Interim Efficacy Analysis Research Articles

Eighteen-Month Interim Analysis of Efficacy and Safety of Givosiran, an RNAi Therapeutic for Acute Hepatic Porphyria, in the Envision Open Label Extension

Eighteen-Month Interim Analysis of Efficacy and Safety of Givosiran, an RNAi Therapeutic for Acute Hepatic Porphyria, in the Envision Open Label Extension

S1169 Twelve-Month Interim Analysis of Efficacy and Safety of Givosiran, an Investigational RNAi Therapeutic for Acute Hepatic Porphyria, in the ENVISION Open Label Extension

INTRODUCTION: Acute hepatic porphyria (AHP) is a family of rare genetic diseases due to enzyme defects in hepatic heme biosynthesis. Induction of 5-aminolevulinic acid synthase 1 (ALAS1), the rate-limiting step in heme biosynthesis, can lead to accumulation of toxic heme intermediates 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), causing neurovisceral attacks and chronic manifestations. Givosiran, an investigational RNAi therapeutic, targets liver ALAS1 to reduce ALA/PBG and ameliorate attacks and clinical manifestations. METHODS: ENVISION (NCT03338816) is an ongoing Phase 3 global, multicenter, randomized, placebo-controlled trial, evaluating the efficacy and safety of subcutaneous monthly doses of 2.5 mg/kg givosiran in AHP patients in a 6-month double-blind (DB) period and an open label extension (OLE) period (up to 30 months). During the OLE, patients received either 2.5 mg/kg or 1.25 mg/kg monthly givosiran. Outcome measures included composite annualized attack rate (AAR) requiring hospitalization, urgent care, or IV-hemin at home, ALA/PBG levels, hemin use, daily worst symptoms, and quality of life (QoL). Analyses were descriptive. RESULTS: As of July 23, 2019, 93 patients entered the OLE: 56 (placebo/givosiran = 29; givosiran/givosiran = 27) received 2.5 mg/kg monthly givosiran, and 37 (placebo/givosiran = 17; givosiran/givosiran = 20) received 1.25 mg/kg. In givosiran patients (both doses), median AAR was 1.1 (range: 0–20.5) through Month 12. In placebo patients who crossed over to givosiran in the OLE, median AAR (DB = 10.65; OLE = 1.81) and proportion of attack-free patients (DB = 17.4%; OLE = 42.2%) were similar to the givosiran group in the DB period (median AAR = 1.04; attack free patients = 48.9%). In addition, sustained lowering of ALA/PBG in the OLE was accompanied by reductions in hemin use, daily worst pain and analgesic use, and improvements in QoL. Among patients on givosiran through Month 12, 62% had ≥1 drug-related adverse event (AE) and 3% had ≥1 drug-related serious AE. There were no new AEs leading to discontinuation and no deaths. No new safety concerns occurred in the OLE. There was a trend toward increased efficacy with the 2.5 mg/kg dose compared to 1.25 mg/kg dose, and safety was acceptable at both doses. CONCLUSION: In an ongoing Phase 3 study, givosiran 2.5 mg/kg monthly demonstrated maintenance or enhancement of clinical efficacy and an acceptable safety profile consistent with that observed in the 6-month DB period.

Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2−, Node-Positive, High-Risk, Early Breast Cancer (monarchE)

PURPOSEMany patients with HR+, HER2− early breast cancer (EBC) will not experience recurrence or have distant recurrence with currently available standard therapies. However, up to 30% of patients with high-risk clinical and/or pathologic features may experience distant recurrence, many in the first few years. Superior treatment options are needed to prevent early recurrence and development of metastases for this group of patients. Abemaciclib is an oral, continuously dosed, CDK4/6 inhibitor approved for HR+, HER2− advanced breast cancer (ABC). Efficacy and safety of abemaciclib in ABC supported evaluation in the adjuvant setting.METHODSThis open-label, phase III study included patients with HR+, HER2−, high-risk EBC, who had surgery and, as indicated, radiotherapy and/or adjuvant/neoadjuvant chemotherapy. Patients with four or more positive nodes, or one to three nodes and either tumor size ≥ 5 cm, histologic grade 3, or central Ki-67 ≥ 20%, were eligible and randomly assigned (1:1) to standard-of-care adjuvant endocrine therapy (ET) with or without abemaciclib (150 mg twice daily for 2 years). The primary end point was invasive disease-free survival (IDFS), and secondary end points included distant relapse–free survival, overall survival, and safety.RESULTSAt a preplanned efficacy interim analysis, among 5,637 randomly assigned patients, 323 IDFS events were observed in the intent-to-treat population. Abemaciclib plus ET demonstrated superior IDFS versus ET alone (P = .01; hazard ratio, 0.75; 95% CI, 0.60 to 0.93), with 2-year IDFS rates of 92.2% versus 88.7%, respectively. Safety data were consistent with the known safety profile of abemaciclib.CONCLUSIONAbemaciclib when combined with ET is the first CDK4/6 inhibitor to demonstrate a significant improvement in IDFS in patients with HR+, HER2− node-positive EBC at high risk of early recurrence.

AS085 - Twelve-month interim analysis of efficacy and safety of givosiran, an investigational RNAi therapeutic for acute hepatic porphyria, in the envision open label extension

AS085 - Twelve-month interim analysis of efficacy and safety of givosiran, an investigational RNAi therapeutic for acute hepatic porphyria, in the envision open label extension

Safety and Efficacy of Tofacitinib in Patients with Active Psoriatic Arthritis: Interim Analysis of OPAL Balance, an Open-Label, Long-Term Extension Study.

IntroductionTofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). We report the interim safety, tolerability, and efficacy of tofacitinib in PsA patients in OPAL Balance, a 3-year, open-label, long-term extension study (data cut-off: August 2017; database not locked, data may change).MethodsEligible patients from two phase (P) 3 (P3) tofacitinib PsA studies (OPAL Broaden, NCT01877668; OPAL Beyond, NCT01882439) entered OPAL Balance ≤ 3 months after completing the P3 study or discontinuing for reasons other than study-drug-related adverse events (AEs). Patients received open-label tofacitinib 5 mg twice daily (BID), with adjustments to 10 mg BID permitted post-month (M) 1. Certain concomitant conventional synthetic disease-modifying antirheumatic drugs were allowed. Primary endpoints were incidence/severity of AEs and laboratory abnormalities, and changes from baseline in laboratory parameters (reported up to M36 and M30, respectively). Efficacy (clinical/patient-reported outcomes) was reported through M30.ResultsA total of 686 patients were treated; at data cut-off, 68.2% remained in the study. Mean (range) treatment duration was 641 (1–1032) days; total treatment duration was 1153.2 patient-years. By M36, 79.6, 13.8, and 8.6% of patients reported AEs, serious AEs, and discontinuations due to AEs, respectively. Five deaths occurred; one within the risk period (incidence rate [IR; patients with events/100 patient-years] 0.1). IRs for AEs of special interest were: all (non-serious and serious) herpes zoster, 1.7; serious infections, 0.9; opportunistic infections, 0.3 (all disseminated/multi-dermatomal herpes zoster); malignancies excluding non-melanoma skin cancer (NMSC), 0.8; NMSC, 1.0; major adverse cardiovascular events, 0.3; pulmonary embolisms, 0.1; and arterial thromboembolisms, 0.4. No patients had deep vein thrombosis. Alanine aminotransferase and aspartate aminotransferase levels were elevated ≥ 3-fold the upper limit of normal in 4.0 and 2.2% of patients, respectively. Changes in laboratory parameters were generally stable over time, although lymphocyte counts decreased slightly. Efficacy was maintained through M30.ConclusionsIn this interim analysis of OPAL Balance, tofacitinib safety and efficacy in patients with PsA appeared to be consistent with those of the P3 studies. Efficacy was maintained over time.Trial RegistrationClinicalTrials.gov identifier: NCT01976364.Electronic Supplementary MaterialThe online version of this article (10.1007/s40744-020-00209-4) contains supplementary material, which is available to authorized users.

Evaluation of the efficacy and safety of intravenous remdesivir in adult patients with severe COVID-19: study protocol for a phase 3 randomized, double-blind, placebo-controlled, multicentre trial

BackgroundCoronavirus disease 2019 (COVID-19), caused by a novel corinavirus (later named SARS-CoV-2 virus), was fistly reported in Wuhan, Hubei Province, China towards the end of 2019. Large-scale spread within China and internationally led the World Health Organization to declare a Public Health Emergency of International Concern on 30th January 2020. The clinical manifestations of COVID-19 virus infection include asymptomatic infection, mild upper respiratory symptoms, severe viral pneumonia with respiratory failure, and even death. There are no antivirals of proven clinical efficacy in coronavirus infections. Remdesivir (GS-5734), a nucleoside analogue, has inhibitory effects on animal and human highly pathogenic coronaviruses, including MERS-CoV and SARS-CoV, in in vitro and in vivo experiments. It is also inhibitory against the COVID-19 virus in vitro. The aim of this study is to assess the efficacy and safety of remdesivir in adult patients with severe COVID-19.MethodsThe protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. This is a phase 3, randomized, double-blind, placebo-controlled, multicentre trial. Adults (≥ 18 years) with laboratory-confirmed COVID-19 virus infection, severe pneumonia signs or symptoms, and radiologically confirmed severe pneumonia are randomly assigned in a 2:1 ratio to intravenously administered remdesivir or placebo for 10 days. The primary endpoint is time to clinical improvement (censored at day 28), defined as the time (in days) from randomization of study treatment (remdesivir or placebo) until a decline of two categories on a six-category ordinal scale of clinical status (1 = discharged; 6 = death) or live discharge from hospital. One interim analysis for efficacy and futility will be conducted once half of the total number of events required has been observed.DiscussionThis is the first randomized, placebo-controlled trial in COVID-19. Enrolment began in sites in Wuhan, Hubei Province, China on 6th February 2020.Trial registrationClinicalTrials.gov: NCT04257656. Registered on 6 February 2020.

Phase II randomized trial of first-line pembrolizumab and vorinostat in patients with metastatic NSCLC (mNSCLC).

