Stopping Rule Research Articles

A Phase I Open Label Study of Fostamatinib, a SYK Inhibitor, in Patients with Lower-Risk Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia

INTRODUCTION: Ineffective hematopoiesis in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) have been associated to upregulated innate immune and inflammatory signals. Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase that is highly expressed in hematopoietic cells and mediates signaling through Toll-like receptors and pattern recognition receptors leading to activation of the ERK, AKT, NF-kB and p38 signaling cascades. Given prior data suggesting that inhibition of these signals might be associated with improved hematopoiesis in MDS we hypothesized SYK inhibition might have therapeutic efficacy in lower-risk MDS and CMML. METHODS: To study this we designed an open label phase I clinical trial of fostamatinib, a SYK inhibitor, for patients with lower-risk MDS or CMML (defined as those with a score <3.5 by the revised International Prognostic Scoring System [IPSS-R]) and no response to prior erythroid stimulating agents or hypomethylating agents (HMAs). Patients with MDS with del(5q) must have received prior therapy with lenalidomide and those with MDS with ring sideroblasts must have received luspatercept. Patients had to be transfusion dependent, defined as prior RBC or platelet transfusions within the past 28 days, or have hemoglobin <10g/dL or platelets <75x109/L. Patients with profound neutropenia (ANC <0.5x109/L) where excluded. The study includes an intra-patient dose escalation design by which patients start therapy at a dose of fostamatinib of 100mg po bid on days 1-28 of a 28-day cycle. If no response to therapy, by IWG 2006 response criteria, is observed after 8 weeks of therapy dose will be escalated to 150mg po bid on days 1-28 of a 28-day cycle and then, in the absence of response after an additional 8 weeks of therapy, to 200mg po bid on days 1-28 of a 28 day cycle. Patients achieving no response after the second dose escalation will be discontinued from study (Figure 1a). The primary endpoint of the study is to assess the safety and tolerability of fostamatinib. Secondary objectives included overall response rates, transfusion independence and survival outcomes. The study includes futility and safety stopping rules. This study is registered at clinicaltrials.gov (NCT05030675). RESULTS: To date, a total of 5 patients have been treated on study as of July 2022 including 3 patients with MDS and ring sideroblasts. Patient characteristics are detailed in Figure 1b. Median age is 71 years (range 59-82). Median number of prior therapies was 5 (range 4-6) including one patient with a prior allogeneic stem-cell transplant. Four (80%) patients had received prior therapy with HMA. Two patients were transfusion dependent of RBC at the time of enrollment with one patient who was eligible based on the presence of thrombocytopenia. At the current data cut off, three patients developed treatment emergent adverse events the main including grade 1-2 diarrhea or constipation. One patient developed COVID-19 infection during the course of therapy and had mild symptomatology. Fostamatinib was not discontinued in this patient. No episodes of expected on-target uncontrolled hypertension or transaminitis have been observed so far. To date, only 4 patients have completed at least 2 cycles of therapy (8 weeks) and are eligible for response, and only 2 patients have dose escalated beyond 100mg po bid: 1 currently at the 150mg po bid dose level, and 1 at the maximum dose of 200mg po bid. With a median follow up of only 2.7 months (95% CI 0-5.6), no responses have been observed. All 5 patients remain on study: 3 (60%) at the 100mg po bid dose, 1 (20%) at 150mg po bid and 1 (20%) at 200mg po bid. CONCLUSIONS: Preliminary data suggests that treatment with fostamatinib at doses of up to 200mg po bid can be safely administered in patients with lower-risk MDS who have failed available therapies. Enrollment is ongoing to determine the potential efficacy of doses of up to 200mg bid. Additional correlative studies to determine predictors of response are underway. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Targeting Hedgehog Signaling with Glasdegib in Patients with Refractory Sclerotic Chronic Graft vs. Host Disease: A Report of Two Phase I/II Trials

