Days Of Study Treatment Research Articles

A Novel JAK1 Inhibitor SHR0302 for Treatment of Chronic Graft-Verse-Host Disease: A Phase I Clinical Trial

Background: Chronic graft-versus-host disease (cGVHD) is a frequent and potentially life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Standard steroid first-line treatment could not satisfy therapeutic need due to its limited efficacy. SHR0302 is a highly selective Janus kinase (JAK) 1 inhibitor, which could alleviate symptoms and improve the survival of cGVHD mice in our preclinical study. Herein, we reported updated safety and efficacy results of SHR0302 plus prednisone as first-line treatment for patients with naïve-treatment moderate or severe cGVHD. Methods: This was a Phase I open-label study. Patients who were aged 18-70, and confirmedly diagnosed with first-episode moderate/severe cGVHD requiring systemic immunosuppressive therapy after allo-HSCT were included in the study. cGVHD was defined according to national institutes of health (NIH) criteria. A 3+3 design including five dose levels (1mg/2mg/4mg/6mg/8mg once a day) was implemented to define the optimal dose of SHR0302. Meanwhile, prednisone was concurrently administrated with a dose of 1mg/kg/d and then gradually tapered after two weeks. The primary endpoint was safety, and the secondary endpoints were overall response rate (ORR) at day 28 and week 24. Dose-limiting toxicities (DLTs) were defined as grade 4 hematologic toxicity or grade 3 non-hematologic toxicity associated with SHR0302 which occurred in the first 28 days of study treatment. Results: From April 2020 to July 2022, 18 patients were enrolled in the trial. Till May 2023, the median follow-up was 17.3 months (range, 1.8-31.7). The median age of the patients was 47 years (range, 31-64). 13 (72.2%) patients had severe cGVHD, and the other 5 had moderate cGVHD. Almost all patients had more than one organ involved, and the most commonly involved organs were skin (66.7%), and mouth (50.0%). In contrast, lung (5.6%) and genital tract (5.6%) involvements were uncommon. Median duration of SHR0302 treatment was 6.3 months (range, 1.5-23.2). Overall, all (100%) patients experienced adverse events (AEs) related to SHR0302 and/or prednisone, and grade 3 or 4 AEs were observed in 7 (38.89%) patients. The most common SHR0302 treatment-related adverse events (TRAEs) included hypercholesterolemia (61.11%, n=11), hypertriglyceridemia (44.44%, n=8), platelet count decreased (38.89%, n=7), and anemia (16.67%, n=3). There were no serious AEs (SAEs) related with SHR0302, and no patient experienced SHR0302 dose reduction / discontinuation or death due to AEs. Only one patient developed DLT (grade≥3 hypercholesterolemia) in the highest dose-level group who had preexisting hypercholesterolemia. The maximum tolerated dose (MTD) was not reached. The ORR and complete remission (CR) rates were 94.44% and 27.77% at week 4, and were 82.35% and 64.71% at week 24, respectively. Among 18 evaluable patients, only 1 patient treated at dose level 1 showed no response at week 4. The event-free survival (EFS) at 24 months was 72.20% (95% CI, 51.40%-93.00%). Prednisone was discontinued in 8 (44.4%) patients at 24 weeks and all immunosuppressants, including SHR0302, were stopped in 4 (22.2%) patients with CR before the 24-week assessment. Conclusions: In summary, SHR0302 in combination with prednisone had a good safety and could achieve a high response for naïve-treatment cGVHD, which suggests that SHR0302 combination might become an optimal choice for naïve-treatment cGVHD.

Phase I Study of SHR0302, a Selective JAK1 Inhibitor, Combined with Prednisone for First-Line Treatment of Chronic Graft-Versus-Host Disease after Allo-HSCT

Background: Chronic graft-versus-host-disease (cGVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) that affects various organs leading to a reduced quality of life, with an incidence of 40% to 70%. The standard first-line therapy for cGVHD is prednisone ± a calcineurin inhibitor, but most patients respond inadequately and prolonged corticosteroid use could cause a variety of side effects. SHR0302 is a Janus kinase (JAK) 1 selective inhibitor which has demonstrated efficacy in preclinical models of GVHD. Herein, we reported the safety and efficacy of SHR0302 plus prednisone as first-line treatment for newly diagnosed cGVHD after allo-SCT. Methods: This was a phase I open-label study. Patients who were aged 18-70, and confirmedly diagnosed with first-episode moderate/severe cGVHD requiring systemic immunosuppressive therapy after allo-HSCT were included in the study. cGVHD was defined according to national institutes of health (NIH) criteria. Patients received SHR0302 plus prednisone daily. For each patient, prednisone was administered at an initial dose of 1 mg/kg/d for two weeks, then tapered according to the response of the patient. A 3 + 3 design was implemented for dose finding of SHR0302 at doses of 1mg/d, 2mg/d, 4mg/d, 6mg/d, and 8mg/d. The primary endpoints were safety and tolerability of the combination therapy of SHR0302 and prednisone assessed by NCI-CTCAE v5.0. And the secondary endpoints included the overall response rate (ORR) at week 4 of treatment and the recommended Phase II dose (RP2D). Dose-limiting toxicities (DLTs) were defined as grade 4 hematologic toxicity or grade 3 non-hematologic toxicity associated with SHR0302 which occurred in the first 28 days of study treatment. Results: As of July 30, 2022, 18 patients were enrolled in the study with 3 patients each in the dose level 1-4, and 6 patients in the dose level 5, with a median follow-up of 27 (4-91) weeks. The median age of the patients was 47 (31-64) years, of which 5 patients (27.8%) had moderate cGVHD, and 13 patients (72.2%) had severe cGVHD. The median cGVHD NIH score was 4 (3-7). The primarily affected organs were skin (61.1%) followed by liver (55.6%), and mouth (50.0%). As of data cutoff, only one patient (5.6%) discontinued therapy due to inadequate response. No DLTs were seen in the first 4 dose levels. Only one DLT, grade ≥3 hypercholesterolemia, was observed among 6 patients who received 8mg/d of SHR0302. The patient who experienced DLT had preexisting hypercholesterolemia. A maximum tolerated dose was not reached. 17 patients (94.4%) experienced adverse events (AEs) related to SHR0302, and 4 patients (22.2%) experienced grade ≥3 AEs related to SHR0302. Hypercholesterolemia (61.1%), hypertriglyceridemia (44.4%), and platelet count decreased (33.3%) were the most common SHR0302 treatment-related AEs. No SHR0302 treatment-related serious adverse events were reported. The ORR at week 4 after the first SHR0302 administration was 94.4%, including 4 patients (22.2%) achieving complete response, and 13 patients (72.2%) achieving partial response. Among 18 evaluable patients, only 1 patient treated at dose level 1 showed no response at week 4. Conclusions: In summary, SHR0302 plus prednisone demonstrated encouraging efficacy with manageable toxicity in patients with steroid-naive cGVHD. Based on the results from the dose-escalation, 6-mg and 8-mg dose were selected for the dose-expansion.

