Interim Efficacy Research Articles

The effects of releasing early results from ongoing clinical trials

Most trials do not release interim summaries on efficacy and toxicity of the experimental treatments being tested, with this information only released to the public after the trial has ended. While early release of clinical trial data to physicians and patients can inform enrollment decision making, it may also affect key operating characteristics of the trial, statistical validity and trial duration. We investigate the public release of early efficacy and toxicity results, during ongoing clinical studies, to better inform patients about their enrollment options. We use simulation models of phase II glioblastoma (GBM) clinical trials in which early efficacy and toxicity estimates are periodically released accordingly to a pre-specified protocol. Patients can use the reported interim efficacy and toxicity information, with the support of physicians, to decide which trial to enroll in. We describe potential effects on various operating characteristics, including the study duration, selection bias and power.

Canaloplasty and Trabeculotomy Combined with Phacoemulsification in Open-Angle Glaucoma: Interim Results from the GEMINI Study.

PurposeTo report interim 6-month safety and efficacy outcomes of 360° canaloplasty and 180° trabeculotomy using the OMNI® Surgical System concomitantly with phacoemulsification in patients with open-angle glaucoma (OAG).SettingFifteen multi-subspecialty ophthalmology practices and surgery centers located in 14 states (Alabama, Arizona, Arkansas, Florida, Georgia, Iowa, Kansas, Montana, Nebraska, North Dakota, Oklahoma, Pennsylvania, Texas, and Wisconsin).DesignProspective, multicenter, IRB approved study of patients treated with canaloplasty (360°) and trabeculotomy (180°). Eligible patients had cataract and mild-moderate OAG with intraocular pressure (IOP) ≤33 mmHg on 1 to 4 hypotensive medications.MethodsMedication washout prior to baseline diurnal IOP (Goldmann). Effectiveness outcomes included mean IOP and medications. Safety outcomes included adverse events (AE), best corrected visual acuity (BCVA) and secondary surgical interventions (SSI). Analysis includes descriptive statistics and t-tests evaluating change from baseline.ResultsA total of 137 patients were enrolled and treated. Mean diurnal IOP after washout was 23.8 ± 3.1 mmHg at baseline. At month 6, 78% (104/134) were medication free with IOP of 14.2 mmHg, a mean reduction of 9.0 mmHg (38%). 100% (104/104) had a ≥ 20% reduction in IOP and 86% (89/104) had IOP ≥6 and ≤18 mmHg. The mean number of medications at screening was 1.8 ± 0.9 and 0.6 ± 1.0 at month 6. AE included transient hyphema (4.6%) and IOP elevation ≥10 mmHg (2%). There were no AE for loss of BCVA or recurring hyphema. There were no SSI.ConclusionCanaloplasty followed with trabeculotomy and performed concomitantly with phacoemulsification has favorable intra and perioperative safety, significantly reduces IOP and anti-glaucoma medications through 6 months in eyes with mild-moderate OAG.

Abstract IA07: The QuEST for an effective immunotherapy for prostate cancer

Abstract Background: Immune checkpoint inhibitors have minimal activity in unselected CRPC patients (pts). Combination regimens that generate a tumor-directed immune response (vaccine) and facilitate the resulting anti-tumor immune activity (checkpoint blockade, cytokines) have shown synergy in preclinical models. BNVax is a therapeutic poxviral vaccine targeting brachyury, a transcription factor involved in invasion and metastasis. BA is a bifunctional fusion protein: anti-PD-L1 monoclonal antibody fused to the TGFb-β-RII receptor extracellular domain (a TGF-β trap). N-803 is an IL-15 superagonist complex. Here we report an interim efficacy analysis of the QuEST1 study, aimed to rapidly interrogate safety and efficacy of immunotherapy combinations in CRPC. Methods: Asymptomatic/minimally symptomatic CRPC pts received BNVax + BA (Arm 2.1) or BNVax + BA + N-803 (Arm 2.2). BNVax is given as 2 prime doses followed by boosts. BA 1,200 mg intravenously and N-803 15 µg/kg subcutaneously are given every 2 weeks. Efficacy is defined as objective response by RECIST v1.1 or PSA decrease ≥ 30% sustained for ≥ 21 days. Safety was a secondary endpoint. Results: As of 10/11/20, 26 CRPC pts enrolled and had 1 to 23 months follow up. 1/13 pts (Arm 2.1) had a PSA response sustained for 13 months. 5/12 (41.6%) pts on treatment for at least 12 weeks (Arm 2.2) had sustained PSA responses, including 2 pts who progressed on enzalutamide. Of 3 patients with measurable disease, 2 had confirmed PR by RECIST. Grade 3 TRAEs: 1 pancreatitis (Arm 2.1), 1 secondary adrenal insufficiency (Arm 2.1), 1 tumor hemorrhage (Arm 2.1), 1 hyperglycemia due to new onset diabetes mellitus (Arm 2.2), 1 cystitis (Arm 2.2), 1 Rash with eosinophilia (Arm 2.2). One patient had grade 4 neutropenia that resolved with growth factor support and oral corticosteroids. Conclusions: BVax + BA + N-803 demonstrated a manageable safety profile and preliminary evidence of efficacy in CRPC. Addition of N-803 in Arm 2.2 was associated with more activity in this small sample. Arm 2.2 met the predetermined threshold for efficacy and will expand (n=25). Citation Format: James L. Gulley. The QuEST for an effective immunotherapy for prostate cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr IA07.

