Finding the (biomarker-defined) subgroup of patients who benefit from a novel therapy: No time for a game of hide and seek.

An important element of precision medicine is the ability to identify, for a specific therapy, those patients for whom benefits of that therapy meaningfully exceed the risks. To achieve this goal, treatment effect usually is examined across subgroups defined by a variety of factors, including demographic, clinical, or pathologic characteristics or by molecular attributes of patients or their disease. Frequently such subgroups are defined by the measurement of biomarkers. Even though such examination is necessary when pursuing this goal, the evaluation of treatment effect across a variety of subgroups is statistically fraught due to both the danger of inflated false-positive error rate from multiple testing and the inherent insensitivity to how treatment effects differ across subgroups.Pre-specification of subgroup analyses with appropriate control of false-positive (i.e. type I) error is recommended when possible. However, when subgroups are specified by biomarkers, which could be measured by different assays and might lack established interpretation criteria, such as cut-offs, it might not be possible to fully specify those subgroups at the time a new therapy is ready for definitive evaluation in a Phase 3 trial. In these situations, further refinement and evaluation of treatment effect in biomarker-defined subgroups might have to take place within the trial. A common scenario is that evidence suggests that treatment effect is a monotone function of a biomarker value, but optimal cut-offs for therapy decisions are not known. In this setting, hierarchical testing strategies are widely used, where testing is first conducted in a particular biomarker-positive subgroup and then is conducted in the expanded pool of biomarker-positive and biomarker-negative patients, with control for multiple testing. A serious limitation of this approach is the logical inconsistency of excluding the biomarker-negatives when evaluating effects in the biomarker-positives, yet allowing the biomarker-positives to drive the assessment of whether a conclusion of benefit could be extrapolated to the biomarker-negative subgroup.Examples from oncology and cardiology are described to illustrate the challenges and pitfalls. Recommendations are provided for statistically valid and logically consistent subgroup testing in these scenarios as alternatives to reliance on hierarchical testing alone, and approaches for exploratory assessment of continuous biomarkers as treatment effect modifiers are discussed.

Resampling-based stepwise multiple testing procedures with applications to clinical trial data.

Endpoints in clinical trials are often highly correlated. However, the commonly used multiple testing procedures in clinical trials either do not take into consideration the correlations among test statistics or can only exploit known correlations. Westfall and Young constructed a resampling-based stepdown method that implicitly utilizes the correlation structure of test statistics in situations with unknown correlations. However, their method requires a "subset pivotality" assumption. Romano and Wolf proposed a more general stepdown method, which does not require such an assumption. There is at present little experience with the application of such methods in analyzing clinical trial data. We advocate the application of resampling-based multiple testing procedures to clinical trials data when appropriate. We have conjectured that the resampling-based stepdown methods can be extended to a stepup procedure under appropriate assumptions and examined the performance of both stepdown and stepup methods under a variety of correlation structures and distribution types. Results from our simulation studies support the use of the resampling-based methods under various scenarios, including binary data and small samples, with strong control of Family wise type I error rate (FWER). Under positive dependence and for binary data even under independence, the resampling-based methods are more powerful than the Holm and Hochberg methods. Last, we illustrate the advantage of the resampling-based stepwise methods with two clinical trial data examples: a cardiovascular outcome trial and an oncology trial.

U.S. Food and Drug Administration approval summary: omacetaxine mepesuccinate as treatment for chronic myeloid leukemia.

On October 26, 2012, the U.S. Food and Drug Administration (FDA) granted accelerated approval to omacetaxine mepesuccinate (Synribo; Teva Pharmaceuticals USA, Inc., North Wales, PA, http://www.tevausa.com) for the treatment of adult patients with chronic phase (CP) or accelerated phase (AP) chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKIs). The approval was based on the FDA review of data from 111 patients with CML in CP or in AP who had received two or more prior TKIs, including imatinib. Major cytogenetic response was achieved in 18% of patients with CP, with a median response duration of 12.5 months. Major hematologic response was achieved in 14% of patients with AP, with a median response duration of 4.7 months. The FDA safety evaluation was based on submitted data from 163 patients with CP or AP CML who had received at least one dose of omacetaxine mepesuccinate. The safety evaluation was limited by the single-arm design of the clinical trials as conducted in a small number of previously treated patients. The most common (≥20%) adverse reactions of any grade in enrolled patients included thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection site reaction, pyrexia, and infection. The FDA concluded that omacetaxine mepesuccinate has shown activity and a favorable benefit-to-risk profile for the studied population of adult patients with CML (CP or AP) with resistance and/or intolerance to two or more TKIs. Further evidence of response durability to verify clinical benefit is pending.