Association of anticoagulant use with clinical outcomes from crizotinib in ALK- and ROS1-rearranged advanced non-small cell lung cancers: A retrospective analysis of PROFILE 1001.

ROS1- and ALK-rearranged advanced NSCLCs are associated with increased thromboembolic risk. We hypothesized that a prothrombotic phenotype offers an evolutionary advantage to subsets of these cancers. The impact of this phenotype could alter outcomes from targeted therapy. In a retrospective analysis of ROS1- and ALK-rearranged NSCLCs treated with crizotinib in a phase 1 trial, we compared progression-free survival (PFS) and objective response rate (ORR) based on the history of anticoagulation use (a possible surrogate of thromboembolism) at baseline (within 90 days before study enrollment) or within 90 days of study treatment. Twelve out of 53 (22.6%) ROS1- and 39 out of 153 (25.5%) ALK-rearranged NSCLCs received anticoagulation before or during the trial. Most ROS1 and ALK patients on anticoagulation received low-molecular-weight heparin (75% and 64.1%, respectively). In the ROS1-rearranged group, the median PFS (95% CI) values were 5.1 (4.4-14.4) and 29.0 (16.5-48.8) months, and the ORR values were 41.7% (95% CI: 15.2 to 72.3) and 80.5% (95% CI: 65.1 to 91.2) among those with and without anticoagulation treatment, respectively. In the ALK-rearranged group, the median PFS (95% CI) was 7.1 (5.4-7.7) and 12.0 (9.4-18.3) months, and the ORR was 41% (95% CI: 25.6 to 57.9) and 74.3% (95% CI: 65.3 to 82.1) among those with and without anticoagulation, respectively. Anticoagulation (as a potential surrogate of a prothrombotic subset) in ROS1- and ALK-rearranged NSCLCs may be associated with a lower PFS and ORR to crizotinib. gov: NCT00585195.

Trial in Progress: Phase 1b/2 Open-Label Study of Lisaftoclax (APG-2575) Monotherapy or in Combination with Lenalidomide/Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma (R/R MM)

Background: Multiple myeloma (MM) is a hematologic malignancy (HM) caused by proliferation of plasma cells in bone and extramedullary sites, with frequent symptoms including hypercalcemia, renal impairment, anemia, and bone lesions. High-dose therapy and autologous hematopoietic stem cell transplantation have been treatment mainstays. More recent introduction of the proteasome inhibitor bortezomib and other agents offers promise. Bortezomib can prevent breakdown of proapoptotic factors by malignant cells, triggering apoptosis, and lenalidomide can stimulate programmed death of malignant cells both directly and indirectly. Despite these and other treatment advances, relapse is virtually inevitable, and MM remains incurable. Lisaftoclax is a novel, potent, selective BCL-2 inhibitor that is under clinical development for HMs. In chronic lymphocytic leukemia, lisaftoclax requires a short ramp-up to help mitigate tumor lysis syndrome and is associated with a potentially lower incidence of neutropenia (Ailawadhi et al. J Clin Oncol 2021;39: abstract 7502).Methods: This open-label, multicenter study is assessing the safety, tolerability, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of lisaftoclax alone or combined with lenalidomide and dexamethasone. The primary aim is to determine dose-limiting toxicity (DLT), maximum tolerated dose, and recommended phase 2 dose (RP2D) of lisaftoclax when administered alone (Arm A) or in tandem with lenalidomide and dexamethasone (Rd; Arm B), each in 28-day cycles. The trial is enrolling adults who have (1) R/R MM with measurable sites and received ≥ 1 prior therapy; (2) ECOG performance status of 0 to 2; and (3) adequate hematologic, hepatic, renal, and coagulation function. Excluded were individuals with (1) lenalidomide intolerance; (2) recent monoclonal antibody (≤ 8 weeks before study onset), CAR-T (≤ 3 months), and other MM treatments (≤ 2 weeks); (3) history of allogenic stem cell transplantation or BCL-2 treatment; (4) other systemic conditions, including POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes), amyloidosis, Fahrenheit macroglobulinemia, non-secretory MM, and plasma cell leukemia; (5) known CNS involvement; and (6) serious and potentially uncontrolled medical disorders, including cardiovascular disease, chronic inflammatory disorders, and active infection warranting systemic treatment (e.g. HIV, hepatitis). Lisaftoclax is administered as monotherapy orally once daily at 3 dose levels (400, 600, and 800 mg) without ramp-up, every 28 days as a cycle in a “3+3” dose escalation in Arm A and similarly in Arm B, which also includes Rd: lenalidomide 25 mg (10 mg for patients with baseline creatinine clearance ≥ 30 mL/min but < 60 mL/min) orally on Days 1 through 21 of each 28-day cycle and dexamethasone 40 mg (or 20 mg for patients aged > 75) orally on Days 1, 8, 15, and 22 of a repeated 28-day cycle. The primary outcome measure is DLT, defined by the rate of some predefined treatment-related adverse events (measured by NCI CTCAE v5) within the first 28 days of study treatment. As of July 19, 2021, three of fifty-seven patients have been enrolled. Internal study identifier APG2575MC101. Clinicaltrial.gov identifier: NCT04674514. DisclosuresChen: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Li: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Men: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Yang: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding. Zhai: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding; Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding.