Phase II study of modulation of sorafenib (SOR)-induced autophagy using hydroxychloroquine (HCQ) in advanced hepatocellular cancer (HCC): Planned interim efficacy and safety analysis.

305 Background: SOR is the first systemic therapy approved for advanced HCC, but has shown only modest improvements in survival. Resistance to SOR in pre-clinical models has been attributed to autophagy induction. Autophagy inhibition with HCQ enhanced SOR-induced cell death and apoptosis in early pre-clinic and clinical studies. Data from the phase I study of SOR plus HCQ in advanced solid tumors at showed clinical safety and efficacy. Therefore, we conducted a prospective study to evaluate efficacy of SOR and HCQ in advanced HCC patients (pts) (NCT03037437) and report planned interim analysis for our first-line cohort. Methods: Prospective phase II study of SOR 400 mg po BID + HCQ 400 mg daily in pts with advanced HCC (CP A-B8 cirrhosis). Cohort 1: first-line SOR/HCQ. Cohort 2: add HCQ upon progressing on SOR. CP B pts started at 200 mg BID, with dose escalation as tolerated. Cycle = 4 weeks. Primary endpoint: mTTP. Secondary endpoints: mOS, response by RECIST; AEs (NCI-CTCAEv3.0); PD analysis for markers of autophagy and immunity. Pts evaluable for efficacy if completed C1. Planned interim efficacy and safety analysis approved by DSMB is reported here. Results: For cohort 1, n = 19. Median age 63.5 (51-80). 80% Male; 65% Hispanics. ECOG 0-1: 100%. CP B cirrhosis: 32%. Etiology of cirrhosis: HCV 84%, ETOH 26%, NASH 5%. BCLC B 21%, C 70%. AFP > 400: 47%, PVT: 32%, metastases: 64%, post-transplant: 21%. Reason off study: PD (n = 10), toxicity (n = 2), lost to f/u (n = 1), withdrew (n = 1). N = 16 completed C1, n = 2 remain on study. mTTP is 4.2 months (95% CI: 3.7-NA). mOS 13.8 months (95% CI: 13.8-NA). Response Rate (CR+PR): 25%. Best response: CR n = 1 (6%), PR n = 3 (19%), SD n = 7 (44%). 4+ cycles: n = 9 (56%). % alive. Median duration of response 7.6 months (3.67-20). Gr 1/2 AEs as expected from SOR. Gr 3: AST elevated (n = 1), diarrhea (n = 1) due to SOR. Gr 2 rash (n = 1) due to HCQ. No Gr 4/5. Dose reduction: 70% for SOR, 0% for HCQ. PD analysis on the 3 responders show favorable immune profile changes (increase in cytotoxic T cells and decrease T Regs). Conclusions: SOR/HCQ had a better response rate (25%) than historically SOR alone (2%) in pts with advanced HCC, predominantly BCLC C, with CP A and B cirrhosis. While immune checkpoint inhibitors (ICIs) are taking the forefront in advanced HCC, SOR/HCQ may have a role in patients with CP B cirrhosis, transplant or contraindications to ICIs. Further, analysis of predictive markers of response is ongoing. Clinical trial information: NCT03037437.