9567 Background: Histone deacetylase inhibitors may enhance tumor immunogenicity through various mechanisms including induced expression of T cell chemokines. A previous phase I trial demonstrated the combination of pembrolizumab (P) with vorinostat (V) in mNSCLC was well tolerated with signals of activity in ICI-pretreated pts. We initiated a randomized trial in the first-line setting with the primary objective to determine if the combination had superior ORR compared to pembrolizumab monotherapy. Methods: Pts with treatment-naïve mNSCLC and PD-L1 expression ≥ 1% were eligible. Pts were randomized open-label 1:1 to receive P 200 mg IV q3 wk as monotherapy [Arm A] or P 200 mg IV q3 wk plus V 400 mg PO daily [Arm B]. The primary endpoint was overall response rate (ORR). Secondary endpoints included DOR, PFS and OS. Tumor biopsies were collected both pre- and on-treatment (day 15-21) for analysis of CD8+ TIL, scored using a 0-3 scale in tumor beds. Here we report results after a preplanned interim analysis for efficacy, with accrual ongoing to a planned total of 39 patients per arm. Results: Between 7/2017 – 1/2019, 49 pts were enrolled, with 47 pts evaluable for response (24 in Arm A and 23 in Arm B). Median age was 69 (range 47 - 87), 49% female, ECOG PS 0/1 in 11%/89%. PD-L1 TPS was ≥50% in 13/24 (54%) of pts in Arm A, and in 13/23 (57%) of pts in Arm B. The most common TRAEs in Arm A included diarrhea (13%), fatigue (8%), and pruritus (8%). 3 pts in Arm A experienced grade ≥ 3 irAEs (including 1 each of grade 3 hepatitis, pneumonitis, and rash). The most common TRAEs in Arm B included anorexia (43%), fatigue (43%), nausea (35%) and increased creatinine (35%). 1 pt in Arm B experienced grade ≥ 3 irAE (1 grade 3 pneumonitis). Pre-treatment CD8+ TIL were not significantly different between Arm A and Arm B (p = 0.85) with the majority of tumors in both arms having a low TIL score of 1 (65% Arm A and 73.7% Arm B). A significant increase from pre-treatment to on-treatment TIL scores was seen in both Arm A (p = 0.001) and Arm B (p = 0.002). The ORR in Arm B pts with low pre-treatment TIL (score = 1) pts was substantially higher (66.7%) than in Arm A (33.3%), suggesting the combination may be especially beneficial against low TIL tumors. Conclusions: The combination arm had a considerably higher ORR compared to pembrolizumab monotherapy, with a manageable toxicity profile. The combination of pembrolizumab plus vorinostat in mNSCLC warrants further investigation. Clinical trial information: NCT02638090 . [Table: see text]

CLO20-054: A Phase 2 Trial of Nivolumab and Temozolomide in Advanced Neuroendocrine Tumors (NETs): Interim Efficacy Analysis

CLO20-054: A Phase 2 Trial of Nivolumab and Temozolomide in Advanced Neuroendocrine Tumors (NETs): Interim Efficacy Analysis

Targeting Danger Associated Molecular Pattern (DAMP) with CD24Fc to Reduce Acute Gvhd: Study Design on a Randomized Double Blind Placebo Controlled Phase III Clinical Trial (CATHY Study)

<h3>Introduction</h3> Allogeneic HCT is the only established curative therapy for high risk hematologic malignancies. The major challenges are leukemia relapse and high grade GVHD. We have developed the CD24Fc fusion protein to selectively inhibit danger-associated molecular pattern (DAMP)-induced inflammation and discovered that it effectively prevents GVHD without affecting the desirable GVL effect in preclinical models. With the support of SBIR awards from the NCI, we have completed a phase II randomized, double blind, multi-center, dose escalation trial comprised of 3 dosing cohorts of 8 patients (3:1 CD24Fc vs. placebo), with a total enrollment of 24 subjects. Notably, clinical data from this trial demonstrate that CD24Fc reduces the incidence of severe GVHD, resulting in statistically significant increases of acute 180-day GVHD-free survival (aGFS). A Phase II expansion cohort to enroll an additional 20 subject is ongoing (NCT02663622). Here we propose a phase III clinical trial with 180 patients (1:1 CD24Fc vs placebo) to test the hypothesis that CD24Fc prophylaxis can significantly improve 180 day acute GVHD-free survival (aGFS) over placebo control. <h3>Study Design</h3> A Randomized, Double-blind, Placebo-controlled, Multi-Center, Phase III Study of CD24Fc for the Prevention of Acute GVHD Following Myeloablative Allogeneic HCT (CATHY) (NCT04095858). This study will compare CD24Fc or Placebo with standard GVHD prophylaxis of tacrolimus and methotrexate in the setting of myeloablative conditioning (MAC), matched unrelated donor (MUD) allogeneic HCT in patients with AML/ALL or MDS. Patients will be randomized 1:1 to receive CD24Fc or placebo at the dose levels of 480mg, 240mg and 240mg on Days -1, +14 and +28, respectively. The primary endpoint is the rate of 180 days grade III-IV acute GVHD-free survival (aGFS). Secondary endpoints are 1 yr DFS, 1 yr OS, and D180 Gr II-IV aGFS. Other exploratory evaluations will be 1 yr chronic GVHD, 1 yr relapse, NRM at 1 year, incidence and rate of infection at 100 days, and rate of Gr III and above mucositis at 28 days. The study will enroll 180 patients, or 90 per arm, with an estimated accrual period of 24 months. <h3>Statistical Consideration</h3> The study will include one interim analysis for efficacy. Z test statistics for comparing the two arms will be compared to the critical values and results be reviewed by the independent DSMB.

