Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure.

BACKGROUND: Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome-positive leukemia are unknown. METHODS: In this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors (TKIs). The primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib. Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months. RESULTS: Patients were heavily pretreated; 70% (105 of 150 patients) had received at least three TKIs. The maximum tolerated dose of asciminib was not reached. Among patients with chronic-phase CML, 34 (92%) with a hematologic relapse had a complete hematologic response; 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 of 14 (57%) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28%) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients. Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia. CONCLUSIONS: Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02081378.).

Pharmacokinetic-pharmacodynamic guided optimisation of dose and schedule of CGM097, an HDM2 inhibitor, in preclinical and clinical studies.

BACKGROUND: CGM097 inhibits the p53-HDM2 interaction leading to downstream p53 activation. Preclinical in vivo studies support clinical exploration while providing preliminary evidence for dosing regimens. This first-in-human phase I study aimed at assessing the safety, MTD, PK/PD and preliminary antitumor activity of CGM097 in advanced solid tumour patients (NCT01760525). METHODS: Fifty-one patients received oral treatment with CGM097 10-400 mg 3qw (n = 31) or 300-700 mg 3qw 2 weeks on/1 week off (n = 20). Choice of dose regimen was guided by PD biomarkers, and quantitative models describing the effect of CGM097 on circulating platelet and PD kinetics. RESULTS: No dose-limiting toxicities were reported in any regimens. The most common treatment-related grade 3/4 AEs were haematologic events. PK/PD models well described the time course of platelet and serum GDF-15 changes, providing a tool to predict response to CGM097 for dose-limiting thrombocytopenia and GDF-15 biomarker. The disease control rate was 39%, including one partial response and 19 patients in stable disease. Twenty patients had a cumulative treatment duration of >16 weeks, with eight patients on treatment for >32 weeks. The MTD was not determined. CONCLUSIONS: Despite delayed-onset thrombocytopenia frequently observed, the tolerability of CGM097 appears manageable. This study provided insights on dosing optimisation for next-generation HDM2 inhibitors. TRANSLATIONAL RELEVANCE: Haematologic toxicity with delayed thrombocytopenia is a well-known on-target effect of HDM2 inhibitors. Here we have developed a PK/PD guided approach to optimise the dose and schedule of CGM097, a novel HDM2 inhibitor, using exposure, platelets and GDF-15, a known p53 downstream target to predict patients at higher risk to develop thrombocytopenia. While CGM097 had shown limited activity, with disease control rate of 39% and only one patient in partial response, the preliminary data from the first-in-human escalation study together with the PK/PD modeling provide important insights on how to optimize dosing of next generation HDM2 inhibitors to mitigate hematologic toxicity.

Phase 2 study of nilotinib in pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is rare in children and accounts for ≤15% of all myeloid leukemia cases. When we initiated this study with nilotinib, imatinib was the only tyrosine kinase inhibitor indicated for pediatric patients with Philadelphia chromosome-positive (Ph+) CML in chronic phase (CP); alternative treatment options were needed, particularly for patients who developed resistance or intolerance (R/I) to imatinib. This phase 2 study enrolled pediatric patients with either Ph+ CML-CP R/I to imatinib or dasatinib or newly diagnosed Ph+ CML-CP. Data presented are from analyses with minimum follow-up of up to 24 cycles (1 cycle is 28 days). Fifty-nine patients with Ph+ CML-CP were enrolled, and 58 were treated (R/I, n = 33; newly diagnosed, n = 25). Major molecular response (MMR) rate at cycle 6 in the R/I cohort was 39.4% (primary end point); 57.6% of patients achieved or maintained MMR and 81.8% achieved or maintained complete cytogenetic response (CCyR) by 24 cycles. In patients with newly diagnosed disease, rates of MMR by cycle 12 and CCyR at cycle 12 were 64.0% each (primary end points); by cycle 24, cumulative MMR and CCyR rates were 68.0% and 84.0%, respectively. The safety profile of nilotinib in pediatric patients was generally comparable with the known safety profile in adults, although cardiovascular events were not observed in this study, and hepatic laboratory abnormalities were more frequent; no new safety signals were identified. In summary, nilotinib demonstrated efficacy and a manageable safety profile in pediatric patients with Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov as #NCT01844765.