Evaluation of pharmacodynamic (PD) and biologic activity in a preoperative window-of-opportunity (WOO) study of giredestrant (GDC-9545) in postmenopausal patients (pts) with estrogen receptor-positive, HER2-negative (ER+/HER2–) operable breast cancer (BC).

577 Background: Modulation of ER activity and/or estrogen synthesis is the mainstay therapeutic strategy in ER+ BC treatment. Giredestrant is a highly potent, nonsteroidal oral selective ER degrader (SERD) that achieves robust ER occupancy and is effective regardless of ESR1 mutation status. The first short-term preoperative WOO study (NCT03916744) of giredestrant in ER+/HER2– operable BC was designed for dose selection, while providing an early readout of PD as measured by traditional immunohistochemistry (IHC) and transcriptional profiling by assessing treatment effects in paired tumor tissue pre/posttreatment. We present an interim analysis. Methods: Pts were assigned to 14 days’ preoperative treatment with 10, 30, or 100 mg PO giredestrant QD. Pts had newly diagnosed, stage I–III operable, ER+/HER2– untreated BC ≥1.5 cm in diameter (by ultrasound). Modulation of ER signaling and cell proliferation were assessed using paired formalin-fixed paraffin-embedded tumor specimens collected before and after ̃14 days of study treatment. ER, progesterone receptor (PR), and Ki67 protein levels were analyzed by IHC. Change from baseline in tumor cell proliferation by Ki67 was the primary endpoint. Gene expression analysis was performed using the Illumina TruSeq RNA Access method. Results: From Jul 26, 2019 to Oct 15, 2020, 46/75 biomarker-evaluable pts were enrolled across three dose cohorts (10 mg: n = 15; 30 mg: n = 18; 100 mg: n = 13). Pt demographics and tumor characteristics were similar across cohorts. Baseline PAM50 analysis classified tumors as Luminal A (77%) or B (23%). Giredestrant treatment resulted in robust and indistinguishable PD and biologic activity at all doses. Geometric mean posttreatment proportional reduction of Ki67 was 79% (95% CI: 69–89; 10 mg: 80%; 30 mg: 76%; 100 mg: 80%), and 51% of tumors exhibited complete cell cycle arrest, defined as Ki67 ≤2.7%. Mean posttreatment proportional reductions of ER and PR H-scores were 71% (95% CI: 67–75) and 60% (95% CI: 51–70), respectively. An analysis of a predefined, experimentally derived set of 38 ER target genes (the ‘ER activity signature’), was completed for 42 paired tumor specimens. Forty-one of 42 pts (98%) showed a posttreatment reduction in ER activity with a mean proportional decrease of 79% (95% CI: 70–88). A wide range of baseline ER activity was observed with no correlation to baseline ER or PR H-score, or Ki67. There were no discontinuations due to adverse events (AEs). A single grade 3 serious AE was reported in each cohort (all assessed as unrelated to giredestrant). No grade 4 or 5 AEs were reported. Conclusions: Giredestrant was well tolerated in the preoperative setting in ER+/HER2– operable BC, and PDs were consistent with the 30 mg dose achieving maximal ER inhibition. Clinical trial information: NCT03916744.

A Phase II Study to Assess the Sustained Response Off Treatment in Patients with ITP Receiving Eltrombopag, Who Had a Previous Insufficient Response to Corticosteroids (TAPER): A Recruitment Update

A Phase II Study to Assess the Sustained Response Off Treatment in Patients with ITP Receiving Eltrombopag, Who Had a Previous Insufficient Response to Corticosteroids (TAPER): A Recruitment Update

A Phase 1/2 Study to Evaluate the Safety and Efficacy of Ponatinib with Chemotherapy in Pediatric Patients with Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL)

