scholarly journals Keyboard: An R Package Suite for Early Phase Dose-finding Designs

2021 ◽  
Author(s):  
Hongying Sun ◽  
Chen Li ◽  
Cheng Cheng ◽  
Tang Li ◽  
Haitao Pan
Keyword(s):  
Phase I ◽  
Drug Combination ◽  
Single Agent ◽  
Optimal Dose ◽  
R Package ◽  
Maximum Tolerated Dose ◽  
Cytotoxic Agents ◽  
Dose Finding ◽  
Operating Characteristics ◽  
Background Phase

Abstract Background: Phase I and/or I/II oncology trials are conducted to find the maximum tolerated dose (MTD) and/or optimal biological dose (OBD) of a new drug or treatment. In these trials, for cytotoxic agents, the primary aim of the single-agent or drug-combination is to find the MTD with a certain target toxicity rate, while for the cytostatic agents, a more appropriate target is the OBD, which is often defined by consideration of toxicity and efficacy simultaneously. However, there still lacks accessible software packages to achieve both yet. Results: Objective of this work is to develop a software package that can provide tools for both MTD- and OBD-finding trials, which implements the Keyboard design for single-agent MTD-finding trials by Yan et al., the Keyboard design for drug-combination MTD-finding trials by Pan et al., and phase I/II OBD-finding method by Li et al., in a single R package, called Keyboard. For each of the designs, the Keyboard package provides corresponding functions that begins with get.boundary( . . . ) to determine the optimal dose escalation and de-escalation boundaries, that begins with select.mtd( . . . ) to select the MTD when the trial is completed, that begins with select.obd( . . . ) to select the OBD at the end of a trial, and that begins with get.oc( . . . ) to generate the operating characteristics. Conclusions: The developed Keyboard R package provides convenient tools for designing, conducting and analyzing single-agent, drug-combination and phase I/II dose-finding trials, which supports Bayesian designs of innovative dose-finding studies.

scholarly journals BOIN12: Bayesian Optimal Interval Phase I/II Trial Design for Utility-Based Dose Finding in Immunotherapy and Targeted Therapies

2020 ◽  
pp. 1393-1402
Author(s):  
Ruitao Lin ◽  
Yanhong Zhou ◽  
Fangrong Yan ◽  
Daniel Li ◽  
Ying Yuan
Keyword(s):  
Phase I ◽  
Trial Design ◽  
Checkpoint Inhibitors ◽  
Optimal Dose ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Operating Characteristics ◽  
T Cell Therapy ◽  
Trade Off ◽  
Optimal Interval

PURPOSE For immunotherapy, such as checkpoint inhibitors and chimeric antigen receptor T-cell therapy, where the efficacy does not necessarily increase with the dose, the maximum tolerated dose may not be the optimal dose for treating patients. For these novel therapies, the objective of dose-finding trials is to identify the optimal biologic dose (OBD) that optimizes patients’ risk-benefit trade-off. METHODS We propose a simple and flexible Bayesian optimal interval phase I/II (BOIN12) trial design to find the OBD that optimizes the risk-benefit trade-off. The BOIN12 design makes the decision of dose escalation and de-escalation by simultaneously taking account of efficacy and toxicity and adaptively allocates patients to the dose that optimizes the toxicity-efficacy trade-off. We performed simulation studies to evaluate the performance of the BOIN12 design. RESULTS Compared with existing phase I/II dose-finding designs, the BOIN12 design is simpler to implement, has higher accuracy to identify the OBD, and allocates more patients to the OBD. One of the most appealing features of the BOIN12 design is that its adaptation rule can be pretabulated and included in the protocol. During the trial conduct, clinicians can simply look up the decision table to allocate patients to a dose without complicated computation. CONCLUSION The BOIN12 design is simple to implement and yields desirable operating characteristics. It overcomes the computational and implementation complexity that plagues existing Bayesian phase I/II dose-finding designs and provides a useful design to optimize the dose of immunotherapy and targeted therapy. User-friendly software is freely available to facilitate the application of the BOIN12 design.

scholarly journals Phase I/II dose-finding design for molecularly targeted agent: Plateau determination using adaptive randomization