KEYNOTE-204: A Multicentre, Randomised, Open-Label, Phase 3 Study of Pembrolizumab &lt;i&gt;versus&lt;/i&gt; Brentuximab Vedotin in Relapsed or Refractory Classical Hodgkin Lymphoma

Background: Programmed death 1 blockade via pembrolizumab monotherapy has demonstrated favourable anti-tumor activity and toxicity in patients with relapsed/refractory classical Hodgkin lymphoma (cHL). KEYNOTE-204 (NCT02684292) was a randomised, international, open-label, phase 3 study of pembrolizumab versus brentuximab vedotin for relapsed/refractory cHL. Here, we present the interim efficacy and safety analyses. Methods: Patients aged ≥18 years ineligible for autologous stem cell transplant (ASCT) or who had relapsed post-ASCT with measurable disease and Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled. Brentuximab vedotin-naive and -exposed patients were eligible. Patients were randomised 1:1 to pembrolizumab 200 mg IV every 3 weeks (q3w) or brentuximab vedotin 1.8 mg/kg IV q3w. The primary endpoint, assessed in the intent-to-treat population, was progression-free survival (PFS) by blinded independent central review per International Working Group 2007 criteria including clinical and imaging data after autologous or allogeneic stem cell transplant. Findings: One hundred fifty-one patients were randomised to pembrolizumab and 153 to brentuximab vedotin. After a median time from randomisation to the data cutoff of 25·7 (IQR 9·6) months, median PFS was 13·2 months for pembrolizumab versus 8·3 months for brentuximab vedotin (HR for disease progression or survival: 0·65 [95% CI 0·48-0·88; p=0·00271]). Grade 3-5 treatment-related adverse events (TRAEs) were experienced by 19·6% of patients with pembrolizumab and 25·0% with brentuximab vedotin; serious TRAEs occurred in 16·2% and 10·5% of patients, respectively. One treatment-related death due to pneumonia occurred in the pembrolizumab arm. Interpretation: Pembrolizumab was superior to brentuximab vedotin and demonstrated statistically significant and clinically meaningful improvement in PFS, with safety consistent with previous reports. These data support pembrolizumab as the preferred treatment option for patients with relapsed/refractory cHL who have relapsed post-ASCT or are ineligible for ASCT. Trial Registration: This study is registered with ClinicalTrials.gov (NCT02684292). Funding: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA) Declaration of Interests: John Kuruvilla: Honoraria: AbbVie, Bristol-Myers Squibb, Amgen, AstraZeneca, Celgene, Gilead Sciences, Janssen, Karyopharm Therapeutics, Merck, Novartis, Roche, Seattle Genetics; Consultancy/Advisory: AbbVie, Bristol-Myers Squibb, Gilead Sciences, Karyopharm Therapeutics, Merck, Roche/Genentech, Seattle Genetics; Research funding: Janssen, Roche Radhakrishnan Ramchandren: Consultancy/Advisory: Seattle Genetics, Sandoz-Novartis, Pharmacyclics/Janssen, Bristol-Myers Squibb; Research funding: Merck, Seattle Genetics, Janssen, Genentech Armando Santoro: Consultancy/Advisory: Bristol-Myers Squibb, Servier, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Sanofi, ArQule; Speaker Bureau: Takeda, Roche, AbbVie, Amgen, Celgene, AstraZeneca, ArQule, Lilly, Sandoz, Novartis, Bristol-Myers Squibb, Servier, Gilead Sciences, Pfizer, Eisai, Bayer, Merck Ewa Paszkiewicz-Kozik: Travel, Accommodations, Expenses: Roche, Takeda, Celgene Robin Gasiorowski: Honoraria: Merck, Takeda, Novartis, AbbVie Nathalie A. Johnson: Honoraria: Roche/Genentech, Merck; Consultancy/Advisory: Roche/Genentech, Merck, Bristol-Myers Squibb, AbbVie; Research funding: AbbVie Laura Maria Fogliatto: No conflicts to disclose Iara Goncalves: Consultancy/Advisory: Janssen; Speaker Bureau: Janssen; Research funding: Janssen, Takeda, Amgen, Bayer, Novartis, Merck, Bayer, Celgene, Glaxo, Bristol-Myers Squibb Jose S. R. de Oliveira: No conflicts to disclose Valeria Buccheri: Consultancy/Advisory: AstraZeneca; Travel, Accommodations, Expenses: AbbVie, Takeda: Research funding: Merck, Roche, Seattle Genetics, Takeda Guilherme Fleury Perini: Honoraria: Janssen, Takeda; Speaker Bureau: AbbVie, Janssen Neta Goldschmidt: No conflicts to disclose Iryna Kriachok: Consultancy/Advisory: Takeda, Janssen; Expert Testimony: Takeda, Janssen; Travel, Accommodations Expenses: Takeda, Merck, AbbVie, Roche; Research funding: Janssen, Bayer, Karyopharm, Merck, Acerta, AbbVie, Debiopharm Michael Dickinson: Honoraria: Merck, Roche, Takeda, Celgene, Novartis; Consultancy/Advisory: Merck, Roche, Takeda, Celgene, Novartis; Speaker Bureau: Merck, Roche, Takeda, Celgene, Novartis; Research funding: Merck, Roche, Takeda, Celgene, Novartis; Mieczyslaw Komarnicki: No conflicts to disclose Andrew McDonald: No conflicts to disclose Muhit Ozcan: Research funding: Merck, Bayer, Roche, Janssen, Celgene, Takeda, Archigen, Novartis, AbbVie; Honoraria: Roche, Takeda, AbbVie, Amgen, Bristol-Myers Squibb Naohiro Sekiguchi: Research funding (institution): Ono, A2 Healthcare, Astellas, Janssen, Merck Sharp & Dohme, Otsuka, Pfizer, PPD-SNBL, Sumitomo Dainippon, Daiichi Sankyo, BristolMyers Squibb Ying Zhu: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA Akash Nahar: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA Patricia Marinello: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and stockholder of Merck & Co., Inc., Kenilworth, NJ, USA; and has received travel expenses from Merck & Co., Inc. Pier Luigi Zinzani: Speakers’ bureaus for Verastem, Celltrion, Gilead, Janssen-Cilag, BristolMyers Squibb, Servier, Sandoz, Merck, Immune Design, Celgene, Portola, Roche, EUSA Pharma, Kyowa Kirin, and Sanofi; Advisory boards: Verastem, Celltrion, Gilead, Janssen-Cilag, Bristol-Myers Squibb, Servier, Merck & Co., Inc., Immune Design, Celgene, Portola, Roche, EUSA Pharma, Kyowa Kirin, and Sanofi; Consultant: Verastem, Merck, EUSA Pharma, and Sanofi. Ethics Approval Statement: The study was approved by the independent institutional review boards for each study site and conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice and the Declaration of Helsinki.