Evaluating and adjusting for premature censoring of progression-free survival.

The intent-to-treat principle, grouping subjects as they were randomized and following all subjects to the endpoint or the end of study, allows valid statistical comparisons. Progression-free survival (PFS) has been used as a decision-making endpoint in oncology. It can be difficult to have a meaningful intent-to-treat analysis of PFS as some studies have extensive loss to follow-up for PFS. In the analysis, subjects lost to follow-up for PFS have their PFS times censored, with the censoring treated as noninformative. We use remaining overall survival to investigate whether premature censoring for PFS is informative and the potential bias in treating such censoring as noninformative.

U.s. Food and Drug Administration approval: carfilzomib for the treatment of multiple myeloma.

The U.S. Food and Drug Administration (FDA) review leading to accelerated approval of carfilzomib is described. A single-arm trial enrolled 266 patients with multiple myeloma refractory to the most recent therapy who had received prior treatment with bortezomib and an immunomodulatory agent (IMID). Patients received carfilzomib by intravenous infusion over 2 to 10 minutes at a dose of 20 mg/m2 on days 1, 2, 8, 9, 15, and 16 of the 28 days of cycle 1, and at a dose of 27 mg/m2 on the same schedule in cycle 2 and subsequent cycles. The primary efficacy endpoint was overall response rate (ORR) as determined by an independent review committee using International Myeloma Working Group Uniform Response Criteria. The safety of carfilzomib was evaluated in 526 patients with multiple myeloma treated with various dosing regimens. The ORR was 23%. The median duration of response was 7.8 months. The most common adverse reactions associated with carfilzomib infusion were fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and fever. The most common serious adverse events were pneumonia, acute renal failure, fever, and congestive heart failure. Infusion reactions to carfilzomib could be reduced by pretreatment with dexamethasone and intravenous fluids. On July 20, 2012, the FDA granted accelerated approval of carfilzomib for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an IMID and who have shown disease progression while on therapy or within 60 days of completion of the last therapy.

U.S. Food and Drug Administration approval summary: brentuximab vedotin for the treatment of relapsed Hodgkin lymphoma or relapsed systemic anaplastic large-cell lymphoma.

The U.S. Food and Drug Administration (FDA) describes the accelerated approval of brentuximab vedotin for patients with relapsed Hodgkin lymphoma and relapsed systemic anaplastic large-cell lymphoma (sALCL). FDA analyzed the results of two single-arm trials, enrolling 102 patients with Hodgkin lymphoma and 58 patients with sALCL. Both trials had primary endpoints of objective response rate (ORR) and key secondary endpoints of response duration and complete response (CR) rate. For patients with Hodgkin lymphoma, ORR was 73% (95% CI, 65-83%); median response duration was 6.7 months, and CR was 32% (95% CI, 23-42%). For patients with sALCL, ORR was 86% (95% CI, 77-95%), median response duration was 12.6 months, and CR was 57% (95% CI, 44-70%). The most common adverse reactions were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory infection, diarrhea, pyrexia, rash, thrombocytopenia, cough, and vomiting. FDA granted accelerated approval of brentuximab vedotin for the treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplantation (ASCT) or after failure of at least two prior multiagent chemotherapy regimens in patients who are not ASCT candidates, and for the treatment of patients with sALCL after failure of at least one prior multiagent chemotherapy regimen.

U.S. Food and Drug Administration approval: ruxolitinib for the treatment of patients with intermediate and high-risk myelofibrosis.

On November 16, 2011, the U.S. Food and Drug Administration (FDA) granted full approval to ruxolitinib, (Jakafi; Incyte Corp.), an inhibitor of the Janus kinases 1 and 2, for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis, postpolycythemia vera myelofibrosis, and postessential thrombocythemia myelofibrosis. This approval was based on the results of 2 large randomized phase III trials that enrolled patients with intermediate-2 or high-risk myelofibrosis and compared ruxolitinib with placebo (study 1) or best available therapy (study 2). The primary efficacy endpoint was the proportion of patients who experienced a reduction in spleen volume of ≥ 35% at 24 weeks (study 1) or 48 weeks (study 2). The key secondary endpoint in study 1 was the proportion of patients who experienced a ≥ 50% improvement from baseline in myelofibrosis total symptom score at 24 weeks. The results of these studies showed that a greater proportion of patients treated with ruxolitinib experienced a ≥ 35% reduction in spleen volume as compared with those treated with placebo (42% vs. 1%, P < 0.0001) or best available therapy (29% vs. 0%, P < 0.0001). A greater proportion of patients in study 1 experienced a ≥ 50% reduction in the myelofibrosis total symptom score during treatment with ruxolitinib than with placebo (46% vs. 5%, P < 0.0001). Ruxolitinib treatment was associated with an increased incidence of grades III and IV anemia, thrombocytopenia, and neutropenia. This is the first drug approved for myelofibrosis.