Disposition of asciminib, a potent BCR-ABL1 tyrosine kinase inhibitor, in healthy male subjects.

Asciminib is a potent, specific BCR-ABL1 inhibitor being developed for the treatment of patients with chronic myelogenous leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL).Here, we present the results of human oral absorption, distribution, metabolism, excretion (ADME) and in vitro studies that together provide an overall understanding of the metabolism, distribution and clearance of asciminib in humans.Asciminib was rapidly absorbed with a maximum plasma concentration at two hours post-dose. Total radioactivity and asciminib showed similar terminal half-lives in plasma.Oral asciminib absorption ranged between a minimum of 33%, and a maximum of 57% based on the metabolite profiles of late time-point feces collections.Asciminib was eliminated mainly through feces via unchanged asciminib excretion and metabolism.Direct glucuronidation and oxidation were major metabolic pathways in human that were catalyzed predominantly by UDP-glucuronosyltransferase (UGT)2B7 and cytochrome P450 (CYP)3A4, respectively.The relative contribution of the glucuronidation pathway to the total clearance of asciminib via metabolism is estimated to range ∼28-58%, whereas the relative contribution of the oxidative pathway is estimated to range ∼37-64%, based upon the maximum oral absorption in humans.

Rationale for optimal obinutuzumab/GA101 dosing regimen in B-cell non-Hodgkin lymphoma.

Obinutuzumab (GA101) is a type II, glycoengineered anti-CD20 monoclonal antibody for the treatment of hematologic malignancies. Obinutuzumab has mechanisms of action that are distinct from those of rituximab, potentially translating into improved clinical efficacy. We present the pharmacokinetic and clinical data from the phase I/II GAUGUIN and phase I GAUDI studies that were used to identify the obinutuzumab dose and regimen undergoing phase III assessment. In phase I (GAUGUIN and GAUDI), non-Hodgkin lymphoma patients received up to a maximum 9 fixed doses (obinutuzumab 50-2000 mg). In GAUGUIN phase II, patients received obinutuzumab 400/400 mg or 1600/800 mg [first dose day (D)1, D8, cycle (C) 1; second dose D1, C2-C8]. The influence of demographic factors on pharmacokinetics and drug exposure on tumor response and toxicity were analyzed using exploratory graphical analyses. Obinutuzumab serum concentrations with 1600/800 mg were compared with a 1000 mg fixed-dose regimen (D1, D8 and D15, C1; D1, C2-C8) using pharmacokinetic modeling simulations. Factors related to CD20-antigenic mass were more influential on obinutuzumab pharmacokinetics with 400/400 versus 1600/800 mg. Higher serum concentrations were observed with 1600/800 versus 400/400 mg, irrespective of CD20-antigenic mass. Tumor shrinkage was greater with 1600/800 versus 400/400 mg; there was no significant increase in adverse events. Fixed dose 1000 mg with an additional C1 infusion resulted in similar serum concentrations to 1600/800 mg in model-based analyses. The obinutuzumab 1000 mg fixed-dose regimen identified in this exploratory analysis was confirmed in a full covariate analysis of a larger dataset, and is undergoing phase III evaluation. GAUGUIN and GAUDI are registered at www.clinicaltrials.gov (clinicaltrials.gov identifier:00517530 and 00825149, respectively).

Pharmacokinetics and safety of subcutaneous rituximab plus fludarabine and cyclophosphamide for patients with chronic lymphocytic leukaemia.