Introduction Sclerotic chronic graft vs. host disease (scGVHD) is characterized by progressive skin fibrosis that often causes limited mobility and poor quality of life. Aberrant activation of hedgehog signaling leading to the differentiation of dermal fibroblasts into collagen-releasing myofibroblasts has been implicated in scGVHD. Targeted inhibition with hedgehog pathway inhibitors ameliorate fibrosis in experimental models. Our objective was to determine the safety and efficacy of glasdegib, an oral antagonist of the hedgehog signalling transducer Smoothened (SMO) in adult patients (pts) with refractory scGVHD. Methods Two independent, single-arm, open-label, phase I/II investigator-initiated studies [NCT03415867, Spanish Transplantation and Cellular Therapy Cooperative Group (GETH); NCT04111497, Fred Hutchinson Cancer Center/Huntsman Cancer Institute/Duke University Medical Center (FHD)] were performed. Adults with active scGVHD after ≥1 (FHD) or ≥2 (GETH) lines of prior therapy were enrolled. The GETH trial followed a 3+3 dose-finding strategy, whereas the FHD trial employed a fixed-dose design. Primary endpoints were dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) in the GETH trial, and safety and tolerability in the FHD trial. Secondary endpoints included efficacy, patient-reported outcomes and biological correlates of response. Glasdegib was administered once daily in continuous 28-day cycles. Individual organs were scored per 2014 NIH cGVHD criteria. A scGVHD partial response (PR) was defined as skin and/or joints score improvement (≥1 point for body surface area [BSA], skin features or joints/fascia scores; ≥2 points for skin/joints tightening or total P-ROM scores) in the absence of worsening in those scores or an increase ≥2 points in the global severity score. Data cut-off was at 12 months from time of glasdegib initiation. Results Twenty (GETH) and 15 (FHD) pts were enrolled who received a median of 4 (range 2-10) and 4 (1-16) prior lines of therapy. The median age was 47 years (range 27-73) and 64 (33-74) in the GETH and FHD studies, respectively. In the GETH trial, 3 pts were included in cohort 1 (50 mg), 3 in cohort 2 (100 mg) and 16 in the expansion cohort (50 mg). All pts in the FHD trial received glasdegib at an initial dose of 50 mg. Frequent treatment-emergent grade (G) ≥2 adverse events (AEs) in the GETH trial included muscle cramps (85%), alopecia (50%) and dysgeusia (35%). Two pts in cohort 2 experienced a DLT (G3 muscle cramps) that resulted in establishment of the MTD at 50 mg. Similarly, G3 muscle cramps were the most frequently reported adverse event (AE) occurring in 33% of pts in the FHD trial. In the FHD study, a pre-specified trial stopping rule was triggered by the emergence of G3 muscle cramps AEs in 5 pts. In the GETH trial, glasdegib dose reductions were undertaken in 10 pts, and 8 pts stopped glasdegib before completion of 12 cycles of therapy. Ten pts remained on treatment beyond 12 months. In the FHD trial, the glasdegib dose was reduced in 5 pts; 12 pts stopped glasdegib before 12 cycles. Two pts remained on treatment for longer than 12 months and one pt remains on glasdegib at 10 months. At the 12-month data cut-off, 9 (45%) pts in the GETH trial achieved a skin BSA score and/or sclerotic features score PR, and 9 (45%) pts had obtained a joints/fascia score response (6 PRs, 3 complete responses). Corresponding findings in the FHD trial were 4 pts (27%; 3 PRs, 1 CR) and 3 pts (20%; 2 PRs, 1 CR). An improvement ≥2 points in the total P-ROM score was observed in 11 (55%) pts in the GETH study and 4 (27%) pts in the FHD study, Additionally, an improvement ≥2 points in the 0-10 skin and/or joint tightening severity scale was reported in 13 (65%) and 4 (31%; 2 pts with missing data) pts in the GETH and FHD trials, respectively. Overall, 13 (65%) pts obtained a scGVHD PR in the GETH trial, with a median time of 2.4 months to response. Likewise, 7 (47%) pts had a scGVHD PR in the FHD group, with a median time of 0.9 months to response. Preliminary correlative studies did not show changes in the distribution of T-cell subpopulations or TCR diversity in the GETH trial. Conclusions Glasdegib demonstrated high rates of clinical activity in heavily pretreated pts with scGVHD, but tolerability was hampered by the emergence of treatment-related muscle cramps. Yet, selected pts derived a sustained benefit from treatment in the absence of limiting toxicities. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase I/II Study of Seclidemstat, an LSD1 Inhibitor, and Azacitidine for Patients with Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia

INTRODUCTION: Hypomethylating agents (HMA) remain the standard of care for myelodysplastic syndromes (MDS) but responses remain transient with loss of response being associated with dismal outcomes. Lysine specific demethylase 1 (LSD1) is a histone demethylase implicated in the maintenance of pluripotency and proliferation genes which is overexpressed in MDS. Given the importance of epigenetic deregulation in MDS and chronic myelomonocytic leukemia (CMML) we hypothesized that LSD1 inhibition, in combination with HMAs, may be synergistic and lead to enhanced antileukemic and pro-differentiation potential in MDS/CMML. METHODS: To study this we designed an open label phase I/II clinical trial of seclidemstat, a selective LSD1 inhibitor, in combination with azacytidine for patients with MDS or CMML with intermediate-1 or higher risk by International Prognostic Scoring System (IPSS) and progression or no response to 6 prior cycles of HMA. Study design includes an initial phase I dose escalation phase evaluating 6 dose levels of seclidemstat (150mg, 300mg, 450mg, 600mg, 900mg and 1200mg administered orally bid on days 1-28 of each 28 day cycle) in combination with azacytidine 75mg/m2 daily on days 1-7 of each 28 day cycle. Following the completion of phase I dose escalation the study will include a dose expansion phase (n=20) to gain further experience at the selected phase 2 recommended dose of seclidemstat. Study primary endpoint is to determine the safety, tolerability and maximum tolerated dose of seclidemstat in combination with azacytidine. Other study objectives include overall response rate and survival outcomes. Responses to therapy will be assessed following 2006 IWG response criteria. The study includes futility and safety stopping rules. This study is registered at clinicaltrials.gov (NCT04734990). RESULTS: To date, a total of 6 patients (3 in dose level 1 of seclidemstat 150mg po bid, and 3 in dose level 2 of 300mg po bid) have been treated on study as of July 2022: 5 with MDS and 1 with CMML. Patient characteristics are shown in Table 1. A total of 4 (67%) patients had higher risk MDS with complex karyotype and/or TP53 mutations after failure to HMA. Median number of prior therapies was 2 (range 1-3). Only 5 patients are evaluable for toxicity and response at the time of data cut off. To date, no DLTs have been observed. All evaluable patients experienced treatment emergent adverse events (AEs) with no treatment-related grade 3 AEs. The most frequently observed AE was transient grade 1 (n=2) and 2 (n=1) creatinine elevation which was observed during the first week of therapy and subsequently reverted to baseline levels. One patient developed QTC prolongation in the context of a right ventricular bundle branch block which was unrelated to study treatment. Dose interruptions were required only in 1 patient due to grade 2 creatinine elevation, and treatment could be resumed after normalization of creatinine levels. With a median follow up of 4.3 months (95% CI 2.0-6.6) and a median of 3 (range 2-4) cycles of therapy, response to therapy was observed in 2 patients including 1 mCR+HI with partial cytogenetic response, who transitioned to allogeneic stem-cell transplant after 3 cycles of therapy, and 1 mCR. Two patients remain on study at the 300mg po bid dose level. CONCLUSIONS: The combination of seclidemstat with azacitidine seems safe at the current dose levels and shows initial signs of potential activity. Further enrollment and follow up continues to further explore this combination. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase II Clinical Trial of "Off-the-Shelf" NK Cells with Allogeneic Stem Cell Transplantation to Decrease Disease Relapse in Patients with High-Risk Myeloid Malignancies