COVID-19 Vaccine: Updates and Role of Pharmacists

The 2019 novel coronavirus (SARS-COV-2 or 2019-nCoV) and coronavirus disease-2019 (COVID-19) pandemic is a global health crisis. As of December 31, 2020, there are over 83.5 million cases and 1.8 million deaths globally(1) and 2.2 million cases and 25,300 deaths in California.(2) The addition of a vaccine to prevent COVID-19 is an essential addition to the public health and safety toolkit alongside recommendations for physical distancing, hand hygiene, masks and face coverings, testing, tracing, quarantining or isolation, and therapeutics. There are currently two vaccines that have received emergency use authorization (EUA) in the United States to prevent COVID-19: the Pfizer-BioNTech mRNA COVID-19(3) and Moderna mRNA COVID-19 vaccines.(4) In the first 3 weeks since its authorization, the U.S. has distributed over 12.4 million and 2.7 million first doses had been administered.(5)The Pfizer-BioNTech (BNT162b2) vaccine, authorized on December 11, 2020, was reviewed and authorized or recommended by the US Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDC)(6), and the Western States Scientific Safety Review Workgroup(7) for the prevention of COVID-19 in individuals 16 years and older. The Phase 3 trial for the BNT162b2 included 43,548 participants from the US, Argentina, Brazil, and South Africa.(8) BNT162b2 was found to be 95% effective in preventing COVID-19 with similar vaccine efficacy observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. The incidence of serious adverse events was low and the safety profile was characterized by local and systemic reactions. Following two reports of anaphylaxis in the United Kingdom, the CDC identified six cases after 272,001 doses were administered in the U.S. and continues to monitor through its surveillance programs.(9) See Table 1 for summary of vaccine characteristics, inducing information on dosing, storage, preparation, and administration.The Moderna (mRNA-1273) vaccine, authorized on December 18, 2020, was reviewed and authorized or recommended by the FDA, CDC(10), and the Western States Scientific Safety Review Workgroup(11) for the prevention of COVID-19 in individuals 18 years and older. The Phase 3 trial for the mRNA-1273 included 30,420 participants from the US.(12) The interim efficacy analysis of BNT162b2 demonstrated vaccine efficacy of 94.5% in preventing symptomatic COVID-19 with similar vaccine efficacy observed across subgroups defined by age, sex, race, ethnicity, and occupational risk factors. The incidence of serious adverse events was low and the safety profile was characterized by local and systemic reactions. See Table 1 for summary of vaccine characteristics, inducing information on dosing, storage, preparation, and administration.See Table 2 for list of clinical resources for both vaccines, including FDA fact sheets, CDC recommendations, and manufacturer resources.Vaccine distribution and allocation is largely being overseen at the federal level with subsequent delegated responsibility to the state, local, and provider level. Both the CDC(13,14,15) and the California Department of Public Health (CDPH)(16) have established guidelines for the phased distribution of COVID-19 vaccine to prioritized groups. The CDC and CDPH have identified populations for Phase 1A, 1B, and 1C while the remaining phases are still to be determined. See Table 3 for the list of phases and tiers of prioritized and sub-prioritized groups.The current phase and tier of allocation may vary on the local level. Generally, most California counties are currently in Phase 1A, tier 1 or 2.Pharmacists are playing a major role in the implementation and distribution of the COVID-19 vaccine. Pharmacists can order and administer the COVID-19 vaccine and intern pharmacists and pharmacy technicians can administer the COVID-19 vaccine.(17,18,19) Pharmacies can receive vaccine allocation through three methods: participation in the Federal Pharmacy Partnership for Long-Term Care (LTC) Program(20,21), participation in Federal Retail Pharmacy Partnership(22,23), or invitation from the local health department (LHD). For more information about provider enrollment through the local jurisdictions, visit the COVIDReadi Platform(24) and contact your LHD.(25)The current status of each program may vary on the local level. Generally, the federal LTC program has been activated and the federal retail and invitations to pharmacies from LHD have not yet been activated in California.The distribution and allocation of the COVID-19 vaccine are still in its initial stages. Ass vaccine supply increases, the remainder of the plans will be activated and pharmacies, pharmacists, pharmacy technicians, and intern pharmacists will play a crucial role in ensuring quick and equitable access to nearly 40 million Californians across all 58 counties.

COVID-19 vaccines - are we there yet?

SUMMARYThe novel coronavirus SARS-CoV-2, the cause of the COVID-19 pandemic, is a highly infectious human respiratory pathogen to which the global population had no prior immunity. The virus will likely continue to cause significant morbidity until there is a broadly effective vaccineAs of mid-December 2020, more than 200 COVID-19 vaccine candidates are in development and 11 have entered phase III clinical trials globally. All generate immunity to the viral spike glycoproteinThree vaccine candidates have agreements for procurement and use in Australia if efficacy and safety requirements are met – one protein-based vaccine, one vaccine using a simian-derived adenovirus vector and one messenger RNA vaccine. The latter two vaccines have published interim analyses and efficacy results of their phase III trials. The messenger RNA vaccine is being rolled out in the UK, USA and CanadaSignificant uncertainties remain. How well will some of those at highest risk of severe disease (such as older people aged >75 years and those with immunocompromising conditions) be protected by a vaccine, and for how long? Also, to what extent will vaccination protect against infection? This will determine the degree of indirect ‘herd’ protection needed through broad vaccine coverage of younger age groups

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

SummaryBackgroundA safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials.MethodsThis analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674.FindingsBetween April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation.InterpretationChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials.FundingUK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D’Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

Isatuximab Plus Carfilzomib and Dexamethasone Versus Carfilzomib and Dexamethasone in Relapsed Multiple Myeloma Patients with Renal Impairment: Ikema Subgroup Analysis

Isatuximab Plus Carfilzomib and Dexamethasone Versus Carfilzomib and Dexamethasone in Relapsed Multiple Myeloma Patients with Renal Impairment: Ikema Subgroup Analysis

Phase 2 Study of the Combination of Daratumumab, Ixazomib, Pomalidomide, and Dexamethasone As Salvage Therapy in Relapsed/Refractory Multiple Myeloma: Stage I Results

