevec to become ineffective. These drugs speed up the metabolism of Gleevec. Co-medications that induce CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or St. John’s Wort) may reduce exposure to Gleevec. No formal study of CYP3A4 inducers has been conducted, but a CML patient on chronic therapy with phenytoin (a CYP3A4 inducer) given 350 mg daily dose of Gleevec had about one fifth of the typical AUC of 20 µg.h/mL (one fifth of the typical drug concentration). This probably reflects the induction of CYP3A4 by phenytoin. This patient stopped responding to Gleevec until phenytoin was discontinued (although the dose of Gleevec was also increased to 500 mg at the same time).
Drugs that INHIBIT CYP 3A4 can INCREASE Gleevec drug concentrations. This can cause increased side effects from Gleevec. Some of these drugs include: ketoconazole, itraconazole, erythromycin, and clarithromycin.
Both the Sarcoma Task Force Report at the National Comprehensive Cancer Network (NCCN), and the GIST consensus Conference of March 20-21, 2004 (ESMO), recommend starting doses of 400 mg day. The consensus conference noted, “Of note, however, both trials reported a superiority in terms of progression-free survival in the 800 mg arm, one reaching a significant statistical value (median progression-free survival 22 months versus not reached; P=0.02), the other being statistically non-significant (median progresson-free survival 22 versus 27 months; P=0.13). Longer follow-up is therefore needed; this conclusion may evolve in the future.”
As follow-up data became available from the EORTC trial, researchers published the additional recommendations that their results suggest that imatinib should be dosed at 400 mg twice a day in patients with tumors bearing KIT exon 9 mutations.
The preliminary report from 2008 GI ASCO suggests that at least one-fourth of GIST patients may be underdosed. Gleevec blood level testing is available, and preliminary results suggest that trough levels should be above approximately 1,100 ng/ml for GIST patients.
An internal Life Raft Group study found that when looking at the dose that patients actually took (versus the dose they started at), a select group of patients (those with initial shrinkage on Gleevec, and that had been on Gleevec for over one year) on more than 400 mg of Gleevec had significantly longer progression-free survival than patients on 400 mg or less. This study was not a controlled randomized trial (these type studies may have bias).
Determining dose seems to be somewhat of a balancing act between response and side effects. Given that there seems to be a weak correlation between dose and response and a strong correlation between dose and side effects, and that side effects seem to improve over time, the dose escalation approach seems to be a logical approach. Exon 9 patients may have a shorter time period for safe dose escalation.
It should be noted that the commonly prescribed doses, 400 mg, 600 mg, and 800 mg were determined by clinical trials. We are aware of a couple of patients that have responded at doses as low as 100 mg and some patients that require 800 mg (or more) to be effective. This also raises the question of doses in between. Might 500 mg or 700 mg be the optimum dose for some individuals? We should note that the only reason the patients that received 100 mg per day did so was because of severe toxicities at higher doses. In other words, the dose was varied by their doctors to achieve the optimum dose for these patients, taking into account both the patients response to the drug and the patients side effects. Doses below 300 mg should generally be avoided.
1.Correlation of target kinase genotype with clinical activity of imatinib mesylate (IM) in patients with metastatic GI stromal tumors (GISTs) expressing KIT (KIT+)
M. C. Heinrich, J. S. Shoemaker, C. L. Corless, D. Hollis, G. D. Demetri, M. M. Bertagnolli, J. A. Fletcher
2. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumors
Maria Debiec-Rychtera, Raf Sciotb, Axel Le Cesned, Marcus Schlemmere, Peter Hohenbergerf, Allan T. van Oosteromc, Jean-Yves Blayg, Serge Leyvrazh, Michel Stula, Paolo G. Casalii, John Zalcbergj, Jaap Verweijk, Martine Van Glabbekel, Anne Hagemeijera, Ian Judsonm and On behalf of the EORTC Soft Tissue and Bone Sarcoma Group, The Italian Sarcoma Group and the Australasian GastroIntestinal Trials Group
3. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumors: a phase I study.
van Oosterom AT, Judson I, Verweij J, Stroobants S, Donato di Paola E, Dimitrijevic S, Martens M, Webb A, Sciot R, Van Glabbeke M, Silberman S, Nielsen OS; European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group
4. Efficacy and Safety of Imatinib Mesylate in Advanced Gastrointestinal Stromal Tumors
George D. Demetri, M.D., Margaret von Mehren, M.D., Charles D. Blanke, M.D., Annick D. Van den Abbeele, M.D., Burton Eisenberg, M.D., Peter J. Roberts, M.D., Michael C. Heinrich, M.D., David A. Tuveson, M.D., Ph.D., Samuel Singer, M.D., Milos Janicek, M.D., Ph.D., Jonathan A. Fletcher, M.D., Stuart G. Silverman, M.D., Sandra L. Silberman, M.D., Ph.D., Renaud Capdeville, M.D., Beate Kiese, M.Sc., Bin Peng, M.D., Ph.D., Sasa Dimitrijevic, Ph.D., Brian J. Druker, M.D., Christopher Corless, M.D., Christopher D.M. Fletcher, M.D., and Heikki Joensuu, M.D
5. Progression-free survival in gastrointestinal stromal tumors with high-dose imatinib: randomised trial*
ProfJaap Verweij MDa, , , Paolo G Casali MDb, ProfJohn Zalcberg MDc, Axel LeCesne MDd, Peter Reichardt MDe, ProfJean-Yves Blay MDf, ProfRolf Issels MDg, ProfAllan van Oosterom MDh, ProfPancras CW Hogendoorn MDi, Martine Van Glabbeke MScj, Rossella Bertulli MDb, ProfIan Judson MDk, for the EORTC Soft Tissue and Bone Sarcoma Group, the Italian Sarcoma Group and the Australasian Gastrointestinal Trials Group
6. Phase III dose-randomized study of imatinib mesylate (STI571) for GIST: Intergroup S0033 early results. (ASCO abstract)
R. S. Benjamin, C. Rankin, C. Fletcher, C. Blanke, M. Von Mehren, R. Maki, V. Bramwell, L. Baker, E. Borden, G. D. Demetri, for the Sarcoma Intergroup; UT MD Anderson Cancer Ctr, Houston, TX; SWOG, San Antonio, TX; Dana-Farber Cancer Institute, Boston, MA; ECOG, Philadelphia, PA; CALGB, New York, NY; NCIC, Calgary, Canada; SWOG, Ann Arbor, MI; DFCI, CALGB, and Sarcoma Intergroup, San Antonio, TX
7. Evaluation of Self-Reported Progression and Correlation of Imatinib Dose to Survival in Patients with Metastatic Gastrointestinal Stromal Tumors: An Open Cohort Study
Jerry Call, Norman J. Scherzer, P. David Josephy, Christopher Walentas