Peripheral Neuropathy Events Research Articles

Phase 2 study of frontline brentuximab vedotin monotherapy in Hodgkin lymphoma patients aged 60 years and older

AbstractOutcomes in older patients with Hodgkin lymphoma (HL) tend to be poor following conventional chemotherapy regimens. Treatment-related toxicity is significant and comorbidities often limit therapeutic options. This phase 2, open-label study evaluated the efficacy and safety of brentuximab vedotin, a CD30-directed antibody-drug conjugate, as frontline therapy in 27 HL patients aged ≥60 years. The objective response rate (ORR) was 92%, with 73% achieving complete remission. All patients achieved stable disease or better, and had decreased tumor volume following treatment. At the time of this analysis, the median duration of objective response for efficacy-evaluable patients (N = 26) was 9.1 months (range, 2.8 to 20.9+ months), median progression-free survival was 10.5 months (range, 2.6+ to 22.3+ months), and median overall survival had not been reached (range, 4.6+ to 24.9+ months). The observed adverse events (AEs) were generally consistent with the known safety profile of brentuximab vedotin. The most common AEs were peripheral sensory neuropathy (78%), fatigue (44%), and nausea (44%), and were ≤ grade 2 for most patients. The incidence of grade 3 peripheral neuropathy events was relatively high (30% overall), particularly among patients with the known risk factors of diabetes and/or hypothyroidism (46% vs 14% for those without). However, these risk factors were not associated with delayed time to resolution/improvement of peripheral neuropathy. Preliminary data showed no substantial age-related changes in brentuximab vedotin pharmacokinetics. Brentuximab vedotin monotherapy may provide a frontline treatment option for older patients who cannot tolerate conventional combination chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01716806.

Frontline Treatment of CD30+ Peripheral T-Cell Lymphomas with Brentuximab Vedotin in Combination with CHP: 3-Year Durability and Survival Follow-up

Frontline Treatment of CD30+ Peripheral T-Cell Lymphomas with Brentuximab Vedotin in Combination with CHP: 3-Year Durability and Survival Follow-up

Exposure-Response Analysis to Assist Selection of Dose and Treatment Duration for Polatuzumab Vedotin As a Single Agent or in Combination with Rituximab for the Treatment of B-Cell Lymphoma

IntroductionPolatuzumab vedotin (PoV), an antibody-drug-conjugate containing the microtubule inhibitor monomethyl auristatin E (MMAE), is in development for the treatment of B-cell lymphoma (BCL). In phase 1 and 2 studies assessing PoV alone or in combination with rituximab (RTX), PoV treatment until disease progression was associated with high discontinuation rates due to peripheral neuropathy (PN) at the dose of 2.4 mg/kg. Therefore, dose and schedule optimization, including justification of body weight-based dosing, dose capping, and selection of dose level and treatment durations, were evaluated to maximize efficacy and reduce the rate of treatment-emergent PN.MethodsPopulation pharmacokinetics (Pop-PK) for antibody-conjugated MMAE (acMMAE) and exposure-response (E-R) analyses were conducted. A Pop-PK model was developed including clinically relevant covariates recorded in phase 1 and 2 studies of PoV administered every 3 weeks (N=155; Table 1). A simulation was performed to compare acMMAE PK variability with body weight-based vs. fixed dosing. Exposure to acMMAE was also simulated in patients ≥101.9 kg (90th percentile of body weight) receiving a hypothetical capped PoV dose of 240 mg. E-R analyses were stratified by histology, with efficacy based on overall response (OR, complete or partial response per revised IWG criteria [Cheson et al. 2007]) and safety based on the incidence of grade ≥2 PN. Logistic regression and time-to-event analyses were conducted. E-R analyses were also performed to compare safety and efficacy through 8 cycles of treatment vs. treatment discontinuation for disease progression or unacceptable toxicity.ResultsPop-PK analysis for acMMAE identified body weight as a significant covariate for both clearance (CLinf) and central volume of distribution (Vc). Simulation suggested that body weight-based dosing (2.4 mg/kg) would result in much lower PK variability than fixed dosing (185.5 mg), with a trend towards slightly higher exposure for patients ≥101.9 kg (Figure 1). This trend of higher exposure was not observed if the PoV dose was capped to 240 mg for these patients.E-R analyses suggested that higher acMMAE exposure was associated with increased likelihood of OR for patients with indolent BCL (including follicular, marginal zone, and small lymphocytic lymphomas; Figure 2) or diffuse large BCL (DLBCL). When acMMAE exposure was translated to the PoV dose, the covariate-adjusted odds ratio (90% confidence interval [CI]) of OR for PoV 2.4 vs. 1.8 mg/kg was 1.73 (1.29-1.74) and 2.39 (1.43-6.13) for indolent BCL and DLBCL, respectively. The effect of adding RTX on PoV efficacy was not statistically significant. Grade ≥2 PN incidence increased with acMMAE exposure for both indolent BCL (Figure 2) and DLBCL. Furthermore, time-to-event analysis indicated that the rate of grade ≥2 PN increased with treatment duration.Based on safety and efficacy through 8 cycles of treatment, the incidence of grade ≥2 PN was decreased, while the higher OR probability for 2.4 mg/kg dose was maintained in both indolent BCL (Figure 2) and DLBCL patients. The time-to-event analysis suggested that treatment with ≤8 cycles of PoV resulted in a model-predicted incidence (90% CI) of grade ≥2 PN events of 28.9% (21.3-34.7%) and 35.1% (26.2-41.7%) for 1.8 and 2.4 mg/kg, respectively.ConclusionsBody weight-based dosing for all patients with capping the PoV dose at 240 mg for heavy patients (≥101.9 kg) provides lower PK variability for all patients than fixed dosing and may mitigate potential safety risks for heavy patients. When given alone or in combination with RTX, a PoV dose of 2.4 mg/kg is associated with a higher likelihood of achieving an OR compared with 1.8 mg/kg. Capping treatment to ≤8 cycles may mitigate treatment-emergent PN risk. Thus, selection of PoV dose and/or capping of treatment duration may offer an optimal benefit-risk profile. Current clinical studies are testing PoV 1.8 mg/kg limited to 6-8 cycles to further mitigate safety risk when given in combination with immunochemotherapy or novel small molecule pathway inhibitors. Future clinical testing at the 2.4 mg/kg dose level may also be warranted. [Display omitted] [Display omitted] [Display omitted] DisclosuresLu:Genentech, Inc.: Employment, Equity Ownership. Off Label Use: Polatuzumab vedotin is an investigational agent and not approved in B-cell lymphoma. Jin:Genentech, Inc.: Employment. Gibiansky:Genentech, Inc.: Consultancy. Gillespie:Genentech, Inc.: Consultancy. Agarwal:Genentech, Inc.: Employment. Jones:Genentech, Inc.: Employment. Chu:Genentech, Inc.: Employment. Wenger:Genentech, Inc.: Employment. Hirata:Genentech, Inc.: Employment, Equity Ownership. Li:Genentech, Inc.: Employment. Girish:Genentech, Inc.: Employment.

