scholarly journals Recil 2017 Criteria Demonstrated Similar Prognostic Value and Detected a Comparable Treatment Difference between Obinutuzumab- and Rituximab-Chemotherapy Compared with Cheson 2007 and Lugano 2014 Criteria in Patients with Previously Untreated Advanced-Stage Follicular Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 25-26
Author(s):  
Lale Kostakoglu ◽  
Andrew Davies ◽  
Michael Herold ◽  
Wolfgang Hiddemann ◽  
Robert Marcus ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Prognostic Value ◽  
Response Assessment ◽  
Phase Iii ◽  
Publicly Traded ◽  
Advisory Committees ◽  
High Concordance ◽  
Dimensional Assessment

Introduction: Lugano 2014 criteria are the current standard for response assessment in lymphoma and incorporate 18F fludeoxyglucose (FDG)-positron emission tomography (PET)-computed tomography (CT) into standard staging of FDG-avid lymphomas (Cheson, et al. J Clin Oncol 2014); bi-dimensional tumor measurements of up to six CT target lesions are used for non-FDG avid lymphomas, and when PET is unavailable. The Response Evaluation Criteria in Lymphoma (RECIL), developed more recently, showed that uni-dimensional measurements of up to three target lesions could provide response assessment at a similar accuracy to the Lugano criteria (Younes, et al. Annals Oncol 2017). In the Phase III GOYA trial (NCT01287741), complete response (CR) status by RECIL criteria showed high concordance with Lugano criteria and was highly prognostic for survival outcome in previously untreated patients (pts) with CD20-positive diffuse large B-cell lymphoma treated with obinutuzumab (G) plus chemotherapy (G-chemo) or rituximab (R)-chemo. Here, we compared the prognostic and predictive performance of the Lugano and RECIL criteria in pts from the Phase III GALLIUM trial (NCT01332968). Methods: Pts were randomized 1:1 to receive G or R plus CHOP, CVP, or bendamustine (stratification factors: chemotherapy regimen, Follicular Lymphoma International Prognostic Index and geographic region). FDG-PET scans were mandatory in the first 170 pts where a PET scanner was available, and optional thereafter, and were performed at screening and end of induction (EOI). Response was assessed by the investigator (INV) and an independent review committee (IRC) using Cheson 2007 criteria, the IRC also assessed EOI response using Lugano 2014 criteria. Response and progression-free survival (PFS) by RECIL 2017 criteria were retrospectively evaluated via a programming algorithm based on IRC-assessed 5PS scores and the individual lesion measurements from INV assessment. Response categories at EOI by RECIL criteria were cross-tabulated against those by Lugano criteria. Estimates of the treatment effect for PFS were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs) using stratified log-rank tests. Landmark analyses of PFS and overall survival (OS) from EOI, by EOI CR/non-CR status were performed. The impact of covariates on the prognostic value for PFS and OS were analyzed using multivariable Cox models. Results: In GALLIUM, 1202 pts with follicular lymphoma (FL) were enrolled (601 per treatment arm), of which 595 had PET evaluable data (R-chemo, n=298; G-chemo, n=297). High concordance between Lugano and RECIL criteria for EOI CR was observed regardless of antibody received, with 416 pts classified as CR by RECIL among the 450 pts achieving complete metabolic response (CMR) by Lugano (416/450 [92.4%]; R-chemo, 199/216 [92.1%]; G-chemo, 217/234 [92.7%]) (Table). However, poor concordance was seen for progressive disease (PD), with 18/21 (85.7%) pts with progressive metabolic disease by Lugano classified as partial/minimal responders by RECIL. A strong correlation was observed between Cheson 2007 and RECIL PFS definitions, with a kappa estimate of 0.63 (95% CI: 0.58-0.69). EOI CR status by RECIL showed prognostic value by Cox multivariable regression analysis adjusted for stratification factors for PFS and OS; this prognostic value was similar with Lugano criteria (Figure). PFS rate by treatment arm for pts with a CR/CMR was higher by RECIL versus Lugano for both R-chemo and G-chemo (PFS rate at 3 years from EOI: RECIL: 86.0% and 89.7%; Lugano: 76.4% and 85.0%, respectively); similar results were seen with OS. G-chemo was associated with improved RECIL-PFS (from randomization) compared with R-chemo (HR, 0.72; 95% CI: 0.57-0.91; p=0.0069), similar to the GALLIUM 5-year updated analysis results by Cheson 2007 (HR, 0.76; 95% CI: 0.62-0.92; p=0.0043) (Townsend, et al. ASCO 2020). Conclusions: RECIL 2017 criteria showed high concordance with Lugano 2014 criteria with EOI CR strongly prognostic for improved outcomes versus non-CR; however, a discordance was observed for PD. A similar treatment difference between arms for PFS was detected with RECIL and Cheson 2007 criteria. RECIL criteria (uni-dimensional assessment of up to three target lesions) may be a suitable alternative to Lugano criteria (bi-dimensional assessment of up to six target lesions) in pts with previously untreated advanced-stage FL. Disclosures Kostakoglu: F. Hoffmann-La Roche: Consultancy. Davies:Roche, Celgene, Kite Pharma, Acerta, Karyopharma, Regeneron, Incyte: Consultancy; Roche, Acerta Pharma, AstraZeneca, Celgene, Gilead, ADC Therapeutics, Gilead: Research Funding; Celegene, Roche, Kite Pharma, Celegene: Honoraria; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Herold:Helios Klinikum Erfurt: Current Employment; F. Hoffmann-La Roche: Research Funding. Hiddemann:F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Marcus:Gilead: Consultancy; F. Hoffmann-La Roche: Honoraria; Janssen: Honoraria, Speakers Bureau. Trotman:Celgene: Research Funding; F. Hoffmann-La Roche: Research Funding; BeiGene: Research Funding; Takeda: Research Funding; PCYC: Research Funding. Knapp:F. Hoffmann-La Roche: Current Employment. Mattiello:F. Hoffmann-La Roche: Current Employment. Nielsen:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Sahin:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Ward:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Younes:AstraZeneca: Current Employment; MSKCC: Ended employment in the past 24 months; Janssen, Curis, Merck, Bristol-Myers Squibb, Syndax Pharmaceuticals, F. Hoffmann-La Roche, Curis (Inst), Johnson & Johnson (Inst), Novartis (Inst): Research Funding; Janssen, AbbVie, Merck, Curis, Epizyme, F. Hoffmann-La Roche, Takeda, Bristol-Myers Squibb, Bayer HealthCare Pharmaceuticals, Celgene, Incyte, Janssen Pharmaceuticals, Merck, Sanofi, Seattle Genetics, Takeda Millennium: Honoraria; BioPath, Xynomic, Epizyme, and F. Hoffmann-La Roche: Consultancy.

scholarly journals Universal: An Allogeneic First-in-Human Study of the Anti-Bcma ALLO-715 and the Anti-CD52 ALLO-647 in Relapsed/Refractory Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 24-25 ◽  
Author(s):  
Sham Mailankody ◽  
Jeffrey V. Matous ◽  
Michaela Liedtke ◽  
Surbhi Sidana ◽  
Shahbaz Malik ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Assessment ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Oncology Research ◽  
Car T ◽  
Grade 3 ◽  
Dose Levels

