Evaluating the impact of stratification on the power and cross-arm balance of randomized phase 2 clinical trials.

Background/aims: Randomized clinical trials often use stratification to ensure balance between arms. Analysis of primary endpoints of these trials typically uses a "stratified analysis," in which analyses are performed separately in each subgroup defined by the stratification factors, and those separate analyses are weighted and combined. In the phase 3 setting, stratified analyses based on a small number of stratification factors can provide a small increase in power.

Blinatumomab for MRD-Negative Acute Lymphoblastic Leukemia in Adults.

Background: Many older adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a relapse despite having a measurable residual disease (MRD)-negative complete remission with combination chemotherapy. The addition of blinatumomab, a bispecific T-cell engager molecule that is approved for the treatment of relapsed, refractory, and MRD-positive BCP-ALL, may have efficacy in patients with MRD-negative remission.

Methods: In a phase 3 trial, we randomly assigned patients 30 to 70 years of age with -negative BCP-ALL (with :: indicating fusion) who had MRD-negative remission (defined as <0.

Randomized study of induction with bendamustine-rituximab ± bortezomib and maintenance with rituximab ± lenalidomide for MCL.

Although initial therapy of mantle cell lymphoma (MCL) is not standardized, bendamustine plus rituximab (BR) is commonly used in older patients. Rituximab (R) maintenance after induction is often used. Thus, the open-label, randomized phase 2 ECOG-ACRIN Cancer Research Group E1411 trial was designed to test 2 questions: (1) does addition of bortezomib to BR induction (BVR) and/or (2) addition of lenalidomide to rituximab (LR) maintenance improve progression-free survival (PFS) in patients with treatment-naïve MCL? From 2012 to 2016, 373 previously untreated patients, 87% aged ≥60 years, were enrolled in this trial.

Correction: Plasmids manipulate bacterial behaviour through translational regulatory crosstalk.

[This corrects the article DOI: 10.1371/journal.pbio.

Follow-up from the A041202 study shows continued efficacy of ibrutinib regimens for older adults with CLL.

A041202 (NCT01886872) is a phase 3 study comparing bendamustine plus rituximab (BR) with ibrutinib and the combination of ibrutinib plus rituximab (IR) in previously untreated older patients with chronic lymphocytic leukemia (CLL). The initial results showed that ibrutinib-containing regimens had superior progression-free survival (PFS) and rituximab did not add additional benefits. Here we present an updated analysis.

A multicenter phase Ib trial of the histone deacetylase inhibitor entinostat in combination with pembrolizumab in patients with myelodysplastic syndromes/neoplasms or acute myeloid leukemia refractory to hypomethylating agents.

Patients with myelodysplastic syndromes/neoplasms (MDS) or acute myeloid leukemia (AML) with hypomethylating agent failure have a poor prognosis. Myeloid-derived suppressor cells (MDSCs) can contribute to MDS progression and mediate resistance to anti-PD1 therapy. As histone deacetylase inhibitors (HDACi) decrease MDSCs in preclinical models, we conducted an investigator-initiated, NCI-Cancer Therapy Evaluation Program-sponsored, multicenter, dose escalation, and expansion phase Ib trial (NCT02936752) of the HDACi entinostat and the anti-PD1 antibody pembrolizumab.

Assessment of the safety of nivolumab in people living with HIV with advanced cancer on antiretroviral therapy: the AIDS Malignancy Consortium 095 Study.

Background: Although immunotherapy has emerged as a therapeutic strategy for many cancers, there are limited studies establishing the safety and efficacy in people living with HIV (PLWH) and cancer.

Methods: PLWH and solid tumors or Kaposi sarcoma (KS) receiving antiretroviral therapy and a suppressed HIV viral load received nivolumab at 3 mg/kg every 2 weeks, in two dose deescalation cohorts stratified by CD4 count (stratum 1: CD4 count > 200/µL and stratum 2: CD4 count 100-199/µL). An expansion cohort of 24 participants with a CD4 count > 200/µL was then enrolled.

The New NCI Precision Medicine Trials.

