Interim Analysis Research Articles

CTNI-26. A PHASE II STUDY OF SACITUZUMAB GOVITECAN IN RECURRENT GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive and common form of primary brain cancer. GBM expresses trophoblast cell-surface antigen 2 (Trop2) which correlates with proliferation rate, microvessel density, histological grade and clinical survival. Sacituzumab Govitecan (SG) is an antibody-drug conjugate targeting Trop2 with a chemotherapy payload, SN-38. This drug has been approved for triple-negative and hormone-receptor positive metastatic breast cancer. METHODS We conducted multi-center (UT Health San Antonio, Cleveland Clinic, Texas Oncology in Austin), open-label, single-arm phase 2 study using a 2-stage adaptive Bayesian design. Patients with recurrent GBM (rGBM), IDH wild-type, following standard-of-care chemoradiation, received SG (10mg/kg IV, days 1 and 8 every 21 days). Patients were assessed by RANO and CTCAE v5. The primary endpoint was PFS of patients on SG as compared to a historical control of lomustine. RESULTS As of interim analysis cutoff, 24 patients have been screened with 20 patients enrolled. The average age was 58.8 years. 65% of patients identified as male. 95% were Caucasian with 20% identifying as Spanish, Hispanic or Latino. Adverse events (AE) include lymphopenia (40%), neutropenia (40%), hypokalemia (35%), elevated alkaline phosphatase (30%), anemia (30%) with most AE being grade ≤ and no grade 5 observed. 4 patients had grade ≥3 neutropenia attributable to SG. 20% had stable disease as best response with the rest being progressive disease. The mean PFS and OS were 7.0 and 2.0 months, respectively. Of 19 evaluable samples, 63% had positive Trop2 expression (H-Score ≥100, mean 123.6±74 [0.6, 269.2]). A post-hoc analysis of OS log survival time vs H-Score (n=19) using an accelerated failure time model showed that survival correlated with H-Score (p=0.0361). CONCLUSIONS In the interim analysis of this study of patients with rGBM, Sacituzumab was found to be well-tolerated. Further study of those patients bearing tumors with elevated H-scores may be warranted.

RADT-49. IMPACT OF SHORT COURSE RADIOTHERAPY IN REDUCING LYMPHOPENIA IN PATIENTS WITH GLIOBLASTOMA (SAGA STUDY)

Abstract INTRODUCTION Lymphopenia attributed to postoperative chemoradiotherapy (CRT) can accelerate tumor recurrence and contribute to poor prognosis in GBM. We hypothesize that short course (1-2 weeks) CRT can mitigate lymphopenia compared to standard course and may provide immune benefits for future combination therapy. METHODS GBM patients were randomized on a multi-site phase II study comparing short course (35Gy/5Fx or 40Gy/10Fx depending on target volume) (Arm A) versus standard dose fractionation (60Gy/30Fx or 40Gy/15Fx, Arm B). All patients received concurrent and adjuvant temozolomide (TMZ). This unplanned interim analysis evaluates changes of absolute lymphocyte count (ALC), CD4 and CD8 prospectively at 3-timepoints: baseline (prior to CRT), end of CRT, and 1-month post-CRT. RESULTS To date, 72 patients enrolled (34 Arm A, 38 Arm B). Median age 66 (35-86), ECOG 0-2. Patients characteristics as followed in Arm A vs. Arm B, respectively: female 47% vs. 42%, MGMT promotor methylated 31% vs. 34%, steroid use 46% vs. 45%, ALC 1310 cells/mm3 (330 –9730) vs. 1480 (750 –7750), CD4 531 cells/mm3 (86 –1368) vs. 662 (318 –1671), and CD8 151 cells/mm3 (56 –940) vs. 272 (68 –875). Lymphocytes data were collected in 49 patients (21 Arm A, 28 Arm B). There were signficantly fewer reductions of ALC, CD4 and CD8 in Arm A. Median ALC changes were 95% and 99% of baseline (Arm A) vs 52% and 61% of baseline (Arm B) at the end of CRT and 1-month post-CRT, respectively (p<0.01). Median CD4 changes 93% and 96% of baseline (Arm A) vs 51% and 49% (Arm B), and median CD8 changes 97% and 98% of baseline (Arm A) vs 57% and 71% (Arm B) at the end of CRT and 1-month post-CRT, respectively (p<0.05). CONCLUSIONS This interim analysis suggests that short course RT could reduce treatment-related lymphopenia and immune suppression compared to standard RT, thus could be potentially beneficial to combine with immunotherapy.