Introduction: Ph+ ALL accounts for 3-5% of pediatric ALL and is associated with improved outcomes when tyrosine kinase inhibitors (TKIs) are added to chemotherapy, with 5-year event-free survival (EFS) and overall survival (OS) of 58-60% and 70-86%, respectively. Ponatinib is a potent third-generation TKI pan-BCR-ABL1 inhibitor that is active against BCR-ABL1 and all identified single resistance mutations, including the gatekeeper alteration, T315I, which confers resistance to other TKIs. Ponatinib has marketing approval in more than 50 countries, which includes the United States and European Union, for adults with chronic-/accelerated-/blast-phase chronic myeloid leukemia or Ph+ ALL that are resistant/intolerant to other TKIs or are T315I+. Ponatinib may also overcome drug resistance in pediatric patients with relapsed or resistant Ph+ ALL. This study will assess the pharmacokinetics, safety, and efficacy of ponatinib in pediatric patients. Methods: This Phase 1/2, single-arm, open-label, multicenter study (NCT04501614) will enroll approximately 18 patients in Phase 1 and 68 patients in Phase 2, including those enrolled in Phase 1 at the recommended Phase 2 dose (RP2D). Patients (aged ≥1 year to ≤21 years) with Ph+ ALL, Ph+ mixed phenotype acute leukemia, or Ph-like ALL (US only) with ABL class lesions will be enrolled. Enrolled patients must have either relapsed or are resistant or intolerant to ≥1 prior therapy with a BCR-ABL1-targeted TKI or have a BCR-ABL1 T315I mutation. Patients &amp;gt;16 years must have a Karnofsky performance status ≥50%; patients ≤16 years must have a Lansky Play Scale ≥50%. During Phase 1, prior to availability of an age-appropriate formulation (AAF), patients must weigh ≥30 kg and be able to swallow tablets. The Phase 1 study will establish the RP2D of ponatinib in combination with the chemotherapy backbone using the adult tablet formulation in patients able to swallow tablets. Patients will receive fixed doses of ponatinib based on body weight ranges. The initially selected doses are expected to achieve systemic exposures that approximately match adult exposures after a 30-mg dose. Dose selection for the AAF will be in a separate cohort and informed by the results of a relative bioavailability study in healthy adult volunteers. A rolling 6 design will be used for both cohorts; additional cohorts may be enrolled at lower or higher doses based on the emerging data. In both Phase 1 and Phase 2, patients will receive two 35-day blocks of therapy (reinduction and consolidation). Each block includes 29 days of study treatment consisting of daily ponatinib and a modified United Kingdom ALL R3 chemotherapy backbone regimen, followed by a rest period of at least 6 days with daily ponatinib only. Disease assessment will occur at the end of each block. Patients will undergo an end-of-treatment visit 25 to 30 days after the last dose of study treatment in the consolidation block, or earlier if the patient is proceeding to alternate therapy or optional ponatinib continuation therapy. For the Phase 1 study, the primary endpoint is the RP2D of ponatinib (tablet and AAF) in combination with chemotherapy. Secondary endpoints are complete response (CR) rate at the end of the reinduction block and characterization of BCR-ABL1 domain mutations prior to and following ponatinib treatment. For the Phase 2 study, the primary endpoint is the CR rate at the end of the reinduction block. Secondary endpoints will be summarized descriptively, and include the proportion of patients in continued CR or who achieve CR at the end of consolidation, the proportion with minimal residual disease-negative status &amp;lt;0.01% at the end of each block, and the proportion who relapsed or progressed, and time-to-event estimates including EFS, progression-free survival, and OS. The study will include approximately 70 study sites in approximately 16 countries. Disclosures Matloub: Takeda: Current Employment. Gore:Amgen, Novartis, Roche: Membership on an entity's Board of Directors or advisory committees. Loh:Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Institutional Research Funding. Pui:Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Hanley:Takeda: Current Employment. Lu:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Leonard:Takeda: Current Employment. Granier:Incyte: Current Employment. Silverman:Servier: Other: advisory board; Syndax: Other: advisory board; Takeda: Other: advisory board. OffLabel Disclosure: Ponatinib has marketing approval in the United States and European Union for adult patients with chronic-/accelerated-/blast-phase chronic myeloid leukemia or Ph+ ALL that are resistant/intolerant to other TKIs or are T315I+. This trials-in-progress abstract describes a study in pediatric patients.

Oncology News / Literature Review / July-December 2019

1. Overall survival (OS) results of a phase III randomized trial of standard-of-care therapy with or without enzalutamide for metastatic hormone-sensitive prostate cancer (mHSPC): ENZAMET (ANZUP 1304), an ANZUP-led international cooperative group trial. Testosterone suppression (TS) is the backbone of treatment for metastatic hormone-sensitive prostate cancer (mHSPC). Overall survival is improved by the addition of early docetaxel (DOC) or abiraterone to TS. The randomised phase 3 ENZAMET trial assessed the effects of enzalutamide (ENZA), a potent androgen receptor (AR) inhibitor, versus a nonsteroidal anti-androgen (NSAA: bicalutamide, nilutamide, or flutamide) in addition to SOC in mHSPC. Men (1125) with mHSPC were randomly assigned 1:1 to receive TS plus either ENZA (160 mg daily, by mouth, until clinical disease progression or prohibitive toxicity) or NSAA (conventional NSAA, by mouth until clinical disease progression or prohibitive toxicity). All participants were to receive standard background therapy with a LHRHA or surgical castration, as per standard of care. The choice of the LHRHA or surgical castration was at the discretion of the treating clinician. Randomization was stratified by: volume of disease (high vs low, according to CHAARTED); planned early DOC; planned anti-resorptive therapy, comorbidity score (ACE-27), and study site. The primary endpoint was overall survival. Subgroup analyses to assess possible modulation of the treatment effect were specified a priori and included planned early docetaxel (yes vs no) and volume of disease (high vs low). After a median follow-up of 33 months. Overall survival was prolonged by ENZA. At 3 years, 36% NSAA vs 64% ENZA were still on their assigned study treatment. Serious adverse events (regardless of attribution) within 30 days of study treatment occurred in 42% ENZA vs 34% NSAA, commensurate with the different durations of study treatment. ENZA significantly improved OS when added to SOC in mHSPC while the benefits appeared lower in those planned to receive early DOC.

Antiplatelet effects of citalopram in patients with ischaemic stroke: A randomized, placebo-controlled, double-blind study

We evaluated the effect of SSRI treatment on platelet aggregation in patients with ischaemic stroke and included patients from the randomized double-blind controlled study of citalopram in acute ischaemic stroke (TALOS). Patients on clopidogrel were included 6 months after acute ischaemic stroke. Platelet parameters, including P2Y12 platelet reactivity using the VerifyNow System, were measured at the last day of study treatment and repeated after a 14-day wash-out period. A total of 60 patients were included (n = 32 randomized to citalopram). Platelet aggregation levels did not differ between the citalopram group (mean 116, 95% CI 89 to 143) and the placebo group (mean 136, 95% CI 109 to 163) (On-treatment, p = 0.14). Similarly, there was no significant change in platelet aggregation in the citalopram group from on-treatment to post-treatment (mean difference 2.0; 95% CI −18 to 14). Platelet count, size and turnover were not affected by SSRI treatment. In conclusion, SSRI therapy did not lead to statistically significant inhibition of platelet aggregation in ischaemic stroke patients treated with clopidogrel.

Overall survival (OS) results of a phase III randomized trial of standard-of-care therapy with or without enzalutamide for metastatic hormone-sensitive prostate cancer (mHSPC): ENZAMET (ANZUP 1304), an ANZUP-led international cooperative group trial.

