August J. Salvado

Phase II Study of Imatinib Mesylate Plus Hydroxyurea in Adults With Recurrent Glioblastoma Multiforme

PURPOSE We performed a phase II study to evaluate the combination of imatinib mesylate, an adenosine triphosphate mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme (GBM). PATIENTS AND METHODS Patients with GBM at any recurrence received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme-inducing antiepileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Assessments were performed every 28 days. The primary end point was 6-month progression-free survival (PFS). RESULTS Thirty-three patients enrolled with progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. With a median follow-up of 58 weeks, 27% of patients were progression-free at 6 months, and the median PFS was 14.4 weeks. Three patients (9%) achieved radiographic response, and 14 (42%) achieved stable disease. Cox regression analysis identified concurrent EIAED use and no more than one prior progression as independent positive prognostic factors of PFS. The most common toxicities included grade 3 neutropenia (16%), thrombocytopenia (6%), and edema (6%). There were no grade 4 or 5 events. Concurrent EIAED use lowered imatinib mesylate exposure. Imatinib mesylate clearance was decreased at day 28 compared with day 1 in all patients, suggesting an effect of hydroxyurea. CONCLUSION Imatinib mesylate plus hydroxyurea is well tolerated and associated with durable antitumor activity in some patients with recurrent GBM.

High-Dose Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: High Rates of Rapid Cytogenetic and Molecular Responses

PURPOSE Long-term clinical outcome data have established imatinib 400 mg/d as standard front-line treatment for newly diagnosed patients with chronic myeloid leukemia (CML). PATIENTS AND METHODS The Rationale and Insight for Gleevec High-Dose Therapy (RIGHT) trial is a multicenter study of imatinib 400 mg twice a day as initial therapy in 115 patients (70% Sokal low risk) with newly diagnosed CML in chronic phase who were observed for both molecular and cytogenetic responses for up to 18 months. Eighty-three patients (72%) completed the study, 10 patients (9%) discontinued the study because of adverse events, and six patients (5%) discontinued because of unsatisfactory therapeutic effect. RESULTS Polymerase chain reaction analysis demonstrated rapid kinetics of major molecular response (MMR), with 48% of patients achieving MMR by 6 months, 54% by 12 months, and 63% by 18 months. Corresponding complete molecular response rates were 39%, 44%, and 55%, respectively. Median dose-intensity was 98%. Overall, 79% of patients who received at least 90% dose-intensity achieved MMR. The most frequent adverse events included myelosuppression, rash, fatigue, and musculoskeletal symptoms. CONCLUSION This study suggests that imatinib 400 mg twice a day results in more rapid reduction in tumor burden than imatinib 400 mg/d with minimal added toxicity.

Phase I pharmacokinetic study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma

This study determined the maximum tolerated dose (MTD) and dose‐limiting toxicities (DLT) of the oral vascular endothelial growth factor receptor (VEGFR) inhibitor, vatalanib, when administered with imatinib and hydroxyurea on a continuous daily schedule among recurrent malignant glioma patients.

Safety and pharmacokinetics of dose-intensive imatinib mesylate plus temozolomide: Phase 1 trial in adults with malignant glioma

We determined the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of imatinib mesylate, an inhibitor of the receptor tyrosine kinases platelet-derived growth factor receptor (PDGFR), the proto-oncogene product c-kit, and the fusion protein Bcr-Abl, when administered for 8 days in combination with temozolomide (TMZ) to malignant glioma (MG) patients. MG patients who had not failed prior TMZ were eligible to receive TMZ at a dose of 150-200 mg/m(2) per day on days 4-8 plus imatinib mesylate administered orally on days 1-8 of each 4-week cycle. Patients were stratified based on concurrent administration of CYP3A4-inducing antiepileptic drugs (EIAEDs). The imatinib dose was escalated in successive cohorts of patients independently for each stratum. Imatinib, at doses ranging from 400 mg to 1,200 mg, was administered with TMZ to 65 patients: 52 (80%) with glioblastoma multiforme (GBM) and 13 (20%) with grade III MG. At enrollment, 34 patients (52%) had stable disease, and 33 (48%) had progressive disease; 30 patients (46%) were on EIAEDs. The MTD of imatinib for patients concurrently receiving or not receiving EIAEDs was 1,000 mg. DLTs were hematologic, gastrointestinal, renal, and hepatic. Pharmacokinetic analyses revealed lowered exposures and enhanced clearance among patients on EIAEDs. Among GBM patients with stable disease at enrollment (n=28), the median progression-free and overall survival times were 41.7 and 56.1 weeks, respectively. Imatinib doses up to 1,000 mg/day for 8 consecutive days are well tolerated when combined with standard TMZ dosing for MG patients. A subsequent phase 2 study is required to further evaluate the efficacy of this regimen for this patient population.

