scholarly journals Bayesian Design for Identifying Cohort-Specific Optimal Dose Combinations Based on Multiple Endpoints: Application to a Phase I Trial in Non-Small Cell Lung Cancer

2021 ◽  
Vol 18 (21) ◽  
pp. 11452
Author(s):  
Bethany Jablonski Horton ◽  
Nolan A. Wages ◽  
Ryan D. Gentzler
Keyword(s):  
Standard Of Care ◽  
Optimal Dose ◽  
Maximum Tolerated Dose ◽  
Future Research ◽  
Primary Study ◽  
Multiple Drug ◽  
Treatment Combination ◽  
Multiple Endpoints ◽  
Bayesian Design ◽  
Negative Findings

Immunotherapy and chemotherapy combinations have proven to be a safe and efficacious treatment approach in multiple settings. However, it is not clear whether approved doses of chemotherapy developed to achieve a maximum tolerated dose are the ideal dose when combining cytotoxic chemotherapy with immunotherapy to induce immune responses. This trial of a modulated dose chemotherapy and Pembrolizumab, with or without a second immunomodulatory agent, uses a Bayesian design to select the optimal treatment combination by balancing both safety and efficacy of the chemotherapy and immunotherapy agents within each of two cohorts. The simulation study provides evidence that the proposed Bayesian design successfully addresses the primary study aim to identify the optimal dose combination for each of the two independent patient cohorts. This conclusion is supported by the high percentage of simulated trials which select a treatment combination that is both safe and highly efficacious. The proposed trial was funded and was being finalized when the sponsoring company decided not to proceed due to negative findings in another patient population. The proposed trial design will continue to be relevant as multiple chemotherapy and immunotherapy combinations become the standard of care and future research will require evaluating the appropriate doses of various components of multiple drug regimens.

Alcohol and Multiple Drug Abuse in Accused Murderers

1983 ◽  
Vol 52 (1) ◽  
pp. 159-164 ◽  
Author(s):  
William R. Holcomb ◽  
Wayne P. Anderson
Keyword(s):  
Drug Abuse ◽  
Violent Behavior ◽  
Demographic Variables ◽  
Future Research ◽  
Multiple Drug ◽  
Drinking Alcohol ◽  
Capital Murder ◽  
Alcohol And Other Drugs

The effects of alcohol and multiple drug abuse on violent behavior were studied with a sample of 110 men charged with first degree or capital murder. Subjects were divided into four groups based upon whether they were sober, drinking alcohol, using alcohol and other drugs in combination, or whether they were abusing only non-alcoholic drugs at the time of the murder. These four groups were compared on 15 sociological, behavioral, and demographic variables. Nine of these variables significantly differentiated the groups. Recommendations for intervention and future research are made.

scholarly journals 149 Virtual Care: A Quality Improvement Project on the Experience of Paediatricians during the COVID-19 Pandemic

2021 ◽  
Vol 26 (Supplement_1) ◽  
pp. e102-e104
Author(s):  
Emma McCrady ◽  
Julie Strychowsky ◽  
Jessica Woolfson
Keyword(s):  
Quality Improvement ◽  
Online Survey ◽  
Local Level ◽  
Standard Of Care ◽  
Subject Area ◽  
Future Research ◽  
Improvement Project ◽  
Diagnostic Uncertainty ◽  
Virtual Care ◽  
Practice Efficiency