Background: Triplet combination regimens have been widely accepted as the standard of care for the management of multiple myeloma (MM) due to improved outcomes as compared to doublet regimens. The combination of daratumumab, pomalidomide, and dexamethasone (DPd) has previously demonstrated deep and durable responses including high rates of minimal residual disease (MRD) negativity in patients with relapsed/refractory (R/R) MM. Quadruplet regimens may further improve these outcomes. We report preliminary findings from an ongoing phase 2 multi-center trial of the addition of ixazomib to DPd (DIPd) in patients with R/R MM. Methods: We are conducting a prospective, multi-center, open-label, single-arm phase 2 study to determine the efficacy and safety of DIPd as salvage therapy in R/R MM. A Simon's optimal 2-stage design includes a safety run-in period at the beginning of Stage 1 where the first 6 patients are enrolled for toxicity assessment. If ≤1 patient experiences any DLT, the study continues to accrue more Stage 1 patients. Key secondary endpoints include progression-free survival (PFS), overall survival (OS) and MRD-negativity rates. Eligible patients may have received ≥1 and ≤3 prior lines of therapy, have had no prior exposure to daratumumab or ixazomib, are lenalidomide refractory, and may have not progressed on prior pomalidomide. The first six patients were treated in a safety run-in with daratumumab 16mg/kg IV weekly x 8 doses, biweekly x 8 doses, then monthly, pomalidomide 4mg orally daily on days 1-21 of a 28-day cycle, ixazomib 4mg orally daily on days 1,8,15 every 28 days, and dexamethasone 20-40mg weekly. Patients continued therapy until disease progression, intolerability or preference. Dose-limiting toxicities (DLT) were defined as grade 3-4 hematologic adverse events (AE) or any AE that required a dose modification of pomalidomide or ixazomib at the lowest dose levels on a dose de-escalation plan. An interim safety review is being performed after the enrollment and completion of the DLT observation period for the 14 planned patients in stage I. An interim efficacy analysis was also planned after all patients had completed 3 months of therapy. Minimal residual disease assessments are being performed by EuroFlow for patients in VGPR or suspected CR. Pharmacodynamic changes in patients' tumor microenvironments were established by custom panel mass cytometry to include T-cell memory and activated subpopulations, B-cell content, NK-cell subpopulations as well as MDSCs, Tregs and T-exhaustive markers, monocytes and dendritic cells. Results: At the time of this analysis, all 14 patients have enrolled and started treatment as part of stage I of the trial. Patients had a median age of 61 (range 52-65) and median number of 1 prior line of therapy (range 1-3). All patients were refractory to lenalidomide and all were pomalidomide naïve. In the safety run-in, all 6 patients experienced ≥ grade 3 neutropenia, and per DSMB recommendation, the starting doses of pomalidomide and ixazomib were both reduced to 3mg for the subsequent 8 patients in stage 1. Common AEs included neutropenia, thrombocytopenia, and upper respiratory infection. Grade 3-4 AEs were predominantly hematologic, including neutropenia and thrombocytopenia. One patient had a grade 3 infusion-related reaction (IRR) with daratumumab administration. No DLTs have occurred. After median follow up of 4.1 months (range 1-22), all 14 patients were evaluable for efficacy. At the time of data analysis, the overall response rate to date is 85%, and the best responses include: 5 (36%) stringent complete response; 1 (7%) very good partial response; 5 (36%) partial responses; and 3 (21%) patients with stable disease. Six (42%) patients are off study treatment: 3 due to disease progression, 1 to undergo salvage autologous SCT, and 2 due to toxicity related to treatment (IRR and upper respiratory infection). MRD and pharmacodynamic data will be presented at ASH. Conclusion: The quadruplet regimen DIPd in patients with R/R MM is a well-tolerated combination and has shown early safety and promising efficacy in the first 14 patients enrolled to stage 1 of the trial. A pre-planned interim efficacy analysis is ongoing prior to future enrollment in stage 2 at multiple sites within the University of California Hematologic Malignancies Consortium. Disclosures Costello: Celgene: Honoraria, Research Funding; Janssen: Research Funding; Poseida Therapeutics: Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Wieduwilt:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Shire: Research Funding; Macrogeneics: Research Funding; Amgen: Research Funding; Leadiant: Research Funding; Merck: Research Funding; Reata Pharmaceuticals: Current equity holder in publicly-traded company. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding.

Ixazomib Based Regimens in Patients with Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis of Clinical Trials

