Relacorilant + Nab-Paclitaxel in Patients With Recurrent, Platinum-Resistant Ovarian Cancer: A Three-Arm, Randomized, Controlled, Open-Label Phase II Study

Relacorilant; Cáncer de ovario recurrente; PlatinoRelacorilant; Càncer d'ovari recurrent; PlatíRelacorilant; Resistant ovarian cancer; PlatinumPURPOSE Despite therapeutic advances, outcomes for patients with platinum-resistant/refractory ovarian cancer remain poor. Selective glucocorticoid receptor modulation with relacorilant may restore chemosensitivity and enhance chemotherapy efficacy. METHODS This three-arm, randomized, controlled, open-label phase II study (ClinicalTrials.gov identifier: NCT03776812) enrolled women with recurrent, platinum-resistant/refractory, high-grade serous or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer, or ovarian carcinosarcoma treated with ≤4 prior chemotherapeutic regimens. Patients were randomly assigned 1:1:1 to (1) nab-paclitaxel (80 mg/m2) + intermittent relacorilant (150 mg the day before, of, and after nab-paclitaxel); (2) nab-paclitaxel (80 mg/m2) + continuous relacorilant (100 mg once daily); or (3) nab-paclitaxel monotherapy (100 mg/m2). Nab-paclitaxel was administered on days 1, 8, and 15 of each 28-day cycle. The primary end point was progression-free survival (PFS) by investigator assessment; objective response rate (ORR), duration of response (DOR), overall survival (OS), and safety were secondary end points. RESULTS A total of 178 women were randomly assigned. Intermittent relacorilant + nab-paclitaxel improved PFS (hazard ratio [HR], 0.66; log-rank test P = .038; median follow-up, 11.1 months) and DOR (HR, 0.36; P = .006) versus nab-paclitaxel monotherapy, while ORR was similar across arms. At the preplanned OS analysis (median follow-up, 22.5 months), the OS HR was 0.67 (P = .066) for the intermittent arm versus nab-paclitaxel monotherapy. Continuous relacorilant + nab-paclitaxel showed numerically improved median PFS but did not result in significant improvement over nab-paclitaxel monotherapy. Adverse events were comparable across study arms, with neutropenia, anemia, peripheral neuropathy, and fatigue/asthenia being the most common grade ≥3 adverse events. CONCLUSION Intermittent relacorilant + nab-paclitaxel improved PFS, DOR, and OS compared with nab-paclitaxel monotherapy. On the basis of protocol-prespecified Hochberg step-up multiplicity adjustment, the primary end point did not reach statistical significance (P < .025). A phase III evaluation of this regimen is underway (ClinicalTrials.gov identifier: NCT05257408)

Machiavellian Ways to Academic Cheating:A Mediational and Interactional Model

Academic cheating has become a pervasive practice from primary schools to university. This study aims at investigating this phenomenon through a nomological network which integrates different theoretical frameworks and models, such as trait and social-cognitive theories and models regarding the approaches to learning and contextual/normative environment. Results on a sample of more than 200 Italian university students show that the Amoral Manipulation facet of Machiavellianism, Academic Moral Disengagement, Deep Approach to Learning, and Normative Academic Cheating are significantly associated with Individual Academic Cheating. Moreover, results show a significant latent interaction effect between Normative Academic Cheating and Amoral Manipulation Machiavellianism: “amoral Machiavellians” students are more prone to resort to Academic Cheating in contexts where Academic Cheating is adopted as a practice by their peers, while this effect is not significant in contexts where Academic Cheating is not normative. Results also show that Academic Moral Disengagement and Deep Approach to learning partially mediate the relationship between Amoral Manipulation and Academic Cheating. Practical implications of these results are discussed

Circadian variation in plasma 5-fluorouracil concentrations during a 24 hour constant-rate infusion