Basket, umbrella, and platform trial designs (master protocols) have emerged over the last decade to study precision medicine approaches in oncology. First-generation trials like NCI-MATCH (Molecular Analysis for Therapy Choice) have proven the principle that studying targeted therapies on a large scale is feasible both from the laboratory and clinical perspectives. However, single-agent targeted therapies have shown limited ability to control metastatic disease, despite careful matching of drug to target.

The NCI-MATCH trial: lessons for precision oncology.

The NCI-MATCH (Molecular Analysis for Therapy Choice) trial ( NCT02465060 ) was launched in 2015 as a genomically driven, signal-seeking precision medicine platform trial-largely for patients with treatment-refractory, malignant solid tumors. Having completed in 2023, it remains one of the largest tumor-agnostic, precision oncology trials undertaken to date. Nearly 6,000 patients underwent screening and molecular testing, with a total of 1,593 patients (inclusive of continued accrual from standard next-generation sequencing) being assigned to one of 38 substudies.

Compensatory mutations reducing the fitness cost of plasmid carriage occur in plant rhizosphere communities.

Plasmids drive bacterial evolutionary innovation by transferring ecologically important functions between lineages, but acquiring a plasmid often comes at a fitness cost to the host cell. Compensatory mutations, which ameliorate the cost of plasmid carriage, promote plasmid maintenance in simplified laboratory media across diverse plasmid-host associations. Whether such compensatory evolution can occur in more complex communities inhabiting natural environmental niches where evolutionary paths may be more constrained is, however, unclear.

Plasmids manipulate bacterial behaviour through translational regulatory crosstalk.

Beyond their role in horizontal gene transfer, conjugative plasmids commonly encode homologues of bacterial regulators. Known plasmid regulator homologues have highly targeted effects upon the transcription of specific bacterial traits. Here, we characterise a plasmid translational regulator, RsmQ, capable of taking global regulatory control in Pseudomonas fluorescens and causing a behavioural switch from motile to sessile lifestyle.

Update on Enrollment of Older Adults Onto National Cancer Institute National Clinical Trials Network Trials.

Background: Older adults are a large and growing proportion of cancer cases in the United States, but concerns persist about whether older adults are adequately represented in the cancer clinical trials that test new options for treatment and cancer care.

Methods: This paper describes adult patient enrollments by age group to the National Cancer Institute's National Clinical Trials Network (NCTN) from 2016 to 2021, compares patient enrollment by age with the estimated incident cancer population across cancer types, and explores possible associations between patient age and patient race, ethnicity, and sex.

Results: This analysis found that patients aged 18 to 69 years were overrepresented in NCTN trials, whereas patients aged 70 years and older were underrepresented compared with the estimated incident cancer population.

Integrating Geriatric Assessment Measures into National Cancer Institute Clinical Trials.

To improve the care of older adults with cancer, the traditional approach to clinical trial design needs to be reconsidered. Older adults are underrepresented in clinical trials with limited or no information on geriatric-specific factors, such as cognition or comorbidities. To address this knowledge gap and increase relevance of therapeutic clinical trial results to the real-life population, integration of aspects relevant to older adults is needed in oncology clinical trials.

Structural insights into the mechanism of adaptive ribosomal modification by Pseudomonas RimK.

Bacteria are equipped with a diverse set of regulatory tools that allow them to quickly adapt to their environment. The RimK system allows for Pseudomonas spp. to adapt through post-transcriptional regulation by altering the ribosomal subunit RpsF.

Implementing Modernized Eligibility Criteria in US National Cancer Institute Clinical Trials.

In 2018, the Cancer Therapy Evaluation Program (CTEP) at the US National Cancer Institute published new protocol template language that focused on organ function and prior and concurrent cancers in an effort to modernize eligibility criteria for cancer treatment trials. We conducted an analysis of CTEP-supported trials to evaluate the uptake and incorporation of the new language. The analysis included evaluation of 122 protocols approved in the years 2018-2020 for inclusion of the modernized eligibility criteria and consistency with new protocol template language related to 7 major eligibility criteria.