Introduction: Multiple myeloma (MM) is an incurable malignancy, and clinical trials with newer agents have shown improved patient outcomes. Ixazomib (Ixa) is a proteasome inhibitor and induces apoptosis in cancer cells. It is commonly used with immunomodulators for the treatment of MM. We conducted a systematic review and meta-analysis to assess the efficacy of Ixazomib alone and in combination with other drugs for the treatment of newly diagnosed multiple myeloma (NDMM). Methods: A literature search was performed on PubMed, Cochrane, Embase, Web of Science, and clinicaltrials.gov. We used the following MeSH and Emtree terms; "ixazomib" AND "Multiple Myeloma" from inception till 06/05/2020. We screened 1,558 articles and included 3 randomized clinical trials (RCTs) (N=901) and 12 non-randomized clinical trials (NRCT) (N=632). We excluded case reports, case series, preclinical trials, review articles, observational studies, meta-analysis, and ongoing clinical trials that did not report interim efficacy outcomes. We used the R programming language (version 4.0.2) to conduct a meta-analysis. Results: In 15 clinical trials (N=1533), Ixa based regimens were used in patients with age range of 39-92 years. (Table 1) In 3 clinical trials (N=170), Ixa with Lenalidomide (Len) and dexamethasone (Dex) yielded a pooled overall response rate (ORR) of 90% (95% CI=0.82-0.94, I2=32%), a pooled complete response (CR) of 23% (95% CI=0.16-0.32, I2=24%) and a pooled ≥very good partial response and better (≥VGPR) of 39% (95% CI=0.24-0.57, I2 =76%) when used as induction therapy for NDMM patients. As consolidation therapy (N=88), pooled ORR was 91% (95% CI=0.79-0.97, I2=0), pooled CR was 36% (95% CI=0.27-0.47, I2=0) and pooled ≥VGPR was 70% (95% CI=0.53-0.84, I2=60%). (Fig 1-3) In 5 clinical trials (N=233), Ixa + cyclophosphamide (Cyc) + Dex yielded a pooled ORR, CR, and ≥VGPR of 76% (95% CI=0.70-0.81, I2 =0), 12% (95% CI=0.07-0.20, I2=44%), and 25% (95% CI=0.14-0.39, I2=78%), respectively. (Fig 1-3) The lower dose of Cyc 300mg/m2 had similar efficacy as 400mg/m2 with better safety profile in elderly patients. In a RCT (N=175) of Ixa with multiple combinations, Ixa + Dex yielded ORR 55% (95% CI=0.40-0.69), CR 14% (95% CI=0.07-0.28) and ≥VGPR 24% (95% CI=0.13-0.39). Ixa+ thalidomide (Thal) + Dex fostered ORR 82% (95% CI=0.70-0.90), CR 15% (95% CI=0.08-0.26), and VGPR 43% (95% CI=0.31-0.55). Ixa + bendamustine + Dex yielded ORR of 73% (95% CI=0.41-0.91), CR 9% (95% CI=0.01-0.44), and ≥VGPR 27% (95% CI=0.09-0.59). In one clinical trial (N=53), Ixa + melphalan (Mel) + prednisone (Pred) combination yielded pooled ORR, CR, and ≥VGPR of 66% (95% CI=0.52-0.77), 13% (95% CI=0.06-0.25), and 30% (95% CI=0.19-0.44), respectively. In a phase II trial (N=40), Ixa + daratumumab (Dara) + Len + Dex yielded an ORR, CR and ≥VGPR of 97% (95% CI=0.84-1), 15% (95% CI=0.07-0.28), and 35% (95% CI=0.22-0.51) respectively. (Fig 1-3) In a phase III RCT by Dimopholous et al. (N=656), Ixa maintenance therapy after stem cell transplant (SCT) yielded an ORR, CR, and ≥VGPR of 76%, 15%, and 54%, respectively. They observed 28% reduction in the risk of progression or death with Ixa vs. placebo, median progression free survival (mPFS) was 26.5 months (95% CI 23·7-33·8) vs 21·3 months [18·0-24·7]; hazard ratio 0·72, 95% CI 0·58-0·89; p=0·0023). Second malignancies were 3% in both ixazomib and placebo group. 27% of the patients in ixazomib group and 20% patients in placebo group experienced serious adverse events. In a clinical trial on unfit and frail patients (N=46) treated with Ixa + daratumumab (Dara) + Dex, pooled ORR and ≥VGPR were 83% (95% CI=0.69-0.91, I2=0), and 33% (95% CI=0.21-0.47, I2=0), respectively. (Fig 1-3) In the phase II trial, ORR, CR, and VGPR with ixazomib and lenalidomide were 64%, 26%, and 53%, respectively. Conclusion: Ixa in combination with Len, Dex, Cyc, Dara, Mel, Pred is effective in the treatment of NDMM patients. In early phase trials, Ixa with Dara, Len, and Dexa showed the highest overall response as induction therapy. Ixazomib maintainance therapy prolongs PFS after SCT as compared to placebo and represents an additional option for post SCT maintainace therapy in NDMM patiens. The safety profile of Ixa was acceptable with most commonly encountered adverse events were hematological including neutropenia and thrombocytopenia. Additional multicenter, double-blind, randomized clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Interim Analysis of ZUMA-12: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) as First-Line Therapy in Patients (Pts) With High-Risk Large B Cell Lymphoma (LBCL)

Interim Analysis of ZUMA-12: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) as First-Line Therapy in Patients (Pts) With High-Risk Large B Cell Lymphoma (LBCL)

A Phase 2 Trial of Ibrutinib and Nivolumab in Patients with Relapsed or Refractory Classical Hodgkin's Lymphoma

A Phase 2 Trial of Ibrutinib and Nivolumab in Patients with Relapsed or Refractory Classical Hodgkin's Lymphoma

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.