LBA2 Background: Testosterone suppression (TS) is the backbone of treatment for mHSPC. OS is improved by the addition of early docetaxel (DOC) or abiraterone to TS. ENZAMET assessed the effects of enzalutamide (ENZA), a potent androgen receptor (AR) inhibitor, versus a nonsteroidal anti-androgen (NSAA: bicalutamide, nilutamide, or flutamide) in addition to SOC (TS with or without DOC) in mHSPC. Methods: Men with mHSPC were randomly assigned 1:1 to receive TS plus either ENZA or NSAA. Randomization was stratified by: volume of disease (high vs low, according to CHAARTED); planned early DOC; planned anti-resorptive therapy, comorbidity score (ACE-27), and study site. The primary endpoint was overall survival. Accrual of 1100 men provided 80% power to detect a 25% reduction in the hazard of death (HR 0.75) with up to 4 interim analyses (IA), the first planned to occur after 235 deaths (50% of total information with a critical p-value threshold &lt;0.0031 by the Lan-DeMets alpha-spending approach with O’Brien-Fleming type shape). Subgroup analyses to assess possible modulation of the treatment effect were specified a priori and included planned early docetaxel (yes vs no) and volume of disease (high vs low). Results: We randomly assigned 1125 patients from 31MAR14 to 24MAR17. The treatment groups were well balanced for all important baseline factors. Criteria for early reporting were met at the first IA (28FEB2019) after a median follow-up of 33 months. Overall survival was prolonged by ENZA (see below). At 3 years, 36% NSAA vs 64% ENZA were still on their assigned study treatment. Serious adverse events (regardless of attribution) within 30 days of study treatment occurred in 42% ENZA vs 34% NSAA, commensurate with the different durations of study treatment. Conclusions: ENZA significantly improved OS when added to SOC in mHSPC. The benefits appeared lower in those planned to receive early DOC. Results of analyses with updated follow-up triggered by this IA will be presented. Clinical trial information: NCT02446405. [Table: see text]

Phase II study of GM-CSF secreting allogeneic pancreatic cancer vaccine (GVAX) with PD-1 blockade antibody and stereotactic body radiation therapy (SBRT) for locally advanced pancreas cancer (LAPC).

TPS4154 Background: Optimal treatment strategy beyond systemic chemotherapy for LAPC remains undefined. SBRT improves local control, but distant metastasis free survival (DMFS) is only 7.7 months. Checkpoint inhibitors are poor monotherapies in pancreas cancer, but may be primed by SBRT via absocopal effect and GVAX, which induces novel lymphoid infiltrates and increased effector T-cells in tumor microenvironment. Methods: This is a single-arm, single-institution, open-label study for pts with LAPC. Eligibility: surgically unresectable LAPC, predominant adenocarcinoma at diagnosis, with ECOG 0-1, who remain metastases free after 4-8 cycles of FOLFIRINOX or gemcitabine/abraxane based-chemotherapy. Exclusion: those off chemotherapy &gt; 49 days prior to study treatment, prior immunotherapy, active immunosuppressive use, autoimmune disease, HIV, HBV, or HCV infection, and non-oncology vaccines within 28 days of study treatment. Pts receive cyclophosphamide (200mg/m2 IV) and pembrolizumab (200mg IV) on day 1, followed by GVAX (six intradermal injections) on day 2 every three weeks for two cycles, with cycle 2 initiating concurrently with five days of SBRT. If non-metastatic, pts undergo surgical resection, nano-knife, or EUS guided biopsy (if non-surgical). Pts receive two further cycles of chemotherapy, and if remain free of metastases, receive q3 week cyclophosphamide, pembrolizumab, and GVAX for six cycles, then are monitored for two years. The primary endpoint is DMFS. Secondary endpoints include overall survival, surgical resectability, pathologic response, quality of life, and toxicity. Exploratory objectives of peripheral antigen specific t-cell responses, and changes in immune parameters of tumor microenvironment. 11 of 54 pts have been enrolled since July 2016. Clinical trial information: NCT02648282.

Consolidation anti-CD22 fractionated radioimmunotherapy with 90Y-epratuzumab tetraxetan following R-CHOP in elderly patients with diffuse large B-cell lymphoma: a prospective, single group, phase 2 trial

Radioimmunotherapy represents a potential option as consolidation after chemoimmunotherapy in patients with diffuse large B-cell lymphoma who are not candidates for transplantation. We aimed to assess activity and toxicity of fractionated radioimmunotherapy using anti-CD22 90Y-epratuzumab tetraxetan as consolidation after front-line induction chemoimmunotherapy in untreated elderly patients with diffuse large B-cell lymphoma. We did a prospective, single-group, phase 2 trial at 28 hospitals in France, with patients recruited from 17 hospitals. Eligible patients were aged 60-80 years with bulky stage 2-3 or stage 3-4 CD20-positive diffuse large B-cell lymphoma, previously untreated, and not eligible for transplantation. Patients received six cycles of R-CHOP (rituximab [375 mg/m2], cyclophosphamide [750 mg/m2], doxorubicin [50 mg/m2], and vincristine [1·4 mg/m2, up to 2 mg] all on day 1, and prednisone [40 mg/m2] daily for 5 days), administered every 14 days. 6-8 weeks after R-CHOP, responders received two doses of 15 mCi/m2 (555 MBq/m2) 90Y-epratuzumab tetraxetan administered 1 week apart. The primary endpoint was 2 year event-free survival in all registered eligible patients who received at least 1 day of study treatment; the safety analysis was done in the same population. This trial is registered with ClinicalTrials.gov, number NCT00906841. Between Oct 22, 2008, and Dec 16, 2010, we recruited 75 patients, of whom four (5%) were excluded after central pathology review; hence, 71 (95%) patients were included in the analysis. All patients started induction treatment; 57 (80%) received radioimmunotherapy. With a median follow-up of 37 months (IQR 30-44), the estimated 2 year event-free survival was 75% (95% CI 63-84). Radioimmunotherapy toxicity consisted of grade 3-4 thrombocytopenia in 48 (84%) of 57 patients and neutropenia in 45 (79%) of 57 patients. One patient developed myelodysplastic syndrome 28 months after receiving radioimmunotherapy and one patient developed acute myeloid leukaemia 5 months after receiving radioimmunotherapy. Fractionated radioimmunotherapy with 90Y-epratuzumab tetraxetan might be appropriate for response consolidation after induction chemotherapy in older patients with advanced diffuse large B-cell lymphoma, but further comparative studies are needed. Immunomedics, Amgen, Canceropôle Grand Ouest, the GOELAMS/LYSA group and the French National Agency for Research (Investissements d'Avenir).