Abstract Primary Subject area Practice/Office Management Background Prior to the COVID-19 pandemic, in-person visits were the standard of care for paediatricians at our centre. With the pandemic onset, virtual care (VC) was adopted at an unprecedented scale and pace. Studies have reported positive patient VC experience; however, few have explored physician experience. This quality improvement (QI) initiative sought to qualify the VC experience of local paediatricians during the pandemic, with the intention of implementing VC clinical practice changes at the department level. Objectives To determine key factors that have supported and challenged the adoption of, and that will support integration of, VC in the future. Design/Methods The Donabedian model for healthcare QI was used to evaluate VC experience through an online survey with a focus on structure, process, and outcome measures. All physicians affiliated with the Department of Paediatrics (generalists and subspecialists in medicine and surgery) were invited to participate via email. Three reminder emails were sent at 2-week intervals. Descriptive statistics were reported. Results The response rate was 32.3% (63 of 195 physicians). The majority of respondents were subspecialists (84.1%), and at academic centres (87.5%) (Table 1). Pre-pandemic, only 30.1% used VC and saw <10% of patients virtually. During March-May 2020, 93.8% transitioned to VC, with > 50% seeing over 75% of patients virtually. By summer 2020, VC use declined, but remained higher than pre-pandemic (53.6% seeing < 25% of patients). OTN and telephone were platforms most used (32.8% and 28.6%, respectively). Most conducted visits from their work location (55.2%) versus home (44.8%). VC experience was considered positive by most physicians (73.6%), and only 18.8% found VC difficult to use despite technical difficulties reported by 41.5% (Figure 1). Physicians with ≤ 5 years in practice were most likely to find VC convenient (93.8%). Challenges with VC included lack of physical exam, diagnostic uncertainty, lower patient volumes, and poor patient VC etiquette. Regardless of practice location, specialty, years in practice, and prior experience, 96% would continue VC to 25% of patients, ideally for patients who live far away (26.4%) and for follow-ups of patients with established diagnoses (21.4%). Conclusion A rapid transition to VC during the COVID-19 pandemic was associated with challenges but also positive experiences. Willingness to continue VC was high. VC experience could be improved with greater patient education and focus on select patient populations. Future research is needed to improve practice efficiency and to inform regulatory guidelines for VC at a local level.

CTNI-01. A PHASE 1-2 CLINICAL TRIAL OF EO1001 (APL-122), A NOVEL IRREVERSIBLE PAN-ERBB INHIBITOR WITH PROMISING BRAIN PENETRATION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi58-vi58
Author(s):  
Sophia Frentzas ◽  
Gary Richardson ◽  
Jeffrey Bacha ◽  
Sarath Kanekal ◽  
Neil Sankar ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Dose Escalation ◽  
Phase 1 ◽  
Standard Of Care ◽  
Maximum Tolerated Dose ◽  
Cns Metastases ◽  
Once Daily ◽  
Adult Participants ◽  
Xenograft Models ◽  
Cns Penetration

Abstract CNS metastases are a prominent driver of cancer morbidity and mortality, especially as targeted therapies have improved systemic outcomes. Mutations in the ErbB/HER kinase family are known oncodrivers in many cancers. Extensive crosstalk among ErbB/HER receptors suggests that inhibition of multiple family members may benefit treatment and limit drug resistance. There is a desperate need for new agents that are more tolerable and effective in treating CNS metastases. EO1001 (APL-122) is a first-in-class, oral, irreversible pan-ErbB inhibitor targeting ErbB1, ErbB2 and ErbB4 with promising CNS penetration in preclinical models. Preclinical data suggests a favorable pharmacokinetic and safety profile and activity against ErbB-driven cancers in patient-derived xenograft models. We report on a first-in-human Phase 1-2 clinical trial in progress. Adult participants with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard-of-care, with adequate bone marrow, renal and liver function are eligible. ESCALATION: One subject per dose cohort is enrolled in an accelerated dose-escalation design until drug-related toxicity (≥G2) is observed in the first cycle, after which dose escalation will revert to a 3 + 3 design to determine the maximum tolerated dose (MTD). Cycle 1: Patients receive a single oral dose of EO1001 on day 1; single-dose pharmacokinetics are measured. Beginning on day 8, EO1001 is administered once daily for 21 days; multi-dose pharmacokinetics are measured. Cycles 2-6: EO1001 is administered once daily in continuous 28-day cycles for up to 20 weeks. EXPANSION: EO1001 will be administered once daily to 20 patients at the MTD in continuous 28-day cycles for up to 6 cycles to determine a recommended Phase 2 dose (RP2D) for further study. Toxicity is assessed based on NCI CTCAEv5 and tumor response is assessed by RECIST 1.1. CNS exposure is evaluated in patients via CSF collection with confirmed CNS disease involvement.