Background Allogeneic (off the shelf) chimeric antigen receptor (CAR) T cell therapy addresses the logistical challenges, availability and variable product quality of autologous CAR T therapy. ALLO-715 is a genetically modified anti-BCMA AlloCAR Ttm cell product in which the TCR alpha constant gene is disrupted to reduce the risk of graft-versus-host disease (GvHD) and the CD52 gene is disrupted with Talen® technology to permit the use of ALLO-647, an anti-CD52 mAb, for selective and prolonged host lymphodepletion (LD). Methods This is an open-label, Phase 1 trial (NCT04093596) in adults with R/R multiple myeloma who have received ≥3 prior lines of therapy including a proteasome inhibitor, immunomodulator, and anti-CD38 mAb. Patients (pts) must be refractory to their last treatment line. Patients receive LD followed by ALLO-715 at 1 of 4 dose levels (DL) in a 3+3 dose escalation design: 40, 160, 320, and 480 x 106 CAR+ T cells. Several LD regimens are being evaluated. These include: FCA (fludarabine (F) 90 mg/m2, cyclophosphamide (C) 900 mg/m2, and ALLO-647 (A) 39 mg divided over 3 days), FCA+ (same F and C but ALLO-647 (A+) dose of 90 mg divided over 3 days); as well as CA (same C and A divided over 3 days, but no F given). Results As of 08 July 2020, 19 pts had enrolled and 15 had received ALLO-715 at 3 DLs: 3 pts at DL1 (3 FCA and 0 CA); 7 pts at DL2 (4 FCA and 3 CA); 5 pts at DL3 (3 FCA and 2 CA). As of the data cutoff, no pts had received FCA+ or ALLO-715 DL4. Patients were heavily pre-treated and in advanced stage of disease with a median of 5 (range 3-11) prior lines of therapy and 31.6% ISS Stage III at screening. All but 1 had a prior autologous stem cell transplant. 52.6% (10/19) of patients had high risk cytogenetics, and 26.3% (5/19) had extramedullary disease. The most common Grade ≥3 adverse events were anemia (41.2%), neutropenia (41.2%), lymphopenia (29.4%), and thrombocytopenia (29.4%). Four episodes of Grade ≥3 infections occurred in 4 pts. Three of these were Grade 3 and included parvovirus B19, staphylococcal bacteremia, and pneumonia, which resolved with treatment. The fourth was a Grade 5 episode that occurred on day 8 post-ALLO-715 infusion in a rapidly progressing, refractory myeloma pt who, on day 1, developed a non-neutropenic fever and multifocal pneumonia with negative blood and sputum cultures. The patient progressed to respiratory failure and only comfort care was pursued. This death was considered related to conditioning (CA). No DLTs to ALLO-715 had been reported as of the data cutoff. In addition, no neurotoxicity (ICANS) or GvHD had been reported as of the data cutoff. Cytokine release syndrome was reported in 4 pts (24%). Three episodes were Grade 1 and 1 was Grade 2 (Lee Grading); all resolved without tocilizumab or corticosteroids. Fifteen pts were efficacy evaluable (defined as receiving ALLO-715, and undergoing at least one response assessment or discontinuing prior to the first response assessment), with a median follow-up of 2 months (range 0, 10 months). A higher dose of ALLO-715 (DL3) was associated with greater anti-cancer activity with 3/5 pts responding per IMWG (60%, 95% CI 14.7, 94.7). In pts who received DL3 FCA, 2/3 responded (1 sCR and 1 VGPR, Table 1). All DL3 pts who responded experienced at least a VGPR and achieved MRD negative status by local MRD testing. All responses were initially observed at day 14. Four (80%) out of the 5 responders were still in response at the time of the data cutoff. ALLO-715 cell expansion by qPCR was observed at all dose levels. Conclusions These early data suggest that ALLO-715 and ALLO-647 have a manageable safety profile. ALLO-715 shows evidence of clinical activity in the allogeneic setting in pts with R/R multiple myeloma and suggests that higher cell doses are associated with greater anti-cancer activity. Enrollment is ongoing in cohorts with higher ALLO-715 (480M CAR+ T-cells) and ALLO-647 (90mg). Updated safety, efficacy, PK/PD data will be presented. Clinical trial information: NCT04093596. Disclosures Mailankody: Physician Education Resource: Honoraria; PleXus Communications: Honoraria; Takeda Oncology: Research Funding; Janssen Oncology: Research Funding; Allogene Therapeutics: Research Funding; Juno Therapeutics, a Bristol-Myers Squibb Company: Research Funding. Matous:Bristol-Myers Squibb Company: Consultancy, Honoraria, Speakers Bureau. Liedtke:Janssen: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Sidana:Janssen: Consultancy. Nath:Actinium: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria. Oluwole:Bayer: Consultancy; Spectrum Pharmaceuticals: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy. Karski:Crisper Therapeutics: Current equity holder in publicly-traded company; Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company; Nektar Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Lovelace:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company. Zhou:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company. Nandakumar:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company. Balakumaran:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company; Merck: Ended employment in the past 24 months. Hari:BMS: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; GSK: Consultancy; Incyte Corporation: Consultancy.

scholarly journals Trial in Progress: The Phase III, Randomized, Open-Label, Multicenter COMMODORE 2 Study Evaluating the Efficacy and Safety of Crovalimab Versus Eculizumab in Adult and Adolescent Patients with Paroxysmal Nocturnal Hemoglobinuria Not Previously Treated with Complement Inhibitors

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-34
Author(s):  
Austin Kulasekararaj ◽  
Guangsheng He ◽  
Talha Munir ◽  
Jeffrey Pu ◽  
Antonio Risitano ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Medical Writing ◽  
Third Party ◽  
Phase Iii ◽  
Publicly Traded ◽  
Open Label ◽  
Advisory Committees ◽  
Complement Inhibitors ◽  
Previously Treated