BACKGROUND: Varying the rate of continuous intravenous infusions of 5-fluorouracil (5FU) chemotherapy over a 24-hour period has been reported to improve patient outcomes. It has been hypothesized that circadian variation in drug disposition is a contributing factor. We analyzed 5-FU concentrations during a 24-hour continuous 5-FU infusion. METHODS: Sixty-four subjects with advanced malignancies including pancreatic, hepatocellular, colorectal as well as other epithelial malignancies and either abnormal hepatic or renal function were treated on a phase I and pharmacokinetic study of weekly 24-hour intravenous infusions of 5-FU and leucovorin. No other concomitant anticancer therapy was administered. Blood samples were collected every three hours from 61 subjects for measurement of plasma 5-FU during the first two weekly infusions. RESULTS: After adjusting for differences in dose, elapsed time from start of infusion and infusion number (2 versus 1), mean 5-FU concentration was highest at 6 am and lowest at 3 pm, with an overall change in the mean from 3 pm to 6 am of +20 percent (95% CI = 12–28%). However, this variation in mean concentration associated with time of day was comparable in magnitude to the between-patient differences, within-patient differences between infusions, and the residual variation within infusion (coefficient of variation = 21%). CONCLUSIONS: Our data show systematic variation by time of day in plasma concentrations of 5-FU administered at a constant rate over 24 hours, but it is small compared to the total variation in plasma concentration contributed by other sources. Circadian variation in men was more pronounced than in women

Progression-free survival by investigator versus blinded independent central review in newly diagnosed patients with high-grade serous ovarian cancer:Analysis of the VELIA/GOG-3005 trial

OBJECTIVE: In the phase 3 VELIA/GOG-3005 trial, veliparib added to carboplatin-paclitaxel and continued as maintenance improved progression-free survival (PFS) compared to carboplatin-paclitaxel alone in patients with newly diagnosed ovarian carcinoma. Primary analysis of PFS was by investigator (INV) assessment, with a supplemental analysis of PFS by blinded independent central review (BICR).METHODS: Patients received veliparib or placebo with carboplatin-paclitaxel (6 cycles) and as maintenance (30 additional cycles). The primary analysis compared PFS in the veliparib-throughout arm to the carboplatin-paclitaxel only arm in the BRCA mutation (BRCAm), homologous recombination deficiency (HRD), and intention-to-treat (ITT) populations. Exploratory analyses of PFS in BRCA wildtype (BRCAwt), homologous recombination proficient (HRP), and HRD + BRCAwt populations were also performed. PFS per BICR and overall concordance rates between INV and BICR assessments were analyzed.RESULTS: Hazard ratios for PFS by INV and BICR were consistent in each of the primary analysis and exploratory populations. In the ITT population, median PFS per INV was 23.5 months in the veliparib-throughout arm versus 17.3 months in the control arm (hazard ratio [HR] 0.683, 95% confidence interval [CI] 0.562-0.831; P &lt; 0.001). Median PFS by BICR was 29.3 months versus 19.2 months (HR 0.687, 95% CI 0.504-0.806). In the ITT population, the overall concordance rates between INV and BICR were 78% and 75% for the veliparib-throughout and control arms, respectively.CONCLUSIONS: Hazard ratios for PFS per BICR and per INV were consistent, with no suggestion of investigator bias. These findings support the reliability of PFS by INV in ovarian cancer trials.</p

A pharmacodynamic study of sirolimus and metformin in patients with advanced solid tumors

BackgroundSirolimus is a mammalian target of rapamycin (mTOR) inhibitor. Metformin may potentiate mTOR inhibition by sirolimus while mitigating its adverse effects. We conducted a pilot study to test this hypothesis.MethodsPatients with advanced solid tumor were treated with sirolimus for 7 days followed by randomization to either sirolimus with metformin (Arm A) or sirolimus (Arm B) until day 21. From day 22 onwards, all patients received sirolimus and metformin. The primary aim was to compare the change in phospho-p70S6K (pp70S6K) in peripheral blood mononuclear cells (PBMC) from day 8 to day 22 using a two-sample t test. Secondary aims were objective response rate, toxicity, and other serum pharmacodynamic biomarkers (e.g., fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-1R, IGF-BP, and leptin).Results24 patients were enrolled, with 18 evaluable for the primary endpoint. There was no significant difference in mean change in pp70S6K in arm A vs. arm B (- 0.12 vs. - 0.16; P = 0.64). Similarly, there were no significant differences in other serum pharmacodynamic biomarkers. There were no partial responses. There were no dose-limiting or unexpected toxicities.ConclusionsAdding metformin to sirolimus, although well tolerated, was not associated with significant changes in pp70S6K in PBMC or other serum pharmacodynamic biomarkers.ImpactCombining metformin with sirolimus did not improve mTOR inhibition

