A phase 3b study of venetoclax and azacitidine or decitabine in an outpatient setting in patients with acute myeloid leukemia.

Venetoclax, a highly selective BCL-2 inhibitor, combined with hypomethylating agents (HMAs) azacitidine or decitabine, is approved for the treatment of newly diagnosed acute myeloid leukemia (ND AML) in patients who are ineligible to receive intensive chemotherapy. Previous clinical studies initiated venetoclax plus HMA in an inpatient setting owing to concerns of tumor lysis syndrome (TLS). This study (NCT03941964) evaluated the efficacy and safety of venetoclax plus HMA in a United States community-based outpatient setting in patients with ND AML (N = 60) who were treatment naïve for AML, ineligible to receive intensive chemotherapy, had no evidence of spontaneous TLS at screening, and were deemed as appropriate candidates for outpatient initiation of venetoclax plus HMA by the investigator. Patients received venetoclax in combination with azacitidine (75 mg/m2) or decitabine (20 mg/m2) for up to 6 cycles during the study. With a median time on study of 18.3 weeks, the best response rate of composite complete remission was 66.7%, and the overall post-baseline red blood cell (RBC) and platelet transfusion independence rate was 55.0%, consistent with results of studies in which treatment was initiated in an inpatient setting. Key adverse events included nausea, anemia, thrombocytopenia, neutropenia, and white blood cell count decrease of any grade (≥50% of patients). The observed safety profile was generally consistent with that of venetoclax plus HMA observed in inpatient AML studies. With close monitoring, 2 cases of TLS were identified, appropriately managed, and the patients were able to continue study treatment. CLINICAL TRIALS REGISTRATION: This study is registered at ClinicalTrials.gov. The registration identification number is NCT03941964.

Dose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib.

Samuraciclib is a selective oral CDK7-inhibitor. A multi-modular, open-label Phase I study to evaluate safety and tolerability of samuraciclib in patients with advanced malignancies was designed (ClinicalTrials.gov: NCT03363893). Here we report results from dose escalation and 2 expansion cohorts: Module 1A dose escalation with paired biopsy cohort in advanced solid tumor patients, Module 1B-1 triple negative breast cancer (TNBC) monotherapy expansion, and Module 2A fulvestrant combination in HR+/HER2- breast cancer patients post-CDK4/6-inhibitor. Core study primary endpoints are safety and tolerability, and secondary endpoints are pharmacokinetics (PK), pharmacodynamic (PD) activity, and anti-tumor activity. Common adverse events are low grade nausea, vomiting, and diarrhea. Maximum tolerated dose is 360 mg once daily. PK demonstrates dose proportionality (120 mg-480 mg), a half-life of approximately 75 hours, and no fulvestrant interaction. In dose escalation, one partial response (PR) is identified with disease control rate of 53% (19/36) and reduction of phosphorylated RNA polymerase II, a substrate of CDK7, in circulating lymphocytes and tumor tissue. In TNBC expansion, one PR (duration 337 days) and clinical benefit rate at 24 weeks (CBR) of 20.0% (4/20) is achieved. In combination with fulvestrant, 3 patients achieve PR with CBR 36.0% (9/25); in patients without detectable TP53-mutation CBR is 47.4% (9/19). In this study, samuraciclib exhibits tolerable safety and PK is supportive of once-daily oral administration. Clinical activity in TNBC and HR+/HER2-breast cancer post-CDK4/6-inhibitor settings warrants further evaluation.

Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial.

Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2-20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1-69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7-13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05-0.87). A total of 56.2% (95% CI 41.1-70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).

Daratumumab, cyclophosphamide, bortezomib, and dexamethasone for multiple myeloma: final results of the LYRA study.

In the primary analysis of LYRA, daratumumab + cyclophosphamide/bortezomib/dexamethasone (DARA + CyBorD) was effective and well tolerated in newly diagnosed multiple myeloma (NDMM) and relapsed multiple myeloma (RMM). We report the final analysis of LYRA (median months of follow-up: NDMM, 35.7; RMM, 35.3) after all patients completed study therapy, were followed for 36 months, or discontinued. Patients received DARA + CyBorD induction, autologous stem cell transplant (if eligible), and 12 months of daratumumab maintenance. Eighty-seven NDMM patients enrolled, 39 underwent transplant, and 63 completed maintenance. Rates of complete response or better were 48.7% and 29.8% for NDMM transplant and NDMM non-transplant patients, respectively, and 36-month progression-free survival rates were 69.3% and 72.6%. Grade 3/4 treatment-emergent adverse events occurred in 61.6% of NDMM patients. Efficacy and safety data are also reported for the smaller RMM cohort (n = 14). DARA + CyBorD followed by daratumumab maintenance was well tolerated and achieved deep, durable responses in NDMM and RMM.

A phase 1b study evaluating the safety and preliminary efficacy of berzosertib in combination with gemcitabine in patients with advanced non-small cell lung cancer.