Background Crovalimab is a novel anti-human complement component 5 (C5) antibody engineered to significantly extend half-life and enable subcutaneous (SC) administration once every 4 weeks in C5-mediated diseases. Based on the promising results of the Phase I/II COMPOSER trial (NCT03157635; Röth et al. Blood. 2020), crovalimab is currently under investigation as a potential therapy for paroxysmal nocturnal hemoglobinuria (PNH), a life-threatening disorder characterized by hemolytic anemia and thrombosis. Eculizumab and ravulizumab are C5 inhibitors currently approved for the treatment of patients with PNH, yet treatment limitations include breakthrough hemolysis due to unsustained C5 inhibition, lack of efficacy in patients with C5 mutational variants, and the treatment burden of regular intravenous (IV) infusions. Study Design and Methods The Phase III, randomized, open-label, active-controlled, multicenter COMMODORE 2 study (NCT04434092) is evaluating the efficacy and safety of crovalimab compared with eculizumab in patients aged ≥ 12 years with PNH not previously treated with complement inhibitors. Patients are randomized 2:1 to receive crovalimab or eculizumab (Figure 1). Two hundred patients in the crovalimab arm will receive a loading series of crovalimab (IV dose on Day 1, followed by weekly SC doses for 4 weeks starting on Day 2). This is followed by SC maintenance dosing every 4 weeks starting at Week 5. Patients in the eculizumab arm receive a weekly IV loading dose of eculizumab for the first 4 weeks, followed by IV maintenance dosing starting at Week 5 and then once every 2 weeks for 24 weeks. After 24 weeks of treatment, patients can continue crovalimab or switch from eculizumab to crovalimab if their physician determines this is in their best interest. The primary efficacy objective of COMMODORE 2 is to evaluate the noninferiority of crovalimab compared with eculizumab based on the co-primary endpoints of (1) the proportion of patients who achieve transfusion avoidance and (2) the proportion of patients with hemolysis control. Secondary efficacy objectives are to evaluate the noninferiority of crovalimab compared with eculizumab in regard to the (1) proportion of patients who experience breakthrough hemolysis, (2) proportion of patients who achieve stabilization of hemoglobin, and (3) mean change in fatigue, as assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire. The safety objective is to evaluate the safety and tolerability of crovalimab compared with eculizumab based on the incidence and severity of adverse events, including infections (meningococcal meningitis and other infections), injection-site reactions, infusion-related reactions, hypersensitivity, and adverse events leading to study drug discontinuation. Pharmacokinetic, immunogenicity, biomarker, and health status utility objectives will also be assessed. Disclosures Kulasekararaj: Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. He:F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; LongBio Pharma: Consultancy, Research Funding. Munir:F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; Alexion: Honoraria. Pu:SUNY Upstate Medical University: Current Employment; Pennsylvania State University: Patents & Royalties; F. Hoffmann-La Roche Ltd: Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biocryst: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; Samsung: Membership on an entity's Board of Directors or advisory committees; Achillion: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Speakers Bureau; RA pharma: Research Funding. Röth:Roche: Consultancy, Honoraria, Research Funding; Apellis: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Biocryst: Consultancy, Honoraria. Sima:F. Hoffmann-La Roche Ltd/Genentech: Current Employment, Current equity holder in publicly-traded company, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Appius:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Sostelly:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Sreckovic:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Vignal:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Nishimura:Alexion: Honoraria, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.

scholarly journals Safety and Effectiveness of Idelalisib in Patients with Double-Refractory Follicular Lymphoma: A Pan-European Cohort of 242 Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1350-1350
Author(s):  
Emmanuel Gyan ◽  
Maria Chiara Tisi ◽  
Francesco Merli ◽  
Luca Baldini ◽  
Francesco Di Raimondo ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Safety Profile ◽  
Research Funding ◽  
Safety Analysis ◽  
Publicly Traded ◽  
Transaminase Elevation ◽  
Advisory Committees ◽  
Effectiveness Data

Abstract Background: Malignant lymphoid cells are characteristically dependent on signals mediated by the phosphatidylinositol 3-kinase delta isoform (PI3Kδ). Idelalisib is an oral, selective, PI3Kδ inhibitor approved by the FDA and EMA as monotherapy for the treatment of advanced follicular lymphoma (FL). The approval was based on a phase 2 trial in patients with indolent non-Hodgkin lymphoma including 72 patients with FL who were refractory to at least 2 prior regimens (NCT01282424; Study 101-09). Interim safety analysis of this large, pan-European, noninterventional study of refractory FL patients treated with idelalisib monotherapy (EUPAS19618; NCT03568929) showed that the adverse event (AE) profile in clinical practice corroborates the known safety profile of idelalisib reported from clinical trials. Herein, we report the effectiveness and updated safety analysis from this study. Methods: This was a non-interventional, retrospective, cohort study. Adult patients treated with idelalisib for FL in routine clinical practice in 10 European countries were included. Data were collected retrospectively from sites by study personnel from remotely source data-verified medical records using electronic case report forms. Safety and effectiveness data for each patient were collected from time of idelalisib initiation until 6 months post-discontinuation of idelalisib, start of next treatment, or death. For this analysis, the data cut-off date was 16 June 2021. Effectiveness of idelalisib was assessed by overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS). The overall safety profile of idelalisib was assessed by estimating the incidence of AEs, serious AEs, adverse drug reactions (ADRs), and serious ADRs. Focus was given to special health outcomes of interest (HOIs), including transaminase elevation, hepatocellular injury, severe diarrhea/colitis, pneumonitis, neutropenia, rash, Stevens-Johnson syndrome, and serious infections. Multivariate Poisson regression analyses are used to estimate rates of ADRs, serious ADRs, and HOIs, and are adjusted for potential confounders. Time-to-event data were analyzed using Kaplan-Meier methods. Results: Overall, there were 257 eligible patients in the study from 85 sites. The Full Analysis Set (FAS) consisted of 242 patients excluding those with deviations (n=10) or those without any data contribution at the cut-off date (n=5). Of the 242 patients, 183 initiated idelalisib at least 12 months prior to data cut-off date and were included in the Effectiveness Analysis Set (EAS; n=49 patients did not have effectiveness data recorded, and 10 did not meet effectiveness inclusion criteria). For the 183 patients in the EAS, median age was 67 years and 54.6% (n=100) were male (Fig. 1A). Median number of prior therapies was 3 (range 1-10) and median time since diagnosis was 5.8 years (range: 0.4-32). At treatment initiation, 64% (n=117) had Ann Arbor stage III/IV disease. Median duration of idelalisib exposure was 6.8 months (IQR 3.0-15.6); 41.5% (n=76) had dose interruptions. Patients received doses of 150 mg only (67.8%), both 150 mg and 100 mg (28.4%), or 100 mg only (3.8%). Patients were observed for a median of 9.8 months (IQR 5.2-19.3). In the EAS, 103/183 patients achieved a response with 30 patients (16.4%) achieving a complete response (CR) and 73 (39.9%) achieving a partial response (PR), yielding a best ORR of 56.3% (95% CI: 48.8-63.6; Fig. 1B). Median DOR, PFS, and TTNT were 22.5 (95% CI: 15.1-27.9), 11.1 (95% CI: 8.1-18.1) and 15.4 months (95% CI: 9.9-22.2), respectively (Fig. 1B, C). Median OS had not been reached at the time of data cut-off (Fig. 1D). Updated safety information was available from the 242 patients in the FAS. The most frequent AEs recorded were infections, diarrhea and/or colitis, and transaminase elevation. The proportion of patients in the FAS experiencing Grade 3/4, severe, common, and HOI TEAEs are presented in Fig. 1E. Conclusions: We report to our knowledge the largest cohort of FL patients treated with idelalisib outside of the clinical trial setting. Our effectiveness findings are remarkably similar to those from the registrational study 101-09 (Gopal 2014 N Engl J Med). Safety profile of idelalisib was consistent with trial experience, and no new safety signals were identified. Idelalisib remains an effective treatment option for FL patients. Figure 1 Figure 1. Disclosures Gyan: Gilead Sciences, Inc.: Consultancy; Novartis: Research Funding; Mundipharma: Research Funding; Fresenius Kabi: Research Funding; Sanofi: Honoraria; AbbVie: Other: Hospitality; AstraZeneca: Honoraria. Tisi: Incyte: 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; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Merli: Takeda: Consultancy; Janssen Pharmaceuticals: Consultancy; Gilead Sciences, Inc.: Consultancy; Novartis: Consultancy. Di Raimondo: Amgen: Honoraria; AbbVie: Honoraria; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria; Janssen Pharmaceuticals: Honoraria; Jazz Pharmaceutical: Honoraria. Mercadal: Gilead Sciences, Inc.: Honoraria, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Puccini: Takeda: Membership on an entity's Board of Directors or advisory committees. Vandenberghe: Janssen Pharmaceuticals: Honoraria; AbbVie: Honoraria. Boland: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Shah Gupta: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. van Troostenburg: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Dunnill: Gilead Sciences, Inc.: Current equity holder in publicly-traded company, Other: Contractor. Ramroth: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Rajakumaraswamy: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Salles: Genentech/Roche: Consultancy; Incyte: Consultancy; Regeneron: Consultancy, Honoraria; Miltneiy: Consultancy; Genmab: Consultancy; Epizyme: Consultancy, Honoraria; Velosbio: Consultancy; Novartis: Consultancy; Ipsen: Consultancy; Morphosys: Consultancy, Honoraria; Allogene: Consultancy; Debiopharm: Consultancy; Janssen: Consultancy; Kite/Gilead: Consultancy; Loxo: Consultancy; Takeda: Consultancy; Rapt: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria.