Development of peripheral neuropathy and its association with survival during treatment with nab-paclitaxel plus gemcitabine for patients with metastatic adenocarcinoma of the pancreas: A subset analysis from a randomised phase III trial (MPACT)

BackgroundIn a phase III trial in patients with metastatic pancreatic cancer (MPC), nab-paclitaxel plus gemcitabine (nab-P/Gem) demonstrated greater efficacy but higher rates of peripheral neuropathy (PN) versus Gem. This exploratory analysis aimed to characterise the frequency, duration, and severity of PN with nab-P/Gem in the MPACT study. Patients and methodsPatients with previously untreated MPC received nab-P/Gem or Gem. PN was evaluated using a broad-spectrum group of Standardised Medical Dictionary for Regulatory Activities Queries (SMQ) and graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. A case report form was completed by physicians on day 1 of each cycle (also graded by NCI CTCAE version 3.0). ResultsIn the nab-P/Gem arm, 227/421 patients (54%) experienced any-grade PN and 70 (17%) experienced grade III PN. No grade IV PN was reported. Most early-onset PN events were grade I, and treatment-related grade III PN occurred in 7% of patients who received up to three cycles of nab-P. Of those who developed grade III PN with nab-P/Gem treatment, 30 (43%) improved to grade ≤I (median time to improvement = 29 days) and 31 (44%) resumed therapy. Development of PN was associated with efficacy; median overall survival in patients with grade III versus 0 PN was 14.9 versus 5.9 months (hazard ratio, 0.33; P < .0001). Conclusionsnab-P/Gem was associated with grade III PN in a small percentage of patients. PN development was associated with longer treatment duration and improved survival. Grade III PN was reversible to grade ≤I in many patients (median ≈ 1 month) NCT00844649.

Brentuximab Vedotin in Combination with RCHOP As Front-Line Therapy in Patients with DLBCL: Interim Results from a Phase 2 Study

Brentuximab Vedotin in Combination with RCHOP As Front-Line Therapy in Patients with DLBCL: Interim Results from a Phase 2 Study

The Aethera Trial: Results of a Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Brentuximab Vedotin in the Treatment of Patients at Risk of Progression Following Autologous Stem Cell Transplant for Hodgkin Lymphoma

The Aethera Trial: Results of a Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Brentuximab Vedotin in the Treatment of Patients at Risk of Progression Following Autologous Stem Cell Transplant for Hodgkin Lymphoma

A Phase 2 Study Of Brentuximab Vedotin In Patients With Relapsed Or Refractory CD30-Positive Non-Hodgkin Lymphomas: Interim Results In Patients With DLBCL and Other B-Cell Lymphomas