RTID-04. A MULTICENTER, RANDOMIZED, CONTROLLED PHASE 2B TRIAL OF SURVIVIN VACCINE SURVAXM PLUS ADJUVANT TEMOZOLOMIDE FOR NEWLY-DIAGNOSED GLIOBLASTOMA (SURVIVE)

Abstract BACKGROUND Glioblastoma cells express high levels of survivin protein, whose presentation by MHC class I gets recognized by antibodies and cytotoxic T-lymphocytes (CTLs). A phase 2a trial (NCT02455557) demonstrated a median overall survival (OS) of 25.9 months in newly-diagnosed glioblastoma (nGBM) patients with 15-amino-acid-peptide-conjugate survivin vaccine (SurVaxM), which also stimulated production of survivin-directed antibodies and anti-tumor CTL. This phase 2b trial aims to further investigate efficacy and safety of SurVaxM plus adjuvant temozolomide (TMZ) for nGBM. METHODS SURVIVE is an ongoing, multicenter, randomized, placebo-controlled, investigator- and patient-blinded, phase 2b trial that randomizes nGBM patients receiving standard-of-care therapies to either SurVaxM (SurVaxM arm) or saline (control arm) in 3:2 ratio at 15 sites. Included patients have age ≥18 years, normal organ function, KPS≥70, and receive surgical resection with ≤1cm3 residual MRI contrast enhancement within 72 hours post-resection plus TMZ. Patients with recurrent, multicentric, brainstem- or cerebellar-origin GBM are excluded as well as patients on TTFields or other immunotherapies. All patients undergo 3 phases: (1) vaccine priming (VP) phase, starting ≤4 weeks after completing chemoradiation – 4 doses of SurVaxM or placebo administered q2weeks; (2) TMZ phase, started after ≥1 VP dose; and (3) vaccine maintenance phase, started 8 weeks after VP, with SurVaxM or placebo given q8weeks. TMZ phase overlaps with VP and VM phases. Primary endpoint is median OS. Assuming 1-year-OS of 75% in SurVaxM arm, based on prior trials, and 60% for control, the required sample size is N=228; 137 in SurVaxM and 91 in control arm. Accounting for dropouts, we aimed to enroll 239 patients. A log-rank test stratified by KPS (70-80 vs 90-100), MGMT methylation status, and IDH mutation status will be used for analysis. Secondary endpoints are OS and PFS at 15, 18, and 24 months, median PFS, and toxicity. A single sequential OS-driven interim analysis is planned when 50% of deaths occur. Trial is fully enrolled (NCT05163080).

TMET-11. IMPACT OF METABOLIC RISK FACTORS ON SURVIVAL IN GLIOBLASTOMA IDH-WILD TYPE

Abstract Altered cellular metabolism is a hallmark of cancer. Systemic metabolic dysregulation has been associated with the pathogenesis of cancer, including glioblastoma. In particular, the metabolic syndrome has been found to increase the risk of developing various systemic cancers, but it is not known how often the metabolic syndrome occurs in patients with glioblastoma or how it affects their clinical outcomes. This study retrospectively investigates the prevalence and impact of metabolic syndrome, and its component risk factors, on survival in patients with glioblastoma IDH-wild type. Interim analysis includes results from 73 patients with anticipation of over 100 patients who received treatment at UC Davis between 2018-2024. Metabolic syndrome prevalence prior to diagnosis was 41% (30/73), higher than the prevalence of 33% in the general population. Patients with metabolic syndrome showed a trend towards reduced overall survival. A significant dose-response association was found between the number of metabolic risk factors and overall survival (p=0.03). Hyperglycemia demonstrated worsened survival (p=0.04), aligning with prior studies. Obesity, hypertension, and dyslipidemia were not significantly associated with survival. These findings highlight the therapeutic potential for targeting systemic metabolic dysregulation, and hyperglycemia in particular, in patients with glioblastoma.