Obinutuzumab (GA101) in Combination with Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (CHOP) or Bendamustine in Patients with Previously Untreated Follicular Lymphoma (FL): Results of the Phase Ib GAUDI Study (BO21000)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3686-3686 ◽  
Author(s):  
Martin JS Dyer ◽  
Andrew Grigg ◽  
Marcos González ◽  
Martin Dreyling ◽  
Simon A. Rule ◽  
...  
Keyword(s):  
Partial Response ◽  
Phase I ◽  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Assessment ◽  
Complete Response ◽  
Type Ii ◽  
Advisory Committees ◽  
Grade 3

Abstract Abstract 3686 GA101 is a glycoengineered, humanized type II anti-CD20 monoclonal antibody (mAb) anticipated to have superior B-cell-depleting activity to rituximab in vivo on the basis of its enhanced FcR binding and because of the direct cell death induced by type II CD20 mAbs. GA101 has shown significant single-agent activity in Phase I and II studies in patients with FL, and activity in combination with CHOP and fludarabine plus cyclophosphamide in patients with resistant/refractory FL in the first part of this Phase I trial (Radford et al. ASH 2011; abstract 270). This report describes the safety, toxicity, and efficacy of remission induction of GA101 in combination with CHOP or bendamustine in 81 patients aged > 18 years with treatment-naïve CD20+ grade 1–3b FL with at least one measurable lesion (longest diameter > 1.5 cm by CT scan). All patients received a flat dose of GA101 (1,000 mg on Days 1 and 8 of Cycle 1 and Day 1 of subsequent cycles) combined with either 6–8 cycles of CHOP (every 3 weeks) or 4–6 cycles of bendamustine (90 mg/m2Days 1 and 2 every 4 weeks) on a per center choice basis. Patients achieving complete response (CR) or partial response (PR) were eligible to receive GA101 maintenance therapy (1,000 mg) every 3 months for 2 years or until progression. The primary objective was safety, and secondary objectives included overall response rate (ORR), CR rate, and pharmacokinetics. Response was assessed at the end of induction using International Working Group response criteria; unconfirmed CRs were classified as PRs. 40 patients received G-CHOP and 41 G-bendamustine. Baseline characteristics were similar for both groups: median age 53.5 and 57 years; bone marrow involvement 53% and 49%; bulky disease (≥ 7 cm) 45% and 41%; Median time from diagnosis was only 1.20 months for both groups, high-risk FLIPI status (3–5) 45% and 46%, and intermediate risk (FLIPI 2) 38% and 34%. 38 G-CHOP and 37 G-bendamustine patients completed all cycles of planned induction therapy. Three patients withdrew without any response assessment. In the G-CHOP arm, one withdrawal was due to a GA101-associated infusion-related reaction [IRR] after Cycle 1 and another patient was found to be ineligible and withdrawn after Cycle 1. In the G-bendamustine arm one patient withdrew consent after Cycle 2. Three other patients were withdrawn after interim response assessment, none for safety reasons (insufficient response in the G-bendamustine arm and administrative reasons for two in the G-CHOP arm). The most frequent adverse events were IRRs (all grades: 58% G-CHOP; 59% G-bendamustine; grade 3/4: 5% G-CHOP; 10% G-bendamustine). No Grade 3/4 IRRs occurred after cycle 3. Grade 3/4 neutropenia was reported in 43% of patients in the G-CHOP arm and 29% of patients in the G-bendamustine arm during induction, resulting in delayed delivery of 7.0% and 4.8% of chemotherapy cycles. All delays but one were no longer than 2 weeks. Grade 3/4 infections occurred in 23% of patients receiving G-CHOP and 10% of patients receiving G-bendamustine. Approximately half of these were neutropenic infections or sepsis and all resolved with appropriate management. ORR at the end of the induction period was 95% (38/40) in the G-CHOP arm (CR rate 35%) and 92.7% (38/41) in the G-bendamustine arm (CR rate 39%) (Table). Serum GA101 concentrations increased during the induction period and were similar for both regimens. Mean Cmax was 300–600 μg/mL and Cmin100–300 μg/mL. Following the final administration, a decline in GA101 serum concentration was seen that was similar for the two treatment combinations. In conclusion, efficacy and safety data for GA101 combined with CHOP and bendamustine are encouraging for first-line treatment of patients with FL. Based on these promising results GA101 is now being studied in combination with various chemotherapy regimens in a randomized Phase III study against the standard of care, rituximab-based immunochemotherapy. Patients, n (%) G-CHOP (n = 40) G-bendamustine (n = 41) Efficacy     Overall response 38 (95.0) 38 (92.7)     Complete response* 14 (35.0) 16 (39.0)     Partial response 24 (60.0) 22 (53.7)     Stable disease 0 1 (2.4)     Progressive disease 0 1 (2.4)     Not assessed 2 (5.0) 1 (2.4) Safety     Grade 3/4 IRRs 2 (5.0) 4 (9.8)     Grade 3/4 neutropenia 17 (43) 12 (29)     Grade 3/4 infections 9 (23) 4 (10) * CRu were classified as PR Disclosures: Dyer: Roche: Consultancy, Research Funding. Off Label Use: Obinutuzumab (GA101) in Combination with Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (CHOP) or Bendamustine in Patients with Previously Untreated Follicular Lymphoma (FL). Grigg:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dreyling:Roche: Honoraria, Support of (other) clinical trials and Scientific Advisory Boards Other. Rule:Roche: Consultancy, Research Funding. Lei:Roche: Employment. Wassner-Fritsch:Roche: Employment. Wenger:Roche: Employment. Marlton:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Comprehensive and Systematic Analysis of Minimal Residual Disease (MRD) Monitoring in Follicular Lymphoma: Results from the Fondazione Italiana Linfomi (FIL) FOLL12 Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 41-41
Author(s):  
Marco Ladetto ◽  
Simone Ferrero ◽  
Ilaria Del Giudice ◽  
Sara Galimberti ◽  
Valter Gattei ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Nested Pcr ◽  
Research Funding ◽  
Phase Iii ◽  
Advisory Committees ◽  
Time Points ◽  
Igh Rearrangement ◽  
Risk Of Relapse