Abstract Background Brentuximab vedotin (ADCETRIS®) is an anti-CD30 monoclonal antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E. Variable CD30 expression has been demonstrated in several B-cell non-Hodgkin lymphoma (NHL) subtypes such as diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBL). Methods A phase 2, open-label, single-arm study is ongoing to evaluate the antitumor activity of brentuximab vedotin in relapsed or refractory CD30-positive NHL, including B-cell neoplasms (Clinical Trials.gov NCT01421667). CD30 expression is determined by immunohistochemistry per local laboratory; any level of CD30-positive expression is permitted for enrollment. Brentuximab vedotin, 1.8 mg/kg, is administered every 3 weeks by IV infusion. Patients who achieve at least stable disease are eligible to receive continued treatment until disease progression or unacceptable toxicity. The primary efficacy endpoint is objective response rate (ORR) as assessed by the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Correlation between antitumor activity and quantitative CD30 expression is also being explored. This subset analysis presents interim data for patients with relapsed/refractory Bcell neoplasms. Results Sixty-two B-cell lymphoma patients with variable CD30 expression by central review (range 0–100%) have been enrolled to date. Diagnoses include DLBCL (n=44) and other B-cell neoplasms (n=18) [grey zone lymphoma (n=6), PMBL (n=6), follicular lymphoma (n=3), and post-transplant lymphoproliferative disorder (n=3)]. The median age of all patients was 55 years (range, 16–85 years), and the majority had an ECOG performance status of 0/1 (92%). Patients had received a median of 2 prior therapies (range, 1 to 19); 11 (18%) had received prior stem cell transplant. Forty patients (65%) had primary refractory disease, and 47 patients (76%) were refractory to their most recent prior therapy. Fourteen patients (23%) had never responded to any prior therapy. At the time of this analysis, patients had received a median of 3 cycles of treatment (range, 1–17 cycles), with a median duration of treatment of 10.5 weeks (range, 2.4 to 57.1 weeks). Twelve (19%) patients remain on treatment. Of the 43 efficacy evaluable DLBCL patients, 40% achieved an objective response [7 complete remission (CR), 10 partial remission (PR)]; the median duration of objective response was 36 weeks (range, 0.1+ to 62.3+ weeks). Of the 18 efficacy evaluable patients with other Bcell neoplasms, 22% achieved an objective response: PMBL (1 CR), PTLD (1 CR), and grey zone lymphoma (2 PRs). The median duration of objective response was 21.7 weeks (range, 6.1 to 37.1 weeks). CD30 expression levels for patients with a CR or PR were variable and ranged from &lt;1% to 90%. There was no statistical correlation between CD30 expression and response rate. Treatment-emergent adverse events (AEs) occurring in &gt;20% of patients included fatigue (40%), nausea and neutropenia (37% each), pyrexia (32%), diarrhea (31%), peripheral sensory neuropathy (26%), vomiting (23%), and anemia and constipation (21% each). Peripheral neuropathy events have been primarily Grade 1 or 2. Neutropenia (29%) was the only Grade 3/4 related AE observed in &gt;10% of patients. AEs led to treatment discontinuation in 6 patients; the most common reason was peripheral sensory neuropathy (2 patients). Conclusions In this interim analysis of 62 patients with highly refractory B-cell lymphomas, compelling antitumor activity has been observed with brentuximab vedotin. Forty percent of DLBCL patients achieved an objective response, with median remission duration of &gt;8 months and a notable proportion of complete remissions. No correlation between CD30 expression and response rate has been observed to date. Safety data are consistent with the profile of brentuximab vedotin. This study continues to enroll patients and updated results will be presented at the meeting. Disclosures: Bartlett: Seattle Genetics, Inc.: Advisory/scientific board membership and travel expenses Other, Research Funding. Off Label Use: Brentuximab vedotin is indicated for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. Sharman:Seattle Genetics, Inc.: Research Funding, Travel expenses Other; Genentech: Research Funding; Gilead: Research Funding. Oki:Seattle Genetics, Inc.: Research Funding. Advani:Millennium: Advisory/scientific board membership, Advisory/scientific board membership Other, Research Funding; Seattle Genetics, Inc.: Advisory/scientific board membership Other, Research Funding; Genentech: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pharmacyclics, Inc.: Research Funding; Janssen R&amp;D: Research Funding; Allos Therapeutics: Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees; Abbott: Research Funding. Bello:Seattle Genetics, Inc.: Research Funding, Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees; Spectrum pharmaceuticals: Speakers Bureau. Winter:Seattle Genetics, Inc.: Research Funding. Yang:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Jacobsen:Seattle Genetics, Inc.: Advisory/scientific board membership Other, Research Funding.

Carfilzomib, Rituximab and Dexamethasone (CaRD) Is Highly Active and Offers a Neuropathy Sparing Approach For Proteasome-Inhibitor Based Therapy In Waldenstrom's Macroglobulinemia

Bortezomib is active in Waldenstrom's macroglobulinemia (WM) but associated with considerable peripheral neuropathy (PN). The proteasome inhibitor carfilzomib (CFZ) is approved in the USA for relapsed/refractory myeloma. Herein, we examined the efficacy and safety of carfilzomib, rituximab, and dexamethasone (CaRD) in 31 proteasome inhibitor and rituximab naive WM patients with symptomatic disease. Median baseline characteristics: age 61, prior therapies 0 (range 0-1), hematocrit 32.3%, hemoglobin 10.7 g/dL, serum IgM 3375 mg/dL, serum M-protein 2.185 g/dL, B2M 3.6 mg/L, and bone marrow disease involvement 60%. Therapy consisted of IV CFZ 20 mg/m2 (cycle 1) then 36 mg/m2 (cycles 2 and beyond) with IV dexamethasone (dex) 20 mg given on days 1,2,8,9 and rituximab 375 mg/m2 on days 2,9 of each 21-day cycle. Treatment consisted of six induction cycles, then maintenance beginning 8 weeks after induction (given every 8 weeks for eight cycles; consisted of CFZ 36 mg/m2, and IV dex 20 mg on days 1,2 and rituximab 375 mg/m2 on day 2). Patients with IgM level >4000 mg/dL underwent plasmapheresis and/or had rituximab held until IgM <4000 mg/dL to prevent symptomatic IgM flare. Patients received oral acyclovir (400 mg twice daily) and famotidine (20 mg twice daily) as concomitant medications. For all 31 patients, median serum IgM levels and M-protein declined to 749 mg/dL and 0.7 g/dL, respectively (p<0.00001). Median hematocrit and hemoglobin rose to 40.9% and 13.7 g/dL, respectively (p<0.00001). A total of 30 patients concluded induction therapy with bone marrow tumor involvement reduced to a median of 7.5% (p=0.0003). The best overall response rate using criteria adapted from the 3rd International Workshop on WM was 81% (1 CR, 8 VGPR, 12 PR, 4 Minor Responses). With a median follow-up of 8 cycles, 22 patients remain on study, including 20 currently on maintenance therapy. Median time to response (for minor responders or better) was 2.1 months. Grade >2 treatment related toxicities included asymptomatic elevation in lipase (12.9%), dex-related hyperglycemia (6.45%), reversible neutropenia (9.67%), and cardiomyopathy (3.22%). There were no grade 2 or greater PN events. Treatment discontinuation occurred for non-response (n=8), cardiomyopathy in a patient with multiple cardiac risk factors (n=1), and progressive disease (n=1). CaRD is highly active and offers a neuropathy sparing approach for proteasome-inhibitor based therapy in WM. Disclosures:Off Label Use: Carfilzomib is a novel proteasome inhibitor, which offers a neuropathic sparing approach on waldenstrom macroglobulinemia disease when used in a combination therapy with rituximab and dexamethasome.