CA-125 KELIM as a Potential Complementary Tool for Predicting Veliparib Benefit:An Exploratory Analysis From the VELIA/GOG-3005 Study

PURPOSE: In VELIA trial, veliparib combined with carboplatin-paclitaxel, followed by maintenance (veliparib-throughout) was associated with improved progression-free survival (PFS) compared with carboplatin-paclitaxel alone in patients with high-grade ovarian carcinomas. We explored the prognostic value of the modeled cancer antigen (CA)-125 elimination rate constant K (KELIM), which is known to be an indicator of the intrinsic tumor chemosensitivity (the faster the rate of CA-125 decline, the higher the KELIM and the higher the chemosensitivity), and its association with benefit from veliparib.PATIENTS AND METHODS: Individual KELIM values were estimated from longitudinal CA-125 kinetics. Patients were categorized as having favorable (≥ median) or unfavorable (&lt; median) KELIM. The prognostic value of KELIM for veliparib-related PFS benefit was explored in cohorts treated with primary or interval debulking surgery, according to the surgery completeness, the disease progression risk group, and the homologous recombination (HR) status (BRCA mutation, HR deficiency [HRD], or HR proficiency [HRP]).RESULTS: The data from 854 of 1,140 enrolled patients were analyzed (primary debulking surgery, n = 700; interval debulking surgery, n = 154). Increasing KELIM values were associated with higher benefit from veliparib in HRD cancer, as were decreasing KELIM values in HRP cancer. The highest PFS benefit from veliparib was observed in patients with both favorable KELIM and BRCA mutation (hazard ratio, 0.28; 95% CI, 0.13 to 0.61) or BRCA wild-type HRD cancer (hazard ratio, 0.43; 95% CI, 0.26 to 0.70), consistent with the association between poly (adenosine diphosphate-ribose) polymerase inhibitor efficacy and platinum sensitivity. In contrast, seventy-four percent of patients with a BRCA mutation and unfavorable KELIM progressed within 18 months while on veliparib. The patients with HRP cancer and unfavorable KELIM might have benefited from the veliparib chemosensitizing effect.CONCLUSION: In addition to HRD/BRCA status, the tumor primary chemosensitivity observed during the first-line chemotherapy might be another complementary determinant of poly (adenosine diphosphate-ribose) polymerase inhibitor efficacy.</p

Moving forward with actionable therapeutic targets and opportunities in endometrial cancer:NCI clinical trials planning meeting report on identifying key genes and molecular pathways for targeted endometrial cancer trials

The incidence and mortality rates from endometrial cancer are increasing. There have been no new drugs approved for the treatment of endometrial cancer in decades. The National Cancer Institute, Gynecologic Cancer Steering Committee identified the integration of molecular and/or histologic stratification into endometrial cancer management as a top strategic priority. Based on this, they convened a group of experts to review the molecular data in this disease. Here we report on the actionable opportunities and therapeutic directions identified for incorporation into future clinical trials

Impact of homologous recombination status and responses with veliparib combined with first-line chemotherapy in ovarian cancer in the Phase 3 VELIA/GOG-3005 study