Abstract Background. Immunochemotherapy is effective in follicular lymphoma (FL), but most patients (pts) eventually relapse. MRD analysis, based on the detection of Bcl-2/IGH rearrangement by highly sensitive PCR-based tools, is effective in identifying pts at risk of relapse [Ladetto Blood 2012; Pott EHA23]. However, several issues are still unresolved, including: i) which is the best tissue source and the most reliable technique; ii) which are the most predictive time points; iii) which is the role of disease kinetics during the long natural history of FL. The FIL FOLL12 prospective, phase III randomized clinical trial (EudraCT: 2012-003170-60) included a systematic MRD analysis on both peripheral blood (PB) and bone marrow (BM) taken at eight different pre-planned time points, by both nested and real time quantitative (RQ)-PCR. Therefore, it allows addressing these unresolved issues. Methods. The FOLL12 compared conventional rituximab maintenance [Salles et al, Lancet 2010] vs a combined PET/MRD response-based post-induction approach in pts with advanced FL after first line chemo-immunotherapy. Clinical results have been already reported [Luminari et al, ICML16]. PB and BM samples were centralized at four Italian Euro-MRD certified laboratories. MRD was assessed with consensus primers on Bcl-2/IGH rearrangements (MBR, mcr and minor rearrangements) by both nested and RQ-PCR at eight time points: baseline, end of induction (EoI) and every six months thereafter till month 36. MRD data were treated as a time-varying covariate and analyzed by means of flexible parametric survival model (Parmar-Royston) with the log cumulative baseline hazard function. MRD data were modeled with restricted cubic spline as function of time. Effect of fixed covariates and landmark analysis were performed with the Cox PH regression. Any estimation was reported with its 95%CI. Results. Overall, 10,702 analytical results were generated, (3,000 for marker screening and 7,702 for MRD). 780 of 786 eligible pts (99%) were screened at baseline for the presence of a molecular marker. 443/780 (57%) had a detectable Bcl-2/IGH rearrangement, as expected. High rates of MRD negativity were observed at EoI, with similar results by both techniques (87% in BM and 95% in PB by nested-PCR, 90% in BM and 95% in PB with RQ-PCR). Overall, the presence of one MRD positive result was associated during the entire follow-up period with an increased risk of relapse in the subsequent six months interval (HR for PFS 2.82, 95% CI 1.84-4.34, p<0.001), independently from randomization arm (heterogenous test for HR in PFS 0.330), treatment received (HR 0.859) and FLIPI-2 (HR 0.302). Most notably, a sharp increase of HR was observed during follow-up, with time points after 6 and particularly after 12 months or later outperforming the earliest evaluation. Interestingly, very similar results were recorded in BM or PB and using nested or RQ-PCR (Figure 1A). Despite inferior performance compared to later timepoints, MRD positivity in BM at EoI was nevertheless predictive of a shorter 4y-PFS (61% vs 75% by nested-PCR and 54% vs 74% by RQ-PCR, p=0.03 and p=0.003, respectively). Moreover, a kinetic analysis showed that pts scoring MRD+ at EoI but converting to MRD- in the following time points showed superimposable outcome to pts persistently MRD- (HR for PFS 0.66, 95% CI 0.24-1.82, p=0.420), while pts scoring MRD- at EoI but then converting to MRD+ showed a worse outcome (HR for PFS 1.75, 95% CI 1.21-2.53, p=0.003) (Figure 1B). Actually, Kaplan Meier landmark analyses stratified by updated MRD results at each punctual timepoint after EoI were overall highly discriminant in terms of PFS, with PB results (Figure 1C) substantially overlapping BM performances from months 12 after EoI (not shown) and thereafter. Conclusions. This comprehensive MRD study in FL clearly indicates that: i) punctual MRD analysis is predictive of poor outcome at multiple pre-planned time points taken over a 36 months period; ii) both nested and RQ-PCR performed adequately, the latter being preferable as broadly used and internationally standardized; iii) BM allows better prediction at the early time points but, starting from month 12 after EoI PB is superimposable to BM, allowing effective and reliable long-term non-invasive MRD monitoring; iv) the high predictive value of punctual time point analysis is further improved by a kinetic approach to the interpretation of MRD results. Figure 1 Figure 1. Disclosures Ladetto: AbbVie, Jazz, Gentili, Incyte, ADC Therapeutics, Acerta, Pfizer: Honoraria; Roche, J&J, Celgene, Novartis, Amgen, Gilead, Beigene, GSK: Honoraria. Ferrero: Servier: Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Morphosys: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding, Speakers Bureau; Clinigen: Membership on an entity's Board of Directors or advisory committees. Del Giudice: Tolero: Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Membership on an entity's Board of Directors or advisory committees. Galimberti: Incyte: Speakers Bureau; AbbVie, Janssen: Honoraria, Other: Travel grants. Gattei: abbVie: Research Funding; Janssen: Research Funding; Menarini: Research Funding. Mannina: Janssen,Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Falini: Rasna Therapeutics: Honoraria. Luminari: Roche, Celgene, Teva Pharmaceuticals, Gilead Sciences, and Takeda Pharmaceuticals: Honoraria.

scholarly journals Gastrointestinal Events and Management Strategies for Patients with Acute Myeloid Leukemia (AML) in First Remission Receiving CC-486 in the Randomized, Placebo-Controlled, Phase III QUAZAR AML-001 Maintenance Trial

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 22-23
Author(s):  
Farhad Ravandi ◽  
Christopher Pocock ◽  
Dominik Selleslag ◽  
Pau Montesinos ◽  
Hamid Sayar ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Initial Treatment ◽  
Older Patients ◽  
Research Funding ◽  
Management Strategies ◽  
Phase Iii ◽  
Publicly Traded ◽  
Advisory Committees ◽  
First Remission ◽  
Over Time