U.S. Food and drug administration approval: rituximab in combination with fludarabine and cyclophosphamide for the treatment of patients with chronic lymphocytic leukemia.

PURPOSE: To describe the clinical studies that led to the FDA approval of rituximab in combination with fludarabine and cyclophosphamide (FC) for the treatment of patients with chronic lymphocytic leukemia (CLL). MATERIALS AND METHODS: The results of two multinational, randomized trials in CLL patients comparing rituximab combined with fludarabine and cyclophosphamide versus FC were reviewed. The primary endpoint of both studies was progression-free survival (PFS). RESULTS: The addition of rituximab to FC decreased the risk of a PFS event by 44% in 817 previously untreated patients and by 24% in 552 previously treated patients. Median survival times could not be estimated. Exploratory analysis in patients older than 70 suggested that there was no benefit to patients when rituximab was added to FC. The safety profile observed in both trials was consistent with the known toxicity profile of rituximab, FC, or CLL. CONCLUSIONS: On the basis of the demonstration of clinically meaningful prolongation of PFS, the FDA granted regular approval to rituximab in combination with FC for the treatment of patients with CLL. The magnitude of the treatment effect in patients 70 years and older is uncertain.

U.S. Food and Drug Administration approval: ofatumumab for the treatment of patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab.

PURPOSE: To describe the data and analyses that led to the U.S. Food and Drug Administration (FDA) approval of ofatumumab (Arzerra, GlaxoSmithKline) for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab. EXPERIMENTAL DESIGN: The FDA reviewed the results of a planned interim analysis of a single-arm trial, enrolling 154 patients with CLL refractory to fludarabine, and a supportive dose-finding, activity-estimating trial in 33 patients with CLL. Patients in the primary efficacy study received ofatumumab weekly for eight doses, then every 4 weeks for an additional four doses; patients in the supportive trial received four weekly doses. In the primary efficacy study, endpoints were objective response rate and response duration. RESULTS: For regulatory purposes, the primary efficacy population consisted of 59 patients with CLL refractory to fludarabine and alemtuzumab. In this subgroup, the investigator-determined objective response rate was 42% [99% confidence interval (CI), 26-60], with a median duration of response of 6.5 months (95% CI, 5.8-8.3); all were partial responses. The most common adverse reactions in the primary efficacy study were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections. Infusion reactions occurred in 44% of patients with the first infusion (300 mg) and 29% with the second infusion (2,000 mg). The most common serious adverse reactions were infections, neutropenia, and pyrexia. CONCLUSIONS: On October 26, 2009, the FDA granted accelerated approval to ofatumumab for the treatment of patients with CLL refractory to fludarabine and alemtuzumab, on the basis of demonstration of durable tumor shrinkage.

Issues in using progression-free survival when evaluating oncology products.

Several challenging and often controversial issues arise in oncology trials with the use of the end point progression-free survival (PFS), defined to be the time to detection of progressive disease or death. While this end point does not directly measure how a patient feels, functions, or survives, it does provide insights about whether an intervention affects the tumor burden process, the intended mechanism through which it is hoped that most anticancer agents will provide benefit. However, simply achieving statistically significant effects on PFS is insufficient to obtaining reliable evidence of important clinical benefit, and even is insufficient to justifying the conclusion that the experimental intervention is "reasonably likely to provide clinical benefit." The magnitude of the effect on PFS in addition to the statistical strength of evidence is of great importance in interpreting the reliability of the evidence regarding clinical efficacy. PFS has several important properties, including being a direct measure of the effect of treatment on the tumor burden process, being sensitive to cytostatic as well as cytotoxic mechanisms of interventions, and incorporating the clinically relevant event of death, increasing its sensitivity to influential harmful mechanisms and avoiding substantial bias that arises when deaths are censored. To obtain reliable evidence about the effect of an intervention on PFS and patient survival, randomized trials should be conducted where all patients are followed to progression and death, and where patients in a control arm do not cross-in at progression unless the experimental regimen has already been established to be effective rescue treatment.