CTNI-34. A RANDOMIZED PROSPECTIVE TRIAL OF POST-OPERATIVE FLUID RESTRICTION TO DECREASE THE INCIDENCE OF DELAYED HYPONATREMIA AND READMISSION AFTER TRANSSPHENOIDAL SURGERY

Abstract BACKGROUND Delayed hyponatremia (hypoNa) is the leading cause of readmission following transsphenoidal surgery (TSS). Some institutions have adopted post-operative fluid restriction (FR) protocols based on retrospective studies. We present results of a prospective randomized controlled trial evaluating post-TSS FR. METHODS 300 participants scheduled for TSS (2016-2023) at a single institution were included. Patients with CKD, CHF, AVP deficiency on postoperative day (POD) 3, chronic hypoNa, untreated adrenal insufficiency/hypothyroidism, and those for whom FR was felt unsafe were excluded. Patients were randomly assigned to control (CON, n=94) or moderate FR (FR1, n=39). Participants in CON group were instructed to drink ad lib. Participants in FR1 were FR to 1.8 liters/day (2 liters/day if > 100 kg) from POD3-14. Based on interim analysis suggesting a trend toward reduced hypoNA, FR was changed to strict FR (FR2, n=62) of 1 liter/day (1.2 liters/day if > 100 kg). Serum sodium (Na) was monitored inpatient and on POD 3, 7, 10, and 14, and readmissions evaluated. Fluid intake and thirst were assessed. RESULTS In the intention-to-treat analysis, incidence of hypoNa (Na < 135 mEq/L) was 31.9% CON, 28.2% FR1, and 21% FR2, and severe hypoNa (Na < 125 mEq/L) 7.4% CON, 5.1% n FR1 and 0% FR2. Readmission for hypoNa occurred in 6.4% (n=6) CON, 7.7% (n=3) FR1 and 1.6% (n=1) FR2. Severe hypoNa occurred more frequently in CON vs. FR2 (P=0.04), and nadir Na was higher in FR2 vs. CON (P=0.02). Although thirst scores were similar among groups, an individual’s thirst score correlated with compliance CONCLUSION Results of this randomized study show a reduction in severe hypoNa and readmission for hypoNa in patients on FR from POD3-14 after TSS vs. patients instructed to drink ad lib. This provides strong evidence that post-TSS FR decreases rate of delayed hypoNa and related readmission.

CTIM-19. A PHASE 1, SAFETY LEAD-IN AND RANDOMIZED, OPEN-LABEL, PERIOPERATIVE STUDY OF VORASIDENIB COMBINED WITH PEMBROLIZUMAB IN RECURRENT OR PROGRESSIVE ENHANCING IDH-1 MUTANT GLIOMA: TRIAL IN PROGRESS

Abstract BACKGROUND Vorasidenib (VOR) is an oral, brain-penetrant dual inhibitor of isocitrate dehydrogenase 1/2 mutant (mIDH1/2) enzymes. VOR is being investigated in a phase 3 study in residual or recurrent grade 2 non-enhancing gliomas, in which interim analysis showed VOR significantly improved progression-free survival and delayed time to next intervention. A prior neoadjuvant perioperative study in recurrent, non-enhancing grade 2/3 gliomas showed that VOR treatment was associated with interferon signal activation and increased T-cell infiltration, suggesting 2-hydroxyglutarate suppression may prime the tumor immune microenvironment for immune checkpoint blockade. This study (NCT05484622) evaluates the safety and tolerability of VOR+pembrolizumab to determine the recommended combination dose (RCD) of VOR (safety lead-in phase) and evaluates CD3+ T-cell infiltration in tumors following a 28-day preoperative period. METHODS Enrollment: US patients with recurrent or progressive grade 2/3 mIDH1 R132H glioma. Key eligibility: measurable enhancing disease, Karnofsky Performance Status ≥70, resectable (perioperative phase only). Following a March 2024 protocol amendment, inclusion criteria were expanded to include patients with oligodendroglioma in addition to patients with astrocytoma. Safety lead-in dosing: Cohort 1, VOR 40mg QD+pembrolizumab 200mg Q3W in 21-day cycles. The perioperative phase is randomized 1:1:1 to preoperative combination, VOR 40mg QD, or untreated for 28 (+7) days; all patients could opt to receive the VOR RCD in combination with pembrolizumab 200mg Q3W postoperatively. Primary objectives: safety and tolerability of VOR RCD administered with pembrolizumab; CD3+ T-cell infiltration in resected tumors following presurgical treatment with combination compared to untreated tumors. RESULTS Seven patients with recurrent or progressive enhancing grade 2/3 astrocytoma with an mIDH1 R132H were dosed in the safety lead-in phase. No dose-limiting toxicities were detected during this phase. CONCLUSION VOR 40mg QD+pembrolizumab 200mg Q3W was confirmed as the RCD for the perioperative phase. This phase was opened to enrollment in May 2023, and recruitment is ongoing.