INTRODUCTION: About 50% of older patients with AML attain remission with intensive induction chemotherapy (IC) but the majority will eventually relapse. Effective, well tolerated maintenance treatments are needed to reduce the risk of relapse and prolong survival for older patients with AML in remission, who are less likely than younger patients to be candidates for hematopoietic stem cell transplant (HSCT). CC-486 is an oral hypomethylating agent that allows for extended dosing schedules to sustain therapeutic activity. In the randomized, phase III QUAZAR AML-001 Maintenance Trial, CC-486 significantly prolonged overall survival (OS) and relapse-free survival (RFS) vs. placebo in patients aged ≥55 years with AML in first remission after IC ± consolidation. Gastrointestinal (GI) events were the most common treatment-emergent adverse events (TEAEs) reported in patients who received CC-486. Here we assess the rates of GI TEAEs and associated management strategies over time with CC-486 treatment in QUAZAR AML-001. METHODS: Eligible patients were aged ≥55 years and had AML with intermediate- or poor-risk cytogenetics and Eastern Cooperative Oncology Group performance status (ECOG PS) scores ≤3. Patients had achieved complete remission (CR) or CR with incomplete blood count recovery (CRi) after IC ± consolidation and were not candidates for HSCT. Within 4 months of achieving CR/CRi, patients were randomized 1:1 to CC-486 300 mg or placebo, administered once-daily on days 1-14 of repeated 28-day treatment cycles. Safety was assessed among patients who received ≥1 dose of study drug, from the date of first dose through 28 days after the last dose. Prophylaxis and treatment of GI TEAEs were allowed but not mandatory. RESULTS: In all, 236 patients received CC-486 and were evaluated for safety. The median age at study entry was 68 years (range 55-86), 202 patients (85.6%) had intermediate-risk cytogenetics at diagnosis, 185 (78.4%) had achieved CR after induction, and 184 (78.0%) received ≥1 course of consolidation before randomization. Overall, nausea, vomiting, and diarrhea (any grade) were reported in 65%, 60%, and 50%, respectively, of patients treated with CC-486. Few patients experienced grade 3 TEAEs (nausea, 3%; vomiting, 3%; diarrhea, 5%) or serious events (0.4%, 0.8%, and 1.3%, respectively), and only 1 grade 4 event (diarrhea) was reported at any time on-study. Rates of GI TEAEs were highest during initial treatment and decreased thereafter. In cycles 1-2, 3-4, and 5-6, respectively, nausea was reported in 53%, 17%, and 15% of patients; vomiting in 49%, 15%, and 10% of patients; and diarrhea in 29%, 16%, and 11% of patients (Figure). The most commonly used concomitant GI medications were 5-HT3 antagonists, metoclopramide, lactulose, and loperamide; use of these agents was also highest during the first 2 treatment cycles and decreased over time (Figure). GI events required CC-486 treatment interruptions for 13% of patients, dose-reductions for 6% of patients, and treatment discontinuation for 5% of patients. DISCUSSION: Most GI-related TEAEs reported by patients treated with CC-486 were low-grade, and events decreased in frequency after initial treatment cycles, indicating these events were well managed. Use of GI medications decreased concurrently, suggesting progressive GI tolerance to CC-486 with continued therapy. Few patients discontinued CC-486 due to GI TEAEs. Prophylaxis and symptomatic intervention of GI events during early CC-486 therapy may facilitate treatment adherence to promote better outcomes. Disclosures Ravandi: Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Selleslag:Alexion: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Teva: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Belgian College: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Sayar:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Safah:Amgen: Honoraria; Astellas: Speakers Bureau; Verastem: Honoraria; Janssen: Speakers Bureau. Hiwase:Novartis Australia: Research Funding. La Torre:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Skikne:Bristol Myers Squibb: Current Employment. Kumar:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Dong: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. Dombret:Otsuka: Consultancy; Abbvie: Consultancy; Servier: Consultancy, Research Funding; Sunesis: Consultancy; Amgen: Consultancy, Research Funding; Jazz Pharma: Consultancy, Research Funding; Celgene: Consultancy; Nova: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Menarini: Consultancy; Janssen: Consultancy; Cellectis: Consultancy; Shire-Baxalta: Consultancy; Immunogen: Consultancy.

scholarly journals Use of Endpoints in Phase III Randomized Controlled Trials for Acute Myeloid Leukemia over the Last 15 Years: A Systematic Review

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4389-4389
Author(s):  
Moazzam Shahzad ◽  
Muhammad Arslan ◽  
Sibgha Gull Chaudhary ◽  
Raheel S Siddiqui ◽  
Ezza Tariq ◽  
...  
Keyword(s):  
Randomized Controlled Trials ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase Iii ◽  
Controlled Trials ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Free Survival ◽  
Randomized Controlled ◽  
Secondary Endpoints

Abstract Background: The use of objective endpoints is critical for the generalization and clinical implications of a study. Overall survival (OS) has traditionally been used as the gold standard for demonstrating the true clinical benefit of therapy or intervention. We systematically evaluated the proportion of different primary and secondary endpoints used in phase III randomized controlled trials (RCTs) for acute myeloid leukemia (AML), and their trends over time. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on three databases (PubMed, Cochrane, and Clinical trials.gov) using MeSH terms and keywords for "Leukemia, Myeloid, Acute" AND "Randomized Controlled Trials as Topic" from January 2006 to March 2021. We screened 3290 articles. After excluding duplicates, reviews, and irrelevant articles, 241 articles reporting only phase III RCTs with primary and secondary endpoints on AML or its subtypes were included for our systematic review. Primary and secondary endpoints data were extracted from the included studies, and the frequency of various endpoints as well as their yearly frequencies were calculated. Disease-free survival (DFS) was used to represent similar outcomes including event-free survival (EFS), progression-free survival (PFS), leukemia-free survival (LFS), and relapse-free survival (RFS). Results: Our study included 241 phase III RCTs on AML. OS was the primary endpoint in 114 (47%) studies, while DFS and complete remission (CR) were reported as primary endpoints in 67 (28%) and 41 (17%) studies, respectively. Safety/adverse events, relapse rate (RR), graft versus host disease (GvHD) free survival, hematological improvement (HI), minimal residual disease (MRD), and non-relapse mortality (NRM) were used as primary endpoints in 10 (4%), 8 (3%), 5 (2%), 4 (2%), 3 (1%), and 2 (1%) studies respectively. Incidence of hospitalization, fungal disease, lung infiltrates, chronic GvHD, and allogeneic stem cell transplant each were used as primary endpoints in 1 (0.4%) study. (Table 1) Secondary endpoints followed a similar pattern as detailed in Table 2. OS (n=74, 31%), DFS (n=77, 32%) and CR (n=73, 30%) were commonly reported secondary endpoints. Safety/adverse effects, RR, mortality, quality of life (QoL), HI, MRD, incidence/length of hospitalization, and acute/chronic GvHD were used as secondary endpoints in 35 (14.5%), 15 (6%), 13 (5%), 9 (4%), 9 (4%), 7 (3%), 7 (3%), 5 (2%), and 4 (2%) studies, respectively. After 2013, increase in the use of OS (31% to 52%) and CR (15% to 17%) as a primary endpoint was noted, while the use of DFS as a primary endpoint decreased from 52% to 21%. (Table 1) For secondary endpoints, a higher trend in the use of DFS (19% to 35%) and OS (31% to 45%) and a lower trend in the use of CR (35% to 29%) was observed after 2013. (Table 2) Conclusion: Overall survival and disease-free survival were the most used primary and secondary endpoints in phase III randomized controlled trials for AML. There has been an increase in the use of clinically meaningful and objective endpoint of OS over the past 15 years in AML phase III RCTs. Figure 1 Figure 1. Disclosures Yacoub: Cara: Current equity holder in publicly-traded company; Dynavex: Current equity holder in publicly-traded company; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Ardelyx: Current equity holder in publicly-traded company; Seattle Genetics: Honoraria, Speakers Bureau; Hylapharm: Current equity holder in publicly-traded company. Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. McGuirk: Pluristem Therapeutics: Research Funding; Novartis: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Gamida Cell: Research Funding; EcoR1 Capital: Consultancy; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Fresenius Biotech: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Bellicum Pharmaceuticals: Research Funding; Astelllas Pharma: Research Funding.