Background Acute myeloid leukemia, myelodysplastic syndrome, and TKI resistant CML continue to be among the most aggressive forms of blood cancer. Allogeneic hematopoietic stem cell transplantation (alloSCT) remains one of the most effective treatments available. Much of the benefit of AlloSCT is due to the immune-mediated graft-versus-leukemia effect to prevent relapse. Nevertheless, disease relapse remains the most important cause of treatment failure after alloSCT. A potential solution to reduce the risk of relapse may be found in Natural Killer (NK) cells, which have a demonstrable ability to eliminate leukemic and virally infected cells. However, naturally produced NK cells seen in patients early post-transplant are functionally impaired. A potential solution would be to provide donor-derived, expanded and activated NK cells in the peri-transplant setting. Natural killer cells are a unique class of lymphocytes, with cytotoxic, and immunoregulatory function which can mediate potent anti-leukemia effects. NK cells are regulated by Killer-cell Immunoglobulin-like Receptors (KIR) receptor-ligand interactions and mediate cytotoxicity. Alloreactive NK cells have been reported to enhance engraftment, reduce GVHD and prevent relapse of leukemia post transplant. This study will utilize NK cells from third party donors as adjuvant treatment to eradicate leukemia and prevent disease relapse after transplantation. Study Design and Methods Our clinical trial is registered as NCT05115630. Inclusion criteria includes age 18 to 65 years old, weighing at least 42 kg, with High risk AML, MDS, or TKI-resistant/intolerant CML who have either an HLA matched related donor, HLA matched unrelated donor, a haploidentical related donor, or a one antigen mismatched unrelated donor. HLA matching includes HLA A, B, C, and DR-B1. Exclusion criteria include patients who are HIV positive or has active hepatitis B or C, uncontrolled infections, liver cirrhosis, CNS involvement within 3 months prior to the transplant, or positive pregnancy test in a woman with child bearing potential. We will also exclude any patient with inability to comply with medical therapy or follow-up, patient with a known history of allergic reactions to any constituents of the product, including a known history of allergic reactions to cellular products or DMSO, other malignancy/cancer diagnosis <2 years ago. We will also exclude any patient requiring systemic corticosteroids with prednisone dose >10 mg or equivalent or who has KDS-1001 Donor specific antibodies (dsa) >5000 MFI units, or has KDS-1001 Donor anti-C1q positive. Statistical considerations and exploratory endpoints This is a single-arm Phase II trial of 3rd party natural killer (NK) cells at a fixed dose added to an allogeneic stem cell transplant for AML/MDS/CML. The goal is to reduce the risk of relapse of the malignancy post transplant, and to improve relapse free survival. The primary endpoint is the adverse event Failure = [graft failure, grade 3-4 GVHD, relapse or non-relapse death within 100 days post-transplant]. The stopping rule for time-to-failure (defined as graft failure, gr 3-4 GHVD, or non-relapse death) will be implemented to avoid waiting 100 days (3 months) to evaluate each patient to perform safety monitoring. The design will be based on T with 3 months follow-up, applying the design of Thall et al. Possibly right-censored values of T for patients treated in the trial will be monitored continuously throughout the trial. The accrual rate is expected to be approximately 2 patients per month, with each patient's follow-up continued until all patients have been followed for 3 months from their date of first NK cell administration. The distributions of time to failure and RFS time will be estimated using the method of Kaplan and Meier. Exploratory analyses with immunophenotyping for NK cell chimerism and persistence will be done as feasible. Immune reconstitution studies or additional future research may be performed.

A pilot study of oral iron therapy in erythropoietic protoporphyria and X-linked protoporphyria

The use of iron supplementation for anemia in erythropoietic protoporphyria (EPP) is controversial with both benefit and deterioration reported in single case reports. There is no systematic study to evaluate the benefits or risks of iron supplementation in these patients. We assessed the potential efficacy of oral iron therapy in decreasing erythrocyte protoporphyrin (ePPIX) levels in patients with EPP or X-linked protoporphyria (XLP) and low ferritin in an open-label, single-arm, interventional study. Sixteen patients (≥18 years) with EPP or XLP confirmed by biochemical and/or genetic testing, and serum ferritin ≤30 ng/mL were enrolled. Baseline testing included iron studies, normal hepatic function, and elevated plasma porphyrins and ePPIX levels. Oral ferrous sulfate 325 mg twice daily was administered for 12 months. The primary efficacy outcome was the relative difference in total ePPIX level between baseline and 12 months after starting treatment with iron. Secondary measures included improvement in serum ferritin, plasma porphyrins, and clinical symptoms. Thirteen patients had EPP (8 females, 5 males) and 3 had XLP (all females) and the mean age of participants was 38.8 years (SD 14.5). Ten patients completed all study visits limiting interpretation of results. In EPP patients, a transient increase in ePPIX levels was observed at 3 months in 9 of 12 (75%) patients. Iron was discontinued in 2 of these patients after meeting the protocol stopping rule of a 35% increase in ePPIX. Seven patients withdrew before study end. Ferritin levels increased on iron replacement indicating an improvement in iron status. A decrease in ePPIX was seen in both XLP patients who completed the study (relative difference of 0.67 and 0.5 respectively). No substantial changes in ePPIX were seen in EPP patients at the end of the study (n = 8; median relative difference: -0.21 (IQR: −0.44, 0.05). The most common side effects of iron treatment were gastrointestinal symptoms. Hepatic function remained normal throughout the study. Our study showed that oral iron therapy repletes iron stores and transiently increases ePPIX in some EPP patients, perhaps due to a transient increase in erythropoiesis, and may decrease ePPIX in XLP patients. Further studies are needed to better define the role of iron repletion in EPP.Trial registration: NCT02979249.