scholarly journals Effects of dance on cognitive function in older adults: a systematic review and meta-analysis

2020 ◽  
Author(s):  
Patricia Hewston ◽  
Courtney Clare Kennedy ◽  
Sayem Borhan ◽  
Dafna Merom ◽  
Pasqualina Santaguida ◽  
...  
Keyword(s):  
Older Adults ◽  
Executive Function ◽  
Cognitive Function ◽  
Learning And Memory ◽  
Optimal Dose ◽  
Future Research ◽  
Trail Making Test ◽  
Global Cognitive Function ◽  
Trail Making ◽  
Complex Attention

Abstract Background dance is a mind–body activity that stimulates neuroplasticity. We explored the effect of dance on cognitive function in older adults. Methods we searched MEDLINE, EMBASE, CENTRAL and PsycInfo databases from inception to August 2020 (PROSPERO:CRD42017057138). Inclusion criteria were (i) randomised controlled trials (ii) older adults (aged ≥ 55 years), (iii) intervention—dance and (iv) outcome—cognitive function. Cognitive domains were classified with the Diagnostic and Statistical Manual of Mental Disorders-5 Neurocognitive Framework. Meta-analyses were performed in RevMan5.3 and certainty of evidence with GradePro. Results we reviewed 3,997 records and included 11 studies (N = 1,412 participants). Seven studies included only healthy older adults and four included those with mild cognitive impairment (MCI). Dance interventions varied in frequency (1–3×/week), time (35–60 minutes), duration (3–12 months) and type. We found a mean difference (MD) = 1.58 (95% confidence interval [CI) = 0.21–2.95) on the Mini Mental State Examination for global cognitive function (moderate-certainty evidence), and the Wechsler Memory Test for learning and memory had an MD = 3.02 (95% CI = 1.38–4.65; low-certainty evidence). On the Trail Making Test-A for complex attention, MD = 3.07 (95% CI = −0.81 to 6.95; high-certainty evidence) and on the Trail Making Test-B for executive function, MD = −4.12 (95% CI = −21.28 to 13.03; moderate-certainty evidence). Subgroup analyses did not suggest consistently greater effects in older adults with MCI. Evidence is uncertain for language, and no studies evaluated social cognition or perceptual–motor function. Conclusions dance probably improves global cognitive function and executive function. However, there is little difference in complex attention, and evidence also suggests little effect on learning and memory. Future research is needed to determine the optimal dose and if dance results in greater cognitive benefits than other types of physical activity and exercise.

scholarly journals Optimizing hydroxyurea therapy for sickle cell anemia

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 436-443 ◽  
Author(s):  
Russell E. Ware
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Fetal Hemoglobin ◽  
Maximum Tolerated Dose ◽  
Sub Saharan Africa ◽  
Future Research ◽  
Published Evidence ◽  
Treatment Indications ◽  
Hydroxyurea Treatment ◽  
Hydroxyurea Therapy