A phase III trial of nab-paclitaxel versus dacarbazine in chemotherapy-naive patients (pts) with metastatic melanoma: Analysis of peripheral neuropathy.

e20025 Background: Peripheral neuropathy (PN) is a common side effect associated with taxane treatment. In a phase III trial, nab-paclitaxel vs dacarbazine demonstrated a significant improvement in progression-free survival (4.8 vs 2.5 months; P = 0.044) and at the interim survival analysis, a trend toward prolonged overall survival (12.8 vs 10.7 months; P = 0.094) for the treatment of chemotherapy-naive patients with metastatic melanoma. Here we report on the PN profile of nab-paclitaxel in this phase III trial. Methods: Pts (median age, 63 years) with chemotherapy-naive stage IV melanoma (M1c stage, 65%; elevated LDH, 28%) and an ECOG performance status 0-1 were randomized to nab-paclitaxel 150 mg/m2 on days 1, 8, and 15 of a 28-day cycle (n = 264) or dacarbazine 1000 mg/m2on day 1 of each 21-day cycle (n = 265). PN events were defined based on the Standardized MedDRA Query (V 12.1, broad scope). Results: As expected, a higher proportion of pts receiving nab-paclitaxel vs dacarbazine had ≥ 1 treatment-related PN event (68% vs 8%; P &lt; 0.001). Treatment-related grade ≥ 3 PN was more frequent with nab-paclitaxel vs dacarbazine (25% vs 0%; P &lt; 0.001); 2 grade 4 events were reported in the nab-paclitaxel arm. Treatment-related grade ≥ 3 PN was 15% in pts who received up to the median of 3 cycles of nab-paclitaxel. PN led to dose reduction in 13% or discontinuation in 15% of nab-paclitaxel–treated pts. The median time to onset of grade ≥ 3 PN was 101 days (95% CI, 85 - 113). Most early-onset PN events, occurring within the first 3 cycles, were grade 1. Grade ≥ 2 PN events peaked by cycle 4 and subsided by cycle 9. Forty-one of the 64 (64%) pts with a grade ≥ 3 PN event had an improvement of ≥ 1 grade, with a median time to improvement of 28 days (95% CI, 17 - 64), and 33 of 64 (52%) pts had improved to grade 1 or better by a median of 67 days from onset (95% CI, 22- upper limit not estimable); 30 of 64 (47%) pts resumed treatment with nab-paclitaxel. Conclusions: In this phase III trial, grade ≥ 3 PN was the main treatment-related toxicity with nab-paclitaxel as observed in other studies. However, PN was rapidly reversible; a majority of pts had improvement of PN symptoms within 1 month and resumed treatment. Clinical trial information: NCT00864253.

Impact of Chemotherapy-Induced Peripheral Neuropathy on Treatment Delivery in Nonmetastatic Breast Cancer

To determine the incidence of dose-limiting (DL) chemotherapy-induced peripheral neuropathy (CIPN) events in clinical practice. This retrospective cohort study included 488 women who received docetaxel or paclitaxel. The primary outcome was a DL event (dose delay, dose reduction, or treatment discontinuation) attributed to CIPN (DL CIPN). The paired t test was used to test the difference in received cumulative dose and planned cumulative dose by dose reduction and treatment discontinuation status. A total of 150 unique DL events occurred in 120 women (24.6%). More than one third (37.3%; n=56) of the events were attributed to CIPN. The 56 DL CIPN events occurred in 50 women (10.2%). DL CIPN incidence differed significantly by agent (docetaxel, 2.4%; n=five of 209; paclitaxel, 16.1%; n=45 of 279; P<.001). DL CIPN occurred in 24.5% and 14.4% of women who received paclitaxel 80 mg/m2 weekly for 12 cycles and 175 mg/m2 biweekly for four cycles, respectively (adjusted odds ratio, 2.11; 95% CI, 0.97 to 4.60; P=.06). The cumulative dose actually received was significantly lower than the planned cumulative dose among women who had a dose reduction or treatment termination attributed to CIPN (9.4% less; P<.001 and 28.4% less; P<.001, respectively). Oncologists limited the dosing of chemotherapy because of CIPN in a significant proportion of paclitaxel recipients, most frequently in those who received a weekly regimen. Patients who had their dose reduced or discontinued received significantly less cumulative chemotherapy than planned. The implications of these DL CIPN events on treatment outcomes must be investigated.