CTNI-85. FINAL RESULTS FROM N2M2/NOA-20

Abstract BACKGROUND MGMT promoter methylation determines benefit from temozolomide (TMZ). Trials aiming at replacing TMZ with targeted agents in not molecularly selected patient populations have failed. Solid evaluation of the MGMT promotor methylation status is critical. METHODS The phase I/IIa umbrella trial NCT Neuro Master Match (N2M2) in patients with newly diagnosed glioblastoma aimed at showing safety, feasibility, and preliminary efficacy of targeted compounds in addition to radiotherapy. In five subtrials (alectinib, idasanutlin, palbociclib, vismogedib and temsirolimus) patients were included according to the best matching molecular alteration. Patients without matching alterations were randomized between atezolizumab, asunercept or TMZ as standard of care. Primary objective of the phase I parts of the trial was dose finding or dose validation. In the phase IIa trials, centrally determined progression-free survival at six months (PFS-6) is used as endpoint for efficacy with interim analyses for futility (H0: p=0.231). RESULTS From May 2018 through July 2022, 301 patients were enrolled and 228 treated in 13 German NOA sites. MGMT was determined locally and confirmed centrally by pyrosequencing as well as methylation arrays. The TMZ subtrial showed a PFS-6 of 18.52% (10/54 patients) (p=0.8311) and a median overall survival (mOS) of 12.1 months. Asunercept: PFS-6 of 15.4% (4/26) (p=0.8825) and mOS of 13.0 months. Atezolizumab: PFS-6 of 21.4% (9/42) (p=0.660) and mOS of 11.7 months. Palbociclib with patients demonstrating CDK4 amplification or CDKN2A/B codeletion: PFS-6 of 24.4% (10/41) (p=0.4823) and mOS of 12.6 months. Temsirolimus with patients demonstrating mTOR activation: PFS-6 of 39.1% (18/46) (p=0.0109) and mOS of 15.4 months. For the other arms, phase IIa has not been reached. CONCLUSIONS There is clinical activity of temsirolimus in patients with tumors harboring an activated mTOR pathway although this is not positively prognostic without mTOR inhibition; there is no clinical activity for asunercept and atezolizumab in not molecularly selected patients nor palbociclib in molecularly selected patients. Potential biomarkers will be discussed.

TRBC1-CAR T cell therapy in peripheral T cell lymphoma: a phase 1/2 trial.

Relapsed/refractory peripheral T cell lymphomas (PTCLs) are aggressive tumors with a poor prognosis. Unlike B cell lymphomas, treatment of PTCL has not benefited from advances in immunotherapy. This is largely due to a lack of suitable target antigens that discriminate malignant from normal T cells, thus avoiding severe immunosuppression consequent to depletion of the entire T cell compartment. We recently described a targeting strategy based on the mutually exclusive expression of T cell antigen receptor beta-chain constant domain (TRBC) 1 and 2. Selective targeting of the T cell antigen receptor beta-chain expressed by the (clonal) malignancy spares normal T cells expressing the other chain. The LibraT1 study is an ongoing, multicenter, international, single-arm phase 1/2 study of TRBC1-directed autologous chimeric antigen receptor (CAR) T cells (AUTO4) in relapsed/refractory TRBC1-positive PTCL. Primary objectives were assessment of safety and tolerability of AUTO4 infusion. Key secondary endpoints included efficacy, CAR T cell expansion and persistence. Here we describe the findings from dose escalation in LibraT1 in the first ten patients, in a non-prespecified interim analysis. AUTO4 resulted in low frequency of severe immunotoxicity, with one of ten patients developing grade 3 cytokine release syndrome. Complete metabolic response was observed in four of ten evaluable patients, with remissions being durable beyond 1 year in two patients. While an absence of circulating CAR T cells was observed, CAR T cells were readily detected in lymph node biopsy samples from sites of original disease suggesting homing to tumor sites. These results support the continuing exploration of TRBC1 targeting in PTCL. ClinicalTrials.gov registration: NCT03590574 .