OBJECTIVE: In the Phase 3 VELIA trial (NCT02470585), PARP inhibitor (PARPi) veliparib was combined with first-line chemotherapy and continued as maintenance for patients with ovarian carcinoma enrolled regardless of chemotherapy response or biomarker status. Here, we report exploratory analyses of the impact of homologous recombination deficient (HRD) or proficient (HRP) status on progression-free survival (PFS) and objective response rates during chemotherapy.METHODS: Women with Stage III-IV ovarian carcinoma were randomized to veliparib-throughout, veliparib-combination-only, or placebo. Stratification factors included timing of surgery and germline BRCA mutation status. HRD status was dichotomized at genomic instability score 33. During combination therapy, CA-125 levels were measured at baseline and each cycle; radiographic responses were assessed every 9 weeks.RESULTS: Of 1140 patients randomized, 742 had BRCA wild type (BRCAwt) tumors (HRP, n = 373; HRD/BRCAwt, n = 329). PFS hazard ratios between veliparib-throughout versus control were similar in both BRCAwt populations (HRD/BRCAwt: 22.9 vs 19.8 months; hazard ratio 0.76; 95% confidence interval [CI] 0.53-1.09; HRP: 15.0 vs 11.5 months; hazard ratio 0.765; 95% CI 0.56-1.04). By Cycle 3, the proportion with ≥90% CA-125 reduction from baseline was higher in those receiving veliparib (pooled arms) versus control (34% vs 23%; P = 0.0004); particularly in BRCAwt and HRP subgroups. Complete response rates among patients with measurable disease after surgery were 24% with veliparib (pooled arms) and 18% with control.CONCLUSIONS: These results potentially broaden opportunities for PARPi utilization among patients who would not qualify for frontline PARPi maintenance based on other trials.</p

Evaluation of Treatment With Talazoparib and Avelumab in Patients With Recurrent Mismatch Repair Proficient Endometrial Cancer

Importance: Although the activity of pembrolizumab and lenvatinib (the only US Food and Drug Administration–approved immunotherapy for mismatch repair proficient endometrial cancer [MMRP EC]) is compelling, there are no biomarkers of response and most patients do not tolerate, do not respond to, or develop resistance to this regimen, highlighting the need for additional, potentially biomarker-driven therapeutic approaches for patients with recurrent MMRP EC. Objective: To assess the potential positive outcomes and safety of the combination of the polyadenosine diphosphate-ribose polymerase inhibitor talazoparib and the programmed cell death ligand 1 (PD-L1) inhibitor avelumab in recurrent MMRP EC. Design, Settings, and Participants: This investigator-initiated, open-label, single-arm, 2-stage, phase 2 study nonrandomized controlled trial patients at 4 institutions in the US. Key eligibility criteria included measurable disease, unlimited prior therapies, and all endometrial cancer histologies. Interventions: Talazoparib, 1 mg, orally, daily, and avelumab, 10 mg/kg, intravenously, every 2 weeks, were administered until disease progression or unacceptable toxic effects. Main Outcomes and Measures: Statistical considerations were developed for 2 coprimary objectives of objective response rate and rate of progression-free survival at 6 months, with a 2-stage design that allowed for early discontinuation for futility. Prespecified exploratory objectives included the association of immunogenomic features (determined by targeted-panel next-generation sequencing and immunohistochemistry) with activity. Results: Thirty-five female patients (mean [SD] age, 67.9 [8.41] years) received protocol therapy; 9 (25.7%) derived clinical benefit after meeting at least 1 of the 2 coprimary end points. Four patients (11.4%) exhibited confirmed objective response rates (4 partial responses), and 8 (22.9%) survived progression free at 6 months. The most common grade 3 and 4 treatment-related toxic effects were anemia (16 [46%]), thrombocytopenia (10 [29%]), and neutropenia (4 [11%]); no patient discontinued receipt of therapy because of toxic effects. Tumors with homologous recombination repair alterations were associated with clinical benefit from treatment with avelumab and talazoparib. Tumor mutational burden, tumor-infiltrating lymphocytes, and PD-L1 status were not associated with clinical benefit. Conclusions and Relevance: The results of this nonrandomized controlled trial suggest that treatment with avelumab and talazoparib demonstrated a favorable toxic effect profile and met the predetermined criteria to be considered worthy of further evaluation in MMRP EC. Immunogenomic profiling provided insights that may inform ongoing and future studies of polyadenosine diphosphate-ribose polymerase and PD-L1 inhibitor combinations in endometrial cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT02912572</p