Nomogram for predicting spontaneous pregnancy after microscopic varicocelectomy in infertile men with normal hormone

IntroductionThe current challenge for the treatment of varicocele is identifying patients who could benefit the most from surgery. We aimed to develop and validate a nomogram for predicting spontaneous pregnancy following microscopic varicocelectomy in infertile men, based on a large cohort.MethodsTwo hundred eighty-two consecutive patients who underwent microscopic varicocelectomy from January 2018 to December 2020 were enrolled as participants in the study. Xiang Hua center (206 patients) as a development cohort. Hu Nan center (76 patients) as a validation cohort. Patient clinicopathologic data were recorded. Multivariate logistic regression was used to build a predictive model with regression coefficients. Then, backward stepwise selection was applied, and the likelihood ratio test with Akaike’s information criterion was used as the stopping rule. The performance of this predictive model was assessed for discrimination, calibration, and clinical usefulness.ResultsPredictors of this model included the age of female partners, diameter of veins, initial and increased total progressively motile sperm count. The model demonstrated good discrimination with an AUROC of 0.925 (p < 0.001) and calibration (Unreliability test, p = 0.522) in the validation cohort. Furthermore, the model was clinically useful, according to decision curve analysis.ConclusionsOur findings indicated that younger female partners, larger diameter of veins, higher initial and increased total progressively motile sperm count were significant predictors of spontaneous pregnancy in infertile men, post microscopic varicocelectomy. This nomogram may assist in individual decision-making on the treatment strategy of varicocele preoperatively and improve the treatment outcome.

ISABR: Safety and Efficacy Results from a Phase II Study of SABR in Combination with Durvalumab for Early-Stage Medically Inoperable NSCLC

<h3>Purpose/Objective(s)</h3> SABR is standard for medically inoperable early-stage NSCLC and results in excellent outcomes. However, rate of regional and distant failures is significant. Addition of immune check point inhibitors improve disease control and overall survival in stage III and IV NSCLC and may improve outcomes in early-stage NSCLC. We report safety and efficacy results of a phase II study of SABR with durvalumab (durva) in early-stage inoperable NSCLC. <h3>Materials/Methods</h3> Eligible patients had newly diagnosed, biopsy proven clinical stage I or IIA NSCLC defined by AJCC 7^th edition. Patient had to be medically inoperable or refused surgery. There was a 15-patient safety lead-in cohort with pre-specified stopping rules based on incidence of grade 3 or 4 treatment-related toxicity. Patients were treated with one cycle of durva at the time of CT simulation, followed by SABR (54 Gy in 3, 50 Gy in 4, or 65 Gy in 10), then up to 4 cycles of durva (1500 mg Q4 wk). No stopping rules were met, but due to slow accrual, the study terminated prematurely in the randomized Phase II portion (1:1; SABR/durva: SABR). A total of 20 patients were enrolled from October 2017 - March 2020. Eighteen patients received SABR/durva and thus form the cohort for analysis. Local control (LC), progression-free survival (PFS), overall survival (OS), and lung cancer specific survival (LCSS) were assessed using the Kaplan Meier method. Incidences of acute (≤ 90 days) and late (> 90 days) treatment-related grade 3+ pulmonary, cardiac, and GI toxicities were tabulated. <h3>Results</h3> Median age was 78.6 years-old with 61% male. Median follow-up time was 2.6 years. Seventy-two percent of the patients had T1 tumor and remaining had T2. Eighty-three percent of the patients had adenocarcinoma histology and remaining had squamous cell. Eighty-nine percent of the patients were former/current smokers. Seventy-eight percent of patients received all 5 cycles of durva, 1 patient received 3 cycles, and 2 patients received 1 cycle. The 1-, 2- year LC rates were 100% and 93.8%, PFS rates were 94.4% and 83.3%, and OS rates were 94.4% and 88.9%. The 2-year cumulative incidence for LCSS was 94.4%. At 2-years, stratified by median gross tumor volume (GTV), OS was 100% (GTV ≤ 7.9 mL) vs. 77.8% (GTV > 7.9 mL), p=0.07. Acute and late grade 3+ treatment-related toxicities were pulmonary (n=3, 16.7%; n=3, 16.7%), cardiac (none; n=3, 16.7%), and GI (none). There was one case of grade 4 pneumonitis. One patient retrospectively identified as having probably fibrotic lung disease at baseline died of respiratory failure, which was conservatively assessed as possibly related to study treatment. <h3>Conclusion</h3> For early-stage NSCLC, SABR/durva resulted in excellent disease specific outcomes, including survival. Safety was promising, but this study underscored the importance of excluding patients with any fibrotic lung disease for safety and optimal interpretation of adverse event data. Results support ongoing phase III trials determining the benefit of SABR/durva in these patients.