High-dose chemotherapy with autologous haemopoietic stem cell transplantation for newly diagnosed primary CNS lymphoma: a prospective, single-arm, phase 2 trial

High-dose methotrexate-based chemotherapy is standard for primary CNS lymphoma, but most patients relapse. High-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) is supposed to overcome the blood-brain barrier and eliminate residual disease in the CNS. We aimed to investigate the safety and efficacy of HCT-ASCT in patients with newly diagnosed primary CNS lymphoma. In this prospective, single-arm, phase 2 trial, we recruited patients aged 18-65 years with newly diagnosed primary CNS lymphoma and immunocompetence, with no limitation on clinical performance status, from 15 hospitals in Germany. Patients received five courses of intravenous rituximab 375 mg/m(2) (7 days before first high-dose methotrexate course and then every 10 days) and four courses of intravenous high-dose methotrexate 8000 mg/m(2) (every 10 days) and then two courses of intravenous rituximab 375 mg/m(2) (day 1), cytarabine 3 g/m(2) (days 2 and 3), and thiotepa 40 mg/m(2) (day 3). 3 weeks after the last course, patients commenced intravenous HCT-ASCT (rituximab 375 mg/m(2) [day 1], carmustine 400 mg/m(2) [day 2], thiotepa 2 × 5 mg/kg [days 3 and 4], and infusion of stem cells [day 7]), irrespective of response status after induction. We restricted radiotherapy to patients without complete response after HCT-ASCT. The primary endpoint was complete response at day 30 after HCT-ASCT in all registered eligible patients who received at least 1 day of study treatment. This trial is registered at ClinicalTrials.gov, number NCT00647049. Between Jan 18, 2007, and May 23, 2011, we recruited 81 patients, of whom two (2%) were excluded, therefore we included 79 (98%) patients in the analysis. All patients started induction treatment; 73 (92%) commenced HCT-ASCT. 61 (77·2% [95% CI 66·1-86·6]) patients achieved a complete response. During induction treatment, the most common grade 3 toxicity was anaemia (37 [47%]) and the most common grade 4 toxicity was thrombocytopenia (50 [63%]). During HCT-ASCT, the most common grade 3 toxicity was fever (50 [68%] of 73) and the most common grade 4 toxicity was leucopenia (68 [93%] of 73). We recorded four (5%) treatment-related deaths (three [4%] during induction and one [1%] 4 weeks after HCT-ASCT). HCT-ASCT with thiotepa and carmustine is an effective treatment option in young patients with newly diagnosed primary CNS lymphoma, but further comparative studies are needed. University Hospital Freiburg and Amgen.

Effect of Aspirin Pretreatment or Slow Dose Titration on Flushing and Gastrointestinal Events in Healthy Volunteers Receiving Delayed-release Dimethyl Fumarate

PurposeIn Phase III trials, delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated significant efficacy and an acceptable safety profile in patients with relapsing-remitting multiple sclerosis. The purpose of the present study was to examine 2 potential mitigation strategies for flushing and gastrointestinal (GI) events associated with DMF treatment: aspirin (ASA) 325 mg pretreatment for flushing, and slow dose titration of DMF for flushing and GI events. MethodsThe 8-week study included 173 healthy volunteers randomized to 4 groups; 172 underwent dosing. The placebo group (n = 44) received placebo ASA 30 minutes before placebo DMF (weeks 1−4), then placebo DMF alone (weeks 5−8). The DMF without ASA group (n = 43) and the DMF with ASA group (n = 43) received placebo ASA or ASA, respectively, 30 minutes before DMF (weeks 1−4), then DMF alone (weeks 5−8); in both groups, DMF was dosed at 120 mg BID (week 1) and 240 mg BID (weeks 2−8). The slow dose titration DMF group (n = 42) received DMF 120 mg once daily (week 1), 120 mg BID (week 2), 240 mg in the morning/120 mg in the evening (week 3), and 240 mg BID (weeks 4−8). Subjects recorded information about flushing and GI-related events by using an eDiary and numerical rating scales. FindingsFlushing and GI-related events were reported in all groups and were mostly rated as mild or moderate in severity. Flushing events were generally ~1 hour in duration and, for most subjects with flushing, initially occurred the first day of study treatment. The duration of GI-related events and time to first GI-related event varied by event type. ASA reduced the incidence, severity, and number of flushing events without affecting duration or time to first flushing event, and had no adverse effect on GI-related events. Dose titration of DMF had no significant effect on flushing or GI events. No subjects discontinued the study due to flushing events. One subject (2%) in the placebo group, 3 subjects (7%) in the DMF without ASA group, 6 subjects (14%) in the DMF with ASA group, and 2 subjects (5%) in the slow dose titration DMF group discontinued treatment because of GI events. ImplicationsASA pretreatment may mitigate flushing associated with DMF, with no adverse effect on GI events. Dose titration of DMF did not have a significant effect on flushing or GI events and is being evaluated further in ongoing clinical trials. ClinicalTrials.gov identifier: NCT01568112.