Niveau, a Phase 3 Study for Pts with B- or T-Cell Aggressive Non-Hodgkin Lymphoma in First Relapse or Progression Not Eligible for High-Dose Chemotherapy (HDT), Testing Nivolumab in Combination with Gemcitabine, Oxaliplatin (GemOx), Plus Rituximab (R) in Case of B-Cell Lymphoma

Niveau, a Phase 3 Study for Pts with B- or T-Cell Aggressive Non-Hodgkin Lymphoma in First Relapse or Progression Not Eligible for High-Dose Chemotherapy (HDT), Testing Nivolumab in Combination with Gemcitabine, Oxaliplatin (GemOx), Plus Rituximab (R) in Case of B-Cell Lymphoma

Interim Results of a First in Man Study with the Fc-Optimized FLT3 Antibody Flysyn for Treatment of Acute Myeloid Leukemia with Minimal Residual Disease

Background: Substantial surface expression of the FLT3 receptor can be measured on blast cells in 70% to 100% of acute myeloid leukemia (AML) patients, while no or only low levels are expressed on healthy cells like monocytes and progenitor stem cells. Thus, FLT3 is a suitable and highly selective target for therapeutic antibodies. FLYSYN is a chimeric Fc-optimized IgG1 antibody and binds specifically and with high avidity to human FLT3 (CD135). Despite achievement of complete remission, roughly half of AML patients display minimal residual disease (MRD) after end of therapy and relapse. Methods: We perform an open-label, single-arm, first in man multicenter trial to assess safety and tolerability as well as preliminary efficacy of FLYSYN as monotherapy in adult (≥18 years) AML patients in complete remission with MRD (NCT02789254). FLYSYN is administered as IV infusion over a 3 hour period. Recruitment started in March 2017 with an estimated maximum number of 31 patients and estimated recruitment until January 2020. The main inclusion criterion was confirmed stable or increasing MRD positivity in two sequential measurements. MRD was measured by central RT-qPCR and/or next generation sequencing (NGS). Sensitivity with RT-qPCR (for NPM1 only) was 10-6 and 10-4 with NGS. Patients with acute promyelocytic leukemia as well as prior hematopoietic stem cell transplantation were excluded. Using a "3 + 3" dose escalation design, five of the planned six cohorts with escalating doses have currently completed treatment (cohort 1: 0.5 mg/m² BSA; cohort 2: 1.5 mg/m² BSA; cohort 3: 5 mg/m² BSA; cohort 4: 15 mg/m² BSA; cohort 5: 45 mg/m²; cohort 6: in total 45 mg/m²; 15 mg/m² on day 1, 15 and 29). Three patients were treated per cohort, except for cohort 4, which was expanded to nine patients. The interim analysis for preliminary efficacy was performed after 18 patients were treated in cohorts 1-4. Response is defined as 1 log MRD reduction. Results: Median age was 60 years (range, 21-80 years). Sixteen patients were MRD positive for NPM1 and one patient each for RUNX1-RUNX1T1 and IDH2. So far, FLYSYN was well tolerated. Only one temporary grade 3 adverse event (AE) occurred (neutrophil decrease on day 3 only) in a patient of cohort 3, which was suspected to be related to FLYSYN treatment. There were no reported dose-limiting toxicities. The most frequently reported AEs were grade 1 and 2 gastrointestinal toxicities and laboratory abnormalities, which all were manageable with supportive care. After treatment, neither human anti-mouse nor anti-human antibodies were detected in any of the patients. Preliminary pharmacokinetic analysis was performed in the first 12 patients of the study and revealed a half-life of FLYSYN of roughly 6.5 days. Regarding preliminary efficacy, 1 patient of cohort 1 achieved permanent MRD negativity in bone marrow (BM; lasting until day 545) and 1 patient a temporary BM MRD reduction (at day 15). One patient of cohort 2 achieved BM MRD negativity (day 22) with MRD progression on day 365, whereas the other 2 patients were BM MRD progressive. None of the patients of cohort 3 achieved a MRD response in BM, but 2 patients achieved a temporary MRD response in peripheral blood. Four patients of cohort 4 achieved non-permanent BM MRD negativity. Overall, 6 patients achieved BM MRD negativity (33 %, 6/18), enduring more than 1 year in 1 patient. Conclusions: Our data suggest that FLYSYN is safe and very well tolerated as monotherapy in MRD positive AML patients. Preliminary efficacy data are promising, and recruiting is ongoing in cohort 6 in which 15 mg/m² FLYSYN is given for three times. Up-dated results will be presented at the ASH meeting. Disclosures Heuser: Bayer Pharma AG, Berlin: Research Funding; Synimmune: Research Funding. Müller-Tidow:MSD: Membership on an entity's Board of Directors or advisory committees. Steiner:Synimmune: Employment, Other: shareholder interest. Grosse-Hovest:SYNIMMUNE: Employment, Other: shareholder interest. Jung:Synimmune: Other: shareholder interest. Salih:SYNIMMUNE: Consultancy, Research Funding.