scholarly journals Two Currently Recruiting Randomized Phase III Trials: COMMODORE 1 and 2 Evaluating Crovalimab Vs Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria with or without Current Anti-Complement Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4313-4313
Author(s):  
Austin G. Kulasekararaj ◽  
Antonio Risitano ◽  
Alexander Roeth ◽  
Guangsheng He ◽  
Jeffrey Pu ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Phase Iii ◽  
Primary Efficacy ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Efficacy Analysis ◽  
To Receive ◽  
Primary Efficacy Analysis

Abstract Background Crovalimab is a novel anti-complement C5 antibody currently being studied as a treatment for paroxysmal nocturnal hemoglobinuria (PNH), a life-threatening disease associated with hemolytic anemia and thrombosis. Treatment with approved C5 inhibitors eculizumab or ravulizumab is effective, but can be limited by breakthrough hemolysis due to unsustained C5 inhibition, inadequate efficacy in patients with C5 mutational variants, and the requirement of regular intravenous infusions. Crovalimab is unique in that its properties allow for subcutaneous injections once every 4 weeks (Q4W) that can be self-administered. Additionally, crovalimab binds to C5 mutational variants. Promising results were obtained in the Phase I/II COMPOSER trial (NCT03157635; Röth et al, Blood. 2020) conducted in patients with PNH, with or without prior anti-C5 treatment. The efficacy and safety of crovalimab vs eculizumab will be evaluated in two Phase III, randomized, open-label trials in patients with PNH, with or without current complement C5 inhibition. Study Design and Methods COMMODORE 1 (NCT04432584) will enroll patients who are currently receiving complement C5 inhibitor therapy. This trial is divided into two parts (Figure). Patients aged ≥ 18 years will be randomized 1:1 to receive either crovalimab (Arm A) or eculizumab (Arm B) and will contribute to the primary efficacy analysis. Patients aged < 18 years can be enrolled in an exploratory descriptive arm (Arm C). Arm A and C patients will receive crovalimab loading and subsequent subcutaneous Q4W maintenance dosing from Week 5. Arm B patients will receive eculizumab intravenous maintenance dosing from Day 1, Q2W for a total of 24 weeks. Patients in Arm A and Arm C can continue to receive crovalimab, and patients in Arm B can switch to crovalimab after 24 weeks of treatment, as determined by the treating physician. The primary efficacy objective is to determine the non-inferiority of crovalimab vs eculizumab based on percentage change in lactate dehydrogenase levels from baseline, averaged over weeks 21, 23, and 25. Secondary efficacy objectives are to determine the proportion of patients who experience breakthrough hemolysis, achieve transfusion avoidance or hemoglobin stabilization, as well as determine mean change in fatigue according to the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire from baseline to Week 25. Safety and tolerability of crovalimab vs eculizumab will also be evaluated along with pharmacokinetic, immunogenicity, biomarker, and health status utility objectives. COMMODORE 2 (NCT04434092) will enroll patients not currently treated with C5 complement inhibitors. This trial is also divided into two parts (Figure). Patients aged ≥ 18 years will be randomized 2:1 to receive either crovalimab (Arm A) or eculizumab (Arm B) and will contribute to the primary efficacy analysis. Patients aged < 18 years will be enrolled in an exploratory descriptive arm (Arm C). Arm A and C patients will receive crovalimab loading and subsequent subcutaneous Q4W maintenance dosing from Week 5. Arm B patients will receive induction doses of eculizumab intravenously QW for 4 weeks followed by maintenance dosing Q2W up to 24 weeks. Patients in Arm A and Arm C can continue to receive crovalimab, and patients in Arm B can switch to crovalimab, after 24 weeks of treatment, as determined by the treating physician. The primary efficacy objective is to determine the non-inferiority of crovalimab vs eculizumab, based on the proportion of patients who 1) achieve transfusion avoidance from baseline to Week 25 and 2) with hemolysis control from Week 5-25 (co-primary efficacy endpoints). Safety and tolerability of crovalimab vs eculizumab will also be evaluated along with pharmacokinetic, immunogenicity, biomarker, and health status utility objectives. Figure 1 Figure 1. Disclosures Kulasekararaj: F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; Akari: Consultancy, Honoraria, Speakers Bureau; Biocryst: Consultancy, Honoraria, Speakers Bureau; Achilleon: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria, Speakers Bureau; Ra Pharma: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Alexion, AstraZeneca Rare Disease Inc.: Consultancy, Honoraria, Other: Travel support. Risitano: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Research Funding, Speakers Bureau; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA Pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Achillion: Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees; Jazz: Other: Lecture fees, Speakers Bureau; F. Hoffmann-La Roche Ltd.: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Lecture fees, Speakers Bureau; Apellis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Speakers Bureau. Roeth: Novartis: Consultancy, Honoraria; Bioverativ, a Sanofi company: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals: Consultancy, Honoraria; Kira: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria. He: LongBio Pharma: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd.: Consultancy. Pu: University of Arizona: Current Employment; Pennsylvania State University: Patents & Royalties; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees. Wright: Genentech, Inc.: Current Employment. Appius: F. Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Sostelly: F. Hoffmann-La Roche Ltd: Current Employment. Sreckovic: F. Hoffmann-La Roche Ltd.: Current Employment. Stanzel: F. Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Munir: F. Hoffmann-La Roche: Consultancy; Alexion: Honoraria. Nishimura: Apellis: Consultancy; Novartis: Consultancy; Chugai: Consultancy; Sanofi: Consultancy; Alexion: Consultancy; Roche: Consultancy; Biocryst: Consultancy.

NCRN CLL207 Study of Alemtuzumab Consolidation In CLL: Final Response Assessment and Early Follow-up (on Behalf of the NCRI CLL Trials Sub-Group)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 60-60 ◽  
Author(s):  
Abraham M Varghese ◽  
Dena Cohen ◽  
Christopher F.E. Pocock ◽  
Andy Rawstron ◽  
Walter M Gregory ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Response Assessment ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Close Monitoring ◽  
Advisory Committees ◽  
End Of Treatment ◽  
Time Point