Long-term, open-label extension study of the efficacy and safety of epicutaneous immunotherapy for peanut allergy in children: PEOPLE 3-year results

The PEPITES (Peanut EPIT Efficacy and Safety) trial, a 12-month randomized controlled study of children with peanut allergy and 4 to 11 years old, previously reported the safety and efficacy of epicutaneous immunotherapy (EPIT) for peanut allergy (250 μg, daily epicutaneous peanut protein; DBV712 250 μg). We sought to assess interim safety and efficacy of an additional 2 years of EPIT from the ongoing (5-year treatment) PEOPLE (PEPITES Open-Label Extension) study. Subjects who completed PEPITES were offered enrollment in PEOPLE. Following an additional 2 years of daily DBV712 250 μg, subjects who had received DBV712 250 μg in PEPITES underwent month-36 double-blind, placebo-controlled food challenge with an optional month-38 sustained unresponsiveness assessment. Of 213 eligible subjects who had received DBV712 250 μg in PEPITES, 198 (93%) entered PEOPLE, of whom 141 (71%) had assessable double-blind, placebo-controlled food challenge at month 36. At month 36, 51.8% of subjects (73 of 141) reached an eliciting dose of ≥1000 mg, compared with 40.4% (57 of 141) at month 12; 75.9% (107 of 141) demonstrated increased eliciting dose compared with baseline; and 13.5% (19 of 141) tolerated the full double-blind, placebo-controlled food challenge of 5444 mg. Median cumulative reactive dose increased from 144 to 944 mg. Eighteen subjects underwent an optional sustained unresponsiveness assessment; 14 of those (77.8%) maintained an eliciting dose of ≥1000 mg at month 38. Local patch-site skin reactions were common but decreased over time. There was no treatment-related epinephrine use in years 2 or 3. Compliance was high (96.9%), and withdrawals due to treatment-related adverse events were low (1%). These results demonstrate that daily EPIT treatment for peanut allergy beyond 1 year leads to continued response from a well-tolerated, simple-to-use regimen.

Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: a prospective, placebo-controlled randomized trial (EVAPORATE): interim results.

Though statin therapy is known to slow coronary atherosclerosis progression and reduce cardiovascular (CV) events, significant CV risk still remains. In the REDUCE-IT study, icosapent ethyl (IPE) added to statin therapy reduced initial CV events by 25% and total CV events by 30%, but its effects on coronary atherosclerosis progression have not yet been fully investigated. Therefore, this study is to determine whether IPE 4 g/day will result in a greater change from baseline in plaque volume measured by serial multidetector computed tomography than placebo in statin-treated patients. EVAPORATE is a randomized, double-blind, placebo-controlled trial. Patients had to have coronary atherosclerosis by coronary computed tomographic angiography (CCTA) (≥1 angiographic stenoses with ≥20% narrowing), on stable statin therapy with low-density lipoprotein cholesterol levels 40-115 mg/dL, and persistently high triglyceride levels (135-499 mg/dL). Patients underwent an interim scan at 9 months and were followed for an additional 9 months with CCTA at 0, 9, and 18 months. Here, we present the protocol-specified interim efficacy results. A total of 80 patients were enrolled, with 67 completing the 9-month visit and having interpretable CCTA at baseline and at 9 months (age = 57 ± 6 years, male = 36, 63%). At the 9-month interim analysis, there was no significant change in low attenuation plaque (LAP) between active and placebo groups (74% vs. 94%, P = 0.469). However, there was slowing of total non-calcified plaque (sum of LAP, fibrofatty, and fibrous plaque) (35% vs. 43%, P = 0.010), total plaque (non-calcified + calcified plaque) (15% vs. 26%, P = 0.0004), fibrous plaque (17% vs. 40%, P = 0.011), and calcified plaque (-1% vs. 9%, P = 0.001), after adjustment by baseline plaque, age, sex, diabetes, baseline triglyceride levels, and statin use. EVAPORATE is the first study using CCTA to evaluate the effects of IPE as an adjunct to statin therapy on atherosclerotic plaque characteristics in a high-risk CV population with persistently high triglyceride levels. It provides important mechanistic data in regards to the reduction in CV events in the REDUCE-IT clinical trial. NCT029226027.

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.

Treatment stratification in B-cell PTLD after solid organ transplantation (SOT) by international prognostic index (IPI) and response to rituximab: Interim results from the PTLD-2 trial.