BMT CTN Protocol 1506: A Phase 3 Trial of Gilteritinib As Maintenance Therapy after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with FLT3-ITD+ AML

BMT CTN Protocol 1506: A Phase 3 Trial of Gilteritinib As Maintenance Therapy after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with FLT3-ITD+ AML

Efficacy and Tolerability of Ixazomib, Daratumumab and Low Dose Dexamethasone (Ixa Dara dex) in Unfit and Frail Newly Diagnosed Multiple Myeloma (NDMM) Patients; Results of the Interim Efficacy Analysis of the Phase II HOVON 143 Study

Efficacy and Tolerability of Ixazomib, Daratumumab and Low Dose Dexamethasone (Ixa Dara dex) in Unfit and Frail Newly Diagnosed Multiple Myeloma (NDMM) Patients; Results of the Interim Efficacy Analysis of the Phase II HOVON 143 Study

Effect of Caspofungin vs Fluconazole Prophylaxis on Invasive Fungal Disease Among Children and Young Adults With Acute Myeloid Leukemia

Children, adolescents, and young adults with acute myeloid leukemia are at high risk of life-threatening invasive fungal disease with both yeasts and molds. To compare the efficacy of caspofungin vs fluconazole prophylaxis against proven or probable invasive fungal disease and invasive aspergillosis during neutropenia following acute myeloid leukemia chemotherapy. This multicenter, randomized, open-label, clinical trial enrolled patients aged 3 months to 30 years with newly diagnosed de novo, relapsed, or secondary acute myeloid leukemia being treated at 115 US and Canadian institutions (April 2011-November 2016; last follow-up June 30, 2018). Participants were randomly assigned during the first chemotherapy cycle to prophylaxis with caspofungin (n = 257) or fluconazole (n = 260). Prophylaxis was administered during the neutropenic period following each chemotherapy cycle. The primary outcome was proven or probable invasive fungal disease as adjudicated by blinded central review. Secondary outcomes were invasive aspergillosis, empirical antifungal therapy, and overall survival. The second interim efficacy analysis and an unplanned futility analysis based on 394 patients appeared to have suggested futility, so the study was closed to accrual. Among the 517 participants who were randomized (median age, 9 years [range, 0-26 years]; 44% female), 508 (98%) completed the trial. The 23 proven or probable invasive fungal disease events (6 caspofungin vs 17 fluconazole) included 14 molds, 7 yeasts, and 2 fungi not further categorized. The 5-month cumulative incidence of proven or probable invasive fungal disease was 3.1% (95% CI, 1.3%-7.0%) in the caspofungin group vs 7.2% (95% CI, 4.4%-11.8%) in the fluconazole group (overall P = .03 by log-rank test) and for cumulative incidence of proven or probable invasive aspergillosis was 0.5% (95% CI, 0.1%-3.5%) with caspofungin vs 3.1% (95% CI, 1.4%-6.9%) with fluconazole (overall P = .046 by log-rank test). No statistically significant differences in empirical antifungal therapy (71.9% caspofungin vs 69.5% fluconazole, overall P = .78 by log-rank test) or 2-year overall survival (68.8% caspofungin vs 70.8% fluconazole, overall P = .66 by log-rank test) were observed. The most common toxicities were hypokalemia (22 caspofungin vs 13 fluconazole), respiratory failure (6 caspofungin vs 9 fluconazole), and elevated alanine transaminase (4 caspofungin vs 8 fluconazole). Among children, adolescents, and young adults with acute myeloid leukemia, prophylaxis with caspofungin compared with fluconazole resulted in significantly lower incidence of invasive fungal disease. The findings suggest that caspofungin may be considered for prophylaxis against invasive fungal disease, although study interpretation is limited by early termination due to an unplanned interim analysis that appeared to have suggested futility. ClinicalTrials.gov Identifier: NCT01307579.

Multi-stage enrichment and basket trial designs with population selection.

As biomarker information from early-phase trials can be unreliable due to high variability, it is logical to take a prospective two-stage approach when designing a late-phase confirmatory trial, ie, refining the target population at the first stage and performing the hypothesis testing at the second stage. The use of a reliable intermediate endpoint at the first stage can further improve the trial efficiency from both time and cost perspectives. Nevertheless, there are needs for expanding such two-stage confirmatory designs to more stages for monitoring efficacy on the refined population. There is limited literature on this matter, particularly for two popular designs with population selection midway, ie, the biomarker enrichment design and the basket design. In this manuscript, we focus on these two popular designs and discuss how to implement the interim efficacy analyses after population refinement while controlling type I error. Power and stopping probability are also explored for the two designs.