Abstract Abstract 60 Background: The length of remission in patients with chronic lymphocytic leukemia (CLL) is dependent on the level of minimal residual disease (MRD) at the end of therapy, regardless of the therapy received. The conversion of remissions from MRD positive to negative should prolong remissions and survival. Several small studies have used alemtuzumab as consolidation therapy following conventional chemotherapy but with concerns over toxicity; primarily due to immune suppression and infections. The dose and timing (i.e. interval between prior chemotherapy and alemtuzumab) seem to be critical. Trial Design: The Phase II NCRN CLL207 Trial assessed alemtuzumab consolidation post-chemotherapy. Between 6 and 24 months from completing treatment (1 to 3 prior therapies) blood was screened for MRD using multi-parameter flow cytometry with a sensitivity of less than a single CLL cell in 10,000 leucocytes (0.01%). The marrow of MRD positive patients was assessed to quantify the CLL before treatment with alemtuzumab at a dose of 30mg given subcutaneously 3 times a week for 6 weeks, at which time the marrow was repeated. MRD negative patients and non-responders stopped therapy; MRD positive patients with at least one log reduction in MRD continued therapy for a further 6 weeks. All patients received prophylaxis with co-trimoxazole and aciclovir as well as weekly cytomegalovirus (CMV) monitoring by PCR. It was pre-determined that at least 14 of up to 54 (26%) patients would need to be converted from MRD positivity to negativity to justify further studies of this treatment strategy. Results: 47 patients received alemtuzumab in NCRN CLL207 with median age of 58 yrs (40-77) and 35 (74.5%) males. There was a median of 2 prior therapies (range 1 to 4) with 46 pts receiving fludarabine combinations as the latest therapy and 9 receiving rituximab-containing combinations. There were a total of 21 SAE's in 17 (36.2%) pts with 2 (4.3%) treatment related deaths (EBV-LPD and a parainfluenza infection). Alemtuzumab was stopped in 6 patients before week 6 mainly due to toxicity, 32 patients received 6–8 weeks of treatment and 9 patients received a 12-week course. G-CSF was given when the neutrophil count fell below 1 × 10^9/l and 14 (30%) patients required G-CSF during alemtuzumab with an additional 13 (28%) receiving G-CSF after completion of alemtuzumab. Positive CMV PCRs were detected in 21 (45%) patients, all of whom were successfully treated with pre-emptive antiviral therapy. Prior to alemtuzumab 24 patients were in complete remission (CR) and 23 were in partial remission (PR). Three months after alemtuzumab 13/23 (56%) PR converted to CR. 39/47 (83%) patients had MRD negative marrows at the end of alemtuzumab, 7 (15%) remained MRD positive and 1 (2%) was not evaluable. Blood MRD assessment 6 months after completing alemtuzumab showed that 15/31 (48%) MRD negative patients became MRD positive, although all except 2 had low CLL levels (below 0.1×10^9/l) at this time-point. Therefore overall 16/39 (41%) patients were MRD negative 6 months after completing alemtuzumab and of these 8/9 (89%) remained MRD negative in the blood at 12 months. Therefore MRD negativity in the blood at 6 months seems to better predict for persistent MRD negativity than the marrow at the end of therapy and appears to be the most appropriate assessment for the outcome of consolidation. Patients who are MRD negative at this time-point usually have durable remissions. 6 of the 9 patients receiving 12 weeks of alemtuzumab were MRD negative at the end of treatment but only 1 (11%) remained MRD negative in the blood at 6 months. In contrast 33/38 patients receiving up to 8 weeks of alemtuzumab were MRD negative at the end of treatment and 15 (39%) remained MRD negative at 6 months suggesting that the patients who benefit most from alemtuzumab consolidation are those who are MRD negative at 6 weeks. Conclusion: Alemtuzumab consolidation results in the eradication of detectable MRD in 83% of patients and 41% remain MRD negative 6 months later. Consolidation with alemtuzumab is associated with mainly infective toxicities, which are largely manageable with prophylaxis and close monitoring. These results justify the continued investigation of this approach in CLL within a clinical trial setting and with appropriate monitoring of patients. To this end we are now commencing a randomized Phase III trial of consolidation with alemtuzumab compared to observation (the CLARET study). Disclosures: Pocock: F.Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rawstron:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BD Bioscience: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Genzyme: Honoraria. Dearden:Roche Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hillmen:Genzyme: Honoraria, Research Funding, Speakers Bureau; Roche Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Glaxo Smith Kline: Honoraria, Research Funding.

scholarly journals Engine: Phase III Randomized Study of Enzastaurin/R-CHOP Versus Placebo/R-CHOP in Frontline High Risk Diffuse Large B Cell Lymphoma Patients with Novel Genomic Biomarker DGM1

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5330-5330 ◽  
Author(s):  
Jun Zhu ◽  
Grzegorz Nowakowski ◽  
Qingyuan Zhang ◽  
Joshua Brody ◽  
Xiuhua Sun ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Randomized Study ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Response Assessment ◽  
Phase Iii ◽  
Advisory Committees

Background: Progress in genome technology allows analysis of previously completed trials to identify subgroups potentially benefiting from therapy. Enzastaurin is a potent inhibitor of protein kinase C beta (PKC-β) and suppresses the phosphoinositide 3-kinase (PI3K)/AKT pathway. The safety and efficacy of Enzastaurin has been tested in more than 60 clinical trials including 2 major studies in DLBCL: (1) PRELUDE (A phase III maintenance trial of Enzastaurin vs Placebo, N=758) (Crump, 2016), and (2) S028 (A randomized phase II study of Enzastaurin/R-CHOP vs R-CHOP in frontline intermediate/high-risk DLBCL, N=101) (Hainsworth, 2016). DNA samples extracted from blood of patients from PRELUDE were retrospectively genotyped using whole genome SNP arrays. From the genome wide screening a novel genetic biomarker, DGM1, was identified showing high correlation with response to Enzastaurin treatment (Luo, ASH 2018). Importantly, these findings were replicated in the phase II S028 study. In the S028 study the hazard ratio (HR) for OS in high-risk (IPI ≥ 3) DGM1 positive (+) patients who received Enzastaurin/R-CHOP was 0.28 (0.1-0.81) when compared to subjects who received R-CHOP, a benefit favoring Enzastaurin (p=0.018). These data suggest that addition of Enzastaurin to R-CHOP may significantly improve outcome in frontline high-risk DGM1 (+) DLBCL. The ENGINE study was initiated to validate this finding in a prospective study. Study Design and Methods: Adult patients must have untreated CD20+ DLBCL, IPI ≥ 3. Patients are randomized 1:1 to Enzastaurin/R-CHOP or Placebo/R-CHOP for 6 cycles during combination phase. Each subject's treatment assignment will be unblinded after response assessment at the end of the combination phase. Subjects randomized to the investigational arm who have a complete or partial response will have the option to continue in the single agent phase to receive Enzastaurin for up to 2 additional years. The study intends to enroll approximately 235 patients with primary endpoint of OS in DGM1 (+) patients. The study is ongoing with 57 sites open in the US and China. As of 20 July 2019, 128 patients have been randomized. Clinical trial information: NCT03263026. Disclosures Nowakowski: Genentech, Inc.: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding. Brody:Acerta Pharma: Research Funding; Merck: Research Funding; Celldex Therapeutics: Research Funding; Genentech: Research Funding; Oncovir, Inc.: Research Funding; BMS: Research Funding; Kite Pharma: Research Funding. Lue:Kymera Therapeutics: Honoraria; Astex Pharmaceuticals: Honoraria. Luo:Denovo Biopharma LLC: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Zhang:Denovo Biopharma LLC: Employment. Han:Denovo Biopharma LLC: Employment. Jivani:TRACON Pharmaceuticals, Inc.: Other: Stock; Denovo Biopharma LLC: Employment. Liu:Denovo Biopharma LLC: Employment. Li:Denovo Biopharma LLC: Employment. Sun:Novartis: Other: Stock; Denovo Biopharma LLC: Employment.

Sign in / Sign up

Export Citation Format

Share Document