Prospective Single-Arm Trial of Preoperative 42.75 Gy in 15 Fractions for Soft Tissue Sarcoma of the Extremity/Trunk

<h3>Purpose/Objective(s)</h3> The standard pre-operative radiation therapy (RT) dose of 50 Gy in 25 daily fractions for soft tissue sarcoma (STS) contributes to excellent local control and is associated with major wound complications (MWC) in approximately 35% of patients. We sought to prospectively investigate whether a radiobiologically equivalent dose given in a 3-week course of 42.75 Gy in 15 daily fractions confers a higher risk of MWC. <h3>Materials/Methods</h3> We conducted a prospective, single-arm, non-randomized trial of hypofractionated pre-operative RT consisting of 42.75 Gy in 15 once-daily fractions followed by surgery 4-8 weeks after RT completion for adult patients with biopsy-confirmed, non-metastatic, previously un-irradiated STS of the extremity or superficial trunk. Patients (n=120) were enrolled from December 2018 to January 2021. The primary outcome of the study was to determine the rate of MWC within 120 days of surgery among patients treated with the trial regimen. Safety was monitored using a Bayesian stopping rule One-Arm Time-To-Event Simulator which compared development of MWC at 120 days post-surgery among patients on study to the historical rate of 35%. The Kaplan-Meier method was used to estimate outcomes. <h3>Results</h3> Median follow-up from surgery was 23 months (interquartile range [IQR] 15-29). Median age was 60 years (IQR 48-69) and median maximum tumor size was 7.6 cm (IQR 4.5-12.8). A majority of the patients had lower extremity (LE) tumors (n=78, 65%; upper extremity (UE), n=20, 17%; trunk, n=22, 18%). Tumor grade was: high in 51% (n=61), intermediate in 23% (n=27), low in 8% (n=9), or not gradable in 19% (n=23). All patients received 42.75 Gy (or CGE) in 15 once-daily fractions with either: IMRT (n=57, 48%), 3D-RT (n=55, 46%), electrons (n=5, 4%), or protons (n=3, 3%). None experienced acute skin toxicity of CTCAE v4.0 > or = grade 3. Thirty-seven (31%, 95% CI: 24-40%) patients developed MWC within 120 days of surgery (median, 37 days (IQR 25-59)). Six patients (5%) developed local recurrence at a median 16 mos (IQR 7-17); 4 in the RT field, 1 at the field margin, and 1 wide of field. Actuarial 2-year local control is 93% (95% CI: 85-97%). <h3>Conclusion</h3> Our prospective non-randomized clinical trial revealed that a hypofractionated pre-operative radiotherapy dosing regimen of 42.75 Gy in 15 once-daily fractions resulted in a MWC rate that was not higher than accepted historical rates. Early analyses show rates of local recurrence that are consistent with those observed with standard fractionation. These data support that this 3-week regimen may offer a safe, effective, and more convenient alternative to 50 Gy in 25 daily fractions for patients undergoing pre-operative RT for STS.

Dose finding studies for therapies with late-onset toxicities: A comparison study of designs.

An objective of phase I dose-finding trials is to find the maximum tolerated dose; the dose with a particular risk of toxicity. Frequently, this risk is assessed across the first cycle of therapy. However, in oncology, a course of treatment frequently consists of multiple cycles of therapy. In many cases, the overall risk of toxicity for a given treatment is not fully encapsulated by observations from the first cycle, and hence it is advantageous to include toxicity outcomes from later cycles in phase I trials. Extending the follow up period in a trial naturally extends the total length of the trial which is undesirable. We present a comparison of eight methods that incorporate late onset toxicities while not extensively extending the trial length. We conduct simulation studies over a number of scenarios and in two settings; the first setting with minimal stopping rules and the second setting with a full set of standard stopping rules expected in such a dose finding study. We find that the model-based approaches in general outperform the model-assisted approaches, with an interval censored approach and a modified version of the time-to-event continual reassessment method giving the most promising overall performance in terms of correct selections and trial length. Further recommendations are made for the implementation of such methods.

Prognostic utility of a multibiomarker panel in patients with suspected myocardial infarction

Abstract Introduction Rapid and accurate evaluation of patients presenting with suspected myocardial infarction (MI) to the emergency department (ED) is crucial due to strongly varying outcomes in these patients. Despite the routine use of circulating biomarkers, among which high-sensitivity cardiac troponin currently dictates diagnostic protocols in chest pain patients, it still remains unclear which biomarkers are of highest utility for prognostic purposes in this patient collective. Purpose We sought to investigate the prognostic utility of a multibiomarker panel with 29 different biomarkers in a contemporary cohort of patients with suspected MI by applying a dual analytical approach. Methods The multibiomarker panel was measured in stored blood samples that were collected directly at admission from 748 prospectively enrolled patients who presented with symptoms suggestive of MI to the ED of a German tertiary center between 2013 and 2017. The final diagnosis of all patients was adjudicated according to the 4th Universal Definition of MI. The investigated endpoint comprised incident major cardiovascular events (MACE) within 1 year after admission. MACE was defined as the composite of cardiovascular death, non-fatal MI (excluding index events), revascularization and cardiac rehospitalization. Log-transformed biomarkers were entered individually into an age-and sex-adjusted Cox regression model to explore the hazard ratio (HR) per one standard deviation increase (SD) for 1-year MACE in the overall cohort. The selection of optimal multimarker models, adjusted for age and sex, was performed using 1) stepwise backward selection via Akaike information criterion as the stopping rule, and 2) Least Absolute Shrinkage and Selection Operator (LASSO) with 5-fold cross-validation. Results Out of 748 patients with available multibiomarker panel, 138 (18.4%) were diagnosed with MI. Median age at admission was 64 (interquartile range [IQR] 50–75) years in the overall cohort, 63.1% were male. At 1 year of follow-up, 160 cases of incident MACE were documented. 16 of the investigated 29 biomarkers were significantly associated with 1-year MACE, amongst which NT-proBNP was the strongest predictor (HR per SD 1.74, 95% confidence interval [CI] 1.44–2.09, p&amp;lt;0.0001; Table 1). Using stepwise backward selection, three biomarkers including NT-proBNP, Apo A-I and Apo C-III remained in the final multivariable model (Figure 1). The LASSO approach confirmed NT-proBNP (HR per SD 1.24) and Apo A-I (HR per SD 0.98) as strong and independent predictors of 1-year MACE while Apo C-III was replaced with KIM-1 (HR per SD 1.06). Conclusions Among 29 biomarkers, numerous provide prognostic utility while NT-proBNP and Apo A-I emerged as the strongest independent predictors of 1-year MACE. Their routine assessment and integration into risk prediction models may improve personalized risk stratification in patients with symptoms suggestive of MI. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The BACC study was supported by the German Center for Cardiovascular Research, an unrestricted grant by Abbott Diagnostics, and Prevencio, which also partly covered the biomarker measurements.