8045 Background: The PTLD-1 trials have established risk-stratified sequential treatment of B-cell PTLD. After rituximab induction, patients (pts) in complete remission (25 %) received rituximab consolidation, while all others received R-CHOP. The PTLD-2 trial tests modified risk-stratification including clinical risk factors. These are the results of the 2nd scheduled interim analysis (40/60 planned pts). Methods: The prospective, multicenter phase II PTLD-2 trial (NCT02042391) enrols treatment-naïve adult SOT recipients with CD20-positive PTLD. Key exclusion criteria are CNS involvement, ECOG > 2, pregnancy, and severe organ dysfunction or severe, active infection. Treatment consists of rituximab (1400 mg SC; first application 375 mg/m2 IV) on days 1, 8, 15 and 22. After restaging, pts in CR as well as those in PR with ≤ 2 IPI risk factors at diagnosis (low-risk group) continue with four three-weekly courses of rituximab. Most other pts (high-risk group) receive 4 cycles of R-CHOP-21, while thoracic SOT recipients who progress under rituximab (very-high-risk group) receive six cycles of alternating R-CHOP-21 and R-DHAOx. The primary endpoint (event-free survival in the low-risk group) is not analyzed here. Secondary endpoints presented here are response and overall response (ORR) by computed tomography, overall survival (OS), time to progression (TTP) and treatment-related mortality (TRM) overall and by risk group. Results: 40 pts were recruited at 12 centers (2015 – 2019). 21/40 were kidney, 11 lung, 4 liver, 3 heart, and 1 liver/kidney transplant recipients. Median age was 54 years. 38/40 PTLD were monomorphic and 15/40 EBV-associated. 38 pts were evaluated for response at interim staging: 13 were allocated to the low-risk, 17 to the high-risk and 8 to the very-high-risk group. ORR was 28/30 (93 %, CR: 16/30 [53 %]). With a median follow-up of 1.9 years, the 1-year/3-year Kaplan-Meier (KM) estimates of TTP and OS in the intention-to-treat population (40 pts) were 85 %/80 % and 70 %/70 %, respectively. In the low-risk group, the 2-year KM estimate of OS was 100 %. The frequency of infections (all grades) was 50 %, and TRM occurred in 3/40 pts (8 %). Conclusions: One third of enrolled pts were treated in the low-risk group and the recruitment goal for evaluation of the primary endpoint will likely be reached. Interim efficacy and toxicity data with rituximab SC and modified risk-stratification are encouraging despite the inclusion of 35 % thoracic SOT recipients. Clinical trial information: NCT02042391 .

Safety and preliminary clinical activity of the MET antibody mixture, Sym015 in advanced non-small cell lung cancer (NSCLC) patients with MET amplification/exon 14 deletion (METAmp/Ex14∆).

9510 Background: Sym015, a mixture of 2 humanized antibodies, triggers MET degradation by a unique mechanism with superior specificity compared to tyrosine kinase inhibitors (TKIs). The Sym015-01 phase (P)1a trial met, the primary objective of identifying the recommended P2 dose (RP2D) as 18 mg/kg on cycle 1 day 1 followed by 12 mg/kg Q2W. The P2a was expanded to enroll METAmp/Ex14∆ NSCLC patients (pts) based on preliminary efficacy findings. Here we present interim safety (n = 45) and efficacy (NSCLC cohort, n = 20) results from P2a. Methods: The expansion NSCLC Cohort enrolled pts with METEx14Δ (n = 12) or METAmp (n = 8 defined as > 5 MET copies by NGS or MET/CEP7 ratio > 2.2 updated to ≥3.0 by in situ hybridization; including 1 with METAmp+Ex14Δ). Tumor MET status was confirmed centrally and longitudinal ctDNA was analyzed by Guardant360. Results: By January 2020, 45 pts (median age 61.7 years) have been treated in P2a. Median duration of exposure (DoE) was 3.8 months (m) (n = 45; range 0.4+ to 22 m). Treatment emergent adverse events occurred in 93%, treatment related AEs (TRAE) in 42.2% and TRAE ≥G3 in 13.3% pts. No pts discontinued or died due to TRAE. The most common TRAE in ≥10% pts were fatigue (13.3%) and peripheral edema (11.1%). Of 20 NSCLC pts, 5 had confirmed PR (ORR 25%; 2/8 METAmp and 3/12 METEx14Δ); 11 had SD (DCR 80%; 6/8 METAmp and 5/12 METEx14Δ); 2 had PD (2/12 METEx14Δ); and 2 were not evaluable. 10 NSCLC pts were MET TKI naive (7 METAmp and 3 METEx14Δ) and had 50% ORR and 100% DCR (5 PR and 5 SD; DoR range 1 to 18.3 m; DoE 1.5 to 22 m); 10 NSCLC pts were prior MET TKI treated (9 METEx14Δ and 1 METAmp+Ex14Δ) with DCR 60%, (6 SD; DoE 0.4-9.6 m). Median PFS was 5.5 m overall (95% CI 3.5-9.7 m). Median PFS for MET TKI naive and MET TKI pre-treated NSCLC pts was 6.5 m (95% CI 3.4-21.9 m) and 5.4 m (95% CI 1.2-9.7 m) respectively. Median OS was not reached for overall or for prior MET TKI subgroups. 89% METEx14∆ tumor tissue to blood concordance (8/9 NSCLC pts) was observed. Conclusions: Sym015 was well-tolerated at the RP2D with a response rate similar to MET TKI in MET-treatment naïve METAmp/Ex14Δ NSCLC and seems to delay disease progression in MET TKI pretreated NSCLC pts. Combination with MET TKI to delay or prevent resistance should be further explored. Clinical trial information: NCT02648724 .