Missing data in biologic oncology products.

The intent-to-treat principle requires analyses according to the treatment groups to which patients were randomized and that patients be followed to the occurrence of the endpoint or the end of study. This provides unbiased comparisons with valid p values. For many trials the limitations of the data will not be known until the data are analyzed. In this article, the loss-to-follow-up with respect to the intent-to-treat principle on the most important efficacy endpoints was evaluated for clinical trials of anticancer biologic products submitted to the FDA from August 2005 to October 2008. We provide recommendations in light of the results.

Continuing reassessment of the risks of erythropoiesis-stimulating agents in patients with cancer.

PURPOSE: Erythropoiesis-stimulating agents (ESA) are approved for the treatment of anemia in patients with nonmyeloid malignancies whose anemia is due to the effect of concomitantly administered chemotherapy. Since the 1993 approval of epoetin alfa in patients with cancer, the risk of thrombovascular events, decreased survival, and poorer tumor control have been increasingly recognized. The risks of ESAs in patients with cancer and the design of trials to assess these risks have been the topic of discussion at two Oncologic Drugs Advisory Committees in 2004 and 2007. EXPERIMENTAL DESIGN: Evaluation of randomized clinical trials comparing use of ESAs to transfusion support alone in patients with active cancer. RESULTS: Six studies (Breast Cancer Erythropoeitin Survival Trial, Evaluation of NeoRecormon on outcome in Head And Neck Cancer in Europe, Danish Head and Neck Cancer, Lymphoid Malignancy, CAN-20, and Anemia of Cancer) investigating ESAs in oncology patients showed decreased survival, decreased duration of locoregional tumor control, and/or increased risk of thrombovascular events. In these six studies, ESA dosing was targeted to achieve and maintain hemoglobin values in excess of current recommendations, and in three of the six studies, ESAs were administered to patients not receiving chemotherapy. CONCLUSIONS: ESAs increase the risk of thrombovascular events and result in decreased survival and poorer tumor control when administered to achieve hemoglobin levels of > or =12 g/dL in patients with nonmyeloid malignancies. No completed or ongoing randomized, controlled trial has addressed safety issues of ESAs in patients with chemotherapy-associated anemia using currently approved dosing regimens in an epidermal tumor type. Additional studies are needed to better characterize these risks.

U.S. Food and Drug Administration approval: panitumumab for epidermal growth factor receptor-expressing metastatic colorectal carcinoma with progression following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

PURPOSE: To describe the Food and Drug Administration review and marketing approval considerations for panitumumab (Vectibix) for the third-line treatment of patients with epidermal growth factor receptor-expressing metastatic colorectal carcinoma. EXPERIMENTAL DESIGN: Food and Drug Administration reviewed a single, open-label, multicenter trial in which 463 patients with epidermal growth factor receptor-expressing metastatic colorectal cancer who had progressed on or following treatment with a regimen containing a fluoropyrimidine, oxaliplatin, and irinotecan were randomized (1:1) to receive best supportive care (BSC) with or without panitumumab (6 mg/kg every other week) administered until disease progression or intolerable toxicity. Progression and response were confirmed by an independent review committee masked to treatment assignment. At progression, patients in the BSC-alone arm were eligible to receive panitumumab. RESULTS: Although median progression-free survival (PFS) was similar in both treatment arms ( approximately 8 weeks), the mean PFS was approximately 50% longer among patients receiving panitumumab than among those receiving BSC alone (96 versus 60 days, respectively) and the objective response rate in patients receiving panitumumab was 8%. However, no difference in overall survival was shown between the two study arms. CONCLUSIONS: Panitumumab received accelerated approval based on improvement in PFS and an independently confirmed response rate of 8%, similar to that observed with other active agents at this advanced stage of disease. Confirmation of clinical benefit will be required for full approval.

On non-inferiority analysis based on delta-method confidence intervals.

For many indications where there is an effective standard therapy, active controlled trials are generally conducted when it is unethical to use a placebo. The efficacy objective of most such trials is the demonstration that the experimental therapy has superior efficacy to the active-control. The efficacy objective of a non-inferiority trial may be to rule out that the experimental treatment loses some prespecified fraction of the active-control effect. The size of the active-control effect may be based on previous trials comparing this active-control with a placebo--for example, through a meta-analysis. Delta-method 95% confidence interval procedures are among the testing procedures that have been proposed to test a non-inferiority hypothesis that an experimental treatment retains more than some prespecified fraction of the active-control effect. For time-to-event endpoints using hazard ratios, we will examine the type I error probability of such testing procedures under the assumption that the current active-control effect has been correctly modeled. Conditions are discussed for when such testing procedures maintain a desired approximate type I error rate and when such testing procedures will not. Two applications (one in Cardiorenalogy and one in Oncology) are given--one maintains the desired approximate type I error probability and the other does not. The delta-method 95% confidence interval procedures will also be contrasted with Fieller 95% confidence intervals. Testing based on Fieller 95% confidence intervals will maintain a desired approximate type I error rate.