Evaluation of side effects events peripheral neuropathy and lipodystrophy in patients with HIV/AIDS who used stavudine in antiretroviral regimens

BackgroundThe use of stavudine in antiretroviral regimens is often associated with undesirable effects such as peripheral neuropathy and lipodystrophy. This study aims to overview the prevalence of adverse events of peripheral neuropathy and lipodystrophy in HIV/AIDS patients who used stavudine in antiretroviral and factors that influence the incidence of side effects of stavudine. Materials and methodsThis study was a retrospective cohort study design. The intervention groups were patients who used stavudine and control groups were patients who used zidovudine. To determine the incidence of peripheral neuropathy used the Subjective Peripheral Neuropathy Screen (SPNS) and the incidence of lipodystrophy used Carr Lipodystrophy Questionnaire and patient's medical records retrospectively. ResultsThe prevalence of peripheral neuropathy was 25.3% and lipodystrophy 40.9% in patients who used stavudine. Differences combination of antiretroviral regimen was factor that significantly influence the incidence of side effects of peripheral neuropathy (p=0.002). Age (p=0.039), duration of stavudine use (p=0.000), previous antiretroviral regimen (p=0.013) and differences combination of antiretroviral regimen (p=0.000) were the factors most significantly influence the side effects of lipodystrophy. Stavudine likely to cause peripheral neuropathy compared zidovudine with relative risk (RR)=3.039 (95% CI, 1629–5670) and odds ratio (OR)=3.178 (95% CI, 1156–6660). Stavudine likely to cause lipodystrophy compared zidovudine with relative risk (RR=1.488 (95% CI) and odds ratio (OR)=3.353 (95% CI, 1876–5992). ConclusionsThe side effects of peripheral neuropathy and lipodystrophy at the use of antiretroviral regimens stavudine was significantly different from antiretroviral regimen zidovudine.

Long-Term Remissions Observed in an Ongoing Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma.

Long-Term Remissions Observed in an Ongoing Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma.

A Phase 1b Dose-Escalation Study of Split-Dose Oprozomib (ONX0912) in Patients with Hematologic Malignancies

AbstractAbstract 203 Background:Oprozomib (OPZ, formerly ONX 0912), a structural analog of carfilzomib (CFZ), is an orally bioavailable, next-generation proteasome inhibitor being evaluated in hematologic malignancies and solid tumors. Similar to CFZ, OPZ is a potent, selective, and irreversible proteasome inhibitor. In an earlier dose-escalation study of once-daily (QD) OPZ in patients with advanced refractory solid tumors, the maximum tolerated dose (MTD) was 150 mg QD, leading to exploration of a split-dose schedule with the drug administered twice daily (BID). The present phase 1 study (NCT01416428) is evaluating OPZ administered using the split-dose schedule in patients with hematologic malignancies. Methods:This is an ongoing, phase 1b, open-label, dose-escalation study of OPZ in patients with hematologic malignancies. The primary objectives are to evaluate safety and tolerability and to determine the MTD. Secondary objectives of the study include pharmacokinetic and pharmacodynamic analyses. OPZ is administered PO on days 1–5 of a 14-day cycle using a standard 3 + 3 dose-escalation scheme. Treatment was initiated at 120 mg (60 mg BID), with an interval of 4–6 h between doses, with escalation in 30-mg increments in successive cohorts until MTD is determined. Tumor response is assessed by investigator. Results:As of June 15, 2012, 9 patients have been enrolled in the study, 3 in each of the 120-mg, 150-mg, and 180-mg dosing cohorts. No dose-limiting toxicities have been observed. Enrollment is ongoing at 210 mg/day. The median age of all patients is 67 years (range 53−81) and prior therapies included a median of 4 chemotherapy regimens (range 2−8). Patients have received a median of 5 cycles of treatment with OPZ, including 4 patients who have received ≥6 cycles. Dose reduction was required by only 1 patient in the 180-mg (90 mg BID) group for Grade 3 diarrhea and abdominal pain. Gastrointestinal (GI) AEs predominantly of Grade 1/2 in severity were the most common, with diarrhea and nausea each occurring in 7 patients, and vomiting occurring in 6 patients. The majority of GI AEs improved or resolved with concomitant medications. Thrombocytopenia was the only Grade 3/4 AE reported in more than 1 patient, occurring in 3 patients (1 at each dose level). Notably, no events of peripheral neuropathy were noted in patients in the first 3 dosing cohorts. AEs led to discontinuation in 2 patients at the 180-mg dose level, and no deaths have been reported. OPZ showed dose-dependent exposure across the 120- to 180-mg dose levels. Patients receiving split dosing had similar total exposure and lower Cmax than patients receiving QD dosing of the same total daily dose, although there was high inter-patient variability. Dose-dependent proteasome inhibition was observed in whole blood and increased from the first to the second of the split daily doses. Proteasome inhibition levels were similar to those achieved with single-dose equivalents and were >80% at the 180-mg dose level. Eight of 9 patients are evaluable for efficacy. There was preliminary evidence of anti-tumor activity of ≥SD across all doses, including 1 patient with chronic lymphocytic leukemia who attained a PR after prior exposure to 3 lines of therapy, and 1 PR and 1 MR in patients with multiple myeloma. Conclusions:Oral OPZ was generally well tolerated using a split-dose schedule in this phase 1 trial in patients with hematologic malignancies. AEs were generally mild and manageable. An MTD has not been reached at cumulative doses up to 180 mg/d (90 mg BID). Dose-dependent proteasome inhibition was observed, with >80% inhibition at the highest dose tested. OPZ also demonstrated encouraging clinical activity across the first 3 dose levels in heavily pretreated patients. Dose escalation will continue until the MTD is reached, with planned phase 2 expansion at the MTD in patients with hematologic malignancies. Disclosures:Off Label Use: Oprozomib is in Phase 1 clinical trials for hematologic malignancies and is not approved by the FDA for any use. Lee:Onyx Pharmaceuticals: Employment. Wong:Onyx Pharmaceuticals: Employment. Lee:Onyx Pharmaceuticals: Employment. Gillenwater:Onyx Pharmaceuticals: Employment. Siegel:Onyx: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Millennium Pharma: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Celgene: Advisory Board Other, Honoraria, Speakers Bureau; Merck: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau.

A Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory CD30-Positive Non-Hodgkin Lymphomas: Interim Results.

A Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory CD30-Positive Non-Hodgkin Lymphomas: Interim Results.

Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma: A Phase 2 Study Update

Abstract 443 Background:Systemic anaplastic large cell lymphoma (sALCL) is a T-cell non-Hodgkin lymphoma (NHL) characterized by the uniform expression of CD30. sALCL accounts for 2–5% of all cases of NHL; approximately 40–65% of patients experience recurrent disease after frontline treatment with few effective treatment options. Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). A phase 2 study was conducted to determine the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory sALCL (ClinicalTrials.gov #NCT00866047); updated results of this trial are presented. Methods:Brentuximab vedotin 1.8 mg/kg was administered every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles of treatment. Determination of efficacy was based on objective response assessments per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Patients were enrolled between June 2009 and May 2010 at 22 clinical sites in the US, Canada, and Europe. Results:58 patients with a median of 2 prior therapies (range 1–6) were treated; 57% were male and the median age was 52 years (range 14–76). Seventy-two percent of patients had ALK-negative disease, 62% had primary refractory disease (defined as no complete remission (CR) or relapse within 3 months of frontline therapy), and 26% had failed a prior autologous stem cell transplant (SCT). As previously reported, the objective response rate (ORR) was 86%, the CR rate was 57%, and 97% of patients had a reduction in tumor volume postbaseline. At the time of this updated analysis (data cut May 2011), all but 2 patients had discontinued treatment with brentuximab vedotin; the median number of treatment cycles was 7 (range 1–16). The median duration of objective response was 13.0 months (range 0.1–19.1+) and the median duration of response for patients achieving a CR was 17.1 months (range 0.7–19.1+). Median progression-free survival (PFS) was 14.6 months and median overall survival was not yet reached. Per investigator assessment, the median PFS with brentuximab vedotin was significantly longer than the median PFS achieved with the most recent prior therapy (20.0 months vs. 5.9 months; P value <0.001). All subgroups of patients analyzed in the study achieved a similar level of antitumor activity, regardless of baseline disease characteristics, tumor burden, or prior treatment history. Responses were particularly noteworthy in patients who had never responded to any previous therapy (n=13); in this subgroup of patients, 10 achieved an objective response (77%) and 4 a CR (31%). After discontinuing treatment in the study, 16 patients (28%) received a hematopoietic SCT (8 allogeneic, 8 autologous). The most common adverse events observed in the study were peripheral sensory neuropathy (41%), nausea (40%), fatigue (38%), pyrexia (34%), diarrhea (29%), rash (24%), constipation (22%), and neutropenia (21%). Most AEs in the study were Grade 1 or 2 in severity. Ten patients (17%) experienced Grade 3 events of peripheral neuropathy as defined in a Standardised MedDRA Query; no Grade 4 events were observed. In patients with neuropathy, 79% (26 of 33) have experienced resolution or some improvement and the median time to resolution or improvement was 13.3 weeks (range 0.3–48.7). Conclusions:Durable complete remissions were achieved with brentuximab vedotin, and treatment was associated with manageable toxicity, in patients with relapsed or refractory sALCL. Approximately half of the responding patients (24 of 50) continued in remission at the time of this analysis; updated results of efficacy and long term safety will be presented at the meeting. Based on the results from this study, a trial evaluating the safety of brentuximab vedotin administered in sequence and in combination with multiagent chemotherapy was initiated and is currently ongoing in frontline sALCL. Disclosures:Advani:Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). It is an investigational agent that is being studied in CD30+ malignancies. Shustov:Millennium: Honoraria; Seattle Genetics, Inc.: Consultancy, Research Funding. Brice:Roche: Honoraria; Seattle Genetics, Inc.: Honoraria, Research Funding. Bartlett:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel Expenses. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Honoraria. Matous:Cephalon: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics, Inc.: Research Funding; Millennium: Speakers Bureau. Ramchandren:Seattle Genetics, Inc.: Research Funding. Fanale:Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Connors:Seattle Genetics, Inc.: Research Funding. Yang:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Pro:Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Prolonged Treatment with Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Hodgkin Lymphoma (HL) or Systemic Anaplastic Large Cell Lymphoma (sALCL),

Prolonged Treatment with Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Hodgkin Lymphoma (HL) or Systemic Anaplastic Large Cell Lymphoma (sALCL),

Bortezomib-Dexamethasone Alone or Plus Cyclophosphamide or Lenalidomide As Second-Line Treatment for Patients with Multiple Myeloma: Final Results From a Phase 2 Study