CTNI-35. EVALUATE THE SAFETY AND PRELIMINARY EFFICACY OF THE COMBINATION OF NAVIFUS SYSTEM WITH RE-IRRADIATION FOR RGBM PATIENTS

Abstract The blood-brain barrier (BBB) remains the major obstacle in treating patients with malignant brain tumors. Radiation therapy (RT) is the mainstay adjuvant modality regardless of the BBB, but its effectiveness is hindered by the hypoxic microenvironment. Focused ultrasound (FUS) combined with systemic microbubbles has been shown to open the BBB and potentially increase regional perfusion. However, no clinical study has investigated the combination of RT with FUS-BBB opening (RT-FUS). Here, we report an interim analysis of an ongoing single-arm, prospective, pilot study (NCT04988750) combining RT-FUS for recurrent malignant high-grade glioma patients, where re-RT was considered for disease control. FUS-BBB opening was conducted within 2 hours before RT. Treatment responses were evaluated by objective response rate (ORR) using magnetic resonance imaging, progression-free survival, overall survival, and adverse events (AEs). In this pilot clinical trial, an interim analysis of six recurrent malignant high-grade glioma patients who underwent a total of 24 RT-FUS treatments was presented. Three patients experienced rapid disease progression after RT-FUS, while the other three patients had at least stable disease after RT-FUS, with or without salvage chemotherapy or targeted therapy. There were no FUS-related AEs, but re-RT-related grade three radiation necrosis was observed. The interim analysis of this ongoing clinical trial showed that the combination of RT-FUS was safe, with no FUS-related adverse effects. Two more cases will be recruited in this trial. A comprehensive analysis of radiation dosimetry and FUS energy distribution is expected after completing the final recruitment.

The role of a Macmillan senior pharmacy technician in a regional cancer centre in Northern Ireland: an evaluation

Abstract Introduction In the UK, up to two-thirds of all cancer patients have at least one comorbidity, with around half having multiple long-term conditions (LTCs).1 Older people with cancer often require multiple medications including cancer-specific treatments, supportive care medications, and medications for pre-existing LTCs. They are therefore at higher risk of the adverse effects of polypharmacy, inappropriate prescribing, drug-drug interactions, and drug-disease interactions. Complexity of medication regimens and treatment burden can cause confusion and medicines mismanagement, thereby influencing a patient's ability to adhere to treatment with the outcome being an increased chance of treatment failure. It is thus essential that medicines be optimised in these patients.2 The Oncology Pharmacy Team based in the North West Cancer Centre, located on the Altnagelvin acute hospital site in the Western Health and Social Care Trust, Northern Ireland, secured Macmillan funding to provide a specialist medicines optimisation service to older patients about to start cancer treatment (the Medicines Optimisation in Older People with Cancer [MOOC] Service). A pharmacy technician and pharmacist were recruited and the service implemented from October 2023. The roles are new and innovative and require extensive evaluation. Aim To evaluate the introduction of the Macmillan senior pharmacy technician into the oncology pharmacy team, analysing impact on medicines optimisation and patient safety. Methods A census approach was taken to include all patients with a new cancer diagnosis and medicines reconciliation (MedRec) completed by the pharmacy technician during the study period. The technician identified and rectified any issues prior to the patient’s first scheduled treatment. Patients with significant medicines-related concerns, or aged ≥65 years and taking ≥8 drugs, were referred to the Macmillan pharmacist for holistic medication review. Data collected included number of MedRecs completed by the pharmacy technician (relative to total completed by the team weekly), cancer diagnosis, medicines-related problems identified, interventions made, other activities completed, and time directed away from the pharmacist. Analysis of patient age and number of medications taken informed whether inclusion criteria for MOOC pharmacist referral were appropriate. Results The specialist medicines optimisation service started in October 2023, however, data collection for the purpose of this study commenced on 1st January and took place over a two-month period.101 patients (aged 69.0 ± 5.7 years, range 57 -74 years)) taking an average of 12.6 medicines (range = 8-18), and recently diagnosed with cancer were reviewed by the pharmacy technician. On average, the technician completed 76.4% of medicines reconciliations each week. 120 medicines-related problems were identified, and 178 interventions made. The service yielded net cost savings of £826.34 (pharmacist time saved). Nine patients were referred to the MOOC pharmacist service; a further five patients did not consent to referral. Discussion / Conclusion Although the evaluation of the MOOC service is ongoing, this interim analysis demonstrated that integration of the pharmacy technician into the oncology team yielded cost savings and reduced and improved provision of patient-centred healthcare and safety. Inclusion criteria for the MOOC pharmacist review were confirmed via analysis of patient age and number of medicines taken.