1821P - Analysis of the efficacy of naloxegol in a real-world 12 weeks of follow-up study, in patients with cancer and opioid-induced constipation with laxative-inadequate response

BackgroundNaloxegol is a peripherally acting, µ-opioid receptor antagonist for treatment of opioid-induced constipation (OIC). The main objective of this study was to analyze the efficacy of naloxegol in patients with cancer in a real-world prospective study. MethodsAn observational, one year of follow-up study was conducted in 16 Spanish centers. Patients older than 18 years, with active oncological disease who were under treatment with opioids for pain control were selected. OIC with inadequate response to treatment with laxative (s) was the main diagnostic. The patients received treatment with naloxegol according to clinical criteria. Efficacy was assessed measuring the response rate and symptoms evolution measured by means of PAC-SYM questionnaire. Data of an intermediate analysis after 12 weeks of treatment are analyzed. ResultsA total of 126 patients were included in the study and 68 of them in this interim efficacy analysis. About 58.2% were men, with an average age of 61.3 years (34-89). Lung cancer was observed in 35.7%, breast cancer in 15.1% and 8,7% had prostate cancer. About 75.5% had metastases. Naloxegol at doses of 12.5mg/day was administered to 14.7% and 25mg/day to 85.3%. Concomitant laxatives were administered to 63.2% of the patients. At 12 weeks, 88.2% of the patients were responders to naloxegol treatment: 80% at doses of 12.5mg/day, and 89.7% with 25mg/day. Furthermore, 75% of patients without concomitant laxative treatment were responders with 12.5mg/day dose of naloxegol and 90.5% were responders with 25mg/day. A total of 24 adverse reactions appeared in 13.5% of the patients (17/126). ConclusionsThe results of this first real-world-data study in patients with cancer confirm the efficacy of naloxegol for the treatment of OIC in this group of patients. Naloxegol is safe and well tolerated in oncologic patients. Legal entity responsible for the studyKyowa Kirin Farmacéutica, S.L.U. Madrid, Spain. FundingKyowa Kirin Farmacéutica, S.L.U. DisclosureA.J. Jiménez López: Full / Part-time employment: Kyowa Kirin Farmacéutica, S.L.U.. I. Huerta González: Full / Part-time employment: Kyowa Kirin Farmacéutica, S.L.U. A. Sanz Yagüe: Full / Part-time employment: Kyowa Kirin Farmacéutica, S.L.U. B. Soler López: Advisory / Consultancy: Kyowa Kirin Farmacéutica, S.L.U. All other authors have declared no conflicts of interest.

898TiP - The extended/phase II study of safety and tolerability of proxalutamide (GT0918) in subjects with metastatic castrate resistant prostate cancer (mCRPC) who failed either abiraterone (Abi) or enzalutamide (Enza)

BackgroundProstate cancer is the most common malignant tumor in men and is the second leading cause of cancer-related deaths in men. Recently there are several 2nd generations of anti-androgen therapies approved and used widely in clinics. However, many patients (pts) relapse after a period of treatment in clinic due to various resistant mechanisms and require new drug or additional therapy. GT0918 is a new chemical entity of androgen receptor (AR) antagonist with more specificity and activity in inhibiting ARs with reduced drug accumulation in the CNS and also show activities on AR mutations including ART878A leading AR drug resistance in cell assays. In early phase I clinical trial of dose escalation study (NCT02826772), GT0918 was shown well tolerated in mCRPC pts progressed lines of standard and experimental therapies with some durable responses. 400mg and 500mg orally once daily were selected warranted for further clinical testing. Trial designThe study is an open-label, randomized, multicenter, trial to assess GT0918 in mCRPC pts progressed after either abi or enza. The primary object is to evaluate the safety and tolerability of GT0918 either 400mg or 500mg daily dose to determine the RP2D for Ph III and/or other confirming studies. The secondary objectives are to evaluate efficacy endpoints including≥ 50% PSA suppression, the percentage of radiographic disease progression, the time to radiographic and bone progression, the time to PSA progression. The key eligibility includes histologically confirmed mCRPC, prior failed therapy either abi or enza (only 1 prior chemotherapy is allowed), progression defined by PCWG 3 criteria, and life expectancy of≥6 months (at screening). 60 pts are enrolled at 12US sites and randomized in a 1:1 ratio to orally take 400mg or 500mg of GT0918 once daily for initial treatment of 6 months. Pts will continue treatment with GT0918 up to 12 months at their assigned dose until disease progression, intolerable toxicities (AEs), or withdrawn consent. The trial started in May 2019. An interim analysis of both safety and efficacy will be performed after 30 pts become evaluable. Clinical trial identificationNCT03899467 (April 2, 2019). Legal entity responsible for the studySuzhou Kintor Pharmaceuticals Inc. FundingSuzhou Kintor Pharmaceuticals Inc. DisclosureN.J. Vogelzang: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Janssen; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Bayer. P. Zhang: Full / Part-time employment: Suzhou Kintor Pharmaceuticals Inc. K. Zhou: Full / Part-time employment: Suzhou Kintor Pharmaceuticals Inc. All other authors have declared no conflicts of interest.

Group sequential adaptive designs in series of time-to-event randomised trials in rare diseases: A simulation study.