Abstract Abstract 1861 Background: Bortezomib plus dexamethasone (VD) has been shown to be effective and well tolerated in patients (pts) with multiple myeloma (MM) as frontline induction therapy and in relapsed pts; however, no studies have prospectively assessed VD as second-line therapy. The addition to VD of cyclophosphamide (VDC) or lenalidomide (VDR) may improve efficacy, but with increased toxicities. This phase 2 study evaluated the efficacy and safety of VD, with the addition of C or R for pts with stable disease (SD) after 4 cycles, in pts with relapsed or refractory MM following 1 prior line of therapy. This is the first prospective study of VD as second-line therapy for MM. Methods: Bortezomib-naïve pts aged ≥18 years with measurable MM and no grade ≥2 peripheral neuropathy (PN) who had relapsed/progressed after 1 previous line of therapy received four 21-day cycles of VD (bortezomib 1.3 mg/m2, days 1, 4, 8, 11; Dex 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12). Pts achieving at least partial response (PR) then received a further 4 cycles of VD. Pts with SD were randomized to a further 4 cycles of VD, or 4 cycles of VDC (VD + C 500 mg, days 1, 8, 15), or VDR (VD + R 10 mg, days 1–14) for Cycles 5–8. Pts with progressive disease (PD) discontinued treatment. The primary end point was response rate; secondary end points included time to response, duration of response (DOR), safety, and improvement in renal function (defined by the Cockcroft-Gault glomerular function rate [GFR], assessed prior to treatment on day 1, Cycles 1–5). Results: A total of 189 pts were enrolled; 26 did not receive therapy and were excluded from the safety/ITT population (N=163). Median age was 63 years (range 34–86), 53% were male, 20% had KPS ≤70; median time from prior therapy was 13.9 months. In the ITT population, 52% of pts (84/163) experienced an OR by Cycle 4 as validated by IDMC. Discontinuations were due to toxicity (N=10), death, PD, and other reasons (6 each). Of 135 remaining pts who started Cycle 4 treatment, 120 pts had a response assessment at Cycle 4; according to investigators, 82% of these pts experienced an overall response (OR) and 2.5% had PD; median time to first and best response was 49 and 85 days, respectively. Nineteen pts had SD and were randomized: 7 to VD, 8 to VDC (1 did not continue treatment), 4 to VDR. Only 11 pts received a third drug, C or R, in addition to VD. Due to the high response rate for the first four cycles, the second randomization arm was not completed. 47% (77/163) had continued treatment up to Cycle 8. Based on IDMC response validation as of June 2011, 122 patients had a Best Confirmed Response: 75% OR, 20% SD, and 4% PD. GFR results at Cycle 8 are shown in the Table. In pts who had baseline and on-study assessments, median GFR was 62.2 mL/min at baseline and increased after Cycles 1, 2, 3, 4, 5, 6, 7, and up to Cycle 8 by 4.5, 5.7, 9.4, 8.7, 6.0, 9.6, 8.9, and 5.5 mL/min, respectively. Of the 26 pts with stage migration from baseline GFR to best GFR at Cycle 4, 12 had a renal response (MR renal). Of the 24 pts with baseline GFR &lt;50 ml/min and renal response with stage migration from baseline GFR to best GFR at Cycle 8, 13 had CR renal, 11 had MR renal. Grade 3/4 adverse events (AEs) occurred in 64% of pts; the most common were thrombocytopenia (17%), anemia (10%), and constipation (6%). 40% of pts had serious AEs, and 46%/29%/12% had AEs resulting in dose reductions/discontinuation/death. Overall rates of sensory PN, polyneuropathy, PN (neuropathy peripheral), and motor PN in Cycles 1–8 were 20%, 18%, 13%,and 1% respectively, including 5%, 5%, 4%, and 1% grade 3/4, respectively; 55% of PN events were reversible, with resolution in 43%. Conclusions: This is the first prospective trial which assessed VD as second-line treatment in MM. VD is effective and well tolerated with less than 10% of pts receiving subsequent C or R added to VD. Overall renal function was shown to improve with treatment. PN was manageable with good reversal rates. VD represents a feasible, active treatment option for pts with relapsed MM. Final efficacy and safety data will be presented. Disclosures: Dimopoulos: Ortho Biotech: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc: Consultancy, Honoraria. Beksac:Celgene: Honoraria, Speakers Bureau; Janssen-Cilag: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Allietta:Covance for Janssen-Cilag: Employment. Broer:Janssen-Cilag: Employment. Couturier:Janssen-Cilag: Employment. Angermund:Janssen-Cilag: Employment. Facon:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

Final Phase I Results of Perifosine In Combination with Lenalidomide and Dexamethasone In Patients with Relapsed or Refractory Multiple Myeloma (MM)

Final Phase I Results of Perifosine In Combination with Lenalidomide and Dexamethasone In Patients with Relapsed or Refractory Multiple Myeloma (MM)

Bortezomib Plus Melphalan and Prednisone Compared With Melphalan and Prednisone in Previously Untreated Multiple Myeloma: Updated Follow-Up and Impact of Subsequent Therapy in the Phase III VISTA Trial

The purpose of this study was to confirm overall survival (OS) and other clinical benefits with bortezomib, melphalan, and prednisone (VMP) versus melphalan and prednisone (MP) in the phase III VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial after prolonged follow-up, and evaluate the impact of subsequent therapies. Previously untreated symptomatic patients with myeloma ineligible for high-dose therapy received up to nine 6-week cycles of VMP (n = 344) or MP (n = 338). With a median follow-up of 36.7 months, there was a 35% reduced risk of death with VMP versus MP (hazard ratio, 0.653; P < .001); median OS was not reached with VMP versus 43 months with MP; 3-year OS rates were 68.5% versus 54.0%. Response rates to subsequent thalidomide- (41% v 53%) and lenalidomide-based therapies (59% v 52%) appeared similar after VMP or MP; response rates to subsequent bortezomib-based therapy were 47% versus 59%. Among patients treated with VMP (n = 178) and MP (n = 233), median survival from start of subsequent therapy was 30.2 and 21.9 months, respectively, and there was no difference in survival from salvage among patients who received subsequent bortezomib, thalidomide, or lenalidomide. Rates of adverse events were higher with VMP versus MP during cycles 1 to 4, but similar during cycles 5 to 9. With VMP, 79% of peripheral neuropathy events improved within a median of 1.9 months; 60% completely resolved within a median of 5.7 months. VMP significantly prolongs OS versus MP after lengthy follow-up and extensive subsequent antimyeloma therapy. First-line bortezomib use does not induce more resistant relapse. VMP used upfront appears more beneficial than first treating with conventional agents and saving bortezomib- and other novel agent-based treatment until relapse.