AIMS: The aim of the phase Ib, two part SAWYER study (BO25341; NCT01292603) was to investigate the pharmacokinetics and safety of subcutaneous (s.c.) rituximab compared with intravenous (i.v.) rituximab, both in combination with fludarabine and cyclophosphamide (FC), as first line treatment for patients with chronic lymphocytic leukaemia (CLL). METHODS: During part 1 (dose-finding), CLL patients received rituximab i.v. followed by a single dose of rituximab s.c. at one of three fixed doses (1400, 1600 or 1870 mg) in cycle 6. The primary objective was to identify a fixed s.c. dose that would achieve comparable rituximab serum trough concentrations (Ctrough ) to those achieved with the standard 4 weekly 500 mg m(-2) rituximab i.v. dose. RESULTS: Fifty-five patients received a fixed dose of rituximab s.c., 16 received 1400 mg, 17 received 1600 mg and 22 received 1870 mg. The 1600 mg dose was predicted to achieve non-inferior Ctrough to standard rituximab i.v. TREATMENT: The rituximab s.c. safety profile was comparable with rituximab i.v., except that local administration-related reactions, mainly mild/moderate injection site reactions, occurred more frequently with rituximab s.c., which was not unexpected. Subcutaneous administration was preferred to i.v. administration by >90% of patients and nurses (n = 112). CONCLUSIONS: SAWYER part 1 data predict that rituximab s.c. 1600 mg will achieve non-inferior Ctrough concentrations to rituximab i.v. 500 mg m(-2) , administered 4 weekly. This fixed s.c. dose is currently undergoing formal non-inferiority assessment in SAWYER part 2. In future, CLL treatment regimens comprising rituximab s.c. and oral FC could substantially reduce i.v. chair time.

Clinical Pharmacology of Asciminib: A Review.

Asciminib is a first-in-class allosteric inhibitor of the kinase activity of BCR::ABL1, specifically targeting the ABL myristoyl pocket (STAMP). This review focuses on the pharmacokinetic (PK) and pharmacodynamic data of asciminib, which is approved at a total daily dose of 80 mg for the treatment of adult patients with chronic myeloid leukemia in chronic phase who are either resistant or intolerant to ≥ 2 tyrosine kinase inhibitors or those harboring the T315I mutation (at a dose of 200 mg twice daily). Asciminib is predicted to be almost completely absorbed from the gut, with an absolute bioavailability (F) of approximately 73%. It should be administered in a fasted state, as food (particularly high-fat meals) reduces exposure. Asciminib displays a slightly greater than dose-proportional increase in exposure, with no time-dependent changes in PK observed following repeated dosing. This drug shows low clearance (6.31 L/h), with a moderate volume of distribution (111 L) and high human plasma protein binding (97.3%). The apparent terminal elimination half-life (t1/2) across studies was estimated to be between 7 and 15 h. The PK of asciminib is not substantially affected by body weight, age, gender, race, or renal or hepatic impairment. Asciminib is primarily metabolized via CYP3A4-mediated oxidation (36.0%) and UGT2B7- and UGT2B17-mediated glucuronidation (13.3% and 7.8%, respectively); biliary secretion via breast cancer resistance protein contributes to about 31.1% to total systemic clearance, which is mainly through hepatic metabolism and biliary secretion through the fecal pathway, with renal excretion playing a minor role. The potential for PK drug interaction for asciminib both as a victim and a perpetrator has been summarized here based on clinical and predicted drug-drug interaction studies. Robust exposure-response models characterized asciminib exposure-efficacy and exposure-safety relationships. In patients without the T315I mutation, the exposure-efficacy analysis of the time course of BCR::ABL1IS percentages highlighted the existence of a slightly positive, albeit not clinically significant, relationship. Higher exposure was required for efficacy in patients harboring the T315I mutation compared with those who did not. The exposure-safety relationship analysis showed no apparent association between exposure and adverse events of interest over the broad range of exposure or dose levels investigated. Asciminib has also been shown to have no clinically relevant effect on cardiac repolarization. Here, we review the clinical pharmacology data available to date for asciminib that supported its clinical development program and regulatory applications.

Relative Bioavailability and Food Effect of Asciminib Pediatric Mini-tablet Formulation Compared to the Reference Tablet Formulation in Healthy Adult Participants.