In rare diseases, fully powered large trials may not be doable in a reasonable time frame even with international collaborations. In a previous work, we proposed an approach based on a series of smaller parallel group two-arm randomised controlled trials (RCT) performed over a long research horizon. Within the series of trials, the treatment selected after each trial becomes the control treatment of the next one. We concluded that running more trials with smaller sample sizes and relaxed α-levels leads in the long term and under reasonable assumptions to larger survival benefits with a moderate increase of risk as compared to traditional designs based on larger but fewer trials designed to meet stringent evidence criteria. We now extend this quantitative framework with more 'flexible' designs including interim analyses for futility and/or efficacy, and three-arm adaptive designs with treatment selection at interim. In the simulation study, we considered different disease severities, accrual rates, and hypotheses of how treatments improve over time. For each design, we estimated the long-term survival benefit as the relative difference in hazard rates between the end and the start of the research horizon, and the risk defined as the probability of selecting at the end of the research horizon a treatment inferior to the initial control. We assessed the impact of the α-level and the choice of the stopping rule on the operating characteristics. We also compared the performance of series based on two- vs. three-arm trials. We show that relaxing α-levels within the limit of 0.1 is associated with larger survival gains and moderate increase of risk which remains within acceptable ranges. Including an interim analysis with a futility rule is associated with an additional survival gain and a better risk control as compared to series with no interim analysis, when the α-level is below or equal to 0.1, whereas the benefit of including an interim analysis is rather small for higher α-levels. Including an interim analysis for efficacy yields almost no additional gain. Series based on three-arm trials are associated with a systematic improvement in terms of survival gain and risk control as compared to series of two-arm trials.

PS1075 ANTITUMOR ACTIVITY OF PEMBROLIZUMAB PLUS DINACICLIB IN PATIENTS WITH DIFFUSE LARGE B CELL LYMPHOMA: THE PHASE 1B KEYNOTE‐155 STUDY

Background:The cyclin‐dependent kinase inhibitor dinaciclib induces apoptosis by CDK9 inhibition with antitumor activity in preclinical syngeneic lymphoma models and early phase trials of hematologic malignancies including diffuse large B‐cell lymphoma (DLBCL). Murine syngeneic tumor models (MC‐38) showed combined anti‐tumor activity of anti‐PD‐1 antibody and dinaciclib via enhanced dinaciclib‐induced immunogenic cell death. KEYNOTE‐155 (NCT02684617) evaluated the antitumor activity of pembrolizumab plus dinaciclib in patients (pts) with relapsed/refractory (rr) CLL, MM, and DLBCL.Aims:To present data from an interim analysis of safety and efficacy in pts with rrDLBCL.Methods:In this phase 1b, two‐part, non‐randomized, open‐label study, pts with rrDLBCL who received ≥2 prior therapies were enrolled into an initial dose‐evaluation phase (two 21‐day cycles of pembrolizumab 200 mg [day 1] and dinaciclib 7 mg/m2 [day 1], 10 mg/m2 [day 8] in cycle 1 and 14 mg/m2 [day 1, day 8] from cycle 2 onwards). The DLBCL expansion cohort was opened for the signal‐detection phase (≥30 patients) if ≤4 pts had dose‐limiting toxicities (DLTs) in the dose‐evaluation phase. Treatment continued for up to 35 cycles or until disease progression (PD) or unacceptable toxicity. Response was assessed every 3 cycles for DLBCL (Revised Response Criteria for Malignant Lymphoma 2007). Pts who discontinued before PD were followed Q12W until documented PD, new anticancer treatment, or death. The primary endpoint was safety and tolerability. Secondary endpoints included ORR by investigator, DOR, PFS, and OS. AEs were graded per National Cancer Institute Common Terminology Criteria for AEs. Efficacy and safety were assessed in all pts who received ≥1 dose of pembrolizumab or dinaciclib.Results:As of Apr 25, 2018, 38 pts with rrDLBCL were enrolled and treated. Median age was 64.5 years (range, 39–85), 22 (58%) pts had ECOG PS 1, and 22 (58%) had ≥3 prior therapies. After a median follow‐up of 2.79 mo (range, 1.5–6.8), 36 (95%) pts discontinued treatment: 21 (55%) PD, 12 (32%) physician decision (10 [26%] clinical progression, 1[3%] logistics, 1 [3%] new therapy), 2 (5%) pt decision, and 1 (3%) AE. Median time on treatment was 51 days (range, 1–471). Among the 12 pts in all disease cohorts enrolled in the dose‐evaluation phase, DLTs occurred in 1 of 6 (17%) evaluable pts (grade 4 thrombocytopenia) with rrDLBCL. Of 38 pts with rrDLBCL, 24 (63%) had a treatment‐related AE. The most common treatment‐related AEs included decreased platelets (21%), lymphopenia (16%), nausea (13%), anemia (13%), diarrhea (13%), and pyrexia (13%). 12 (32%) pts had a grade 3–4 treatment‐related AE. The most common grade 3–4 treatment‐related AEs included lymphopenia (13%), decreased neutrophils (11%), decreased platelets (8%), leukopenia (8%), and laboratory tumor lysis syndrome (5%). There was no clinical TLS and no treatment‐related deaths. ORR was 18% (95% CI, 8–34) (3 CR and 4 PR) and median DOR was 4.9 mo (range, 2.1–13.8); 2 pts remained on treatment at data cutoff. With 36 (95%) events, median PFS was 2.1 mo (95% CI, 2–3) with 6‐mo and 12‐mo PFS rates of 13% and 8%, respectively. 19 (50%) pts died, with median OS of 9.8 mo (95% CI, 3 to not reached), and 12‐mo OS rate of 43%.Summary/Conclusion:Despite limited overall response, the observed CRs and durability (up to 13 mo) provide proof of concept for activity of this combination in rrDLBCL and rationale for further studies to define optimal dosing of dinaciclib, given the brevity of CDK9 inhibition observed in preclinical models.