Abstract S2-03: Preoperative window of opportunity study of the PI3K inhibitor pictilisib (GDC-0941) plus anastrozole vs anastrozole alone in patients with ER+, HER2-negative operable breast cancer (OPPORTUNE study)

Abstract Background: Preclinical and clinical data support a key role for the PI3K pathway in resistance to endocrine therapy in patients with ER+ breast cancer and suggest that combining PI3K inhibitors with endocrine therapy may overcome resistance. Short-term preoperative window of opportunity (WOO) studies are a validated strategy for novel treatments to provide proof-of-concept and define the most appropriate patient population by directly assessing treatment effects in tumour tissue before and after treatment. This is the first WOO study with the PI3K inhibitor pictilisib (GDC-0941) in combination with anastrozole (ANA). Methods: 73 postmenopausal patients (pts) have been randomized (2:1 in favour of the combination) to receive 2-week preoperative treatment with ANA plus pictilisib (n=50, "ANA+PIC" arm) or ANA alone (n=23, "ANA" arm). Pts had newly diagnosed, operable, ER+, HER2-negative breast cancer of ≥1 cm size. Pts receiving HRT were excluded. Treatment effects and correlative studies were assessed using FFPE and frozen tumour biopsies taken before and after 14 days of study treatment. The primary endpoint was inhibition of tumour-cell proliferation, as measured by change in Ki67 expression, determined centrally by 2 investigators. Secondary endpoints include induction of apoptosis (Caspase3) and safety. Comprehensive biomarkers analyses include targeted NGS of a comprehensive cancer panel of &amp;gt;400 genes, copy number analyses, and pre- and post-treatment reverse-phase protein arrays (RPPA) and RNA profiling. Results: Baseline (BL) disease characteristics were similar between both study arms. PAM50 analysis showed that 53% and 47% of tumors were Luminal (Lum) A and B, respectively. 65% of tumors had &amp;gt;14% Ki67-positive cells. Observed treatment-emergent AEs were consistent with those previously described for single-agent pictilisib and anastrozole. Mean post-treatment percentage reduction of Ki67 was 84% (95% CI, 75%-89%) for ANA+PIC and 72% (54%-87%) for ANA. Ki67-response (≥50% drop in % of Ki67+ cells) was 86% for ANA+PIC and 60% for ANA. By using the definition that pts with a natural logarithm of %Ki67+ cells of ≤1 or 1-2 have a day 15 anti-proliferative response, 93% [ln(ki67): &amp;lt;1, 46%; 1-2, 46%] of ANA+PIC were responders compared with 60% [&amp;lt;1, 47%; 1-2, 13%] of ANA-treated pts (p = 0.01). Preplanned subgroup analyses showed a significant interaction of response to ANA+PIC with molecular subtype and Ki67 levels. Patients with LumB tumors or high BL Ki67 (&amp;gt;14%) had a higher Ki67 response with ANA+PIC compared to ANA (LumB, 83% vs 38%; Ki67&amp;gt;14%, 94% vs 55%), whereas Ki67 response was similar for both treatments for LumA tumors (ANA, 75%; ANA+PIC, 73%) or tumors with low BL Ki67. Mean post-treatment % reduction of Ki67 in LumB tumors was 87% (95% CI, 49%-96%) for ANA+PIC and 56% (16%-77%) for ANA (p=0.03). Additional data on apoptosis and comprehensive pre- and post-treatment biomarkers analyses will be presented. Conclusions: This first report of a preoperative WOO study evaluating a PI3K inhibitor in early breast cancer demonstrated addition of pictilisib to ANA was associated with increased anti-proliferative response over single-agent ANA. Citation Format: Peter Schmid, Sarah E Pinder, Duncan Wheatley, Jane Macaskill, Charles Zammit, Jennifer Hu, Robert Price, Nigel Bundred, Sirwan Hadad, Alice Shia, Louise Lim, Shah-Jalal Sarker, Patrycja Gazinska, Natalie Woodman, Darren Korbie, Matt Trau, Paul Mainwaring, Peter Parker, Arnie Purushotham, Alastair M Thompson. Preoperative window of opportunity study of the PI3K inhibitor pictilisib (GDC-0941) plus anastrozole vs anastrozole alone in patients with ER+, HER2-negative operable breast cancer (OPPORTUNE study) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S2-03.

Paramedic Initiated Lisinopril For Acute Stroke Treatment (PIL-FAST): results from the pilot randomised controlled trial

BackgroundHigh blood pressure (BP) during acute stroke is associated with poorer stroke outcome. Trials of treatments to lower BP have not resulted in improved outcome, but this may be because...

Efficacy and Safety of Piroxicam Patch versus Piroxicam Cream in Patients with Lumbar Osteoarthritis

In order to assess the efficacy and safety of a new patch containing 14 mg of piroxicam (CAS 36322-90-4) 1%, applied once daily, in comparison with a reference marketed formulation, piroxicam 1% cream applied three times a day, placebo patch applied once daily, a randomized, placebo-controlled, parallel-group clinical trial was carried out by general practitioners in patients with lumbar osteoarthritis aged between 18 and 75 years. Pain during daily activities scored on a 100 mm visual analogue scale was the primary outcome measure. Other secondary outcome measures were pain on isometric contraction, on full passive motion, and on pressure, and functional disability. Statistical analysis was performed on the differences between the three groups in the intention-to-treat population (ITT). One hundred and eighty patients were enrolled. The available ITT population comprised 179 patients. The compliance was very good. Decrease in pain score during daily activities after the eight days of study treatment (at the final visit, Vf) was 42.2%, 41.7% and 25.8% in the piroxicam patch, piroxicam cream and placebo groups, respectively. The difference between the pain scores in two active treatments arms was not statistically significant at the Vf whereas the differences between the pain scores of two active treatment arms vs the placebo arm were statistically significant validating the study design. All efficacy measures improved during the study, for both the active treatment groups, and the results for the secondary efficacy variables were generally consistent with those concerning the main efficacy criterion. The difference between the two active treatments in pain during daily activities were statistically significant at the final visit; in fact the 95% CI of the difference between the mean of responder rate of the piroxicam patch and piroxicam cream was -18.3%, +24.4% indicating a trend of superiority of the piroxicam patch versus the cream (per-protocol analysis). The data obtained during the intermediate visit (V2, day 4) allow us to assess that the piroxicam patch was on average better than the piroxicam cream in terms of fast pain reduction (change from baseline: - 29.1% for piroxicam patch in comparison to -24.6% for piroxicam cream). Moreover the piroxicam patch proved to be on average more effective than the piroxicam cream in terms of secondary efficacy endpoints. Safety was considered satisfactory in all groups. The piroxicam patch is effective in the treatment of lumbar osteoarthritis and has demonstrated to be well tolerated and it improves patients compliance. The piroxicam patch offers a comparable alternative to the marketed piroxicam cream for the treatment of lumbar osteoarthritis with the advantage of a better compliance with the once a day application of the patch compared to three daily applications for the piroxicam cream.

