7513 Background: Standard treatment is lacking for patients with relapsed indolent NHL (iNHL). PI3K inhibitors reported a median PFS of < 1 y in R/R iNHL. The immunomodulatory agent lenalidomide shows enhanced activity with rituximab (ie, R2), which recently reported a 39.4-mo median PFS in R/R iNHL patients (AUGMENT; Leonard. ASH 2018:445). Methods: MAGNIFY is a multicenter, non-registrational phase IIIb trial in patients with R/R FL grade 1-3a and MZL designed to determine the optimal duration of lenalidomide. Lenalidomide 20 mg/d, d1-21/28 + rituximab 375 mg/m2/wk c1 and q8wk c3+ (R2) are given for 12c followed by 1:1 randomization in patients with stable disease or better to continued R2 vs rituximab maintenance. These analyses evaluate the primary endpoint of ORR by 1999 IWG criteria for induction R2 in efficacy-evaluable patients receiving ≥ 1 treatment with baseline/post-baseline assessments. Results: At a median 16.7 mo follow-up, 370 patients (80% FL grade 1-3a; 20% MZL) were enrolled with a median age of 66 y, 83% stage III/IV disease, and a median of 2 prior therapies (95% prior rituximab-containing). Efficacy-evaluable patients showed a 73% ORR and 45% CR (Table). Median TTR was 2.7 mo, median DOR was 36.8 mo, and median PFS was 36.0 mo. 142 of 370 patients have been randomized and entered maintenance. The most common all-grade AEs were 48% fatigue, 40% neutropenia, 35% diarrhea, 30% nausea, and 29% constipation. Grade 3/4 AE neutropenia was 34%; all other grade 3/4 AEs were < 6%. Conclusions: R2 therapy is active with a tolerable safety profile in patients with R/R FL and MZL, and in patients refractory to rituximab. Clinical trial information: NCT01996865. [Table: see text]
7502 Background: Chemoresistant patients with FL and those who progress within 2 y after initial diagnosis have poor outcomes (Casulo. JCO. 2015) and highlight an unmet need. Methods: MAGNIFY (NCT01996865) is a phase IIIb, multicenter, open-label study of relapsed/refractory (R/R) NHL patients, including grades 1-3b or transformed FL (tFL). Patients receive 12 cycles of lenalidomide plus rituximab (R2); those with stable disease or better are randomized 1:1 to maintenance R2 or rituximab alone. The primary endpoint is progression-free survival (PFS). This analysis focuses on FL: double-refractory (DR) patients are refractory to both rituximab (as monotherapy or combination) and an alkylating agent, and early relapse (ER) patients progressed or relapsed within 2 y of initial diagnosis. Results: As of July 19, 2016, the R/R FL population (N = 117) included 32 (27%) DR and 43 (37%) ER patients, median ages of 64 and 65 y, respectively, mostly grade 1-3a FL (94%; 91%) and 2 tFL (1 DR; 1 ER); 72% and 49% were stage IV at study entry. Patients had a median of 2 prior regimens (DR 3; ER 2). Of ER patients, 31 had first-line R-chemo vs 12 with R-mono/other. Response rates are in Table 1. Median time to response was 2.8 mo for DR and 2.7 mo for ER patients, with median duration not reached. 1-y PFS for FL patients was 66% (DR 66%; ER 45%); 1-y PFS for ER patients with first-line R-chemo was 50% vs 27% in others. Common grade ≥3 treatment-emergent AEs for DR and ER patients were neutropenia (53%; 33%), leukopenia (9%; 12%), and lymphopenia (9%; 5%). Conclusions: R2 followed by maintenance showed favorable activity and tolerable safety profiles in FL patients who are double-refractory or had early relapse ( < 2 years) after initial diagnosis. Enrollment in MAGNIFY is ongoing. Clinical trial information: NCT01996865. [Table: see text]
Background:Lenalidomide is an immunomodulatory agent with direct and immune-mediated mechanisms of action, as well as clinical activity in NHL. Recent studies in frontline and relapsed/refractory NHL show high activity for lenalidomide plus rituximab (R2), supporting further study of this combination. Methods: MAGNIFY (NCT01996865) is a phase IIIb, multicenter, open-label study of subjects with grades 1-3b FL (including transformed lymphoma [TL]), MZL, or MCL who received >=1 prior therapy and had stage I-IV, measurable disease (>1.5 cm). Subjects received 12 cycles of R2 induction, consisting of oral lenalidomide 20 mg/day, days 1-21 per 28-day cycle (d1-21/28) plus intravenous rituximab 375 mg/m2, days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 3, 5, 7, 9, and 11 (28-day cycles). Subjects with stable disease (SD) or better after induction were then were randomized 1:1 to R2 vs. rituximab maintenance. Stratification to the 2 maintenance arms was based on histology (FL grade 1-3b and TL vs. MZL vs. MCL), number of prior lines of antilymphoma therapy (<=2 vs. >2), and age (<65 vs. >=65 years).Maintenance R2 consisted of lenalidomide 10 mg/day, d1-21/28, cycles 13-30 plus rituximab 375 mg/m2, day 1 of cycles 13, 15, 17, 19, 21, 23, 25, 27, and 29 (Arm A). Rituximab maintenance alone was on the same schedule (Arm B). Subjects receiving R2 maintenance after 18 cycles are eligible to continue maintenance lenalidomide monotherapy 10 mg/day, d1-21/28 (optional per subject and/or investigator discretion) until disease progression as tolerated. The primary endpoint isprogression-free survival (PFS) comparing maintenance arms using a two-sided test with alpha=0.05 and HR=0.67. Secondary endpoints include safety, overall survival, and response rates. Efficacy is evaluated per modified 1999 IWG criteria and safety per NCI CTCAE version 4.03. Results: As of Jan 11, 2016, 135 subjects have been enrolled, including 91 (67%) with FL, 24 (18%) with MZL, 19 (14%) with MCL, and 1 (1%) with TL. At the time of enrollment, subjects had