Asciminib, a first-in-class allosteric BCR::ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP) is used in the treatment of chronic myeloid leukemia. We describe a randomized, single-dose, open-label, four-period crossover study in healthy adult participants (N = 24) which evaluated the relative bioavailability of a single 40-mg dose of asciminib in pediatric formulation (1-mg mini-tablets) compared with the reference adult tablet under fasted conditions. Additionally, the effect of food on the bioavailability of the mini-tablet formulation was evaluated. Under fasted conditions, asciminib exposure was similar for both formulations (geometric mean [Gmean ] area under the concentration-time curve from time 0 to infinity [AUCinf ] 5970 and 5700 ng ×h/mL, respectively). Food decreased the AUCinf and maximum plasma concentration (Cmax ) of the asciminib mini-tablets; this effect was more pronounced with a high-fat meal (Gmean ratios [90% confidence interval]: fasted/low-fat meal, 0.42 [0.38-047], 0.32 [0.28-0.37], respectively; fasted/high-fat meal, 0.30 [0.27-0.34], 0.22 [0.19-0.25], respectively). The mini-tablets were assessed to be easy to ingest with good palatability. Asciminib doses for a pivotal pediatric clinical trial will be defined using physiologically based pharmacokinetic modeling, which will consider the age and the higher food effect observed with the mini-tablets.

Pharmacokinetic drug interactions of asciminib with the sensitive cytochrome P450 probe substrates midazolam, warfarin, and repaglinide in healthy participants.

Asciminib, a first-in-class BCR-ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP), is a new treatment option for patients with chronic myeloid leukemia who no longer benefit from currently approved tyrosine kinase inhibitors. In vitro, asciminib reversibly inhibits cytochrome P450 (CYP) 3A4/5, CYP2C9, and CYP2C8. This phase I, open-label, two-stage study in healthy participants evaluated the effect of asciminib (40 mg b.i.d. at steady-state) as a potential perpetrator on single-dose pharmacokinetics of a two-drug cocktail containing midazolam (CYP3A substrate) and warfarin (CYP2C9 substrate) in stage 1 (n = 22), and of repaglinide (CYP2C8 substrate) in stage 2 (n = 25). For midazolam plus asciminib versus midazolam, geometric mean (Gmean ) ratios (90% confidence interval) for midazolam area under the curve from zero to infinity (AUCinf ) and maximum plasma concentration (Cmax ) were 1.28 (1.15, 1.43) and 1.11 (0.96, 1.28), respectively. For warfarin plus asciminib versus warfarin, Gmean ratios for S-warfarin AUCinf and Cmax were 1.41 (1.37, 1.45) and 1.08 (1.04, 1.13), respectively. Results for R-warfarin were in line with those for S-warfarin. For repaglinide plus asciminib versus repaglinide, Gmean ratios for AUCinf and Cmax were 1.08 (1.02, 1.14) and 1.14 (1.01, 1.28), respectively. The treatments were generally well tolerated, and the asciminib safety profile was consistent with previous studies of asciminib in the absence of probe substrates. Overall, the results indicate that asciminib (40 mg b.i.d.) is a weak inhibitor of CYP3A and CYP2C9 and has no meaningful effect on CYP2C8.

Pharmacokinetics of asciminib in the presence of CYP3A or P-gp inhibitors, CYP3A inducers, and acid-reducing agents.

Asciminib is a first-in-class inhibitor of BCR::ABL1, specifically targeting the ABL myristoyl pocket. Asciminib is a substrate of CYP3A4 and P-glycoprotein (P-gp) and possesses pH-dependent solubility in aqueous solution. This report summarizes the results of two phase I studies in healthy subjects aimed at assessing the impact of CYP3A and P-gp inhibitors, CYP3A inducers and acid-reducing agents (ARAs) on the pharmacokinetics (PK) of asciminib (single dose of 40 mg). Asciminib exposure (area under the curve [AUC]) unexpectedly decreased by ~40% when administered concomitantly with the strong CYP3A inhibitor itraconazole oral solution, whereas maximum plasma concentration (Cmax ) decreased by ~50%. However, asciminib exposure was slightly increased in subjects receiving an itraconazole capsule (~3%) or clarithromycin (~35%), another strong CYP3A inhibitor. Macroflux studies showed that cyclodextrin (present in high quantities as excipient [40-fold excess to itraconazole] in the oral solution formulation of itraconazole) decreased asciminib flux through a lipid membrane by ~80%. The AUC of asciminib was marginally decreased by concomitant administration with the strong CYP3A inducer rifampicin (by ~13-15%) and the strong P-gp inhibitor quinidine (by ~13-16%). Concomitant administration of the ARA rabeprazole had little or no effect on asciminib AUC, with a 9% decrease in Cmax . The treatments were generally well tolerated. Taking into account the large therapeutic window of asciminib, the observed changes in asciminib PK following multiple doses of P-gp, CYP3A inhibitors, CYP3A inducers, or ARAs are not considered to be clinically meaningful. Care should be exercised when administering asciminib concomitantly with cyclodextrin-containing drug formulations.