Approval summary: imatinib mesylate capsules for treatment of adult patients with newly diagnosed philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase.

PURPOSE: The purpose is to describe the Food and Drug Administration (FDA) review and approval of imatinib (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ) for treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in chronic phase. EXPERIMENTAL DESIGN: The FDA reviewed data in electronic format from a randomized controlled clinical trial of 1106 adult patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase, comparing imatinib with the combination of IFN-alpha and cytarabine. RESULTS: Imatinib showed clinically and statistically significantly better results for time-to-progression to accelerated phase or blast crisis, progression-free survival, complete hematological response rate, and cytogenetic response rate. With a median follow-up of 14 months, a maximum follow-up of 19.5 months, and an expected median survival of 5-6 years on the IFN-alpha/cytarabine control arm, few of the expected progressions to accelerated or blast phase or deaths have occurred. Imatinib was also better tolerated. Edema, nausea, rigors, neutropenia, and headache were more frequent in women. Only 57% of the IFN-alpha target dose was administered, and only 68% of patients received any cytarabine. However, this does not appear to adequately explain the superiority of imatinib observed in this trial. Results of a population pharmacokinetic study in a subgroup of 371 patients and a separate rifampin-imatinib drug-drug interaction study in healthy volunteers are presented. CONCLUSIONS: On December 20, 2002, imatinib was granted accelerated approval under subpart H, rather than regular approval. Follow-up is short compared with the natural history of chronic phase CML or more mature results with established therapies such as IFN-alpha or transplantation. If imatinib should stop working after 1.5-2 years, the results could be importantly different from the present analysis. As a Phase IV postmarketing commitment, the applicant has agreed to provide follow-up reports on this imatinib study annually for the next 6 years.

Design and analysis of non-inferiority mortality trials in oncology.

The recent revision of the Declaration of Helsinki and the existence of many new therapies that affect survival or serious morbidity, and that therefore cannot be denied patients, have generated increased interest in active-control trials, particularly those intended to show equivalence or non-inferiority to the active-control. A non-inferiority hypothesis has historically been formulated in terms of a fixed margin. This margin was historically designed to exclude a 'clinically meaningful difference', but has become recognized that the margin must also be no larger than the assured effect of the control in the new study. Depending on how this 'assured effect' is determined or estimated, the selected margin may be very small, leading to very large sample sizes, especially when there is an added requirement that a loss of some specified fraction of the assured effect must be ruled out. In cases where it is appropriate, this paper proposes non-inferiority analyses that do not involve a fixed margin, but can be described as a two confidence interval procedure that compares the 95 per cent two-sided CI for the difference between the treatment and the control to a confidence interval for the control effect (based on a meta-analysis of historical data comparing the control to placebo) that is chosen to preserve a study-wide type I error rate of about 0.025 (similar to the usual standard for a superiority trial) for testing for retention of a prespecified fraction of the control effect. The approach assumes that the estimate of the historical active-control effect size is applicable in the current study. If there is reason to believe that this effect size is diminished (for example, improved concomitant therapies) the estimate of this historical effect could be reduced appropriately. The statistical methodology for testing this non-inferiority hypothesis is developed for a hazard ratio (rather than an absolute difference between treatments, because a hazard ratio seems likely to be less population dependent than the absolute difference). In the case of oncology, the hazard ratio is the usual way of comparing treatments with respect to time to event (time to progression or survival) endpoints. The proportional hazards assumption is regarded as reasonable (approximately holding). The testing procedures proposed are conditionally equivalent to two confidence interval procedures that relax the conservatism of two 95 per cent confidence interval testing procedures and preserve the type I error rate at a one-sided 0.025 level. An application of this methodology to Xeloda, a recently approved drug for the treatment of metastatic colorectal cancers, is illustrated. Other methodologies are also described and assessed - including a point estimate procedure, a Bayesian procedure and two delta-method confidence interval procedures. Published in 2003 by John Wiley & Sons, Ltd.

Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors.