VP.13 Updates on the development of the spinal muscular atrophy - person-reported outcome (SMA-PRO): A caregiver and self-proxy performance measure for child

There is a need for person-reported outcome measures for SMA. The PEDI-CAT is a caregiver-reported measure used to describe functional skill performance. Convergent validity of the PEDI-CAT with SMA phenotypes was established, and Rasch analysis of the full item bank revealed representation of abilities for SMA III and for daily activities for SMA II, but a floor effect for SMA I. Results led to the development of a new measure to include a larger item bank with caregiver and self-proxy options. Goals were 1) To describe the SMA PRO test development, including focus groups and cognitive-testing for item content 2) To describe the development of branching logic for data collection and 3) To report interim results on data collected with the new measure. Clinicians with expertise in SMA participated in 4 focus groups. Clinicians reviewed the results of the Rasch analysis and discussed content, scoring and clarity for the 76 daily activities and 105 mobility items. Thirty mobility and 69 daily activities items were added to address the floor effect and include items for infants and adults. A power wheelchair domain was created with 35 items and illustrations including "maintaining hand on wheelchair joystick while driving on uneven terrain." Illustrations were re-created to increase relevance for adults and children. The new items and illustrations were reviewed and several items were discarded due to perception of redundancy. Clinicians then conducted cognitive interviews with 15 study participants (7 caregivers and 8 adolescents and adults with SMA). A maximum of 30 items with accompanying illustrations were reviewed at each interview with probing questions including, "In your own words, what do you think this question is asking?" and "Does the illustration match the item wording?" Cognitive interview results were collated and items were further edited. The final items and illustrations were added to a database, and branching logic was established based on pre-determined "stopping rules" to minimize the total number of items required for each respondent. Item surveys were sent to participants and caregivers via a secure email, and data was collected prospectively. At the time of this interim study point, 58 surveys had been completed (16 "non-sitters," 38 "sitters" and 25 "walkers") across 4 functional domains. Data collection is underway, and a full analysis will be performed in order to validate the measure.

AML-391 Phase 1/2, Open-Label, Dose Escalation, Dose Expansion Study of Menin Inhibitor DSP-5336 in Adult Patients With Acute Leukemia With and Without Mixed-Lineage Leukemia (MLL)– Rearrangement or Nucleophosmin 1 (NPM1) Mutation

Patients who relapse after initial acute leukemia (AL) treatment have median survival <6 months for AML and <1 y for ALL, especially AML or ALL with MLL rearrangements (MLLr) or relapsed AML with NPM1 mutations. Translocations of the MLL gene (5% to 10% of adult patients) produce an aggressive subtype, with a median overall survival (OS) of approximately 9 months. The NPM1 mutation (NPM1m) occurs in 30%-35% of adult de novo AML and is associated with a favorable prognosis. However, 40%-50% of these patients have concurrent FLT3-internal tandem duplication mutations negating this favorability. DSP-5336, a novel oral small-molecule, was developed to prevent menin protein binding to MLL fusion proteins that drive leukemogenesis. Nonclinical DSP-5336 studies showed selective growth inhibition against human AL cell lines with MLLr or NPM1m. Evidence of antitumor activity and survival advantage was demonstrated in 3 AML xenograft models with MLLr and/or NPM1m. Treatment with DSP-5336 may reduce leukemic cells and benefit patients with relapsed or refractory (R/R) MLLr or NPM1m AML or patients with R/R MLLr ALL. An open-label, single-arm, phase 1/2 study (NCT04988555) will evaluate the safety and efficacy of DSP-5336 and determine the recommended phase 2 dose (RP2D) in adults aged ≥18 y with relapsed/refractory AML or ALL after at least one line of therapy. Key inclusion criteria are ECOG performance status 0-2 and adequate organ function. Patients will be dosed twice daily in 28-day cycles. In phase 1, 21-30 patients will be enrolled into multiple dose cohorts (1-6 patients per dose level), with dose escalation determined using a two-parameter Bayesian logistic regression model. The RP2D will be informed by the maximum biologic effect or maximum tolerated dose, whichever is lower. The phase 2 study will include two arms (R/R AML with MLLr and R/R AML with NPM1m). Patients will be treated at the RP2D to evaluate clinical activity and safety and monitored using Bayesian posterior probability to optimize enrollment with Bayesian stopping rules. Bayesian monitoring of responses begins after the first 10 enrolled patients are evaluable for efficacy. This study is recruiting in the United States and Japan.

