Assessment of Multiple Myeloma Patient Preferences on Treatment Choices: An International Discrete Choice Study

Abstract Introduction: Patients' individual preferences for specific treatment attributes are an important factor to consider in treatment decisions. This area of research is relatively underexplored for patients with multiple myeloma (MM). Aims: To understand MM patients' strength of preference for method of administration and for avoiding specific adverse events (AEs). Methods: AEs were selected from trials of MM treatments used globally across the disease course: lenalidomide (FIRST, MM-009/010), bortezomib (VISTA, APEX, MMY-3021), thalidomide (IFM 99-06), pomalidomide (MM-003), and carfilzomib (PX-171-003, -004, -005). AEs selected for evaluation were narrowed down to 12, based on discussions with MM patients, from a list of hematologic and non-hematologic AEs with a grade 3/4 incidence > 5% and the greatest difference in rate of occurrence across trials: bone pain, febrile neutropenia, hypokalemia, hyponatremia, infection, lymphopenia, neuralgia, neutropenia, peripheral neuropathy, renal adverse reaction, and thrombocytopenia and thromboembolic events. MM patients were recruited to complete an online survey. Following an introductory tutorial, patients completed 14 discrete choice cards on which they selected their preferred option between 2 hypothetical treatments with varying combinations of AEs (absent/present), route of administration (oral, subcutaneous [SC], intravenous [IV]), and progression-free survival (PFS; 22, 24, or 26 months, based on evidence of first-line MM treatment). Results were expressed as odds ratios (ORs) and coefficients. Strength of preference was converted into a willingness to trade (WTT) PFS months to receive preferred choice of treatment. Results: Four hundred patients from 8 countries participated in the survey: Canada (13; 3.3%), Denmark (9; 2.3%), France (68; 17.0%), Germany (65; 16.3%), Italy (89; 22.3%), Spain (81; 20.3%), Sweden (11; 2.8%), and the United Kingdom (64; 16.0%). Of the respondents, 28.8% were on their first treatment, 70.0% of patients reported having switched treatment. The majority (58.7%) were male, with a mean age of 40 years. Patients showed a preference for oral vs IV administration (OR, 0.875 [95% CI, 0.78-0.98]; P = .020), and there was a trend toward preferring oral over SC administration (OR, 0.897 [95% CI, 0.80-1.01]; P = .067). Strength of preference declined in patients with prior treatments. Patients expressed a statistically significant preference (P < .01) to avoid (OR < 1) all presented grade 3/4 AEs, except for hematologic AEs: thrombocytopenia (OR [P value]: 0.904 [.23]), neutropenia (0.911 [.30]), and lymphopenia (0.916 [.39]) for first treatment patients, and neutropenia (0.907 [.08]) for patients with prior therapy. The relative importance of bone pain, infection, and thromboembolic events was lower in patients with prior therapies, while the relative importance of grade 3/4 neuralgia, febrile neutropenia, and renal adverse reaction increased. The table shows patient preferences as coefficients, and by months of PFS WTT. Example: Patients on their first treatment would be WTT 4.33 mos of PFS to receive oral vs IV administration. Conclusions: Study results display important findings concerning preferences of younger, working-age MM patients on individual AEs and methods of administration. Patients expressed smaller preference for avoiding hematologic AEs, such as neutropenia, lymphopenia, and thrombocytopenia, and an increasing relative importance to avoiding some symptomatic AEs (eg, neuropathy, neuralgia, renal adverse reaction, and febrile neutropenia) over the course of their disease. Patient preference should be considered when making treatment decisions. Future analyses could explore subgroups based on demographics and disease history, including prior AEs. Figure 1. Figure 1. Disclosures Leleu: Amgen: Patents & Royalties; Novartis: Honoraria; Celgene Corporation: Honoraria; Janssen: Honoraria; BMS: Honoraria. Mateos:Janssen-Cilag: Consultancy, Honoraria; Onyx: Consultancy; Celgene: Consultancy, Honoraria; Takeda: Consultancy. Delforge:Novartis: Honoraria; Celgene Corporation: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Lewis:Celgene Corporation: Employment, Equity Ownership. Schindler:Celgene Corporation: Employment, Equity Ownership. Gibson:Celgene Corporation: Employment, Equity Ownership. Yang:Analysis Group: Employment. Weisel:Amgen: Consultancy, Honoraria, Other: Travel Support; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; Novartis: Other: Travel Support; Onyx: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: Travel Support; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Noxxon: Consultancy.

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Evaluation of Oral Azacitidine Using Extended Treatment Schedules: A Phase I Study

Blood ◽

10.1182/blood.v116.21.603.603 ◽

2010 ◽

Vol 116 (21) ◽

pp. 603-603 ◽

Cited By ~ 2

Author(s):

Guillermo Garcia-Manero ◽

Steven D. Gore ◽

Christopher R. Cogle ◽

Elias J. Jabbour ◽

M. Renee Ward ◽

...

Keyword(s):