Pharmacokinetics of Asciminib When Taken With Imatinib or With Food.

Asciminib, a first-in-class, Specifically Targeting the Abelson kinase Myristoyl Pocket (STAMP) inhibitor with the potential to overcome resistance to adenosine triphosphate-competitive tyrosine kinase inhibitors, is being investigated in leukemia as monotherapy and in combination with tyrosine kinase inhibitors including imatinib. This phase 1 study in healthy volunteers assessed the pharmacokinetics of asciminib (40 mg single dose) under 2 conditions: when taken with imatinib (steady state; 400 mg once daily) and a low-fat meal (according to imatinib prescription information), or when taken as single-agent under different food conditions. Asciminib plus imatinib with a low-fat meal increased asciminib area under the plasma concentration-time curve from time 0 to infinity and maximum plasma concentration (geometric mean ratios [90% confidence interval], 2.08 [1.93-2.24] and 1.59 [1.45-1.75], respectively) compared with asciminib alone under the same food conditions. Asciminib plus food decreased asciminib area under the plasma concentration-time curve from time 0 to infinity compared with asciminib taken under fasted conditions (geometric mean ratios: low-fat meal, 0.7 [0.631-0.776]; high-fat meal, 0.377 [0.341-0.417]). Asciminib plus imatinib was well tolerated with no new safety signals. Overall, coadministration of asciminib with imatinib and a low-fat meal results in a moderate increase in asciminib exposure compared with asciminib alone under the same food condition. Food itself decreases asciminib exposure, indicating that single-agent asciminib should be administered in the fasted state to prevent potential suboptimal exposures.

Pharmacokinetics of Asciminib in Individuals With Hepatic or Renal Impairment.

Asciminib is an investigational, first-in-class, specifically targeting the ABL myristoyl pocket (STAMP) inhibitor of BCR-ABL1 with a new mechanism of action compared with approved ATP-competitive tyrosine kinase inhibitors. This report describes the findings from 2 phase 1 studies assessing the pharmacokinetic (PK) profile of a single dose of asciminib (40 mg) in individuals with impaired renal function (based on absolute glomerular filtration rate; NCT03605277) or impaired hepatic function (based on Child-Pugh classification; NCT02857868). Individuals with severe renal impairment exhibited 49%-56% higher exposure (area under the curve [AUC]), with similar maximum plasma concentration (Cmax ), than matched healthy controls. Based on these findings, as per the protocol, the PK of asciminib in individuals with mild or moderate renal impairment was not assessed. In individuals with mild and severe hepatic impairment, asciminib AUC was 21%-22% and 55%-66% higher, respectively, and Cmax was 26% and 29% higher, respectively, compared with individuals with normal hepatic function. Individuals with moderate hepatic impairment had similar asciminib AUC and Cmax than matched healthy controls. The increase in asciminib AUC and Cmax in the mild hepatic impairment cohort was mainly driven by 1 participant with particularly high exposure. Asciminib was generally well tolerated, and the safety data were consistent with its known safety profile. In summary, these findings indicate that renal or hepatic impairment has no clinically meaningful effect on the exposure or safety profile of asciminib, and support its use in patients with varying degrees of renal or hepatic dysfunction.

Physiologically Based Pharmacokinetic Modeling to Supplement Nilotinib Pharmacokinetics and Confirm Dose Selection in Pediatric Patients.

In adult patients, nilotinib is indicated for chronic myeloid leukemia at an approved oral dose of 300 or 400 mg BID. Physiologically based pharmacokinetic (PBPK) model was developed to describe and supplement limited PK data in the pediatric population ranging from 2 to less than 6 years of age and ultimately inform dosing regimen. An adult Simcyp PBPK model was established and verified with clinical pharmacokinetic data after a single or multiple oral doses of 400 mg nilotinib (230 mg/m2). The model was then applied to a pediatric PBPK model, taking account of ontogeny profiles of metabolizing enzymes and pediatric physiological parameters. The model was further verified using observed pediatric PK data in 12- to <18-year-old and from 6- to <12-year-old patients. The PBPK models were able to recover, describe, and supplement the limited nilotinib concentration-time data profile in 2- to <6-year-old patients after a single dose and Cmin,ss after BID dosing. The exposure (Cmax,ss, Cmin,ss, and AUCtau,ss) was predicted to be similar across age groups. PBPK model simulations confirmed that body surface area-normalized dosing regimen of 230 mg/m2 is considered appropriate for pediatric patients >2 to <18 years of age.

