Novartis To Submit Gleevec sNDA In September For GI Stromal Tumors

Novartis expects to submit a Gleevec sNDA for treatment of gastrointestinal stromal tumors (GIST) in September, Novartis President Daniel Vasella, MD, told analysts June 5. The sNDA will be based on results from a single Phase II study.

Preliminary data on 86 patients from a 148-patient Phase II study were presented at the mid-May American Society of Clinical Oncology meeting in San Francisco. About 1,000 patients are being treated for GIST in trials with Gleevec (imatinib mesylate, or STI571), according to Novartis.

Gleevec received accelerated approval May 10 for treatment of patients in accelerated and blast crisis phase chronic myeloid leukemia (CML), as well as those in chronic phase after failure of interferon. Approval was based on Phase II studies in all three populations (see related stories, pp. 3 & 5).

Preliminary results from the Phase II GIST study showed a 59% overall response rate in 86 patients who had at least three months of follow-up, Gleevec investigator Charles Blanke, MD, Oregon Health and Science University, reported at an ASCO plenary session.

This result was "notable considering there is no standard chemotherapy that helps GIST patients at all," Blanke said during an ASCO press briefing. Gleevec "is the first effective non-surgical therapy for GIST, a cancer that has historically been resistant to chemotherapy and radiation," he said.

The randomized, open-label trial, which began in July 2000, enrolled 148 patients with unresectable or metastatic GIST. Patients received either 400 or 600 mg/day Gleevec. Patients progressing on the lower dose were allowed to receive the higher dose, and those progressing on the higher dose were removed from the trial. Patients who did not progress were allowed to remain on study for 24 months, Blanke said.

The study's primary endpoint is assessment of clinical and biological activity of Gleevec as measured by objective response. Secondary endpoints include time to progression (TTP), overall survival and definition of mutational status as it relates to drug response.

Half of the 86-patient subset receiving 400 mg/day and 68% of those on 600 mg/day had a partial response, for an overall response of 59%. "Many of these [patients] continue to have tumor shrinkage, including some on study for more than 10 months," Blanke said. Twenty-six percent of patients had stable disease, while 13% progressed (21% on 400 mg, 5% on 600 mg).

Toxicity caused dose reduction, treatment delay, or drug discontinuation in 25% of patients. Severe to life-threatening drug-related toxicities were seen in 21% of patients, the most common being GI bleeding, liver toxicity, neutropenia, infection and edema.

Patients on the higher dose did not have a higher rate of toxicity. In terms of efficacy, "a trend toward higher response rate" was seen with the 600 mg dose. Blanke recommended interpreting the dose data cautiously, saying the "dose intensity question should definitively be answered by the current Phase III intergroup GIST trial."

The National Cancer Institute cooperative group Phase III study, which began December 2000, is randomizing patients with metastatic or unresectable GIST to either Gleevec 400 mg q.d. or 400 mg b.i.d.

The same treatment regimen is being evaluated in a Phase III European Organization for Research and Treatment of Cancer (EORTC) trial. Both trials will enroll 600 patients. The EORTC trial has accrued 137 patients, while the NCI study has accrued over 260, Allan van Oosterom, MD, University Hospital Gasthusiberg (Leuven, Belgium), reported.

Based on results of a two-year, dose-finding EORTC study, van Oosterom suggested that the optimal Gleevec dose is 400 b.i.d. for GIST patients. A 500 mg b.i.d. dose, which was the highest used in the study, produced five dose-limiting toxicities in eight patients, he said. The trial involved 40 advanced soft tissue sarcoma patients, 36 of whom had GIST.

Four of the GIST patients progressed in the first eight weeks of treatment. "Objective responses were seen in 69% of GIST patients, including 13 confirmed partial responses (36%) and 12 as-yet unconfirmed partial responses or 20%-29% regressions," Novartis said. The company reported that 89% (24 of 27) of "clinically symptomatic patients showed improvement, often within one week after starting treatment."

In addition to ongoing GIST and CML trials, Gleevec is in pilot studies for hormone refractory prostate cancer, glioma and small-cell lung cancer.

The dose-escalation study of Gleevec in recurrent or malignant glioma or meningioma, conducted by the NCI-sponsored North American Brain Tumor Consortium, opened December 2000. The trial consists of a four-week, 36-patient, Phase I dose-escalation segment to determine a maximum tolerated dose, and a four-week Phase II segment in 40-60 patients.

The trial's primary objectives are to determine the safety profile in glioma/meningioma patients, assess pharmacokinetics of Gleevec in relation to concurrent enzyme inducing anti-epileptic drugs, and evaluate in vivo and in vitro angiogenic activity. Efficacy will be evaluated through six-month progression-free survival and objective tumor response.

A Phase II study in hormone-refractory prostate cancer has closed enrollment with 40 patients. The study is using a 400 mg dose. A pilot study has also begun in newly diagnosed prostate cancer patients, using a 600 mg dose for six weeks.

Researcher interest in Gleevec will propel studies in other cancers, Novartis Oncology President David Epstein told investors May 15. Clinicians "have so many ideas of other places they might want to use [Gleevec], that I would expect to see a significant number of investigator-generated protocols start up over the coming weeks and months," he said.

Patient interest in Gleevec is also high, Charles Schiffer, MD, Wayne State University, Schiffer said at a May 11 Novartis educational symposium. "Virtually every patient who comes in to our clinic spends five or ten minutes talking to their doctor about the use of [Gleevec] in their particular tumors." Researchers do not yet know "whether it works in other tumors," he said, noting that while a single genetic abnormality drives CML and GIST, other tumors are likely to have more than one genetic abnormality.

Gleevec investigators at ASCO also emphasized the importance of testing for the appropriate genetic marker before treating any patient with the agent. The C-KIT gene is implicated in most cases of GIST. In the Phase II GIST study, 86% of patients tested expressed the C-KIT mutation, according to Blanke.

"Having C-KIT alone is not sufficient," van Oosterom said. "There has to be evidence that C-KIT is responsible for that cancer cell being neoplastic." To use Gleevec without screening for the tyrosine kinase produced by C-KIT is "irresponsible behavior," he said.