Febrile Neutropenia ◽

Phase I ◽

Research Funding ◽

Phase I Study ◽

Treatment Schedule ◽

Employment Equity ◽

Transfusion Independence ◽

Clinical Responses ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 603 Parenteral azacitidine (AZA) is approved for administration on days 1–7 of a 28-day treatment schedule. Based on the short plasma half-life of AZA, S-phase restricted incorporation into DNA, and rapid re-methylation of DNA, it is possible that chronic daily exposure could enhanced its clinical activity. An oral formulation would be convenient and allow evaluation of lower doses administered on extended schedules. The initial phase I study of oral AZA, administered daily on a 7-day schedule demonstrated that it was bioavailable, safe, and clinically active in patients with MDS and AML (Garcia-Manero G, et al. Blood 2009;114:A117). Here, we report the results of a multicenter phase I exploration of extended oral AZA schedules, including dose-limiting toxicities (DLTs), safety, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary response data. Patients aged ≥ 18 years with MDS, CMML or AML (not candidates for other therapies) were enrolled in the study. Inclusion criteria were a hemoglobin level of ≤ 9.0 g/dL, and/or platelet count of ≤ 50 × 109/L, and/or be RBC transfusion-dependent; prior azanucleoside therapy was not permitted. Patients received oral AZA daily (QD) or twice daily (BID) on 14- or 21-days schedules, with starting at a dose of 300 mg for QD dosing and 200 mg for BID dosing. Patients were enrolled into cohorts of 6 and evaluated for DLTs at the end of Cycle 1. Patients were monitored continuously for adverse events (AEs) and assessed for disease response at the end of every second cycle. During Cycle 1, on the first and last day of treatment, PK parameters were derived from AZA concentrations in the plasma after the first dose of the day. PD samples were collected during the first 2 cycles and DNA methylation changes were evaluated using a LINE-1 assay. To date, 25 patients (median age 68 years [range 44–87]; 14 male and 11 female) with MDS (n = 13), AML (n = 7 de novo and n = 3 transformed), and CMML (n = 2) have received oral AZA on extended treatment schedules. Two DLTs, grade 3 nausea and grade 3 vomiting, occurred in 1 of 6 DLT-evaluable patients treated at 14-days QD (n = 7). No DLTs were observed on the 21-day QD (n = 6) or 14-day BID (n = 6) schedules; safety evaluation for the 21-day BID schedule is ongoing (n = 6). The maximum tolerated dose has not been reached on these schedules; no patient has received > 300 mg per dose. Overall rates of all grades nausea, vomiting, diarrhea, constipation, and abdominal pain with the extended schedules were similar to those observed with the oral 7-day schedule. The rate of febrile neutropenia (all grades) was higher in the 21-day QD cohort. This was observed in 4 patients with baseline ANC < 500 and/or AML diagnosis. Most common grade 3/4 AEs in the QD schedules were febrile neutropenia (14-day, 1/7; 21-day, 4/6), anemia (14-day, 1/7; 21-day, 0/6), thrombocytopenia (14-day, 1/7; 21-day, 1/6), diarrhea (14-day, 0/7; 21-day, 1/6), nausea (14-day, 1/7; 21-day, 0/6), and vomiting (14-day, 1/7; 21-day, 0/6). Extended BID schedules are under evaluation. PK data have been generated for 19 of 25 patients. For the 300 mg 14-day QD, 300 mg 21-day QD, and 200 mg 14-day BID schedules, using mean AUC (first and last day) results, extrapolated cumulative exposures per cycle were ~28%, 42% and 26%, respectively, compared with historical exposure observed following subcutaneous administration. AZA exposure increased with increasing dose, but was not dose-proportional. Clinical responses were observed for MDS/CMML patients on both extended QD schedules, with assessment ongoing for BID schedules (Table). In summary, extended (14- and 21-day) dosing of oral AZA is generally well tolerated, with no AZA accumulation, and promising clinical responses were observed, including complete remission (CR), marrow CR (mCR), and hematologic improvement (HI). Table. Parameter, n (%) Oral AZA Treatment Schedule MDS/CMML Responders/Evaluable patients, (%) 14-day QD 21-day QD Overall response* (CR, mCR, any HI) 5/6 (83) 3/3 (100) CR 0/6 2/3 (67) mCR 0/6 3/3 (100) HI 5/6 (83) 3/3 (100) HI-erythroid 3/5 (60) 1/1 (100) HI-platelet† 2/5 (40) 3/3 (100) HI-neutrophil 0/1 0/1 Transfusion independence 3/4 (75) 1/2 (50) RBC 1/2 (50) 1/1 (100) Platelet 2/2 (100) 0/1 * International Working Group 2006 criteria, patients only counted once for overall response, but may be counted more than once in individual response categories. † Includes patients achieving partial (≥ 50%) or complete platelet transfusion independence. Disclosures: Gore: Celgene: Consultancy, Equity Ownership, Research Funding. Cogle:Celgene: Research Funding, Speakers Bureau. Ward:Celgene: Equity Ownership. MacBeth:Celgene: Employment, Equity Ownership. Laille:Celgene: Employment. Giordano:Celgene: Employment, Equity Ownership. Kantarjian:Celgene: Research Funding. Skikne:Celgene: Employment.

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Evaluation of Immune Mechanisms to Understand Idelalislib-Associated Diarrhea-Colitis

Blood ◽

10.1182/blood.v128.22.5588.5588 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5588-5588

Author(s):

Richard R. Furman ◽

Michael Hallek ◽

Jeffrey P. Sharman ◽

Peter Hillmen ◽

Andrew D. Zelenetz ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Research Funding ◽

T Cell Subsets ◽

Employment Equity ◽

Lower Baseline ◽

Equity Ownership ◽

Grade 3 ◽

Temporal Profiles ◽

Support Research

Abstract Introduction: Idelalisib (IDELA) is a selective, small molecule inhibitor of PI3Kd that has shown significant efficacy in treatment of patients (pts) with relapsed chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). A common adverse event (AE) observed in IDELA studies is diarrhea/colitis (DC): grade ≥3 ~15%. Published preclinical data suggests that PI3Kd plays a critical role in regulating the function and development of regulatory T-cells (T-regs). This biomarker analysis aimed to evaluate possible immune mechanisms that may have contributed to DC in IDELA-treated pts. Methods: Longitudinal absolute peripheral blood T (CD4+ and CD8+), NK (CD16+/CD56+) cell subsets, cytokines, and chemokine levels from patients treated with IDELA were analyzed (Table 1). Since absolute numbers of T-reg cells were not available, we utilized epigenetic qPCR method (Kleen T. et. al. J Immunother Cancer 2015) to assess the status of T-regs by quantifying FOXP3 utilizing banked peripheral blood mononuclear cells (PBMCs). The following cytokines and chemokines were measured: IL-12p40, IL-17A, IFNγ, TNFα, G- CSF, MIP1α (CCL3), CCL5 (RANTES), IL-10, IL-1RA, IL-6, IL-7, IL-8, IL-15, CRP, and IP-10 (CXCL10). We evaluated the association of changes from baseline of these biomarker(s) with the occurrence and severity of DC events during IDELA treatment. Association of cytomegalovirus (CMV) with DC was not addressed in this study and is being presented separately. Results: There were no differences in absolute numbers of T (CD4+ or CD8+) and NK cells between pts treated with IDELA in both trials with grade ≥3 DC vs those with no DC. Consistently, results from epigenetic qPCR analysis also demonstrated no differences in temporal profiles for peripheral T-cell subsets (CD3+, CD8+, or FOXP3+) in CLL pts treated with IDELA with grade ≥3 DC vs no DC. Baseline and on-treatment changes in peripheral T-cell subsets were not predictive of DC. Analysis of T-cell subsets from the visit immediately prior (t-1) to the first occurrence of grade ≥3 DC was not predictive, and revealed no differences compared to pts with no DC. Lower levels of CD3+, CD8+, and FOXP3+ were noted longitudinally as well as at t-1 visits in grade 1/2 DC vs non-DC pts, but these changes were not predictive of grade 1/2 DC. Increased levels of circulating pro-inflammatory cytokines (IL-15, IFN-γ, and CLL5) were noted in both CLL and indolent non-Hodgkin lymphoma (iNHL) pts treated with IDELA. IL-17A level was significantly higher at the t-1 visit in CLL pts with grade ≥3 DC vs no DC. However, Receiver Operating Characteristic analysis deemed that neither individual cytokine/chemokine or in combination was not predictive for DC occurrence. CLL/iNHL pts with grade ≥3 DC vs no DC were noted to have higher on treatment IL-8. CLL pts presented lower baseline IL-6 and G-CSF levels in patients with grade ≥3 DC vs no DC (Table 2). There were no associations between baseline circulating plasma markers and DC in pts with iNHL. Conclusion: With currently available data, no single circulating immune biomarker is associated with or is predictive for the development of DC during treatment with IDELA. Lower levels of CD3+, CD8+, and FOXP3+ were noted longitudinally in grade 1/2 DC vs no DC pts. No differences were observed in temporal profiles for T-cell subsets in pts with grade ≥3 DC vs those with no DC. However, higher on-treatment IL-8 and lower baseline IL-6 and G-CSF were noted in the relapsed CLL pts with grade ≥3 DC when compared with no DC pts. While quantitative analysis of these T-cell subsets was not associated with grade ≥3 DC, the qualitative function of T-cells may play a role in mediating DC. Functional assays for T-cells were not explored in this study. In addition, our concurrent analysis of colonic biopsies and association with CMV in pts with IDELA associated DC will be presented separately. Disclosures Furman: Pharmacyclics: Consultancy, Speakers Bureau; Gilead Sciences: Consultancy; Janssen: Consultancy; Genentech: Consultancy; Abbvie: Consultancy, Honoraria. Hallek:Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau. Sharman:Gilead Sciences, Inc.: Honoraria, Research Funding. Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding. Zelenetz:Gilead Sciences: Research Funding. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Jurczak:Gilead Sciences: Research Funding; Janssen: Research Funding; Celltrion, Inc: Research Funding; Acerta: Research Funding; Bayer: Research Funding. Munugalavadla:Gilead Sciences: Employment, Equity Ownership. Xiao:Gilead Sciences: Employment, Equity Ownership. Zheng:Gilead Sciences: Employment, Equity Ownership. Rao:Gilead Sciences: Employment, Equity Ownership. Dreiling:Gilead Sciences: Employment, Equity Ownership. Salles:Roche/Genentech: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Gilead: Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Mundipharma: Honoraria. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria.

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Age Differences in Disease Characteristics, Patterns of Care, and Outcomes of Follicular Lymphoma (FL) in the United States (US): Report From the National Lymphocare Study (NLCS)

Blood ◽

10.1182/blood.v120.21.3708.3708 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3708-3708

Author(s):

Chadi Nabhan ◽

Michelle Byrtek ◽

Shadi Latta ◽

Keith L Dawson ◽

Xiaolei Zhou ◽

...

Keyword(s):

Research Funding ◽

Age Groups ◽

Age Group ◽

Employment Equity ◽

Disease Characteristics ◽

Baseline Factors ◽

Equity Ownership ◽

Grade 3 ◽

The Impact ◽

To Receive

Abstract Abstract 3708 Background: There are few prospective studies on disease characteristics, patterns of care, response, and outcomes in elderly FL patients (pts) in the US. The NLCS is a Genentech-sponsored prospective multicenter registry study that collects this information without study-specific treatment. We utilized the NLCS database to better understand the impact of age on FL outcome. Patients and Methods: All evaluable pts with FL histology in the NLCS were included except pts with FL plus other lymphoma histology or pts who progressed before first treatment or before being assigned to watchful waiting (WW). Using Pearson Chi-Square tests, associations of age groups (≤60, 61–70, >70) with disease characteristics and overall response (ORR) were examined. Median PFS and OS by treatment regimen were estimated using Kaplan-Meier methods for each age group. Cox proportional hazards regression adjusted for baseline factors (grade, number of nodal sites, LDH, Hgb, stage, performance status (PS), bone marrow (BM) involvement, race, and treatment center type) were used to assess treatment differences in PFS and OS and the significance of age by treatment interactions. Results: Of 2,647 pts, 47% (n=1,254) were ≤60 yrs, 25% (n=666) were 61–70 yrs, and 27% (n=727) were >70 yrs (min age of 22; max of 97). Compared with pts ≤60 yrs, pts 61–70 and >70 were more likely to be white (93% >70, 92% 61–70, and 88% ≤60, P=.02 and .02 respectively), have stage I/II disease (37% >70, 36% 61–70, and 29% ≤60, P=.0008 and .0003), have <5 nodal sites (73% >70, 69% 61–70, and 61% ≤60, P=.001 and <.0001), and have poor-risk FLIPI (53% >70, 51% 61–70, and 15% ≤60, P<.0001 and <.0001). Compared with pts ≤60, elderly pts (>70) were more likely to have FL grade 3 (24% vs 18%, P=.01). While there were no differences in geographic distribution by age, elderly pts were more likely to receive therapy at community practices (86%) versus academic institutions than pts ≤60 (77%, P<.0001) or 61–70 (81%, P=.004). Treatments varied significantly by age (P<.0001). More elderly pts were observed compared to pts ≤60 (23% vs19%). When treated, elderly pts (22%) were more likely to receive rituximab (R) monotherapy compared with patients aged 61–70 (12%) or ≤60 (10%). When chemotherapy alone or plus R was given, elderly pts were less likely to receive anthracyclines (45% vs 65% (61–70) and 68% (≤60)). Among all variables, only grade 3 histology predicted anthracycline use in all age groups. Lack of BM involvement predicted anthracycline use for younger pts (≤60 and 61–70). Of those ≤60, white pts were more likely to receive anthracyclines, and of those 61–70, those with ≥5 nodal sites were more likely to receive anthracyclines. ORRs were similar across age groups receiving similar regimens with R plus chemo providing the highest ORR. Adjusting for baseline factors, treatment (WW, R, R-Chemo, or other) benefit varied for each age group in terms of PFS (P=.02), with treatment outcomes being most differentiated among younger pts (Table). PFS appeared shorter in elderly pts regardless of the treatment received. No significant interaction between age and efficacy of anthracycline in terms of PFS or OS was observed (P-values >.65), but the overall effect of anthracycline for all pts was beneficial for PFS (HR=0.80, P=.02) and OS (HR=0.67, P=.003). Median OS was 8 years for elderly and not reached for others. After adjusting for baseline factors, no significant differences in treatment impact by age on OS were seen. Elevated LDH, reduced Hgb, stage III/IV, PS ≥1, and BM involvement were all significantly associated with shortened OS. These factors were also significantly associated with treatment choice, as worse-prognosis elderly pts were more likely to receive either R or R+chemo than WW or other treatment. Conclusions: FL pts >70 yrs more commonly received R alone and less commonly received anthracyclines when treated with chemotherapy. The impact of anthracyclines on PFS did not vary by age, but differences in PFS for other treatment regimens showed a stronger association among younger pts Disclosures: Nabhan: Genentech: Research Funding, Speakers Bureau. Byrtek:Genentech, Inc., a member of the Riche Group: Employment, Equity Ownership. Dawson:Genentech, Inc., a member of the Riche Group: Employment, Equity Ownership. Link:Genentech, Inc., a member of the Riche Group: Consultancy; Celgene: Consultancy; Spectrum: Consultancy. Friedberg:Genentech: Consultancy. Cerhan:Genentech: National LymphoCare Scientific Advisory Board Other. Flowers:Celgene: Consultancy; Prescription Solutions: Consultancy; Seattle Genetics: Consultancy; Millennium: Consultancy, Research Funding; Genentech: Consultancy; GIlead: Research Funding; Spectrum: Research Funding; Janssen: Research Funding; Lymphoma Research Foundation: Membership on an entity's Board of Directors or advisory committees.

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Safety and Efficacy of Oral Azacitidine (CC-486) Administered in Extended Treatment Schedules to Patients with Lower-Risk Myelodysplastic Syndromes

Blood ◽

10.1182/blood.v120.21.424.424 ◽

2012 ◽

Vol 120 (21) ◽

pp. 424-424 ◽

Cited By ~ 3

Author(s):

Guillermo Garcia-Manero ◽

Steven D. Gore ◽

Suman Kambhampati ◽

Bart L Scott ◽

Ayalew Tefferi ◽

...

Keyword(s):

Febrile Neutropenia ◽

Myelodysplastic Syndromes ◽

Lower Risk ◽

Research Funding ◽

Employment Equity ◽

Once Daily ◽

Hematologic Response ◽

Dosing Regimens ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 424 Background: Azacitidine for injection has been shown to prolong overall survival in patients (pts) with higher-risk myelodysplastic syndromes (MDS) compared with conventional care regimens (CCR) (Lancet Oncol, 2009). An oral formulation of azacitidine (CC-486) is in development. Oral azacitidine may maximize convenience, eliminate injection-site reactions, and if administered in extended dosing schedules, may enhance and prolong the therapeutic effects of azacitidine. Oral azacitidine administered once-daily (QD) for 7 days (d) of repeated 28d cycles has been shown to be bioavailable, biologically and clinically active, and well-tolerated in pts with MDS and acute myeloid leukemia (Garcia-Manero, J Clin Oncol, 2011). Preliminary evidence suggests that extending oral azacitidine dosing to 14d or 21d of the 28d cycle may enhance pharmacodynamic and epigenetic activity (Laille, Leuk Res, 2011). Purpose: To evaluate hematologic response and safety associated with extended dosing regimens of oral azacitidine in pts with lower-risk MDS. Methods: This ongoing, multicenter, phase 1 study, enrolled pts with lower-risk (IPSS Low or INT-1) MDS who were RBC transfusion dependent (TD) and/or thrombocytopenic (average platelet count ≤50,000 within 56d prior to the first dose) at baseline. Pts were sequentially assigned to receive oral azacitidine 300mg QD for either 14d or 21d of repeated 28d cycles. Hematologic assessments were made every 2 weeks. Hematologic response was assessed using IWG 2006 criteria (Cheson, Blood, 2006). Adverse events (AEs) were graded using NCI-CTCAE version 3.0. Results: At data cut-off (May 18, 2012), 53 pts with lower-risk MDS had enrolled (300mg oral azacitidine QDx14d, n=26; QDx21d, n=27). Demographic and disease characteristics at baseline were similar in the 14d and 21d treatment cohorts (Table 1). Median (range) hematology counts at baseline were Hgb 8.7 g/L (6.0–13.0), ANC 1.6×109/L (0–30.3), and platelets 56.0×109/L (6.0–564.0). At study entry, 40% of pts had received no prior MDS treatment (except transfusions), 45% had received erythropoiesis-stimulating agents, and 15% had received WBC growth factors. The number of oral azacitidine treatment cycles received ranged from 1 to 12 (median numbers of oral azacitidine cycles were 6 in the QDx14d and 4 in the QDx21d cohorts). Four pts in the 21d cohort and 1 pt in the 14d cohort received reduced oral azacitidine doses (200mg QD). Overall, 10 pts discontinued the study, including 6 pts (3 pts in each cohort) who discontinued due to AEs that may have been treatment-related (gastrointestinal [n=2] or intracranial [n=1] hemorrhage, febrile neutropenia [n=1], pneumonia [n=1], thrombocytopenia [n=1]). Overall response rates (ORR), which included complete (CR) and partial remission (PR), any hematologic improvement (HI), and transfusion independence (TI), ranged from 38.5% in the QDx14d cohort to 29.6% in the QDx21d cohort, and RBC TI was achieved by 47% and 33%, respectively, of pts who were RBC TD at baseline (Table 2). For pts who received at least 4 cycles of oral azacitidine (14d, n=19; 21d, n=14), ORR was 47.4% in the 14d and 50.0% in the 21d cohorts, and RBC TI rates in RBC TD pts (n=16) were 67% in the 14d and 57% in the 21d cohorts. The most frequent (≥5%) grade 3/4 hematologic AEs in the QDx14d cohort were anemia (11.5%), thrombocytopenia (11.5%), and neutropenia (7.7%); and in the QDx21d cohort were neutropenia (14.8%), anemia (7.4%), and febrile neutropenia (7.4%). Most frequent grade 3/4 non-hematologic AEs were gastrointestinal, including vomiting (7.7%) in the QDx14d cohort, and diarrhea (11.1%) and vomiting (7.4%) in the QDx21d cohort. Conclusions: Oral azacitidine 300mg QD administered in extended dosing schedules of 14d or 21d of repeated 28d cycles was effective and well-tolerated in these pts with lower-risk MDS. Beside hematologic AEs, the most frequently observed AEs with oral azacitidine were gastrointestinal and were manageable. Efficacy and safety outcomes with 300mg QD oral azacitidine were generally comparable between the 14d and 21d extended dosing regimens. Based on these data, oral azacitidine administered once-daily in extended dosing schedules is active and well-tolerated and warrants further investigation in randomized, controlled trials. Disclosures: Garcia-Manero: Celgene: Research Funding, Speakers Bureau. Gore:Celgene Corporation: Consultancy, Research Funding. Scott:Celgene Corporation: Honoraria, Research Funding, Speakers Bureau. Hetzer:Celgene Corporation: Employment, Equity Ownership. Kumar:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership.

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Risk of Febrile Neutropenia (FN) in Select Myelosuppressive Chemotherapy Regimens

Blood ◽

10.1182/blood.v126.23.3257.3257 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3257-3257 ◽

Cited By ~ 2

Author(s):

Leila Family ◽

Su-Jau Yang ◽

Zandra Klippel ◽

Yanli Li ◽

John H Page ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Practice ◽

Febrile Neutropenia ◽

Neutrophil Count ◽

Clinical Trial Data ◽

Antibiotic Use ◽

Employment Equity ◽

Myelosuppressive Chemotherapy ◽

Equity Ownership ◽

Grade 3

Abstract Introduction Febrile neutropenia (FN) is a serious adverse effect of myelosuppressive chemotherapy, which often results in hospitalization and chemotherapy dose modification. FN risk depends on patient characteristics and chemotherapy regimen risk. Understanding the FN risk associated with individual chemotherapy regimens can help guide the use of prophylactic granulocyte colony-stimulating factor (G-CSF) and patient monitoring. To this end, the NCCN has classified regimens into high (≥20%), intermediate (10%-20%), or low (<10%) FN risk based primarily on clinical trial data. However, even for the same regimen, the FN risk is often higher in clinical practice than in clinical trials. In this study, we assessed the FN risk associated with several regimens for which FN risk has not been determined or has shown substantial variability outside of a clinical trial setting, using data from Kaiser Permanente Southern California (KPSC), a large, community-based practice. Methods Included were patients diagnosed with incident non-Hodgkin's lymphoma (NHL), breast cancer (BC), or multiple myeloma (MM) between 2008 and 2013 at KPSC who initiated the following chemotherapy regimens: bendamustine ± rituximab for NHL; docetaxel, carboplatin, and trastuzumab (TCH) or docetaxel and cyclophosphamide (TC) for BC; or Q4W lenalidomide 25 mg/dexamethasone for MM. Bendamustine ± rituximab, TCH, and lenalidomide are not classified by NCCN; TC is classified as intermediate FN risk but has shown considerable variability of FN incidence when used in clinical practice. Data on cancer diagnosis, chemotherapy use, G-CSF use, neutrophil count, and infections were obtained from KPSC's electronic medical records to estimate the incidence proportions of FN and grade 3 and 4 neutropenia. FN was defined as (1) hospitalization with absolute neutrophil count (ANC) <1000/µL or (2) hospitalization with primary or secondary diagnosis codes of neutropenia (ICD-9 288.0x) and fever (ICD-9 780.6), diagnosis code for bacterial/fungal infection, or antibiotic use. Grade 3 neutropenia was defined as ANC ≥500/µL to <1000/µL; grade 4 neutropenia as ANC <500/µL. Patients who received prophylactic G-CSF within 5 days of chemotherapy initiation were excluded from analysis. Results Overall, 40 (12%) NHL patients; 149 (24%) and 340 (28%) BC patients who received TCH and TC, respectively; and 0 (0%) MM patients were excluded due to prophylactic G-CSF. Over the first 6 cycles of bendamustine (median 338.4 mg/m2) ± rituximab for NHL patients (n = 307), 7.2% experienced FN, 4.2% grade 3 neutropenia, and 17.6% grade 4 neutropenia. Over the first 6 cycles of TCH for BC patients (n = 462), 24.2% experienced FN, 10.6% grade 3 neutropenia, and 44.6% grade 4 neutropenia. Over the first 6 cycles of TC for BC patients (n = 859), 20.5% experienced FN, 9.5% grade 3 neutropenia, and 37.5% grade 4 neutropenia. Over the first 4 cycles of lenalidomide/dexamethasone for MM patients (n = 186), 3.8% experienced FN, 5.9% grade 3 neutropenia, and 18.3% grade 4 neutropenia (Table 1). Conclusions Using NCCN criteria, bendamustine ± rituximab for NHL and lenalidomide/dexamethasone for MM would be classified as low-FN-risk regimens (<10%). By contrast, BC regimens TCH and TC would be classified as high-FN-risk regimens (>20%) based on our data. These results could help inform prophylactic G-CSF use for the selected regimens in clinical practice. Table 1. Number and Incidence Proportion of Neutropenic Outcomes Overall and by Cycle Cancer: Regimen Cycle Patients n FN Events n (%) Grade 3 Neutropenia Events n (%) Grade 4 Neutropenia Events n (%) NHL: Bendamustine ± rituximab Overall 307 22 (7.2) 13 (4.2) 54 (17.6) 1 307 12 (3.9) 5 (1.6) 28 (9.1) 2 225 3 (1.3) 4 (1.8) 21 (9.3) 3 173 2 (1.2) 4 (2.3) 15 (8.7) 4 130 2 (1.5) 4 (3.1) 10 (7.7) 5 92 4 (4.4) 4 (4.4) 8 (8.7) 6 69 2 (2.9) 2 (2.9) 0 (0) BC: TCH Overall 462 112 (24.2) 49 (10.6) 206 (44.6) 1 462 70 (15.2) 39 (8.4) 138 (29.9) 2 326 13 (4.0) 15 (4.6) 42 (12.9) 3 282 17 (6.0) 9 (3.2) 39 (13.8) 4 247 6 (2.4) 8 (3.2) 31 (12.6) 5 199 4 (2.0) 6 (3.0) 25 (12.6) 6 169 8 (4.7) 3 (1.8) 12 (7.1) BC: TC Overall 859 176 (20.5) 82 (9.5) 322 (37.5) 1 859 126 (14.7) 51 (5.9) 266 (30.9) 2 649 21 (3.2) 42 (6.5) 82 (12.6) 3 571 19 (3.3) 23 (4.0) 62 (10.9) 4 511 14 (2.7) 22 (4.3) 45 (8.8) 5 94 1 (1.1) 3 (3.2) 9 (9.6) 6 84 2 (2.4) 1 (1.2) 2 (2.4) MM: Lenalidomide / dexamethasone Overall 186 7 (3.8) 11 (5.9) 34 (18.3) 1 186 2 (1.1) 8 (4.3) 17 (9.1) 2 101 3 (3.0) 5 (5.0) 14 (13.9) 3 63 2 (3.2) 2 (3.2) 8 (12.7) 4 37 0 (0) 0 (0) 4 (10.8) Disclosures Family: Amgen Inc.: Research Funding. Klippel:Amgen Inc.: Employment, Equity Ownership. Li:Amgen Inc.: Employment, Equity Ownership. Page:Amgen Inc.: Employment, Equity Ownership.

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A Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Recombinant Crisantaspase Produced in Pseudomonas Fluorescens (RC-P) in Healthy Adults

Blood ◽

10.1182/blood-2019-123695 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3817-3817

Author(s):

Martha Hernandez-Illas ◽

Tong Lin ◽

Andres Rey ◽

Jack Jenkins ◽

Reddy Chandula ◽

...

Keyword(s):

Phase 1 ◽

Healthy Adults ◽

Employment Equity ◽

Phase 1 Study ◽

Post Dose ◽

Dose Cohort ◽

E Coli ◽

Equity Ownership ◽

Grade 3 ◽

To Receive

Introduction: L-asparaginase has been an important component of acute lymphoblastic leukemia (ALL) therapy for over 30 years and is standard therapy during ALL remission induction and consolidation phases. L-asparaginase hydrolyzes the nonessential amino acid asparagine, depleting plasma levels and selectively killing cancer cells. Due to their bacterial origin, currently available L-asparaginases are immunogenic and can induce hypersensitivity reactions and high titers of neutralizing antibodies that may limit their therapeutic effect. The inability to receive asparaginase secondary to hypersensitivity has important prognostic implications for ALL patients (pts) and has been associated with significantly worse outcomes (Silverman LB, et al. Blood. 2001;97(5):1211-1218). Additionally, high-risk and slow early-responding standard-risk ALL pts who do not complete their prescribed asparaginase courses have a significantly inferior event-free survival (Gupta S, et al. J Clin Oncol. 2019;37:[suppl; abstract 10005]), demonstrating the negative effects of incomplete asparagine depletion. Therefore, to ensure that pts who develop dose-limiting hypersensitivity to E. coli-derived asparaginase products receive an adequate therapeutic course, similar alternative preparations are warranted. A recombinant crisantaspase such as RC-P, with no immunologic cross-reactivity to E. coli-derived asparaginase, may address this clinical need. JZP458-101 was a single-center, open-label, phase 1 study to evaluate the safety, tolerability, and pharmacokinetics (PK) of a single RC-P dose in healthy adults in order to facilitate the selection of a start dose and dosing regimen of RC-P for use in a pivotal phase 2/3 study in ALL pts. Methods: Eligible subjects (sbj) were aged 18 to 55 years and in good general health as determined by the investigator. In Dose Cohort 1, sbj were randomized (1:1) to receive a single RC-P dose (25 mg/m2) by either a 2-hour intravenous (IV) infusion (N = 6) or an intramuscular (IM) injection (N = 6). After the safety, tolerability, and PK of RC-P in Dose Cohort 1 was evaluated to determine the need for another dosing cohort, Dose Cohort 2 randomized sbj (1:1) to receive a single RC-P dose of either 37.5 mg/m2 IV (N = 6) or 12.5 mg/m2 IM (N = 6). RC-P was administered in the inpatient clinical unit; sbj were discharged on Day 5 with safety follow-up calls on Days 6 and 30. The primary objective was to assess safety and tolerability of RC-P by IV and IM dosing for each cohort. Secondary objectives included characterization of RC-P PK by IV and IM administration based on serum asparaginase activity (SAA). Results: Among the 24 RC-P sbj enrolled, demographic characteristics (mean ± SD) included: age (38.4 ± 8.30 years), weight (77.04 ± 10.00 kg), and body surface area (1.91 ± 0.15 m2). Additionally, 63% of sbj were male, 97% were of Hispanic/Latino ethnicity, 83% were white, and 17% were black/African American. Both safety and PK were evaluated in this study. For safety, 8/12 (67%) sbj had ≥1 adverse event (AE; IV = 4 sbj; IM = 4 sbj) in Dose Cohort 1. In Dose Cohort 2, 11/12 (92%) sbj had ≥1 AE (IV = 6 sbj; IM = 5 sbj). No serious AEs (SAEs) or grade ≥3 AEs were reported for any sbj in either dosing cohort. The most common treatment-emergent AE occurring in ≥2 sbj in each dosing cohort was nausea (Table 1). Dyspepsia was the most common AE in sbj who received RC-P 12.5 mg/m2 IM (Table 1). PK assessment showed that when administered IM, RC-P SAA levels achieved ≥0.1 IU/mL in 6/6 (100%) sbj at 48 and 72 hours post-dose in the 12.5 and 25 mg/m2 dose cohorts. Following IV administration, SAA levels achieved ≥0.1 IU/mL in 6/6 (100%) sbj at 48 hours and 4/6 (67%) sbj at 72 hours post-dose at the 25 mg/m2 dose level, while 6/6 (100%) sbj achieved ≥0.1 IU/mL at 48 and 72 hours post-dose at the 37.5 mg/m2 dose level (Table 2). Conclusions: RC-P administration in healthy adults was well tolerated and there were no unanticipated AEs, no reported SAEs, and no grade ≥3 AEs. SAA levels ≥0.1 IU/mL, a surrogate marker for asparagine depletion, were achieved in all sbj receiving IM and IV RC-P at 48 hours. SAA levels ≥0.1 IU/mL were also achieved by all sbj at 72 hours after RC-P dosing, except for 2 sbj in the 25 mg/m2 IV group. Based on the totality of PK and safety data from this study, the recommended phase 2/3 starting dose is 25 mg/m2 for the IM route of administration and 37.5 mg/m2 for the IV route of administration on a Monday/Wednesday/Friday dosing schedule. Disclosures Hernandez-Illas: QPS Miami Research Associates: Employment. Lin:Jazz Pharmaceuticals: Employment, Equity Ownership. Rey:QPS Miami Research Associates: Employment. Jenkins:Jazz Pharmaceuticals: Employment. Chandula:Jazz Pharmaceuticals: Employment, Equity Ownership. Choi:Jazz Pharmaceuticals: Employment, Equity Ownership. OffLabel Disclosure: The abstract presents data from an investigational agent.

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Phase I Study to Assess the Safety and Tolerability of AZD1152 In Combination with Low Dose Cytosine Arabinoside In Patients with Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v116.21.656.656 ◽

2010 ◽

Vol 116 (21) ◽

pp. 656-656 ◽

Cited By ~ 6

Author(s):

Hagop M. Kantarjian ◽

Mikkael A. Sekeres ◽

Vincent Ribrag ◽

Philippe Rousselot ◽

Guillermo Garcia-Manero ◽

...

Keyword(s):

Febrile Neutropenia ◽

Board Of Directors ◽

Cytosine Arabinoside ◽

Research Funding ◽

Low Dose ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 656 Background: Aurora B kinase is a key mitosis regulator that is overexpressed in a range of malignancies, including AML. AZD1152 is a potent selective inhibitor of Aurora B kinase. This ascending dose cohort study was designed to assess the safety and tolerability of AZD1152 in combination with low dose cytosine arabinoside (LDAC), the only agent that has currently demonstrated a survival advantage over palliative care in older patients with AML. Methods: Patients aged ≥60 years with newly diagnosed AML unfit for intensive induction chemotherapy were included. Cohorts of 6 patients received escalating doses of a 7-day continuous iv infusion of AZD1152, at doses of 800 mg up to the monotherapy maximum tolerated dose (MTD) of 1200 mg, in combination with LDAC 20 mg sc injection twice daily for 10 days. AZD1152 and LDAC were administered in 28-day cycles. If 1 or fewer dose-limiting toxicities (DLTs) were observed in a cohort, AZD1152 dose was escalated. A DLT was an adverse event (AE) or laboratory abnormality considered related to AZD1152, which was a Common Terminology Criteria for Adverse Events (CTCAE) grade ≥3 non-hematological toxicity (despite adequate supportive care). If 2 or more of 6 patients had a DLT, the dose was reduced or enrollment was stopped into that cohort. The MTD was defined as the dose at which 0 or 1 of 6 patients experienced a DLT. Following determination, the MTD cohort was expanded to 12 patients. Objective response was evaluated by the investigators using AML International Working Group clinical response criteria. AEs and serious AEs (SAEs) were evaluated according to CTCAE version 3. Blood samples were taken pre-dose and at selected times post dose for 3 cycles to determine levels of AZD1152, its active metabolite AZD1152 hQPA and LDAC. Results: At the data cut-off on 02/08/10 (data validation ongoing), 22 patients had been treated with the combination of LDAC plus AZD1152 (n=6 800 mg; n=13 1000 mg; n=3 1200 mg). Mean age (range) across the 3 cohorts was 71.1 (61–82) years, 14 (64%) were male, 21 were Caucasian and 1 was African American. The mean age of the 800 mg cohort was older (75.2 years) compared with the 1000 mg and 1200 mg cohorts (70.3 and 67.3 years, respectively). At baseline, 8 (36%) patients had de novo AML, and 7 (32%), 2 (9%) and 1 (5%) had AML secondary to myelodysplastic syndrome, myeloproliferative disorder and chemotherapy, respectively. All 22 patients had newly diagnosed AML. All patients received at least 1 cycle of treatment, 10 received ≥2 cycles and 1 received 5 cycles. One patient received an AZD1152 dose reduction (1000 mg to 800 mg) for their second cycle due to a high creatinine level, which was present at pre-dosing. Two patients in the 1200 mg group had DLT episodes of CTCAE grade 3 mucositis. The MTD of AZD1152 in combination with LDAC was defined as 1000 mg. All patients had at least 1 AE, the most common were myelosuppression (febrile neutropenia, anemia and thrombocytopenia in 50%, 36% and 27% of patients, respectively), stomatitis/mucosal inflammation, nausea, diarrhea and infection (each in 45% of patients). The most common grade 3/4 CTCAEs were febrile neutropenia, infection, thrombocytopenia and anemia. There were 3 (13.6%) deaths, 1 in each cohort; 2 were due to SAEs of febrile neutropenia (multiple-organ failure) and hypoxia (fungal pulmonary infection) and 1 was due to an unknown cause. Nine of 21 patients (43%) were reported by the investigators to have had a clinical response (CR + CRi) (Table). Conclusion: The MTD of AZD1152 in combination with LDAC in older patients with newly diagnosed AML was 1000 mg. AZD1152 at a dose of 1000 mg combined with LDAC had an acceptable tolerability profile. Two patients had DLTs of mucositis at the monotherapy MTD of 1200 mg. AEs of febrile neutropenia, thrombocytopenia and anemia were slightly higher than those in patients treated with either agent alone, although many patients experienced these AEs at study entry. The investigator-reported clinical response rate (CR + CRi) was 43%. The development of AZD1152 is continuing with a Phase II study in older patients with AML considered unfit for intensive chemotherapy. Disclosures: Kantarjian: AstraZeneca: Research Funding. Off Label Use: Low-dose cytosine arabinoside is an approved agent for the treatment of patients with AML; this study evaluated low-dose cytosine arabinoside in combination with AZD1152, an investigational agent that inhibits Aurora Kinase B . Sekeres:Celgene Corp: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Ribrag:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; LFB Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Celgene: Research Funding; LFB: Research Funding. Owen: AstraZeneca: Employment, Equity Ownership. Stockman:AstraZeneca: Employment, Equity Ownership. Oliver:AstraZeneca: Employment, Equity Ownership.

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A Phase I Trial of Janus Kinase (JAK) Inhibition with INCB039110 in Acute Graft-Versus-Host Disease (aGVHD)

Blood ◽

10.1182/blood.v128.22.390.390 ◽

2016 ◽

Vol 128 (22) ◽

pp. 390-390 ◽

Cited By ~ 8

Author(s):

Mark A. Schroeder ◽

H. Jean Khoury ◽

Madan Jagasia ◽

Haris Ali ◽

Gary J. Schiller ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Janus Kinase ◽

Cell Transplant ◽

Employment Equity ◽

Advisory Committees ◽

Daily Dose ◽

Equity Ownership ◽

Grade 3 ◽

Steroid Refractory

Abstract Background: Corticosteroids are considered standard first-line systemic therapy for patients with aGVHD, but this approach is effective in only approximately half of all cases. For patients who progress or do not respond to corticosteroids, no specific agent has been identified as standard, and regimens are typically selected based on investigator experience and patient co-morbidities. In preclinical models, JAK inhibition has been shown to impair production of cytokines as well as the differentiation and trafficking of T cells implicated in the pathogenesis of aGVHD. Retrospective studies have suggested that JAK1/JAK2 inhibition with ruxolitinib treatment provides clinical benefit in patients with steroid-refractory GVHD (Zeiser et al, Leukemia 2015;29:2062-2068). Herein, we report preliminary safety results from a prospective randomized, parallel-cohort, open-label phase 1 trial evaluating the potent and selective JAK 1 inhibitor INCB039110 in patients with aGVHD. Methods: Male or female patients 18 years or older who underwent their first allo-hematopoietic stem cell transplant (HSCT) from any donor source and developed grades IIB-IVD aGVHD were eligible for the study. Patients were randomized 1:1 to either a 200 or 300 mg oral daily dose of INCB039110 in combination with corticosteroids, and were stratified based on prior treatment status (treatment-naive [TN] versus steroid-refractory [SR]). The primary endpoint of the study was safety and tolerability; secondary endpoints included overall response rate at Days 14, 28, 56, and 100, non-relapse mortality, and pharmacokinetic (PK) evaluations. Patients were assessed through Day 28 for dose-limiting toxicities (DLTs) and response. A Bayesian approach was used for continuous monitoring of DLTs from Days 1-28. Treatment continued until GVHD progression, unacceptable toxicity, or withdrawal from the study. Acute GVHD was graded according to MN-CIBMTR criteria; adverse events (AEs) were graded according to NCICTCAE v 4.03. Results: Between January and June 2016, 31 patients (TN, n=14; SR, n= 17) were randomized. As of July 25, 2016, data were available from 30 patients who received an oral daily dose of 200 mg (n=14) or 300 mg (n=16) INCB039110 in combination with 2 mg/kg methylprednisolone (or equivalent dose of prednisone). The median durations of treatment were 60.8 days and 56.5 days for patients receiving a daily dose of 200 mg and 300 mg INCB039110, respectively. One DLT of Grade 3 thrombocytopenia was reported. The most frequently reported AEs included thrombocytopenia/platelet count decrease (26.7%), diarrhea (23.3%), peripheral edema (20%), fatigue (16.7%), and hyperglycemia (16.7%). Grade 3 or 4 AEs occurred in 77% of patients and with similar frequency across dose groups and included cytomegalovirus infections (n=3), gastrointestinal hemorrhage (n=3), and sepsis (n=3). Five patients had AEs leading to a fatal outcome, including multi-organ failure (n=2), sepsis (n=1), disease progression (n=1), and bibasilar atelectasis, cardiopulmonary arrest, and respiratory distress (n=1); none of the fatal events was attributed to INCB039110. Efficacy and PK evaluations are ongoing and will be updated at the time of presentation. Conclusion: The oral, selective JAK1 inhibitor INCB039110 can be given safely to steroid-naive or steroid-refractory aGVHD patients. The safety profile was generally consistent in both dose groups. Biomarker evaluation, PK, and cellular phenotyping studies are ongoing. The recommended phase 2 dose will be selected and reported based on PK studies and final safety data. Disclosures Schroeder: Incyte Corporation: Honoraria, Research Funding. Khoury:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jagasia:Incyte Corporation: Research Funding; Therakos: Research Funding; Janssen: Research Funding. Ali:Incyte Corporation: Research Funding. Schiller:Incyte Corporation: Research Funding. Arbushites:Incyte Corporation: Employment, Equity Ownership. Delaite:Incyte Corporation: Employment, Equity Ownership. Yan:Incyte Corporation: Employment, Equity Ownership. Rhein:Incyte Corporation: Employment, Equity Ownership. Perales:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. DiPersio:Incyte Corporation: Research Funding.

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Daratumumab (DARA) Maintenance Therapy Improves Depth of Response and Results in Durable Progression-Free Survival (PFS) Following Dara Plus Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) Induction Therapy in Multiple Myeloma (MM): Update of the Lyra Study

Blood ◽

10.1182/blood-2019-122497 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 863-863 ◽

Cited By ~ 4

Author(s):

Robert M. Rifkin ◽

Jason M. Melear ◽

Edward Faber ◽

William I. Bensinger ◽

John M Burke ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Induction Therapy ◽

Safety Profile ◽

Employment Equity ◽

Advisory Committees ◽

Depth Of Response ◽

Equity Ownership ◽

Grade 3

Background: DARA, a human IgGκ monoclonal antibody targeting CD38, is approved in combination with bortezomib, melphalan, and prednisone (VMP) and bortezomib and dexamethasone (Vd) for newly diagnosed MM (NDMM) and relapsed MM (RMM), respectively. CyBorD is a commonly used immunomodulatory drug-sparing regimen for MM. In the LYRA (NCT02951819) study, DARA plus CyBorD (DARA-CyBorD) demonstrated efficacy and a tolerable safety profile at the end of induction. Here, we present updated findings examining the effect of monthly DARA maintenance on the efficacy and safety of DARA-CyBorD in NDMM and RMM. Methods: LYRA is an ongoing, single-arm, open-label, phase 2 study conducted at US community oncology centers. Patients (pts) were aged ≥18 years with documented MM per IMWG criteria, an ECOG performance score (PS) of 0-2, and ≤1 prior line of therapy. Pts received 4-8 induction cycles of DARA-CyBorD (cyclophosphamide 300 mg/m2 PO on Days 1, 8, 15, and 22; bortezomib 1.5 mg/m2 SC on Days 1, 8, and 15; and dexamethasone 40 mg PO or IV weekly [qw]) every 28 days. DARA was given at 8 mg/kg IV on Days 1 and 2 of C1, 16 mg/kg qw from C1D8 through C2, 16 mg/kg q2w for C3-6, and 16 mg/kg q4w for C7-8. After induction, eligible pts could undergo autologous stem cell transplantation (ASCT). All pts received up to 12 maintenance cycles with DARA 16 mg/kg IV q4w. Results: A total of 101 (87 NDMM, 14 RMM) pts were enrolled; 100 (86 NDMM, 14 RMM) pts received ≥1 treatment dose. Median age was 63 years; most pts were white (81%), male (64%), had ECOG PS 0-1 (94%) and had IgG (57%) MM; 36% of pts had high cytogenetic risk, defined as a del(17p), t(4:14) or t(14;16) abnormality. NDMM and RMM pts received a median of 6 and 8 cycles, respectively, of induction therapy. Thirty-nine NDMM pts and 1 RMM pt underwent ASCT. Fifty percent of pts received plerixafor; median stem cell yield for NDMM pts was 6.2 x 106 (range 2-15 x 106) CD34+ cells/kg. A total of 85 (75 NDMM, 10 RMM) pts received ≥1 dose of maintenance treatment; 63 (56 NDMM, 7 RMM) pts have received all 12 maintenance cycles. In NDMM pts, ORR was 87%, with 64% ≥VGPR and 12% ≥CR, by the end of induction. By the end of maintenance, ORR, ≥VGPR and ≥CR rates were 97%, 82% and 51% in NDMM pts who underwent ASCT and 83%, 70% and 30% in NDMM pts who did not receive ASCT. In RMM pts, ORR, ≥VGPR and ≥CR rates were 79%, 71% and 29% by the end of induction and 86%, 71% and 64% by the end of maintenance. At a median follow up of 24.8 mo in NDMM pts and 26.6 mo in RMM pts, median duration of response was not reached (NR). Median PFS (Figure) was NR in NDMM pts, regardless of transplant status, and was 21.7 mo in RMM pts; median OS was NR in NDMM pts and was 30.1 mo in RMM pts. In NDMM pts the 24-mo PFS rate was 89% in pts who underwent ASCT and 72% in pts who did not receive ASCT. The 24-mo OS rate was 90% for NDMM pts. In RMM pts, the 24-mo PFS and OS rates were 48% and 64%, respectively. All treated pts had ≥1 TEAE. Common TEAEs (≥25%) included fatigue, nausea, cough, diarrhea, upper respiratory tract infection, back pain, vomiting, insomnia, dyspnea, constipation, and headache. Grade 3/4 TEAEs were reported in 62% of pts; the most common (≥10%) was neutropenia (14%). Serious TEAEs occurred in 33% of pts; the most common (>2%) were pneumonia, atrial fibrillation and pulmonary embolism. TEAEs led to permanent treatment discontinuation in 7% of pts, with 2% related to treatment. TEAEs resulted in death in 2 pts (nephrotic syndrome, sudden death); both unrelated to treatment. Infusion reactions (IRs) occurred in 56% of pts including grades 1-2 in 52% of pts, grade 3 in 3% of pts and grade 4 in 1% of pts. Most common (>5%) IRs were chills, cough, dyspnea, nausea, pruritus, flushing and nasal congestion. Conclusion: Maintenance with DARA monotherapy for 12 mo increased the >CR rate in NDMM and RMM pts, consistent with observations in prior studies that longer DARA treatment improves depth of response. Importantly, the increase in ≥CR rate was associated with durable PFS and OS. The 24-mo PFS rates in NDMM and RMM pts compare favorably with results for DARA-VMP and DARA-Vd in NDMM and RRMM, respectively. Safety profile was consistent with previous reports of DARA, with no new safety concerns observed with longer follow-up. These data indicate that DARA-CyBorD is a safe, effective MM treatment and that DARA maintenance increases depth of response and achieves durable remissions. Disclosures Rifkin: Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Melear:Texas Oncology: Employment; DARA: Speakers Bureau. Faber:Cardinal Health: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant. Burke:Gilead: Consultancy; Celgene: Consultancy; Roche/Genentech: Consultancy. Narang:Celgene: Speakers Bureau. Stevens:Astellas: Consultancy. Gunawardena:Janssen: Employment, Equity Ownership. Lutska:Janssen: Employment. Qi:Janssen: Employment. Ukropec:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment. Lin:Janssen: Employment, Equity Ownership. Yimer:Amgen: Consultancy; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership; Celgene: Honoraria; Seattle Genetics: Honoraria; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau.

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The Combined Safety and Tolerability Profile of Vorinostat-Based Therapy for Solid or Hematologic Malignancies.

Blood ◽

10.1182/blood.v114.22.1710.1710 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1710-1710 ◽

Cited By ~ 1

Author(s):

David Siegel ◽

Pamela N Munster ◽

Eric Rubin ◽

Marian Iwamoto ◽

Simon van Belle ◽

...

Keyword(s):

Cancer Patients ◽

Advanced Cancer ◽

Hematologic Malignancies ◽

Tolerability Profile ◽

Employment Equity ◽

Advisory Committees ◽

Common Drug ◽

Equity Ownership ◽

Grade 3 ◽

Dose Modifications

Abstract Abstract 1710 Poster Board I-736 Introduction Treatment regimens for cancer are typically based on cytotoxic chemotherapy, which is poorly tolerated. There is an unmet medical need for new therapies that retain efficacy, but combine this with an improved safety and tolerability profile. Vorinostat is a histone deacetylase (HDAC) inhibitor, approved in the United States for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients who have progressive, persistent, or recurrent disease on or following 2 systemic therapies. Vorinostat is also being investigated as a treatment for various other solid and hematologic malignancies, in which HDACs are further implicated as key regulators of transcription. Herein we present an overview of the safety and tolerability profile of vorinostat, gathered from prior clinical experience. Methods Safety and tolerability data, including adverse events (AEs), QTc interval data and incidence of thromboembolic events (TEE), were collated from patients who received vorinostat, administered as monotherapy or in combination therapy for solid or hematologic malignancies. Results (adverse events) In Phase I and II clinical trials, 498 patients who received vorinostat were analyzed. A total of 341 patients received vorinostat monotherapy (107 with CTCL, 105 other hematologic malignancies, 129 solid tumors) and the most common drug-related AEs in this group were: fatigue (61.9%), nausea (55.7%), diarrhea (49.3%), anorexia (48.1%), and vomiting (32.8%); Grade 3/4 AEs included fatigue (12.0%) and thrombocytopenia (10.6%), and 3 drug-related deaths (ischemic stroke, tumor hemorrhage, unspecified) occurred. Thirty-eight patients (11.1%) discontinued due to drug-related AEs, 71 patients (20.8%) required dose modifications, and 1 patient (0.3%) discontinued due to Grade 2 chest pain. The remaining 157 patients received vorinostat combination therapy (with pemetrexed/cisplatin for advanced cancer [n=46], bortezomib for multiple myeloma [n=34], bexarotene for CTCL [n=23], and erlotinib [n=30], gemcitabine/platin [n=21] or carboplatin/paclitaxel [n=3] for non-small-cell lung cancer). The most common drug-related AEs in this group were: nausea (48.4%), diarrhea (40.8%), fatigue (34.4%), and vomiting (31.2%); the most common Grade 3/4 AE was fatigue (13.4%), and 1 drug-related death (hemoptysis) occurred. Thirty-one patients (19.7%) discontinued due to drug-related AEs and 27 patients (17.2%) required dose modifications. Results (QTcF interval) A trial of 24 patients with advanced cancer was undertaken for rigorous assessment of QTcF interval. In this trial, a single supratherapeutic 800 mg dose of vorinostat did not prolong QTcF interval (monitored over 24 hours). The upper limit of the 90% confidence interval for the placebo-adjusted mean change-from-baseline of vorinostat was <10 msec at every timepoint, no patient had a QTcF change-from-baseline value >30 msec, and 1 patient had a QTcF interval >450 msec (after both vorinostat and placebo administration). The most common drug-related AE in this trial was nausea. There were no serious clinical or laboratory AEs, no discontinuations due to an AE and no patients experienced a cardiac-related AE. Results (incidence of TEE) A review of vorinostat clinical trials, published literature and post-marketing surveillance reports was conducted by a committee of independent academic experts to determine the incidence of TEE in cancer patients who had received vorinostat. In >1845 patients reviewed through November 3, 2008, 107 patients (<5.8%) reported TEE as a serious AE (SAE), 47 (<2.6%) of which were recorded as being related to vorinostat, and 4/47 (<0.3%) TEE SAEs were fatal. Conclusions In this review, the majority of observed AEs were 'Grade 2, there was no observed prolongation of the QTcF interval, and the incidence of TEE with vorinostat was similar to reported rates of TEE in advanced cancer patients. Vorinostat is generally well tolerated when administered as monotherapy or in a combination regimen in cancer patients. Disclosures Siegel: Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celegne: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rubin:Merck: Employment, Equity Ownership. Iwamoto:Merck: Employment, Equity Ownership. Hussein:Celgene: Employment. Belani:Merck: Consultancy. Hardwick:Merck: Employment, Equity Ownership. Rizvi:Merck: Employment, Equity Ownership.

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