Clinical Pharmacokinetic and Pharmacodynamic Overview of Nilotinib, a Selective Tyrosine Kinase Inhibitor.

Nilotinib, an oral inhibitor of the tyrosine kinase activity of Abelson protein, is approved for the treatment of patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase and patients with CML in chronic phase or accelerated phase resistant or intolerant to prior therapies. This review describes the pharmacokinetic and pharmacodynamic data of nilotinib in patients with CML and in healthy volunteers. Nilotinib is rapidly absorbed, with a peak serum concentration approximately 3 hours after dosing. The area under the plasma drug concentration-time curve over 24 hours and the peak serum concentration of nilotinib were dose proportional from 50-400 mg once daily. The metabolism of nilotinib is primarily via hepatic cytochrome P450 (CYP) 3A4 according to in vitro studies. In the clinical setting, exposure to nilotinib was significantly reduced by the induction of CYP3A4 with rifampicin and significantly increased by the inhibition of CYP3A with ketoconazole. Additionally, nilotinib is a competitive inhibitor of CYP3A4/5, CYP2C8, CYP2C9, CYP2D6, and uridine diphosphate glucuronosyltransferase 1A1. The bioavailability of nilotinib is increased by up to 82% when given with a high-fat meal compared with fasted state. There is a positive correlation between the occurrences of all-grade total bilirubin elevations and the steady-state nilotinib trough concentrations. Fredericia method corrected QT interval change from baseline was observed to have a correlation with nilotinib exposure. No significant relationship between nilotinib exposure and major molecular response at 12 months was seen at therapeutic doses of nilotinib 300-400 mg, probably due to the narrow range of the doses investigated.

Comparison of subcutaneous versus intravenous administration of rituximab as maintenance treatment for follicular lymphoma: results from a two-stage, phase IB study.

PURPOSE: This two-stage phase IB study investigated the pharmacokinetics and safety of subcutaneous (SC) versus intravenous (IV) administration of rituximab as maintenance therapy in follicular lymphoma. PATIENTS AND METHODS: In stage 1 (dose finding), 124 patients who responded to rituximab induction were randomly assigned to SC rituximab (375 mg/m2, 625 mg/m2, or an additional group at 800 mg/m2) or IV rituximab (375 mg/m2). The objective was to determine an SC dose that would yield a rituximab serum trough concentration (Ctrough) in the same range as that of IV rituximab. In stage 2, 154 additional patients were randomly assigned (1:1) to SC rituximab (1,400 mg) or IV rituximab (375 mg/m2) given at 2- or 3-month intervals. The objective was to demonstrate noninferior rituximab Ctrough of SC rituximab relative to IV rituximab 375 mg/m2. RESULTS: Stage 1 data predicted that a fixed dose of 1,400 mg SC rituximab would result in a serum Ctrough in the range of that of IV rituximab. Noninferiority (ie, meeting the prespecified 90% CI lower limit of 0.8) was then confirmed in stage 2, with geometric mean Ctrough SC:Ctrough IV ratios for the 2- and 3-month regimens of 1.24 (90% CI, 1.02 to 1.51) and 1.12 (90% CI, 0.86 to 1.45), respectively. Overall safety profiles were similar between formulations (in stage 2, 79% of patients experienced one or more adverse events in each group). Local administration-related reactions (mainly mild to moderate) occurred more frequently after SC administration. CONCLUSION: The fixed dose of 1,400 mg SC rituximab predicted by using stage 1 results was confirmed to have noninferior Ctrough levels relative to IV rituximab 375 mg/m2 dosing during maintenance, with a comparable safety profile. Additional investigation will be required to determine whether the SC route of administration for rituximab provides equivalent efficacy compared with that of IV administration.