OBJECTIVES: Berzosertib (formerly M6620, VX-970) is an intravenous, highly potent and selective, first-in-class ataxia telangiectasia and Rad3-related (ATR) protein kinase inhibitor. We assessed the safety, tolerability, preliminary efficacy, and pharmacokinetics (PK) of berzosertib plus gemcitabine in an expansion cohort of patients with advanced non-small cell lung cancer (NSCLC). The association of efficacy with TP53 status and other tumor markers was also explored. MATERIALS AND METHODS: Adult patients with advanced histologically confirmed NSCLC received berzosertib 210 mg/m2 (days 2 and 9) and gemcitabine 1000 mg/m2 (days 1 and 8) at the recommended phase 2 dose established in the dose escalation part of the study. RESULTS: Thirty-eight patients received at least one dose of study treatment. The most common treatment-emergent adverse events were fatigue (55.3%), anemia (52.6%), and nausea (39.5%). Gemcitabine had no apparent effect on the PK of berzosertib. The objective response rate (ORR) was 10.5% (4/38, 90% confidence interval [CI]: 3.7-22.5%). In the exploratory analysis, the ORR was 30.0% (3/10, 90% CI: 9.0-61.0%) in patients with high loss of heterozygosity (LOH) and 11.0% (1/9, 90% CI: 1.0-43.0%) in patients with low LOH. The ORR was 33.0% (2/6, 90% CI: 6.0-73.0%) in patients with high tumor mutational burden (TMB), 12.5% (2/16, 90% CI: 2.0-34.0%) in patients with intermediate TMB, and 0% (0/3, 90% CI: 0.0-53.6%) in patients with low TMB. CONCLUSIONS: Berzosertib plus gemcitabine was well tolerated in patients with advanced, pre-treated NSCLC. Based on the observed clinical efficacy, future clinical trials should involve genomically selected patients.

Daratumumab, bortezomib, cyclophosphamide and dexamethasone in newly diagnosed and relapsed multiple myeloma: LYRA study.

This United States community study evaluated the combination of daratumumab, bortezomib, cyclophosphamide and dexamethasone (D-VCd) in newly diagnosed multiple myeloma (NDMM) and relapsed multiple myeloma (RMM). Patients received 4-8 induction cycles of bortezomib 1·5 mg/m2 , cyclophosphamide 300 mg/m2 and dexamethasone 40 mg weekly. Intravenous daratumumab 16 mg/kg was administered as approved except for a split-first dose in Cycle 1. Eligible patients underwent autologous stem cell transplantation. All patients received ≤12 daratumumab maintenance doses monthly. Eighty-six NDMM and 14 RMM patients received ≥1 treatment dose. In NDMM patients, very good partial response or better (≥VGPR) and overall response rates after 4 induction cycles were 44% (primary endpoint) and 79%, respectively, and 56% and 81% at end of induction. The 12-month progression-free survival (PFS) rate was 87%. Efficacy was also observed in RMM patients. Fatigue (59%) and neutropenia (13%) were the most frequent treatment-emergent adverse event (TEAE) and grade 3/4 TEAE, respectively. Infusion reactions occurred in 54% of patients, primarily during the first dose, and were mild (2% grade 3). The first 2 daratumumab infusions were 4·5 and 3·8 h (median). Overall, D-VCd was well tolerated, split-first daratumumab dosing was feasible, the ≥VGPR rate after 4 cycles was 44% and the 1-year PFS rate was 87%.

Hematologic aspects of liver transplantation for Budd-Chiari syndrome with special reference to myeloproliferative disorders.

BACKGROUND: Patients who undergo orthotopic liver transplantation (OLT) for Budd-Chiari syndrome (BCS) traditionally have been anticoagulated with warfarin postoperatively. Because a significant proportion of BCS patients are found to have an underlying myeloproliferative disorder (MPD), antiplatelet therapy may be a more rational treatment strategy for this subgroup. METHODS: All patients who underwent OLT for the diagnosis of BCS at our institution through March 2000 were included in this analysis. Posttransplant therapy consisted of hydroxyurea and aspirin for those with MPDs. Standard anticoagulation or no antithrombotic treatment was given to BCS patients with other causes. Major posttransplantation complications (thrombosis and bleeding) and mortality were determined. RESULTS: Seventeen patients underwent OLT for BCS at our institution. The mean follow-up was 68.4 months. Two of seventeen patients died; one patient died of recurrent thrombosis (124 months after OLT) and the other patient died of acute hepatitis B (7 months after OLT). Twelve patients (71%) had evidence of a MPD. Two of the MPD patients were treated with warfarin before the initiation of hydroxyurea and aspirin therapy. The remaining 10 MPD patients were placed on only hydroxyurea and aspirin after OLT. Anagrelide was used in place of hydroxyurea in two patients because of cytopenias caused by the latter agent. The mean follow-up of this group of 10 patients was 59.9 months. Only one patient experienced recurrent thrombosis, which occurred more than 10 years after the original transplant. There were no major bleeding complications and posttransplant liver biopsies were well tolerated. CONCLUSIONS: Antiplatelet therapy that consists of hydroxyurea and aspirin is a safe and effective alternative to anticoagulation to prevent recurrent thrombosis in MPD patients with BCS after liver transplantation. For patients with a hypercoagulable state corrected by OLT, antithrombotic therapy probably is not required. For those patients with conditions not corrected by OLT or with idiopathic BCS, anticoagulation or other therapy to control the hypercoagulable state should be given.