Abstract Hydroxyurea has proven efficacy in numerous clinical trials as a disease-modifying treatment for patients with sickle cell anemia (SCA) but is currently under-used in clinical practice. To improve the effectiveness of hydroxyurea therapy, efforts should be directed toward broadening the clinical treatment indications, optimizing the daily dosage, and emphasizing the benefits of early and extended treatment. Here, various issues related to hydroxyurea treatment are discussed, focusing on both published evidence and clinical experience. Specific guidance is provided regarding important but potentially unfamiliar aspects of hydroxyurea treatment for SCA, such as escalating to maximum tolerated dose, treating in the setting of cerebrovascular disease, switching from chronic transfusions to hydroxyurea, and using serial phlebotomy to alleviate iron overload. Future research directions to optimize hydroxyurea therapy are also discussed, including personalized dosing based on pharmacokinetic modeling, prediction of fetal hemoglobin responses based on pharmacogenomics, and the risks and benefits of hydroxyurea for non-SCA genotypes and during pregnancy/lactation. Another critical initiative is the introduction of hydroxyurea safely and effectively into global regions that have a high disease burden of SCA but limited resources, such as sub-Saharan Africa, the Caribbean, and India. Final considerations emphasize the long-term goal of optimizing hydroxyurea therapy, which is to help treatment become accepted as standard of care for all patients with SCA.

Phase 1/2a Study of ABT-263 in Relapsed or Refractory Lymphoid Malignancies.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1711-1711 ◽  
Author(s):  
Wyndham H Wilson ◽  
Owen A O'Connor ◽  
Myron S Czuczman ◽  
Ann LaCasce ◽  
John Gerecitano ◽  
...  
Keyword(s):  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Human Tumor ◽  
Progression Free Survival ◽  
Optimal Dose ◽  
Maximum Tolerated Dose ◽  
Cutaneous Lesions ◽  
Dosing Schedule ◽  
Lymphoid Malignancies

Abstract Abstract 1711 Poster Board I-737 Bcl-2 family members are associated with tumor initiation and drug resistance, and are compelling therapeutic targets. ABT-263 is a novel, orally bioavailable, small molecule inhibitor of antiapoptotic Bcl-2 family proteins that binds with high affinity (Ki '1 nM) to Bcl-2, Bcl-xL, and Bcl-w. ABT-263 displays potent preclinical mechanism-based targeted cytotoxicity (EC50 '1 μM) against human tumor cell lines (small cell lung carcinomas and T and B lymphoid malignancies) that over express Bcl-2. Toxicities are mechanism-based, with Bcl-2, Bcl-xL and Bcl-w mediating effects on lymphocytes, platelet survival and testicular toxicity, respectively. The objective of this study was to assess safety/pharmacokinetics (PK) and maximum tolerated dose of ABT-263. Study M06-814 is a phase 1/2a, dose-escalation, single-agent international study employing a modified Fibonacci 3+3 of ABT-263 in relapsed/refractory lymphoid malignancies. Patients (pts) were dosed on Days (d) 1-14 of a 21-d dosing cycle with 10-440 mg ABT-263, or continuous 21/21-d dosing (21-d cycle) with 200-325 mg ABT-263 following a 150 mg lead-in dose. Tumor responses were evaluated using the IWG criteria. To date, 50 pts (38 on a 14/21-d and 12 on a 21/21-d dosing schedule) have been dosed with ABT-263. The median pts age is 59 y [range, 20-81]).The PK profile of ABT-263 on the 14/21-d schedule was linear and dose proportional from 10-440 mg with a t½ of 14-20 h. Platelet nadirs were transient, occurring on d 3-5, and preliminary data suggests a 1-week low dose lead-in at 150 mg ABT-263 followed by a 21/21-d dosing schedule minimizes platelet nadir and cycle variability. The median progression-free survival is 88 d [95% CI: 46, 170]. Of the 50 pts enrolled, 1 NK-T cell lymphoma had a 75% reduction in cutaneous lesions, 1 follicular lymphoma had an unconfirmed partial response (PR) and 7 CLL pts had PR's due to decreases in lymphadenopathy with 7 other achieving at least a 50% decrease in circulating lymphocytes. 4 pts on the 14/21-d schedule had dose-limiting toxicities (DLT); 1 at 160 mg (bronchitis), 2 at 315 mg (elevated ALT and Grade 4 Thrombocytopenia [TCP]) and 1 at 440 mg (worsening pleural effusion in a pt with underlying afib and hypotension). Among the 12 pts on the 21/21-d schedule, 1 experienced DLT at 275 mg (Grade 4 TCP). Overall, TCP was predictable and manageable. Of the 3 pts who had discontinued therapy at the time of this analysis, 2 discontinued due to PD and 1 withdrew consent. ABT-263 is well tolerated with a linear PK, toxicity secondary to on-target activity and antitumor activity in pts with relapsed or refractory lymphoid malignancies. Toxicities were predictable and manageable; identification of optimal dose and schedule for phase 1 trials continues. Disclosures Off Label Use: ABT-263 is an experimental drug that is not yet registered. It is designed to induce apoptosis in tumor cells.. O'Connor:Abbott: Research Funding. Czuczman:Abbott and Genentech: Consultancy. Tulpule:Abbott: Research Funding. Xiong:Abbott: Employment. Chiu:Abbott: Employment. Busman:Abbott: Employment. Enschede:Abbott: Employment. Krivoshik:Abbott: Employment. Humerickhouse:Abbott: Employment.