A phase II study of BP1001 (liposomal Grb2 antisense oligonucleotide) in patients with hematologic malignancies.

TPS7561 Background: The growth factor receptor bound protein-2 (Grb2) is vital to oncogene signaling and tumor progression. BP1001 is a liposome-incorporated Grb2 antisense oligonucleotide that inhibits Grb2 expression. Grb2 inhibition suppresses cancer growth and survival. A Phase I/Ib single center study in patients with refractory/relapsed leukemias demonstrated the safety of BP1001 up to 90 mg/m2 dose and the efficacy of BP1001 in combination with low dose cytarabine (LDAC) in refractory/relapsed acute myeloid leukemia (AML) patients (Ohanian, Lancet Haematol 2018). Based on pharmacokinetic (PK) considerations, the recommended Phase II dose was 60 mg/m2. A phase II study was initiated to explore the clinical impact of BP1001 in combination with LDAC in untreated AML patients. Interim safety and efficacy of BP1001 + LDAC in untreated AML patients was presented at the 2018 Annual ASH Meeting. BP1001 was safely administered to 25 patients with untreated AML, who were considered unfit for standard chemotherapy. Efficacy data compared favorably to what has been reported with available options for unfit patients largely with secondary AML or adverse-risk AML. Since the Interim Data presentation, the study was amended to investigate BP1001 + decitabine combination and include myelodysplastic syndrome (MDS) patients. This is because BP1001 enhanced decitabine anti-leukemic effects in preclinical studies. Methods: This is a multi-center, open-label study with 2 parallel cohorts of BP1001 + decitabine treatment in untreated AML/high risk MDS patients and refractory/relapsed AML/high risk MDS patients who are considered by the investigator unsuitable for or refused intensive chemotherapy. BP1001 is given intravenously (IV) at 60 mg/m2 twice weekly. Decitabine is given 20 mg/m2 IV daily for 5 consecutive days. Each cycle is 28 days. Each cohort can enroll 19 patients, with a decision to stop or proceed to 54 patients. The primary objective of this study is to assess whether BP1001 + decitabine provides higher complete remission rates than decitabine alone (by historical comparison) in AML/high risk MDS patients. The secondary objectives of this study are to assess: Safety of BP1001 + decitabine; partial remissions and blast count reductions; overall survival, time to response and duration of response; minimal residual disease status in patients who achieve complete remission; and plasma PK profile of BP1001. The exploratory objective of this study is to evaluate the association of treatment response with cytogenetic and molecular characteristics. Clinical trial information: NCT02781883 .

Efficacy, safety, and immune priming effect of tazemetostat in patients with epithelioid sarcoma.

11564 Background: Epithelioid sarcoma (ES) is a rare, aggressive soft tissue sarcoma characterized by loss of inhibitor of integrase 1 (INI1), allowing enhancer of zeste homologue 2 (EZH2) to repress cell differentiation and promote tumorigenesis. Tazemetostat (TAZ) is a selective inhibitor of EZH2 approved by the FDA for treatment of patients (pts) aged ≥16 years with metastatic or locally advanced ES ineligible for complete resection. Methods: This open-label, multicenter, multi-cohort phase 2 study (NCT02601950) evaluated safety and efficacy of TAZ in pts with INI1-negative tumors. ES pts were enrolled in Cohorts 5 and 6; pts in Cohort 6 underwent mandatory pre-dose (at screening) and post-dose biopsies (at Day 1 of cycle 2). Herein, we report the interim efficacy and safety data from Cohort 6. Results: As of July 31 2019, 44 pts were enrolled into Cohort 6 and treated with TAZ 800 mg BID. The objective response rate (ORR) was 11.4%; 4 pts (9.1%) had a partial response and 1 pt (2.3%) had a complete response (Table). Another 17 pts (38.6%) had stable disease (SD). 18 pts had progressive disease; 13 of these pts remained on study beyond progression. Progression-free survival (PFS) and overall survival (OS) at 56 weeks were 19.4% and 59.4%, respectively. In a pooled posthoc analysis of 106 ES pts from Cohorts 5 (n = 62), and 6, ORR was 13.2%. Grade 3–4 adverse events (AEs) were reported in 16 pts (36.4%), most commonly anemia (6.8%; n = 3) and tumor pain (6.8%; n = 3). 3 pts (6.8%) experienced grade 3–4 treatment-related AEs. One pt discontinued study drug and there were no treatment-emergent dose reductions or treatment-related deaths. These safety data from Cohort 6 are consistent with previously reported data from Cohort 5. 19 paired biopsies were included for translational endpoint analyses. Preliminary RNA seq and pathway analyses are currently ongoing and updated data, including additional biomarker data will be presented. Conclusions: Consistent with previously reported data from the completed Cohort 5, TAZ demonstrated clinically meaningful, durable, single agent activity in ES pts. Efficacy data from Cohort 6 continue to mature with 8 patients still on treatment. TAZ was well tolerated with a low incidence of treatment related AEs. Clinical trial information: NCT02601950 . [Table: see text]