A Randomized Phase 2 Trial of Bortezomib–Dexamethasone Versus Bortezomib–Dexamethasone with Added Cyclophosphamide or Lenalidomide in Multiple Myeloma Patients Achieving Stable Disease After Four Cycles of Bortezomib–Dexamethasone Administered as Second-Line Treatment.

Abstract 4937Bortezomib (Velcade®) plus dexamethasone (Vel/Dex) is known to be effective and well tolerated in patients with multiple myeloma (MM). As demonstrated in the frontline setting, the addition to Vel/Dex of cyclophosphamide (VCD) or lenalidomide (Revlimid®; VRD) may lead to improved efficacy, but may be associated with increased toxicities; however, few studies have prospectively assessed Vel/Dex as second-line therapy. This randomized, open-label, parallel-group, phase 2 study in patients who have relapsed after or are refractory to primary MM therapy is designed to evaluate the safety and efficacy of an additional 4 cycles of Vel/Dex, VCD, or VDR in patients achieving stable disease (SD) after 4 cycles of Vel/Dex. Bortezomib-naïve patients aged ≥18 years, with measurable MM, KPS ≥60, life expectancy ≥6 months, adequate hematologic and hepatic function, and without grade ≥2 peripheral neuropathy (PN) received 4 3-week cycles of Vel/Dex (Vel 1.3 mg/m2 IV on days 1, 4, 8, and 11, and Dex 20 mg PO on days 1, 2, 4, 5, 8, 9, 11, and 12). Patients then received a further 4 cycles of therapy as follows: patients achieving at least a partial response (PR) received Vel/Dex; patients with SD underwent central randomization to receive Vel/Dex, VCD, or VRD; patients with progressive disease (PD) discontinued treatment. Here we report efficacy and renal function improvement in patients who had the opportunity to complete the initial 4 cycles of Vel/Dex as of April 2009, and safety data for patients who received at least 1 dose of study drug. Response was assessed by IMWG uniform response criteria based on measurement of serum and urine M-protein prior to treatment on day 1 of each cycle, at end of treatment, and monthly thereafter. Renal function as defined by calculated glomerular filtration rate (GFR; Cockcroft–Gault formula) was assessed prior to treatment on day 1 of cycles 1–5. Adverse events (AEs) were graded using NCI CTCAE v3.0. A total of 122 patients have been enrolled; by data cut-off (July 21 2009), 24 (20%) had not completed a single treatment cycle and are excluded from the safety population (N=98). Eighteen had received <4 cycles at data cut-off. Of the remaining 80 who were eligible for response, 63 had completed 4 cycles, 6 discontinued prior to completing 4 cycles (due to PD in 3 patients, death in 1, drug-related AEs in 2), 9 were not under treatment at data cut-off, and 2 had died. Their median age was 62 years (range 34–86), 55% were male, 21.3% had KPS ≤70; median time from prior therapy was 18.6 months. Response rate in the efficacy population was 41/80 (51%) after 4 cycles, including 8% CR. Median times to first and best response were 37 and 57 days, respectively. Patient renal function (by GFR) at baseline, median improvement in GFR, and responses achieved by the 10 patients in whom GFR improved by at least one renal function group are shown in the Table. Among the 98 patients who received at least one treatment dose, mean cumulative doses of bortezomib and dexamethasone were 14.6 mg/m2 (4.9, 4.5, 4.4, and 4.3 mg/m2 in cycles 1–4) and 478 mg (151.8, 145.6, 145.4, and 144.0 mg for cycles 1–4), respectively. Most patients (90%) reported AEs, including 39% with grade 3/4 AEs and 23% with serious AEs, within the first 4 cycles. The most common grade 3/4 AEs included thrombocytopenia (13%), anemia (7%), and pneumonia (6%). AEs resulting in dose reductions/treatment stop were seen in 21%/10% of patients. Incidence of sensory PN and PN was 29% (3% grade 3/4); most PN events were reversible, with 68% resolving within a median 53 days. Updated efficacy and safety data for the first 4 cycles of Vel/Dex for all patients enrolled by July 31 will be presented.Table:Improvement in renal function (as measured by GFR)*Renal function group at baseline, n†<15 mL/min315–<30 mL/min630–<60 mL/min33≥60 mL/min36Median GFR (median improvement from previous cycle), mL/minAt baseline58.3After cycle 164.4 (4.8)After cycle 268.9 (2.9)After cycle 368.6 (9.9)After cycle 473.5 (9.4)Renal improvement by at least 1 grade, n (response achieved)10<15 to 15–<30 mL/min1 (1 CR)15–<30 to 30–<60 mL/min1 (1 PR)30–<60 to ≥60 mL/min8 (2 CR, 1 VGPR, 3 PR, 2 SD)*1 patient only had a baseline GFR measurement and was not included in the renal analysis†1 patient had no baseline GFR measurement DisclosuresDimopoulos:Ortho Biotech: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Honoraria. Beksac:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau. Langer:Celgene: Consultancy; Ortho Biotech: Consultancy. Facon:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees.