scholarly journals Matching Adjusted Indirect Comparison (MAIC) of Oral Azacitidine (Oral-AZA) Versus Injectable AZA in Patients (pts) with Acute Myeloid Leukemia (AML) in First Remission after Intensive Induction Chemotherapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3015-3015
Author(s):  
Clara Chen ◽  
Gerwin A. Huls ◽  
Heather Cameron ◽  
Beatrice Suero ◽  
Alberto Vasconcelos ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Indirect Comparison ◽  
Sensitivity Analyses ◽  
Publicly Traded ◽  
Phase 3 ◽  
Eligibility Criteria ◽  
Free Survival ◽  
First Remission ◽  
Adjusted Indirect Comparison ◽  
Rbc Transfusion

Abstract INTRODUCTION: Oral-AZA was approved in the United States in September 2020 for continued treatment (Tx) of adult patients (pts) with AML in first remission after intensive chemotherapy (IC). The phase 3 QUAZAR AML-001 trial showed that Oral-AZA significantly improved overall and relapse-free survival (OS/RFS) vs placebo (PBO) and was generally well-tolerated (Wei, NEJM 2020). In the phase 3 HOVON97 trial, subcutaneous (SC) AZA maintenance Tx significantly improved disease-free survival vs observation, but did not show an OS benefit (Huls, Blood 2019). Although Oral-AZA and SC AZA contain the same active drug, they are not bioequivalent. Oral administration allows extended exposure to lower drug concentrations, which could increase the number of diseased progenitor cells exposed to AZA and maximize therapeutic effects (eg, drug incorporation into RNA leading to apoptosis), and may improve tolerability by decreasing AZA-related exacerbations of existing cytopenias. In the absence of head-to-head trials, a matching adjusted indirect comparison (MAIC), which adjusts for potential Tx effect modifiers, was previously conducted to evaluate the relative OS benefit with Oral-AZA vs SC AZA (Chen, EHA 2021). This MAIC was performed to determine the relative safety profile and health care resource utilization (HCRU) with Oral-AZA vs SC AZA maintenance therapy in pts with AML in first remission after IC. METHODS: Anchored MAIC analyses of serious Tx-emergent adverse events (SAEs) and HCRU were performed using individual pt data (IPD) from QUAZAR AML-001 to match to baseline (BL) summary statistics from HOVON97. IPD from QUAZAR AML-001 were removed when a pt did not meet HOVON97 eligibility criteria. Remaining QUAZAR AML-001 pt data were weighted using a method-of-moments propensity score model. Matched and adjusted variables were BL age, platelet count, neutrophil count, ECOG performance score, cytogenetic risk, and response status. Analysis endpoints were times to first SAE, hospitalization, and platelet or red blood cell (RBC) transfusion. In HOVON97, pts could receive SC AZA for up to 12 cycles; therefore, QUAZAR AML-001 outcomes were limited to the first 12 cycles of Tx. Hospitalizations for SC AZA administration only in HOVON97 were excluded from analyses. Endpoints are adjusted for pt-years of drug exposure and compared between studies by calculating relative risks (RR). Exposure to SC AZA in HOVON97 was imputed based on the number of pts entering each Tx cycle, and relies on the assumption that events/censoring happened at the end of the cycle and led to Tx discontinuation. Sensitivity analyses of model robustness relaxed these assumptions, comparing only the difference in cumulative hazard vs PBO/observation using a cloglog link binomial model. RESULTS: IPD for 398/469 pts (85%) in the QUAZAR AML-001 safety population (Oral-AZA n=203, PBO n=195) met the eligibility criteria of the HOVON97 population and were adjusted to the comparator. For all endpoints, rate ratios for Oral-AZA vs PBO were less than those for SC AZA vs observation (Table). MAIC-weighted safety comparisons showed the risk of SAEs was reduced by 65% for patients treated with Oral-AZA vs SC AZA (RR 0.35 [95% CI: 0.18-0.68]). Similarly, the risks of hospitalization requirements, platelet transfusion, and RBC transfusion were reduced with Oral-AZA vs SC AZA by 59% (RR 0.41 [95% CI: 0.24-0.71), 54% (RR 0.46 [0.23-0.93]), and 47% (RR 0.53 [0.28-1.00]), respectively. All findings were robust to the sensitivity analyses relaxing assumptions of imputed Tx exposure in HOVON97, which showed pts treated with Oral-AZA are 70% less likely to experience SAEs than pts treated with SC AZA (hazard ratio: 0.30 [95% CI: 0.09-1.02]), and hazard reductions for hospitalization and transfusions ranged from -51% to -58% (Table). CONCLUSIONS : These data suggest that in controlled clinical trials with pts in first remission after IC, Oral-AZA maintenance therapy not only significantly improves OS, but also provides a better safety profile and requires less HCRU than SC AZA maintenance therapy. Interpretation of results should be limited to the differences in the rate to first SAE while on Tx, as stronger generalizations are limited by competing risks and informative censoring. Figure 1 Figure 1. Disclosures Chen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Huls: Universaity Medical Center Groningen: Current Employment. Cameron: Bristol Myers Squibb: Consultancy. Suero: Bristol Myers Squibb: Consultancy. Vasconcelos: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Gaugler: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Beach: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

scholarly journals Comparative Effectiveness of Pegcetacoplan Versus Ravulizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria Previously Treated with Eculizumab: A Matching-Adjusted Indirect Comparison

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 37-38
Author(s):  
Rachel Y Bhak ◽  
Nikita Mody-Patel ◽  
Scott B. Baver ◽  
Colin Kunzweiler ◽  
Christopher Yee ◽  
...  
Keyword(s):  
Comparative Effectiveness ◽  
Research Funding ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Indirect Comparison ◽  
Publicly Traded ◽  
Phase 3 ◽  
Fatigue Score ◽  
Study Results ◽  
Adjusted Indirect Comparison ◽  
Previously Treated

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematological disease characterized by complement-mediated hemolysis, resulting in anemia, thrombosis, and bone marrow failure. Currently available treatment options for PNH include the C5 inhibitors eculizumab and ravulizumab, which target intravascular hemolysis through terminal complement inhibition. Pegcetacoplan is a targeted C3 inhibitor being developed to control both intravascular and extravascular hemolysis, to improve hematologic and clinical outcomes. There is no head-to-head study of pegcetacoplan vs ravulizumab in patients with PNH. We assessed the comparative effectiveness of pegcetacoplan to ravulizumab through comparison of phase 3 study results, using matching-adjusted indirect comparison (MAIC) methodology, anchoring on the common comparator arm in the studies, eculizumab. We also acknowledge inherent limitations to MAIC (eg, lack of generalizability beyond the analyzed population). METHODS Individual patient data from PEGASUS, an ongoing, randomized, phase 3 study comparing pegcetacoplan and eculizumab among patients with PNH previously treated with eculizumab, were used to adjust for baseline differences compared to aggregate, published results from the randomized 302 study (Kulasekararaj AG, et al. Blood. 2019;133(6):540-549), which compared ravulizumab and eculizumab among patients with PNH with previous eculizumab. Both studies had similar eligibility criteria. However, PEGASUS also required hemoglobin <10.5 g/dL and absolute reticulocyte count >1.0× the upper limit of normal; these criteria were not applicable in the 302 study. To adjust for cross-study differences in baseline characteristics, propensity score weighting was used to balance demographic and clinical characteristics. Outcomes assessed included transfusion avoidance, total number of units of packed red blood cells (PRBCs) transfused, hemoglobin stabilization, and change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score. Outcomes were assessed from PEGASUS at week 16 and from the 302 study at week 26. Unadjusted mean and least-squares mean change in FACIT-Fatigue score were compared for PEGASUS and the 302 study, respectively. Weighted Wald tests and 95% confidence intervals (CIs) were computed for comparisons of categorical and continuous outcomes (ie, chi-square and z tests, respectively). RESULTS Sixty-eight patients from PEGASUS (36 pegcetacoplan; 32 eculizumab) and 195 from the 302 study (97 ravulizumab; 98 eculizumab) were included. Among pegcetacoplan and ravulizumab patients, mean age was 46.4 years, 48.5% were female, and 51.5% were white. Overall, 51.5% received ≥4 transfusions in the 12 months before screening in PEGASUS. The adjusted difference in proportion of transfusion avoidance was 71.4% (95% CI, 53.5-89.3%; P < 0.0001) for pegcetacoplan vs ravulizumab, indicating that pegcetacoplan is associated with 71.4% more transfusion avoidance than ravulizumab. The difference in mean number of units of PRBCs transfused during follow-up was -5.7 units (95% CI, -7.2 to -4.2; P < 0.0001) for pegcetacoplan vs ravulizumab, indicating that pegcetacoplan is associated with 5.7 fewer units of PRBCs transfused during treatment than ravulizumab. The adjusted difference in proportion of hemoglobin stabilization was 75.5% (95% CI, 56.4-94.6%; P < 0.0001), suggesting that pegcetacoplan is associated with 75.5% more patients who achieved hemoglobin stabilization than ravulizumab. The adjusted difference in mean change from baseline in FACIT-Fatigue score was 8.8 points (95% CI, 4.2-13.3; P < 0.0001), suggesting that pegcetacoplan is associated with an improvement ~3 times greater than the clinically meaningful improvement of 3 points than ravulizumab. See the Figure for additional details. CONCLUSIONS MAIC methodology allowed the examination of the comparative effectiveness of pegcetacoplan vs ravulizumab in the absence of a head-to-head trial. Results suggest an improvement in transfusion avoidance, hemoglobin stabilization, and fatigue and a reduction in the total number of units of PRBCs transfused for patients who received pegcetacoplan, a C3 inhibitor, in PEGASUS, vs patients who received ravulizumab, a C5 inhibitor, in the 302 study. As PEGASUS progresses, week 26 data will be used to refresh these analyses. Disclosures Bhak: Apellis: Research Funding. Mody-Patel:Apellis: Current Employment, Current equity holder in publicly-traded company. Baver:Apellis: Current Employment, Current equity holder in publicly-traded company. Kunzweiler:Apellis: Research Funding. Yee:Apellis: Research Funding. Sundaresan:Apellis: Research Funding. Swartz:Apellis: Research Funding. Duh:Pharmacyclics: Research Funding; Takeda Oncology: Research Funding; GlaxoSmithKline: Research Funding; AstraZeneca: Research Funding; Blueprint Medicine: Research Funding; Novartis: Research Funding; Shire: Research Funding; Apellis: Research Funding; Merck: Research Funding. Krishnan:Apellis: Current Employment, Current equity holder in publicly-traded company. Sarda:Apellis: Current Employment, Current equity holder in publicly-traded company. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria

Tazemetostat Is Associated with Lower Risk for Safety Outcomes Versus the PI3-Kinases Idelalisib, Duvelisib and Copanlisib, in Patients with Relapsed/Refractory Follicular Lymphoma Who Have Received at Least 2 Prior Systemic Treatments: A Matching-Adjusted Indirect Comparison of Single-Arm Trials

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 16-16
Author(s):  
David Proudman ◽  
Dave Nellesen ◽  
Deepshekhar Gupta ◽  
Deyaa Adib ◽  
Jay Yang ◽  
...  
Keyword(s):  
Adverse Event ◽  
Relative Risk ◽  
Indirect Comparison ◽  
Drug Discontinuation ◽  
Publicly Traded ◽  
Efficacy Outcome ◽  
Safety Outcomes ◽  
Adjusted Indirect Comparison ◽  
Baseline Characteristics ◽  
Grade 3

Background: Tazemetostat, a first-in-class, oral enhancer of zeste homolog 2 (EZH2) inhibitor was recently approved by the US Food and Drug Administration in patients with relapsed/refractory (R/R) follicular lymphoma (FL) after demonstrating single-agent, antitumor activity in patients with wild-type (WT) or mutant (MT) EZH2. The PI3K inhibitors idelalisib, duvelisib, and copanlisib are indicated for third-line or later (3L+) treatment of R/R FL, but they are associated with safety concerns, and clinical studies with these agents did not include grade 3B or transformed FL. However, tazemetostat idelalisib, duvelisib, and copanlisib were all approved based on single-arm studies and have not been compared in head-to-head randomized trials for the treatment of 3L+ R/R FL. Here, we present an indirect treatment comparison (ITC) of tazemetostat with idelalisib, duvelisib, and copanlisib for the treatment of 3L+ R/R FL. Methods: A systematic literature review identified clinical trial publications for idelalisib (DELTA), duvelisib (DYNAMO), and copanlisib (CHRONOS-1 Part B) for use in an ITC with tazemetostat for 3L+ treatment of R/R FL. Matching-adjusted indirect comparison (MAIC) methodology was selected as all comparator trials were single-arm and individual patient data (IPD) were available for the tazemetostat E7438-G000-101 trial (n=99). Three MAIC analyses were conducted by weighting individual patients treated with tazemetostat to baseline characteristics reported from each comparator trial. FL subpopulation baseline characteristics and outcomes data were available for matching idelalisib (n=72); full trial mixed-NHL populations were reported for duvelisib (n=129, 64% FL) and copanlisib (n=142, 73% FL). Baseline characteristics for matching-adjustment were chosen using clinical advice, an evaluation of prognostic factors associated with outcomes, and published data availability. Characteristics included: age, ECOG performance status, disease stage, histology (tumor grade, transformed FL), number of prior lines of treatment, prior stem cell therapy, and refractory status (to last therapy). Only the tazemetostat trial included patients with grade 3b or transformed FL, or recorded EZH2 mutation status. Safety and efficacy outcome definitions were similar across trials. Primary safety outcomes included risk of any grade ≥3 treatment-emergent adverse event (TEAE), any treatment-emergent serious adverse event (TESAE), and TEAEs leading to dose reduction, drug discontinuation, or interruption. The primary efficacy outcome was objective response rate (ORR), reported across all trials. Rates of individual grade ≥3 TEAEs also were compared. Limitations of such indirect methods include inability to account for any unmeasured covariates that may be effect modifiers, and reductions in the effective sample size. Results: After matching, all baseline characteristics were successfully balanced. Matched patients treated with tazemetostat had lower relative risk for all safety outcomes compared with all treatments, including any grade ≥3 TEAE (vs idelalisib: RR=0.45; vs duvelisib: RR=0.35; vs copanlisib: RR=0.37; all, P<0.001), any TESAE, and any TEAE leading to dose reduction, drug discontinuation, or interruption. These results were statistically significant (where comparator data were reported) for all but 2 safety outcomes (Figure). Several grade ≥3 TEAEs occurred at a significantly lower incidence with tazemetostat compared with matched patients treated with idelalisib, duvelisib, or copanlisib, including neutropenia (vs idelalisib: 3% vs 22%; vs duvelisib: 3% vs 25%; vs copanlisib: 4% vs 24%; all, P<0.05). The ORR was similar after matching for tazemetostat versus all treatments, with no statistically significant difference between therapies (vs idelalisib: 43% vs 56%, P=0.16; vs duvelisib: 48% vs 47%, P=0.91; vs copanlisib: 49% vs 61%, P=0.11). Conclusion: More tolerable treatment options are needed for 3L+ treatment of R/R FL because patients in this setting are often elderly and have exhausted multiple prior lines of treatment. Results from this ITC indicate that, after adjusting for baseline population differences, tazemetostat addresses this unmet need, as it is associated with lower relative risk for safety outcomes versus idelalisib, duvelisib, or copanlisib while achieving similar efficacy outcomes. Disclosures Proudman: Analysis Group, Inc.: Consultancy. Nellesen:Analysis Group, Inc.: Consultancy. Gupta:Analysis Group, Inc.: Consultancy. Adib:Epizyme, Inc.: Consultancy; Alacrita: Current Employment. Yang:Epizyme, Inc.: Current Employment. Keith:Epizyme: Current Employment, Current equity holder in publicly-traded company. Mamlouk:Epizyme: Current Employment, Current equity holder in publicly-traded company.

Prognostic Factors of Long-Term Outcomes In Low- or Int-1-Risk MDS with del5q Treated with Lenalidomide (LEN): Results From a Randomized Phase 3 Trial (MDS-004)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4027-4027
Author(s):  
Pierre Fenaux ◽  
Aristotles Giagounidis ◽  
Odile Beyne-Rauzy ◽  
Ghulam Mufti ◽  
Moshe Mittelman ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase 3 ◽  
Advisory Committees ◽  
Free Survival ◽  
Lower Baseline ◽  
Younger Age ◽  
Equity Ownership ◽  
Rbc Transfusion

Abstract Abstract 4027 Background: Transfusion dependence is a significant negative predictor of overall survival (OS) and risk of AML-progression in MDS (Malcovati L, et al. JCO 2007;25:3503-10). LEN 5 mg and 10 mg induced significant RBC-transfusion independence (TI) versus placebo (PBO) in a randomized, phase 3, multicenter, double-blind (DB) study (MDS-004) in RBC transfusion-dependent patients (pts) with Low- or Int-1-risk MDS with del5q (Fenaux P, et al. Blood 2009;114:Abstract 944). The aim of this analysis is to identify prognostic factors for AML-free survival and OS during LEN treatment in the MDS-004 study after prolonged follow-up (pts enrolled between July 8, 2005 and July 26, 2007; last pt visit June 14, 2010; final data cutoff July 9, 2010). Methods: LEN-naïve pts with RBC transfusion-dependent Low- or Int-1-risk del5q MDS were randomized to receive LEN 5 mg on days 1–28 or LEN 10 mg on days 1–21, both of every 28-day cycle, or PBO. First response was assessed at 16 wks. Responders continued DB treatment for up to 52 wks, until erythroid relapse or disease progression. Pts who completed 52 wks of therapy could enter an open label (OL) extension phase at their current LEN dose. PBO and LEN 5 mg recipients who did not respond by wk 16 or who had erythroid relapse could receive LEN 5 or 10 mg, respectively, in the OL phase. This analysis included data through completion of the OL phase for pts randomized to LEN 5 and 10 mg combined in the DB phase; pts randomized to PBO were excluded as all except 11 pts crossed-over to LEN 5 mg. LEN 5 and 10 mg dose groups were comparable, allowing data for the two groups to be combined. A Cox proportional hazard model was used to evaluate effect of potential baseline risk factors, with RBC-TI ≥ 26 wks and cytogenetic response (CyR) as time-dependent covariates on AML-free survival and OS. The full model with all covariates and the final model, based on backward model selection method, are presented. Results: All 138 pts randomized to LEN who received ≥ 1 dose were included: median age 68 y (range 36–86); 74% of pts were female; 66% had an isolated del5q abnormality and 28% had ≥ 1 additional abnormality; and 43% of pts had WHO-based Prognostic Scoring System (WPSS) low/int risk, 32% high/very high, and 25% missing data. At baseline, median time since diagnosis was 2.7 y (range 0.2–29.2) and median RBC transfusion requirement was 6 units/8 wks (range 1–25). Duration of LEN was 12.9 mo (range 0.3–36.7); 54 of 62 responders entered the OL phase. Median follow-up for the cohort was 36 mo (range 0.4–59.4). Overall, 31 (22%) pts progressed to AML (median time to AML progression 4.01 y; 95% confidence interval [CI] 3.17–4.03) and 66 (48%) died (median OS 3.68 y; 95% CI 2.93–not estimable). The cumulative 3-year AML-progression rate was 34.8% and the 3-year OS rate was 56.0%. Multivariate results are presented in the Table. Achieving RBC-TI ≥ 26 wks was associated with a 45% and 51% reduction in the risk of AML progression (P=0.022) and death (P=0.008), respectively. Lower baseline ferritin level and younger age were associated with a reduced risk of AML-progression and death. Conclusion: Achievement of RBC-TI with LEN was associated with a significantly reduced risk of AML progression and death. Other predictors for longer AML-free survival and OS were lower baseline ferritin levels and younger age. Disclosures: Fenaux: Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; J&J: Honoraria; Merck: Honoraria; Cephalon: Honoraria; Novartis: Honoraria. Giagounidis:Celgene: Consultancy, Honoraria. Beyne-Rauzy:Amgen: Consultancy; Celgene: Consultancy, Research Funding; Roche: Research Funding; Novartis: Consultancy. Mufti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mittelman:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Muus:Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Sanz:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Backstrom:Celgene: Employment, Equity Ownership. Fu:Celgene: Employment, Equity Ownership. Hellström-Lindberg:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Matching-Adjusted Indirect Comparison (MAIC): Sensitivity Analyses And Graphical Diagnostics

2017 ◽  
Vol 20 (9) ◽  
pp. A771
Author(s):  
J Signorovitch ◽  
W Gao ◽  
V Rybkin ◽  
Z Yao ◽  
M Hellstern
Keyword(s):  
Indirect Comparison ◽  
Sensitivity Analyses ◽  
Adjusted Indirect Comparison ◽  
Graphical Diagnostics

scholarly journals Comparison of Clinical Outcomes Among Patients with Relapsed/Refractory Follicular Lymphoma Treated with Tisagenlecleucel in the Elara Trial Versus a Real-World External Control Arm of Patients Treated with Standard of Care

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2419-2419
Author(s):  
Yanni Hao ◽  
Wei-Chun Hsu ◽  
Craig S Parzynski ◽  
C Lobetti Bodoni ◽  
Evgeny Degtyarev ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Indirect Comparison ◽  
Standard Of Care ◽  
Sensitivity Analyses ◽  
External Control ◽  
Publicly Traded ◽  
Primary Analysis ◽  
Advisory Committees ◽  
Individual Patient Level

Abstract Introduction: In the single-arm phase 2 ELARA trial (NCT03568461), tisagenlecleucel demonstrated efficacy and favorable safety profile in patients with relapsed/refractory (r/r) follicular lymphoma (FL) after ≥ 2 lines of prior therapy, including in high-risk sub-populations (Schuster, et al. ASCO 2021). To contextualize these results, we performed a retrospective non-interventional study to compare the efficacy of tisagenlecleucel seen in the single-arm ELARA trial with the standard-of-care (SoC) using individual patient-level data from the US Flatiron Health Research Database (FHRD). FHRD is a database derived from electronic health records from over 280 cancer clinics. The objective was to assess the effect of prescribing tisagenlecleucel vs SoC in patients who participated in ELARA. Methods: Individual patient-level data from FHRD were used to create an external control arm to carry out an indirect comparison with the ELARA trial. Eligible inclusion and exclusion criteria from ELARA were applied to the external control arm. A single eligible line was selected using propensity scores when patients were qualified at multiple lines. Key prognostic factors including age, race, gender, number of prior treatment lines, group stage at initial FL diagnosis, number of months between initial FL diagnosis and indication of index treatment, double refractoriness, and disease progression within 24 months were included in a propensity score model to reduce confounding due to systematic differences in ELARA patients from FHRD patients at baseline for the selected line. Weighting by odds of receiving tisagenlecleucel was used to estimate the average treatment effect on progression-free survival (PFS), overall survival (OS), time to next treatment (TTNT), overall response rate (ORR), and complete response rate (CRR). The rates and difference in rates were calculated for CRR and ORR. Kaplan-Meier (KM) analysis and Cox proportional hazards model were used to analyze all time-to-event endpoints. 95% confidence interval (CI) was calculated using bootstrapping. Data from the first 24 months after enrollment in ELARA or after treatment in FHRD were used for the follow-up period in the time to event endpoints, as few patients in ELARA trial had > 24 month data (Figure). Results were reported based on the post-weighting sample by incorporating a weight factor in the above analyses. A series of sensitivity analyses were conducted to assess the robustness of the primary analysis. Results: As of Mar 29, 2021, 98 patients were enrolled in the ELARA trial, of which 97 were included in this indirect comparison (median follow-up, 15 months). In the FHRD cohort (data cut-off, Jun 30, 2020), 98 patients with ≥ 3 treatment lines who met the ELARA eligibility were included (median follow-up, 14 months in the post-weighted sample) (Table 1). In the ELARA vs FHRD cohorts, after applying weighting by odds, the ORR was 85.6% vs 58.1%, and the CRR was 69.1% vs 17.7%. The difference in CRR (51.4%; 95% CI: 21.2, 68.8) was clinically meaningful (Table 2). The median TTNT or death was not reached in the ELARA cohort and was 19.0 months in the FHRD cohort after weighting (HR = 0.34 [95% CI: 0.15, 0.78]) (Table 2). The median OS was not reached for both ELARA and FHRD cohorts in the first 24-month period. KM estimate of OS at 12 months was 96.6% in the ELARA cohort and 84.5% in the FHRD cohort, post weighting. The estimated 59% risk reduction was in favor of tisagenlecleucel over SoC (hazard ratio [HR] = 0.41 [95% CI: 0.11, 1.47]) (Table 2). The median PFS was not reached in the ELARA cohort and was 9.9 months in the FHRD cohort, after weighting. In the ELARA vs FHRD cohorts, the 12-month PFS was 73.2% vs 41.8%, with a HR of 0.45 indicating a 55% reduction in the risk of progression and death with tisagenlecleucel vs SoC. The median PFS considering new anti-cancer therapy as an event was not reached for ELARA and was 9.9 months for FHRD; the estimated probability of being progression-free at 12 months was 70.5% in the ELARA cohort and 39.4% in the FHRD cohort (Table 2). Sensitivity analyses results were consistent with that of primary analysis. Conclusion: In the weighted analyses with adjustment for baseline prognostic factors, there was a consistent trend towards greater CRR, TTNT, OS and PFS in favor of tisagenlecleucel vs SoC in patients with r/r FL. These results support the clinically meaningful treatment benefit of tisagenlecleucel observed in the ELARA trial. Figure 1 Figure 1. Disclosures Hao: Novartis: Current Employment. Hsu: Novartis: Consultancy. Parzynski: Novartis: Consultancy. Lobetti Bodoni: Spouse: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Spouse: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Spouse: Celgene: Honoraria; Spouse: Harlcok Healthcare: Current holder of individual stocks in a privately-held company; Spouse: Takeda: Consultancy, Honoraria, Speakers Bureau; Spouse: NHS: Ended employment in the past 24 months; Spouse: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spouse: F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company; Gilead: Other: Travel sponsorship in June 2019; Novartis: Current Employment, Current equity holder in publicly-traded company. Degtyarev: Novartis: Current Employment, Current equity holder in publicly-traded company. Hampson: Novartis: Current Employment. Masood: Novartis: Current Employment, Current holder of stock options in a privately-held company. Wu: Novartis: Consultancy. OffLabel Disclosure: Tisagenlecleucel (Kymriah) an autologous CD19-directed CAR-T-cell therapy, has been approved for children and young adults with relapsed/refractory (r/r) acute lymphoblastic leukemia and, adults with r/r diffuse large B-cell lymphoma.

scholarly journals A Phase 3 Study of the Hepcidin Mimetic Rusfertide (PTG-300) in Patients with Polycythemia Vera

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1504-1504
Author(s):  
Srdan Verstovsek ◽  
Andrew T. Kuykendall ◽  
Ronald Hoffman ◽  
Yelena Ginzburg ◽  
Naveen Pemmaraju ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Polycythemia Vera ◽  
Board Of Directors ◽  
Research Funding ◽  
Data Safety Monitoring Board ◽  
Publicly Traded ◽  
Phase 3 ◽  
Eligibility Criteria ◽  
Advisory Committees ◽  
To Receive

Abstract Background. Polycythemia vera (PV) patients are treated with periodic therapeutic phlebotomy (TP) alone or in combination with either hydroxyurea (HU), ruxolitinib (RUX) or interferon (IFN) to maintain hematocrit (HCT) levels below 45% as per NCCN guidelines. Since patients are seen periodically, PV patients may spend significant time with HCT levels above 45%, thereby increasing their risk of thrombosis [Marchioli NEJM 2013]. PV is associated with systemic symptoms with fatigue. These fatigue-related symptoms are found to be the most prevalent and severe as reported in an international survey among PV patients [Scherber Cancer 2016]. Symptomatic iron deficiency represents an unaddressed clinical challenge to PV patients as most PV patients have iron deficiency at diagnosis due to increased iron utilization [Ginzburg Leukemia 2018]. The iron deficiency worsens after repeated TP. We have demonstrated in a phase 2 study that rusfertide (PTG-300) has a good tolerability profile and achieves HCT control in PV patients with improvement in iron deficiency. Methods. This is a Phase 3, multicenter, global, randomized trial that compares the efficacy and safety of rusfertide compared to placebo when added on to current therapy for PV (Figure 1). The study population is PV subjects who require frequent phlebotomies to control their hematocrit with or without concurrent therapy. This is a three-part study in subjects with polycythemia vera: - Part 1a: randomized, double-blind, placebo-controlled, add-on parallel-group period for 32 weeks. Subjects will be stratified by their ongoing PV treatment and randomized 1:1 to rusfertide or placebo added-on to their ongoing PV treatment. - Part 1b: open-label treatment phase during which all subjects who complete Part 1a successfully will receive rusfertide for 20 weeks (Week 32 through Week 52). - Part 2: Long term extension (LTE) phase during which all subjects who complete Part 1b will continue to receive rusfertide for 32 weeks (Week 52 to Week 84). Inclusion Criteria: Approximately 250 subjects will be randomized. Eligibility criteria include PV diagnosis (by 2016 WHO criteria) and frequent phlebotomies with or without concurrent cytoreductive therapy to maintain HCT below 45% in the 6 months prior to enrollment in Part 1. Eligible subjects will continue to receive their therapy at screening for PV (phlebotomy alone (TP) or cytoreductive therapy + TP) and must have a hematocrit <45% at Week 0 prior to randomization. Subjects who meet the eligibility criteria will be stratified by ongoing PV therapy (TP only, TP+hydroxyurea, TP+ruxolitinib, TP+interferon, TP+other) and randomized 1:1 to treatment with rusfertide or placebo added on to the subject's ongoing PV therapy at Week 0. The "add on" design allows subjects to receive standard cytoreductive therapy to control WBC and/or platelets and to receive rusfertide/placebo. The dose of cytoreductive therapy in Part 1a and Part 1b may be decreased for safety but may not be increased for efficacy including control of hematocrit, elevated platelets and/or WBC. Primary endpoint: Proportion of subjects achieving a response starting at Week 20 through Week 32 (inclusive) who receive rusfertide compared to placebo. A response is defined as absence of phlebotomy eligibility defined as either: 1. a confirmed hematocrit ≥45% and that is at least 3% higher than the baseline hematocrit (value immediately prior to randomization at Week 0); confirmation required within 1 to 7 days, or 2. a hematocrit ≥48%. Key words: Hepcidin, Hematocrit, Rusfertide, PTG-300, Polycythemia Vera, PV, Therapeutic Phlebotomy Figure 1 Figure 1. Disclosures Verstovsek: Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; PharmaEssentia: Research Funding; Protagonist Therapeutics: Research Funding; CTI BioPharma: Research Funding; Ital Pharma: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Genentech: Research Funding; Blueprint Medicines Corp: Research Funding; Celgene: Consultancy, Research Funding; Promedior: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Kuykendall: Pharmaessentia: Honoraria; Protagonist: Consultancy, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene/BMS: Honoraria; Abbvie: Honoraria; Incyte: Consultancy; Blueprint: Honoraria. Hoffman: AbbVie Inc.: Other: Data Safety Monitoring Board, Research Funding; Novartis: Other: Data Safety Monitoring Board, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Kartos Therapeutics, Inc.: Research Funding. Pemmaraju: Incyte: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; MustangBio: Consultancy, Other; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; DAVA Oncology: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Protagonist Therapeutics, Inc.: Consultancy; Roche Diagnostics: Consultancy; LFB Biotechnologies: Consultancy; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; Samus: Other, Research Funding; Sager Strong Foundation: Other; Aptitude Health: Consultancy; Affymetrix: Consultancy, Research Funding; CareDx, Inc.: Consultancy; Springer Science + Business Media: Other; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Valone: Protagonist Therapeutics: Consultancy, Current equity holder in publicly-traded company. Modi: Protagonist Therapeutics: Current Employment. Khanna: Protagonist: Current Employment, Current equity holder in publicly-traded company. O'Connor: Protagonist Therapeutics: Current Employment. Gupta: Protagonist Therapeutics: Current Employment. Kiladjian: Taiho Oncology, Inc.: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

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