PURPOSE: Imatinib mesylate (Gleevec; Novartis, East Hanover, NJ)is a receptor tyrosine kinase inhibitor approved previously in 2001 by the United States Food and Drug Administration for the treatment of chronic myelogenous leukemia in blast crisis, accelerated phase, or in chronic phase after failure of IFN-alpha therapy. We review herein the clinical profile of this drug and the regulatory review leading to the approval of a supplemental New Drug Application for the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors (GISTs). EXPERIMENTAL DESIGN: We discuss the efficacy and side effects of imatinib mesylate in a Phase II trial of 147 patients with metastatic and/or unresectable malignant GISTs, the basis for marketing approval, and postmarketing commitments by the drug's manufacturer. RESULTS: Imatinib was assessed in a single, open-label trial involving one European center and three centers in the United States. Seventy-three patients were randomly allocated to receive 400 mg of imatinib daily, and 74 patients received 600 mg daily. At the study report cutoff date, an objective response was confirmed in 56 patients; the overall response rate for the combined study arms was 38% (95% confidence interval, 30-46%). These responses were all partial responses. There was no statistically significant difference in response rates between the two dose groups. Adverse events included edema, fluid retention, nausea, vomiting, diarrhea, myalgias, skin rash, bone marrow suppression, bleeding, and elevations in aspartate aminotransferase, alanine aminotransferase, or bilirubin. Bleeding into the gastrointestinal tract or intratumoral sites occurred in 7 patients (5%) and was not correlated with thrombocytopenia or tumor bulk. The pharmacokinetics of imatinib in GIST patients were similar to those of chronic myelogenous leukemia patients. CONCLUSIONS: On February 1, 2001, imatinib mesylate was approved by the United States Food and Drug Administration for the treatment of malignant metastatic and/or unresectable GISTs. The recommended dose is 400 or 600 mg daily.

Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia.

PURPOSE: Chronic myelogenous leukemia (CML) results from the breakpoint cluster region-Abl fusion gene product, a tyrosine kinase involved in cell division and apoptosis. Imatinib, an orally administered inhibitor of the breakpoint cluster region-Abl tyrosine kinase, is capable of blocking proliferation and inducing apoptosis in CML cell lines. In this report, we describe the preclinical profile of imatinib and the data submitted in the New Drug Application that led to its marketing approval. EXPERIMENTAL DESIGN: Chemistry manufacturing and controls, animal toxicology, and biopharmaceutical data are described. Results of Phase I and Phase II clinical studies in patients with CML in blast crisis (CML-BC), in accelerated phase (CML-AP), and in chronic phase disease-resistant or intolerant to IFN-alpha (CML-CP) are summarized. The basis for marketing approval and postmarketing commitments by the pharmaceutical company are discussed. RESULTS: Toxicology studies in the rat, dog, and monkey show the hematological, renal, and hepatobiliary toxicity of imatinib. Pharmacokinetic studies in patients with CML demonstrate 98% imatinib bioavailability. The elimination half-lives of the parent drug and the major active metabolite, CGP74588, from plasma are approximately 18 and 40 h, respectively. Approximately 81% of the drug is eliminated in 7 days, 68% in the feces and 13% in the urine. Cytochrome P-450 3A4 is the main enzyme responsible for imatinib metabolism. Phase I and II clinical studies were conducted. The Phase I study, in 83 CML patients, evaluated oral imatinib doses from 25 to 1000 mg/day. Dose-limiting toxicity was not observed. The three Phase II studies, in CML-CP, CML-AP, and CML-BC, enrolled 1027 patients. CML-CP patients received 400 mg/day imatinib, whereas CML-AP and CML-BC patients generally received 600 mg/day imatinib. Primary study endpoints were cytogenetic response rate (CML-CP) and hematological response rate (CML-AP and CML-BC). The cytogenetic response rate for CML-CP patients was 49%. The hematological response rate of CML-AP and CML-BC patients was 63 and 26%, respectively. The most common imatinib adverse events were nausea, vomiting, myalgia, edema, and diarrhea. Elevated liver enzymes and/or bilirubin were reported in 27 patients (2.6%). CONCLUSIONS: On May 10, 2001, imatinib mesylate (Gleevec, formerly known as STI-571 and Glivec), manufactured and distributed by Novartis Pharmaceuticals, East Hanover, NJ, was approved by the United States Food and Drug Administration for the treatment of CML in three clinical settings: CML-BC, CML-AP, and CML-CP. This report summarizes the Food and Drug Administration's review of the New Drug Application.