A phase I multicentric trial of combined chemotherapy with gemcitabine plus S-1 in patients with advanced pancreatic cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14047-14047
Author(s):  
S. Ohkawa ◽  
A. Amano ◽  
M. Ueno ◽  
K. Miyakawa ◽  
K. Sugimori ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Phase I Trial ◽  
Advanced Pancreatic Cancer ◽  
Optimal Dose ◽  
Maximum Tolerated Dose ◽  
Combined Chemotherapy ◽  
Concurrent Administration ◽  
Standard Drug ◽  
Level 3

14047 Background: While gemcitabine (GEM) is the standard drug for chemotherapy against advanced pancreatic cancer, the development of multidrug therapies for improved outcome is important. We conducted multicentric combined chemotherapy with GEM and S-1 and report the results of the phase I trial. Methods: The subjects had unresectable pancreatic ductal cancer. The method of administration was single administration of GEM on the first day of the week from Level 1 to Level 4 at 400 to 1000 mg/m2, with concurrent administration of S-1 at 40 to 100 mg/day × 7 days, repeated every other week as a collaborative trial conducted at 3 facilities. The purpose was to determine the optimal dose with adverse events as an indicator. Results: Eighteen patients were enrolled (3 each at Levels 1, 2, 3 and 4’, 6 at Level 4). Average age was 60.9 years (38 - 71 years). There was no dose limiting toxicity (DLT) up to Level 3. Level 4 was the maximum tolerated dose since DLT was observed in 4/6 patients (mucositis 2, rash 1, anorexia 1), and no DLT was observed in 3 additional patients at Level 4’. The resulting recommended dose was Level 4 (GEM 1000 mg/m2, S-1 100 mg/day). For reference, partial response was observed in 5 patients, and median survival time at this stage is 336±39 days. Conclusions: The recommended dosage of GEM + S-1 combined chemotherapy for unresectable advanced pancreatic cancer was determined in a phase I trial. We intend to proceed to a phase II trial. No significant financial relationships to disclose.

Phase I study of ABT-751 in combination with CAPIRI (capecitabine and irinotecan) and bevacizumab in patients with advanced colorectal cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13553-13553
Author(s):  
W. A. Messersmith ◽  
M. A. Rudek ◽  
D. Laheru ◽  
M. Zhao ◽  
P. He ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Combination Therapy ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Advanced Colorectal Cancer ◽  
Standard Of Care ◽  
Maximum Tolerated Dose ◽  
Total Daily Dose ◽  
Dose Escalation Study