The Phase 3 KEYLYNK-006 Study of Pembrolizumab plus Olaparib versus Pembrolizumab plus Pemetrexed as Maintenance Therapy for Metastatic Nonsquamous Non–Small-Cell Lung Cancer

Poly (ADP-ribose) inhibitors, including olaparib, upregulate programmed cell death ligand 1 (PD-L1), which may increase efficacy of anti-PD-(L)1 therapies. In the phase 3 KEYLYNK-006 trial (NCT03976323), eligible adults with previously untreated metastatic nonsquamous NSCLC without targetable genetic alterations who had complete response (CR), partial response (PR), or stable disease (SD) following induction therapy with 4 cycles of pembrolizumab 200 mg Q3W, pemetrexed 500 mg/m2 , and carboplatin AUC5 or cisplatin 75 mg/m2 were randomized 1:1 to olaparib 300 mg orally twice daily or pemetrexed Q3W, both given with ≤31 cycles of pembrolizumab Q3W. Dual primary endpoints were progression-free survival (PFS) and overall survival (OS). PFS was tested at interim analysis 2 (IA2; ie, final PFS analysis), OS at final analysis (FA). Of 1003 patients who received induction therapy, 672 (67.0%) were randomized to pembrolizumab plus olaparib (n=337) or pembrolizumab plus pemetrexed (n=335) in the intention-to-treat population. Median follow-up at FA was 39.9 (range, 28.1-51.5) months. At IA2, median (95% CI) PFS was 7.1 (5.6-8.7) months versus 8.3 (6.9-11.5) months in the olaparib versus pemetrexed groups (HR, 1.12; 95% CI, 0.92-1.36; P=0.87). At FA, median (95% CI) OS was 20.7 (18.0-24.8) months versus 23.0 (19.0-26.4) months (HR, 1.04; 95% CI, 0.87-1.25; P=0.6649). Grade 3-5 maintenance treatment-related AEs occurred in 26.1% versus 30.1% patients. Pembrolizumab plus maintenance olaparib did not improve PFS or OS versus pembrolizumab plus pemetrexed in previously untreated metastatic nonsquamous NSCLC without targetable genetic alterations.

Interim analysis of robot-assisted radical hysterectomy in Japan: a multicenter, prospective interventional single-arm clinical trial

ObjectiveTo investigate the efficacy and safety of robot-assisted radical hysterectomy (RARH) as a minimally invasive procedure in patients with cervical cancer that is curable by surgery.Materials and methodsThis study was a multicenter, open-label, single-arm clinical trial. The short-term outcome of open radical hysterectomy was used as the historical control. The primary endpoint was successful surgery with minimal blood loss (300 mL or less) and negative surgical margins. Secondary endpoints included surgical outcomes, recurrence-free survival (RFS), and overall survival (OS) rates.ResultsOverall, 101 cases were enrolled in this study at 10 participating medical institutions and 100 underwent RARH. Among these cases, 89 met the primary endpoint, exceeding the threshold of 0.75 set by the lower limit. At 2 years postoperatively, 17 cases had recurrences, 4 were classified as International federation of Obstetrics and Gynecology Stage IB1 or lower, while 13 as IB2 or higher. There were three deaths, including one in Stage IB1 and two in Stage IIB in the second postoperative year, all of which had lymph node metastasis. The oncological outcomes for all cases showed RFS and OS rates of 82.7% and 96.9%, respectively, over a median observation period of 37 months. For cases with Stage IB1, RFS and OS were 94.1% and 98.5%, respectively.ConclusionRARH demonstrated a significant reduction in blood loss while ensuring radicality, indicating the safety and efficacy of this procedure compared to conventional RH. Although it is conceivable that the results of this oncological analysis could change, as the data collection has not been fully completed, we plan to further evaluate the oncologic outcomes of RARH in future studies.Trial registrationUMIN-CTR: UMIN000022278, registered on 11th May 2016.

Phase IV adaptive randomised clinical trials evaluating efficacy and cost-efficacy of pre-emptive pharmacogenetic genotyping strategies in the Spanish National Health System: iPHARMGx Master Protocol and PREVESTATGx nested clinical trial

IntroductionGenetic variations impact drug response, driving the need for personalised medicine through pre-emptive pharmacogenetic testing. However, the adoption of pre-emptive pharmacogenetic testing for commonly prescribed drugs, such as statins, outside...