Developing an Item Bank of Computerized Adaptive Testing for Eating Disorders in Chinese University Students

We aimed to develop an item bank of computerized adaptive testing for eating disorders (CAT-ED) in Chinese university students to increase measurement precision and improve test efficiency. A total of 1,025 Chinese undergraduate respondents answered a series of questions about eating disorders in a paper-pencil test. A total of 133 items from four well-validated Chinese-version scales of eating disorders were used to construct the item bank of CAT-ED with the following analysis. First, unidimensionality, model fit, local independence, item fit, discrimination and differential item functioning (DIF) were tested. Then, two simulation studies were applied to test the CAT-ED’s effectivity and rationality by calculating concurrent criterion-related validity, sensitivity and specificity. The final item bank comprised 77 items, which met the requirements of local independence, item fit, high discrimination and no differential item functioning in CAT. The mean number of administered items in CAT with the stopping rule fixed at SE ≤ 0.3 was 11 items. The obtained results showed that CAT-ED had acceptable reliability, validity, sensitivity and specificity.

A Study of Stopping Rules in the Steepest Ascent Methodology for the Optimization of a Simulated Process

Competitiveness motivates organizations to implement statistical approaches for improvement purposes. The literature offers a variety of quantitative methods intended to analyze and improve processes such as the design of experiments, steepest paths and stopping rules that search optimum responses. The objective of this paper is to run a first-order experiment to develop a steepest ascent path to subsequently apply three stopping rules (Myers and Khuri stopping rule, recursive parabolic rule and recursive parabolic rule enhanced) to identify the optimum experimentation stop from two different simulated cases. The method includes the consideration of the case study, the fitting of a linear model, the development of the steepest path and the application of stopping rules. Results suggest that procedures’ performances are similar when the response obeys a parametric function and differ when the response exhibits stochastic behavior. The discussion section shows a structured analysis to visualize these results and the output of each of the stopping rules in the two analyzed cases.

Legal Reconstruction of the Termination of Highway Traffic Accident Investigation Based on the Values of Justice

The research aims to analyze the weaknesses of the current rules for stopping the investigation of road traffic accident cases and how to reconstruct the rules for stopping the investigation of road traffic accident cases based on the value of justice. To achieve this goal, an empirical juridical approach is used. The research specification is descriptive analysis. Primary data was obtained directly from the field. Collecting data through field studies (interviews) and literature studies. The data is presented in the form of descriptions that are arranged systematically, logically, and rationally, and analyzed using qualitative descriptive techniques. Research shows that the weaknesses are caused by the imposing conditional crimes which include the following: (1) the legal substance, related laws, and regulations have not accommodated the unique traffic accident cases. (2) Legal structure, not all Resort Police (Polres) implement traffic accident cessation based on restoration justice. (3) The legal culture and public views on stopping the investigation of road traffic accident cases have not been fully understood by the public. and based on this, the legal Reconstruction of stopping investigations of road traffic accident cases based on the value of justice can be done by encouraging the immediate ratification of the Draft Criminal Code into the National Criminal Code, by expanding the basic criminal sanctions on traffic accident cases in the form of humanitarian assistance based on the agreement of the litigants. With the following formulas: 1. The agreement of the litigating parties is requested for a resolution/deed of reconciliation to the Court Judge. 2. The decree/deed of peace has legal force and executorial power as well as control by state institutions outside the police as investigators. 3. The deed of peace from the judge is used as the basis for stopping the investigation for the sake of the law because the application of restorative justice is needed in order to realize a fair and transparent law.

A formalism for sequential estimation of neural membrane time constant and input–output curve towards selective and closed-loop transcranial magnetic stimulation * * Matlab Code is available at https://github.com/smmalavi/TMS-tau-IOC-estim-fixed-tp.

Objective. To obtain a formalism for real-time concurrent sequential estimation of neural membrane time constant and input–output (IO) curve with transcranial magnetic stimulation (TMS). Approach. First, the neural membrane response and depolarization factor, which leads to motor evoked potentials with TMS are analytically computed and discussed. Then, an integrated model is developed which combines the neural membrane time constant and IO curve. Identifiability of the proposed integrated model is discussed. A condition is derived, which assures estimation of the proposed integrated model. Finally, sequential parameter estimation (SPE) of the neural membrane time constant and IO curve is described through closed-loop optimal sampling and open-loop uniform sampling TMS. Without loss of generality, this paper focuses on a specific case of commercialized TMS pulse shapes. The proposed formalism and SPE method are directly applicable to other pulse shapes. Main results. The results confirm satisfactory estimation of the membrane time constant and IO curve parameters. By defining a stopping rule based on five times consecutive convergence of the estimation parameters with a tolerances of 0.01, the membrane time constant and IO curve parameters are estimated with 82 TMS pulses with absolute relative estimation errors (AREs) of less than 4% with the optimal sampling SPE method. At this point, the uniform sampling SPE method leads to AREs up to 16%. The uniform sampling method does not satisfy the stopping rule due to the large estimation variations. Significance. This paper provides a tool for real-time closed-loop SPE of the neural time constant and IO curve, which can contribute novel insights in TMS studies. SPE of the membrane time constant enables selective stimulation, which can be used for advanced brain research, precision medicine and personalized medicine.

A Bayesian adaptive design for clinical trials of rare efficacy outcomes with multiple definitions.