13553 Background: ABT-751 (A) is an orally (PO) bioavailable sulfonamide with antimitotic properties. We are performing a non-randomized phase I/II dose-escalation study of A in combination with capecitabine (C), irinotecan (I) and bevacizumab (B) to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) in patients with advanced colorectal cancer (1st or 2nd line). Methods: Patients are treated with A QD for 7d (lead-in) and then begin 21-d cycles of treatment with A (QD) and C (BID) d1–14 PO, I d1 IV, and B d1 IV. Dose escalation started at dose level (DL) 1 at A 150 mg, I 200 mg/m2, and C 1600 mg/m2 (total daily dose) and escalated to full dose CAPIRI (I 250 mg/m2, and C 2000 mg/m2) for DL2. B was then added as standard of care at 7.5 mg/kg for DL2b (and later, DL1b). Blood samples were collected for pharmacogenomics (PG), pharmacodynamics (PD), steady-state PK of A and A metabolites when administered alone or in combination with C, I, and B, and PK of I and I metabolites. Serial dynamic contrast MRI’s, before and after the ABT-751 monotherapy lead-in period, are being performed in a subset of subjects. Results: Eight patients have been treated at dose levels 1 (3), 2 (2), and 2b (3). One patient on DL2 experienced g3 transaminitis and another on DL2b had F&N which were dose-limiting. Dose level 1 is being expanded to 6 patients, now with B (DL1b). Other g3/4 toxicities have included g4 neutropenia (1 subject DL2, 1 DL2b). The formation of A glucuronide appears decreased during combination therapy (see table). I PK, PD, and PG samples were collected and analysis is pending. Of 8 subjects, there have been 4 PD and 4 SD after 2 cycles. Conclusions: The combination therapy of A 150 mg and 20% dose-reduced CAPIRI appears well-tolerated. Patient accrual continues at DL1b. [Table: see text] No significant financial relationships to disclose.

Bortezomib, IV cyclophosphamide, and dexamethasone (VelCD) as induction therapy in newly diagnosed multiple myeloma: Results of an interim analysis of the German DSMM Xia trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8516-8516 ◽  
Author(s):  
S. Knop ◽  
P. Liebisch ◽  
H. Wandt ◽  
M. Kropff ◽  
W. Jung ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Interim Analysis ◽  
Standard Of Care ◽  
Dose Finding ◽  
Optimum Dose ◽  
Primary Study ◽  
Induction Treatment ◽  
Newly Diagnosed ◽  
Study Objective ◽  
Grade 3

8516 Background: Cytoreductive induction followed by HD-MEL and ASCT is considered standard of care for younger patients (pts) with multiple myeloma (MM). The success of this combined procedure partially depends on the efficacy of induction treatment. Bortezomib-containing induction regimens have already been shown to be superior to standard VAD. In order to further improve the efficacy of induction treatment we combined Vel with intravenous (IV) cyclophosphamide (C) and dexamethasone (D). Methods: This trial is an open, prospective, multicenter, uncontrolled phase II/III study with a planned recruitment of 400 pts. The first 30 pts were included in the dose finding study to determine the optimum dose of IV C in conjunction with Vel and D. The following 170 pts up to 60 years of age with untreated MM were enrolled to receive 3 cycles of induction with Vel 1.3 mg/m2 IV d1, 4, 8, 11; D 40 mg/d d1, 2, 4, 5, 8, 9, 11, 12; and C 900mg/m2 IV d1. Primary study objective is response rate (≥ PR) to VelCD according to the EBMT criteria. Results: Data from the first completed 200 pts (mean age: 52 years; 74% stage III) from 36 German centers were analyzed as ITT population. Response rates are given in Table and were documented in 82% of the subjects with 13q-, in 94% with t(4;14) and in 70% with 17p-. SAEs (n=84) occurred in 24.5% of the pts and were related to Vel, C or D in 16%, 14.5% or 9.5% respectively. The mortality rate of 1% is low, 53% of the patients experienced grade 3 + 4 AEs, infections of grade 3 and 4 were reported in 2% and grade 3 paraesthesia occurred in 2%. Conclusions: This interim analysis demonstrates that bortezomib combined with dexamethasone and intravenous cyclophosphamide (VelCD) is a highly effective induction regimen for pts ≤ 60 years with newly diagnosed MM regardless of cytogenetic risk factors. [Table: see text] [Table: see text]

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