Effect of high-flow nasal therapy on patient-centred outcomes in patients at high risk of postoperative pulmonary complications after cardiac surgery: update to the statistical analysis plan for NOTACS, a multicentre adaptive randomised controlled trial

BackgroundThe NOTACS trial will assess the efficacy, safety and cost-effectiveness of high-flow nasal therapy (HFNT) compared to standard oxygen therapy (SOT) on the outcomes of patients after cardiac surgery.Methods/designNOTACS is an adaptive, international, multicentre, parallel group, randomised controlled trial, with a pre-planned interim sample size re-estimation (SSR). A minimum of 850 patients will be randomised 1:1 to receive either HFNT or SOT. The primary outcome is days alive and at home in the first 90 days after the planned surgery (DAH90), with a number of secondary analyses and cost-effectiveness analyses also planned. The interim SSR will take place after a minimum of 300 patients have been followed up for 90 days and will allow for the sample size to increase up to a maximum of 1280 patients.ResultsThis manuscript provides detailed descriptions of the design of the NOTACS trial and the analyses to be undertaken at the interim and final analyses. The main purpose of the interim analysis is to assess safety and to perform a sample size re-estimation. The main purpose of the final analysis is to examine the safety, efficacy and cost-effectiveness of HFNT compared to SOT on the outcomes of patients after cardiac surgery.DiscussionThis manuscript outlines the key features of the NOTACS statistical analysis plan and was submitted to the journal before the final analysis in order to preserve scientific integrity under an adaptive design framework. A previous version of this SAP was published prior to the interim analysis (Dawson, 2022). The NOTACS SAP closely follows published guidelines for the content of SAPs in clinical trials (Gamble, 2017).Trial registrationISRCTN14092678. (13 May 2020).

A phase 1/2 study of gilteritinib in combination with chemotherapy in newly diagnosed patients with AML in Asia.

This interim analysis of a phase 1/2, open-label, single-arm study assessed the safety, efficacy, and pharmacokinetics of gilteritinib plus chemotherapy in adults with newly diagnosed FLT3 mutation-positive acute myeloid leukemia. In sequential phase 1 and 2 studies, induction and consolidation therapy with gilteritinib 120 mg/day plus chemotherapy (induction: idarubicin/cytarabine once daily; consolidation: cytarabine twice daily) was followed by maintenance gilteritinib 120 mg/day monotherapy. Endpoints included maximum tolerated dose (MTD), recommended expansion dose (RED), and dose-limiting toxicity (phase 1), and complete remission (CR) rate following induction therapy (primary endpoint), overall survival (OS), safety, and pharmacokinetics (phase 2). In phase 1, MTD was not reached and RED was 120 mg/day. In phase 2, the CR rate was 50.0% after induction (90% confidence interval [CI] 40.4, 59.6); however, the lower confidence limit did not exceed the pre-defined 55% benchmark. Composite CR (CRc) rates were high following induction (86.6%, 95% CI [77.3, 93.1]), consolidation, and maintenance therapy (87.8%, 95% CI [78.7, 94.0], each). The probability of OS was 86.6% at 12 months. No new safety findings were reported. In this interim analysis, gilteritinib 120 mg/day in combination with chemotherapy was well tolerated, with similar CRc rates to previous studies.

Pilot Trial of Perampanel on Peritumoral Hyperexcitability in Newly Diagnosed High-grade Glioma.

Glutamatergic neuron-glioma synaptogenesis and peritumoral hyperexcitability promote glioma growth in a positive feedback loop. The objective of this study was to evaluate the feasibility and estimated effect sizes of the targeted AMPA receptor antagonist perampanel on peritumoral hyperexcitability. An open-label trial was performed comparing perampanel with standard of care (SOC) in patients undergoing resection of newly diagnosed radiologic high-grade glioma. Perampanel was administered as a preoperative loading dose followed by maintenance therapy until progressive disease or up to 12 months. SOC treatment involved levetiracetam for 7 days or as clinically indicated. The primary outcome of hyperexcitability was defined by intraoperative electrocorticography high-frequency oscillation (HFO) rates. Seizure freedom and overall survival were estimated by the Kaplan-Meier method. Tissue concentrations of perampanel, levetiracetam, and correlative biomarkers were measured by mass spectrometry. HFO rates were similar between patients treated with perampanel and levetiracetam. The trial was terminated early after a planned interim analysis, and outcomes assessed in 11 patients (seven perampanel treated; four treated with SOC). Over a median 281 days of postenrollment follow-up, 27% of patients had seizures, including 14% maintained on perampanel and 50% treated with SOC. Overall survival in perampanel-treated patients was similar to that in a glioblastoma reference cohort. Glutamate concentrations in surface biopsies were positively correlated with HFO rates in adjacent electrode contacts and were not significantly associated with treatment assignment or drug concentrations. Glioma peritumoral glutamate concentrations correlated with high-gamma oscillation rates. Targeting glutamatergic activity with perampanel achieved similar electrocorticographic hyperexcitability levels as in levetiracetam-treated patients.