Score Correlates With C. difficile Outcomes

VANCOUVER, B.C. – A simple scoring of five bedside assessments when Clostridium difficile infection is first diagnosed correlates significantly with cure rate. “The higher the score, the lower the cure rate,” said Mark Miller, MD, head of the division of infectious diseases and chief of the department of microbiology at SMBD–Jewish General Hospital, McGill University, Montreal, who presented the findings at the Annual Meeting of The Infectious Diseases Society of America. The five parameters are age, temperature, leukocytosis, albumin, and systemic concomitant antibiotic use, ATLAS for short. The first four are rated on a 0-2 scale; 2 is added to the score if the patient is on systemic antibiotics, 0 if not. ATLAS scores range from 0 to 10. The score also correlates with recurrence, but the correlation is not statistically significant. Dr. Miller said there is a need to be able to categorize patients by C. difficile infection (CDI) severity to determine who should be treated aggressively, assign and assess outcomes in clinical studies, and communicate with other medical workers. “If someone calls up and says ‘I have a case of moderate CDI,’ it's pretty much left up to the imagination about what they are talking about” at present, he said. Although much work has been done previously to create a prognostic system for CDI, proposed systems have not been adequately validated, Dr. Miller said. However, “if you look at all these publications, it's all the same risk factors,” he added. So Dr. Miller and his colleagues combined them. “What we came up with was a simple combination of the bedside risk factors that are easy to collect and, we feel, should be most associated with cure and recurrence.” C. difficile strain type was omitted because it's not usually known at the time of diagnosis; baseline serum creatinine isn't either, so its elevation above baseline also was excluded. ATLAS was tested using patient data from a large North American trial comparing fidaxomicin to vancomycin for CDI. The ATLAS scores of 516 patients were calculated at their time of diagnosis and matched against their cure rates following 10 days of study treatment. There was “an excellent correlation with cure rate,” Dr. Miller said. (R2 0.88, P value less than .001). Patients with an ATLAS score of 0 had a 98% cure rate; the rate dropped incrementally with higher scores. ATLAS scores of 7 corresponded to a 55% cure rate. Dr. Miller and his colleagues then checked the 450 subjects cured after treatment to see who had gotten another C. difficile infection. “With recurrence, the ATLAS score didn't fair quite so well,” he said. Recurrence rates climbed with higher scores; 11% of patients with a 0 score had a recurrence, 43% with a score of 6. But the correlation was weak (R2, 0.32) and insignificant (P, .14). A subgroup analysis found that 229 patients assigned to the vancomycin arm threw the recurrence results off (R2, 0.02, P, .762). ATLAS scores predicted recurrence better in 221 fidaxomicin subjects (R2, 0.70, P, .009). Recurrence rates in the vancomycin arm were much higher, not neatly distributed along a curve, which might have thrown off the results, Dr. Miller said. Perhaps, there may also “be some additional refinement of the systemic antibiotics score that would improve” ATLAS's correlation with recurrence, he said. A second study presented in Vancouver showed significant correlation between ATLAS scores and 30-day CDI mortality in 308 adults aged 60 years or older. “ATLAS score appears to … predict severity in CDI in our patient population,” according to the abstract, of which Dr. Miller was a coauthor. Dr. Miller disclosed that he is a scientific adviser and grant investigator to several pharmaceutical companies, including Merck & Co., Novartis Pharmaceutical, and Optimer Pharmaceuticals, makers of fidaxomicin. M. Alexander Otto is a freelance writer based in Tacoma, Wash.

Dynamic contrast-enhanced magnetic resonance imaging biomarkers predict survival and response in hepatocellular carcinoma patients treated with sorafenib and metronomic tegafur/uracil

Sorafenib plus metronomic tegafur/uracil therapy can induce tumor stabilization in advanced hepatocellular carcinoma (HCC) patients. This study evaluated the correlation of vascular response measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and the clinical outcome. DCE-MRI was performed in advanced HCC patients treated with sorafenib (800 mg/d) plus tegafur/uracil (250 mg/m(2)/d based on tegafur) at baseline and after 14 days of treatment. An operator-defined region of interest was placed in the most strongly enhanced area of the tumor to measure the pharmacokinetic parameter K(trans). Changes in K(trans) after treatment were correlated with the best tumor response and survival. Thirty-one patients were evaluable. There were one partial response (PR), 18 stable disease (SD), and 12 progressive disease (PD) according to the Response Evaluation Criteria in Solid Tumors (RECIST). Baseline K(trans) was higher in patients with PR or SD (median 1215.2 × 10(-3)/min, range 582.5-4555.3 × 10(-3)/min) than patients with PD (median 702.0 × 10(-3)/min, range 375.2-1938.0 × 10(-3)/min, p = 0.008). After 14 days of study treatment, the median K(trans) change was -47.1% (range -87.0 to -18.0%) in patients with PR or SD, and 9.6% (range -44.8 to +81%) in those with PD (p<0.001). A vascular response, defined by a 40% or greater decrease in K(trans) after 14 days of study treatment, correlated with longer progression-free survival (median 29.1 vs. 8.7 weeks, p = 0.033) and overall survival (median 53.0 vs. 14.9 weeks, p = 0.016). Percentage of K(trans) change after treatment is an independent predictor of tumor response, progression-free survival, and overall survival. K(trans) measured by DCE-MRI correlated well with tumor response and survival in HCC patients who received sorafenib plus metronomic tegafur/uracil therapy.

Efficacy, Safety and Tolerability of E5501 (AKR501) In a 6-Month Extension Study In Subjects with Chronic Immune Thrombocytopenia (ITP).

Efficacy, Safety and Tolerability of E5501 (AKR501) In a 6-Month Extension Study In Subjects with Chronic Immune Thrombocytopenia (ITP).