Bayesian adaptive designs for clinical trials have gained popularity in the recent years due to the flexibility and efficiency that they offer. We consider the scenario where the outcome of interest comprises events with relatively low risk of occurrence and different case definitions resulting in varying control group risk assumptions. This is a scenario that occurs frequently for infectious diseases in global health research. We propose a Bayesian adaptive design that incorporates different case definitions of the outcome of interest that vary in stringency. A set of stopping rules are proposed where superiority and futility may be concluded with respect to different outcome definitions and therefore maintain a realistic probability of stopping in trials with low event rates. Through a simulation study, a variety of stopping rules and design configurations are compared. The simulation results are provided in an interactive web application that allows the user to explore and compare the design operating characteristics for a variety of assumptions and design parameters with respect to different outcome definitions. The results for select simulation scenarios are provided in the article. Bayesian adaptive designs offer the potential for maximizing the information learned from the data collected through clinical trials. The proposed design enables monitoring and utilizing multiple composite outcomes based on rare events to optimize the trial design operating characteristics.

Markov Moment Problem and Sandwich Conditions on Bounded Linear Operators in Terms of Quadratic Forms

As is well-known, unlike the one-dimensional case, there exist nonnegative polynomials in several real variables that are not sums of squares. First, we briefly review a method of approximating any real-valued nonnegative continuous compactly supported function defined on a closed unbounded subset by dominating special polynomials that are sums of squares. This also works in several-dimensional cases. To perform this, a Hahn–Banach-type theorem (Kantorovich theorem on an extension of positive linear operators), a Haviland theorem, and the notion of a moment-determinate measure are applied. Second, completions and other results on solving full Markov moment problems in terms of quadratic forms are proposed based on polynomial approximation. The existence and uniqueness of the solution are discussed. Third, the characterization of the constraints T1≤T≤T2 for the linear operator T, only in terms of quadratic forms, is deduced. Here, T1, T,and T2 are bounded linear operators. Concrete spaces, operators, and functionals are involved in our corollaries or examples.

Alternative stopping rules to limit tree expansion for random forest models

Random forests are a popular type of machine learning model, which are relatively robust to overfitting, unlike some other machine learning models, and adequately capture non-linear relationships between an outcome of interest and multiple independent variables. There are relatively few adjustable hyperparameters in the standard random forest models, among them the minimum size of the terminal nodes on each tree. The usual stopping rule, as proposed by Breiman, stops tree expansion by limiting the size of the parent nodes, so that a node cannot be split if it has less than a specified number of observations. Recently an alternative stopping criterion has been proposed, stopping tree expansion so that all terminal nodes have at least a minimum number of observations. The present paper proposes three generalisations of this idea, limiting the growth in regression random forests, based on the variance, range, or inter-centile range. The new approaches are applied to diabetes data obtained from the National Health and Nutrition Examination Survey and four other datasets (Tasmanian Abalone data, Boston Housing crime rate data, Los Angeles ozone concentration data, MIT servo data). Empirical analysis presented herein demonstrate that the new stopping rules yield competitive mean square prediction error to standard random forest models. In general, use of the intercentile range statistic to control tree expansion yields much less variation in mean square prediction error, and mean square prediction error is also closer to the optimal. The Fortran code developed is provided in the Supplementary Material.

P01.06.B Interim results from CAR-Study B: An ongoing randomized trial on the effect of SRS or WBRT on cognitive performance in patients with 11-20 brain metastases

Abstract Background Both stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT) have proven to be effective treatments for multiple brain metastases (BM) with similar overall survival. Cognition and Radiation (CAR) Study B is a randomized trial on the effect of Gamma Knife radiosurgery (GKRS) or WBRT on cognitive performance in patients with 11-20 BM. The primary and secondary aim of this interim analysis were to check whether Bayesian stopping rules for cognitive failure were met, and to compare cognitive changes after treatment respectively, for the first 45 patients enrolled. Material and Methods Patients with 11-20 newly diagnosed BM on a triple-dose contrast-enhanced MRI-scan, expected survival &amp;gt;3 months and Karnofsky Performance Status (KPS) ≥70, were stratified by age, histology, total BM volume, systemic treatment, KPS, and baseline Hopkins Verbal Learning total recall (HVLT-R TR) score, and randomized 1:1 (minimization) to GKRS or WBRT. Neuropsychological tests were administered before (T0) treatment (n=21 vs n=20), and at 3 (T3; n=16 vs n=14) and 6 (T6; n=9 vs n=9) months thereafter. A decline of ≥5 points in HVLT-R TR score was considered a cognitive failure. The trial would be halted if the posterior probability for a higher cognitive failure rate in one group versus the other was &amp;gt;0·975 at T3 or T6 according to the employed beta (2.09,2.91) prior (prior mean of 42%), based on the average failure rates at 4 months reported by Chang et al. (2009). Between-group differences in changes of test performances over 6 months were analyzed using mixed ANOVAs. Proportions of cognitive changes (T0-T6) at the individual level based on reliable change indices correcting for practice effects, were determined. Results HVLT-R TR failure rates in the GKRS versus WBRT group were 31% versus 29% at T3, and 0% versus 33% at T6. The observed failure rates after WBRT at T3 and T6 were lower than the average failure rates of Chang et al. (2009). Posterior probabilities were 0·451 at T3 and 0·918 at T6. Over 6 months, changes in performance on tests of immediate (p=·003) and delayed recall (p=·024), and information processing speed (p=·003) were significantly different between groups (large effect sizes), with significant declines after WBRT, but not after GKRS. Over 6 months, at the individual patient level, there were no declines in performances across all tests in the GKRS group (n=8) while performances declined in 4 out of 8 patients in the WBRT group. Conclusion The stopping rules were not met since the posterior probabilities did not cross the threshold. Other preliminary findings in this small sample suggest that cognitive decline, both at group and individual level, is more pronounced after WBRT compared to GKRS. Accrual is continued (NCT02953717; ZonMw 842003006).