a median age of 66 years (range, 41-91); 81% had stage III/IV disease. Subjects had received a median of 2 prior therapies (range, 1-10), with 36% refractory to rituximab (defined as SD/PD to or PR/CR for <6 months with prior rituximab). The most common prior regimens were rituximab (41%), BR (25%), R-CHP (14%), R-CHOP (11%), and R-CVP (7%). At data cut-off, 45 (33%) subjects discontinued treatment before the maintenance period. Primary reasons for discontinuation of lenalidomide and/or rituximab, respectively, were due to AEs in 16 (12%) and 14 (10%) subjects, PD in 15 (11%) subjects for either treatment, withdrawal by subject in 6 (4%) and 7 (5%) respectively, and death 3 (2%) in either treatment. In the safety population (n=124), treatment-emergent adverse events (AE) during induction that led to dose reduction/interruption of lenalidomide or rituximab occurred in 55% or 24% of subjects, respectively, mainly due to neutropenia for lenalidomide and infusion-related symptoms for rituximab. The most common grade 3/4 AEs during induction were 27% neutropenia, 9% leukopenia, 6% thrombocytopenia, and 5% fatigue. 11 subjects have died (5 due to PD, 3 AEs, 3 other). At a median duration of 23.1 weeks (range, 0.1-51.1) of induction, 90 subjects were evaluable for response. Best responses to induction were 56 (62%) subjects with ORR, 8 (9%) CR, 12 (13%) CRu, 36 (40%) PR, and 22 (24%) SD. Responses with R2 treatment were observed in all histologies (Table 1). At data cut-off, 19 subjects have completed induction and 18 have proceeded to maintenance (n=7 R2, n=11 rituximab alone). Continued study and follow-up are ongoing to enroll more subjects in the induction and maintenance arms. Conclusions: R2 induction therapy shows favorable activity and a tolerable safety profile in subjects with advanced-stage, relapsed/refractory FL, MZL, MCL, and TL. Continued study is ongoing to determine the effect of R2 vs. rituximab maintenance following 1 year of R2 induction. Disclosures Andorsky: Gilead: Research Funding; Celgene: Consultancy, Research Funding; CTI: Research Funding. Yacoub:Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Alexion: Honoraria. Bitran:Oncology Specialists: Employment. Melear:Texas Oncology: Employment. Foon:Celgene: Employment. Rizvi:Celgene: Employment, Equity Ownership. Llorente:Celgene: Employment. Li:Celgene: Employment, Equity Ownership. Sharman:Genentech: Consultancy; Celgene: Consultancy; TG Therapeutics: Consultancy; Gilead: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy.
Background: Current anti-angiogenic drugs interfere with the vascular endothelial growth factor (VEGF) signaling pathway. PTC299 is an orally delivered, small-molecule investigational drug designed to inhibit the expression of VEGF and other angiogenic cytokines within tumors. PTC299 also induces a parallel interruption of tumor cell division at the G1/S phase of the cell cycle, offering several potential mechanisms of action. In multiple models of human cancers grown as xenografts in mice, including breast cancer, single-agent PTC299 decreases tumor and plasma VEGF levels and results in significant tumor regression or delay of tumor growth. Data from Phase 1a testing in healthy volunteers supported initiation of this Phase 1b, 2-stage, open-label, dose-ranging, escalating-dose, safety, pharmacokinetic (PK), and pharmacodynamic study evaluating PTC299 monotherapy and PTC299 combination therapy with hormonal agents in adult women with metastatic breast cancer.Materials and Methods: In Stage 1, patients have received PTC299 monotherapy in repeated 6-week cycles, each comprising a 4-week course of PTC299 administered on a twice daily (BID) schedule, followed by a 2-week washout period. The study was designed to enroll 3 successive cohorts of 3 to 6 patients at progressively higher dose levels of 0.3 mg/kg/dose BID, 0.6 mg/kg/dose BID, or 1.2 mg/kg/dose BID, with treatment given until disease progression or unacceptable toxicity. Safety, PK, and antitumor activity have been assessed.Results: Stage 1 enrolled 9 subjects (3 at each dose level) with a median [range] of 53 [31-76] years old and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (n=1) or 1 (n=8). Patients were extensively pretreated with hormonal (patient n=3), chemotherapy (n=9), and/or antiangiogenic agents (n=6). No dose-limiting toxicity was observed. Adverse events have generally been infrequent, low-grade, and do not appear to be PTC299-related. No hypertension, bleeding, thromboembolism, or proteinuria has been seen. Drug plasma concentrations have exceeded the maximally active plasma trough level identified in nude mouse xenograft models. Disease stabilization through multiple cycles (∼6 months and ∼4.5 months, respectively) has been observed in 2 subjects at the highest PTC299 dose level (1.2 mg/kg/dose BID). In these subjects, improvements in tumor-related markers of angiogenesis/inflammation have been observed.Discussion: PTC299 may offer safety, efficacy, and convenience advantages relative to current anti-angiogenic drugs. In Stage 1 of this Phase 1b study, PTC299 has been well tolerated, has achieved target plasma concentrations, and has shown suggestions of antitumor and pharmacodynamic activity. Accrual to Stage 2, in which subjects receive PTC299 combination therapy with hormonal agents, is ongoing.Supported by a translational breast cancer research grant award from the Congressionally Directed Medical Research Programs of the Department of Defense Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6092.
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