A study of the comparative effectiveness of dual antiplatelet therapy and a combination of acetylsalicylic acid with colchicine in patients in the acute period of “minor” ischemic atherothrombotic stroke during hospitalization. Interim analysis of data from the «COLCHIDA» study

Influence on inflammation is currently becoming a priority target for the prevention of recurrent atherothrombotic events, including stroke. In 2022, we planned the KOLCHIDA study, a two-center, prospective, randomized, open-label, controlled clinical trial with endpoint assessment (ClinicalTrials.gov identifier: NCT06102720). The purpose of this study is to conduct a comparative assessment of the clinical effectiveness of dual antiplatelet therapy with acetylsalicylic acid (ASA) and clopidogrel and the combination of ASA with colchicine in patients in the acute period of “minor” ischemic atherothrombotic stroke. The purpose of this publication is to present the basic concept of the protocol, its design and the first intermediate results. Material and methods. The intervention consisted of colchicine 0.5 mg/day in addition to ASA versus dual antiplatelet therapy (DAPT) in patients with non-severe ischemic stroke. 31 patients were included in the colchicine and ASA group, and 34 patients were included in the DAPT group. Results. In the comparison group, 7 (20.6%) recurrent non-fatal strokes were recorded, in contrast to the colchicine group, where acute vascular events were recorded in only two patients (6.5%) [RRR 2.2, NNT = 7, χ2 = 2, 9, p = 0.09]. There were no clinically significant bleeding or other adverse events in both groups. Conclusion. Interim results of the study indicate possible confirmation of the hypothesis that anti-inflammatory therapy with low doses of colchicine in combination with standard therapy is not inferior to the combination of ASA and clopidogrel, and perhaps more effectively reduces the number of early neurological deteriorations and recurrent ischemic strokes in patients in the acute period of mild atherothrombotic stroke with equal security profile.

Comparison of the Predictive and Prognostic Capacities of Neutrophil, Lymphocyte and Platelet Counts and Tumor-infiltrating Lymphocytes in Triple-negative Breast Cancer: Preliminary Results of the PERCEPTION Study.

Triple-negative breast cancer (TNBC) is the most heterogeneous breast cancer subtype, posing numerous challenges in clinical decision-making. Biomarkers are essential to personalize management of TNBC patients. While tumor infiltrating lymphocytes (TILs) are validated prognostic biomarkers, the requirement for tumor biopsy limits their routine use. Therefore, more accessible and reliable quantitative biomarkers are needed. Given the significant role of systemic inflammatory response in tumor onset and progression, assessing inflammatory cells via liquid biopsies emerges as a promising alternative. The PERCEPTION study, conducted at Centre Jean Perrin in France, aims to determine the correlation between TILs and peripheral blood components at diagnosis. An interim analysis was conducted after enrolling 50% of the estimated population, to evaluate study feasibility and preliminary correlations between blood cell counts and TILs. Sixty-one patients were enrolled over 4.5 years, demonstrating a good inclusion rate with minimal missing data. Preliminary results for 36 analyzable patients showed no correlation between the neutrophil-to-lymphocyte ratio (NLR) and TILs (rs=-0.19, 95%CI=-0.49-0.16, p=0.3). However, a moderate, positive, statistically significant correlation was found between NLR and the CD8/FoxP3 TILs ratio (rs=0.36, 95%CI=0.03-0.64, p=0.043). The probabilistic index of 0.7 (p=0.06) between NLR-high and NLR-low groups for this ratio supports the correlation. The interim analysis of the PERCEPTION study confirms the feasibility of correlating blood cell counts with TILs in TNBC. Although no significant correlation was observed between NLR and TILs, the moderate positive correlation between the CD8/FoxP3 ratio and TILs suggests a potential link between systemic inflammation and local immune response. These findings underscore the potential of blood-based markers as non-invasive surrogates for TILs, encouraging further research to enhance prognosis and guide treatment strategies in TNBC.

P192 CaboCombo: interim analyses from an international real-world study assessing the use of cabozantinib plus nivolumab (CaboNivo) as first-line (1L) treatment for advanced Renal Cell Carcinoma (aRCC)

P192 CaboCombo: interim analyses from an international real-world study assessing the use of cabozantinib plus nivolumab (CaboNivo) as first-line (1L) treatment for advanced Renal Cell Carcinoma (aRCC)

P067 An interim analysis of the multi center retrospective study PROVIDENCE: Artificial intelligence-based models for estimating the risk of biochemical recurrence with clinical data

P067 An interim analysis of the multi center retrospective study PROVIDENCE: Artificial intelligence-based models for estimating the risk of biochemical recurrence with clinical data