Early effects of imatinib mesylate on the expression of insulin-like growth factor binding protein-3 and positron emission tomography in patients with gastrointestinal stromal tumor

Imatinib has demonstrated marked clinical efficacy against gastrointestinal stromal tumor (GIST). Microarray technology, real‐time polymerase chain reaction (PCR) validation, and fluorodeoxyglucose‐positron emission tomography (FDG‐PET) imaging were used to study the early molecular effects of imatinib antitumor activity in GIST.

The Signature Program: Bringing the Protocol to the Patient.

Early‐phase clinical development in oncology has evolved dramatically with the deciphering of the human genome in 2004. Genomic analysis and the tools identifying genetically disrupted pathways within a patients tumor have been a driving force for personalized medicine and for the development of highly targeted novel therapies. Tumors are often genetically heterogeneous, with multiple concurrent genetic abnormalities. On the other hand, tumors arising from different tissues may share identical molecular drivers.

A Phase 1 study of imatinib mesylate in combination with cytarabine and daunorubicin for c-kit positive relapsed acute myeloid leukemia

The c-kit receptor is expressed in 95% of relapsed acute myeloid leukemias (AMLs) and mediates leukemic proliferation. We conducted a Phase 1 study of the c-kit inhibitor, imatinib mesylate (IM), in combination with cytarabine and daunorubicin (7+3) in c-kit+ relapsed AML. IM was dose escalated using a 3 by 3 design. Phosphorylated STAT5 was absent to minimally present in residual blasts on day 14 bone marrows. The maximum tolerated dose of IM was 300 mg. The dose-limiting toxicity was Grade 3-4 hepatic toxicity. The CR/CRp rate was 57%. Cytotoxic therapy that includes IM for relapsed AML is well-tolerated and effective.

Treatment of polycythemia vera with imatinib mesylate

We treated 37 patients with polycythemia vera with imatinib mesylate (IM). The overall response rate was 49%. Thirty percent had a complete response, and 19%, a partial response. Thirty-one patients were treated for >120 days. Frequent side effects included nausea, diarrhea, edema, and skin rash. Whereas IM was effective in controlling erythropoiesis and reducing spleen size it was ineffective in controlling thrombocytosis. Normocellular marrow developed in 4 patients who had a complete response. Progression to overt myelofibrosis occurred in 3. Nevertheless, 6 patients have had a sustained complete response while on IM for >6 years. These patients were young, had high phlebotomy requirements, and only slightly elevated platelet counts. Therefore, we believe there may be a role for IM in patients with these characteristics whose disease cannot be controlled by, or as an alternative to, other myelosuppressive treatments.

Signature program: a platform of basket trials

Investigating targeted therapies can be challenging due to diverse tumor mutations and slow patient accrual for clinical studies. The Signature Program is a series of 8 phase 2, agent-specific basket protocols using a rapid study start-up approach involving no predetermined study sites. Each protocol evaluated 1 agent (buparlisib, dovitinib, binimetinib, encorafenib, sonidegib, BGJ398, ceritinib, or ribociclib) in patients with solid or hematologic malignancies and an actionable mutation. The primary endpoint of each study was the clinical benefit rate (ie, complete or partial response, or stable disease) at 16 weeks. A total of 192 individual sites were opened in the United States, with a median start-up time of 3.6 weeks. The most common tumor types among the 595 treated patients were colorectal (9.2%), non-small cell lung adenocarcinoma (9.1%), and ovarian (8.4%). Frequent genetic alterations were in PIK3CA, RAS, p16, and PTEN. Overall, 30 partial or complete responses were observed with 6 compounds in 16 tumor types. The Signature Program presents a unique and successful approach for rapid signal finding across multiple tumors and allowed various agents to be evaluated in patients with rare alterations. Incorporating these program features in conventional studies could lead to improved trial efficiencies and patient outcomes.

Phase I Pharmacokinetic Study of the VEGFR Tyrosine Kinase Inhibitor Vatalanib (PTK787) plus Imatinib and Hydroxyurea for Malignant Glioma

This study determined the maximum tolerated dose (MTD) and dose‐limiting toxicities (DLT) of the oral vascular endothelial growth factor receptor (VEGFR) inhibitor, vatalanib, when administered with imatinib and hydroxyurea on a continuous daily schedule among recurrent malignant glioma patients.