2016 ◽  
Vol 27 (2) ◽  
pp. 466-479 ◽  
Author(s):  
Marie-Karelle Riviere ◽  
Ying Yuan ◽  
Jacques-Henri Jourdan ◽  
Frédéric Dubois ◽  
Sarah Zohar
Keyword(s):  
Phase I ◽  
Late Onset ◽  
Optimal Dose ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Targeted Agents ◽  
Weighted Likelihood ◽  
Operating Characteristics ◽  
Phase I Clinical Trials ◽  
Molecularly Targeted Agents

Conventionally, phase I dose-finding trials aim to determine the maximum tolerated dose of a new drug under the assumption that both toxicity and efficacy monotonically increase with the dose. This paradigm, however, is not suitable for some molecularly targeted agents, such as monoclonal antibodies, for which efficacy often increases initially with the dose and then plateaus. For molecularly targeted agents, the goal is to find the optimal dose, defined as the lowest safe dose that achieves the highest efficacy. We develop a Bayesian phase I/II dose-finding design to find the optimal dose. We employ a logistic model with a plateau parameter to capture the increasing-then-plateau feature of the dose–efficacy relationship. We take the weighted likelihood approach to accommodate for the case where efficacy is possibly late-onset. Based on observed data, we continuously update the posterior estimates of toxicity and efficacy probabilities and adaptively assign patients to the optimal dose. The simulation studies show that the proposed design has good operating characteristics. This method is going to be applied in more than two phase I clinical trials as no other method is available for this specific setting. We also provide an R package dfmta that can be downloaded from CRAN website.

Clofarabine Combinations in Acute Myeloid Leukemia (AML) Salvage: A Dose-Finding Phase I Study of Clofarabine Plus Idarubicin and Clofarabine/Idarubicin Plus Cytarabine (ara-C).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2803-2803
Author(s):  
Stefan Faderl ◽  
Alessandra Ferrajoli ◽  
William Wierda ◽  
Farhad Ravandi ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Single Agent ◽  
Response Rates ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Unrelated Donor ◽  
Acute Leukemias ◽  
First Relapse ◽  
Dose Levels

Abstract Clofarabine is a second-generation nucleoside analog with single agent activity in acute leukemias. To try and improve efficacy, various combination trials are being conducted. In studies of clofarabine plus ara-C we reported overall response rates of 41% (CR 24%) in AML salvage and 60% (CR 52%) in untreated elderly AML with acceptable toxicity profile. To explore additional clofarabine combinations in AML we conducted a phase I study of clofarabine (C) with idarubicin (I) [CI] alone and with ara-C (A) [CIA] in pts with relapsed AML and high-grade MDS. Dose-limiting toxicities (DLT) were defined as ≥ grade 3 drug-related toxicities. Maximum tolerated dose (MTD) was determined by “3+3” method. Thirty-three patients (18 on CI and 15 on CIA) have been treated and are evaluable. Of 18 pts on CI, 6 were primary refractory and 12 in first relapse (median first remission duration [CRD1] 2 mos. [range 0–9]. Eleven pts had abnormal cytogenetics. Fourteen pts received prior ara-C-based regimens, 2 relapsed from allogeneic transplant (SCT). Median age: 57 yrs (range 24–71). Four dose levels have been explored. When C was given at 22.5mg/m2 i.v. daily x 5d and I at 12mg/m2 i.v. daily x 3d, 2 ≥ gr. 3 toxicities (diarrhea, rash, ↑ bili) occurred necessitating dose de-escalation. Subsequent levels included C at 15mg/m2 x 5d/I at 8mg/m2 x 3d (6 pts, 1 ≥ gr.3 toxicity [↑ bili]), C at 18 mg/m2 x 5d, I at 10mg/m2 x 3 d (3 pts, no DLT), and C at 22.5mg/m2 x 5d, I at 10mg/m2 x 3d (3 pts, no DLT). Three (17%) responses (2 CRp, 1 CR) occurred. Of 15 pts on CIA, 4 were primary refractory and 11 in first relapse. Median CRD1 was 9 mos (0–24). Eight pts had an abnormal karyotype. Seven pts received prior ara-C-based regimens and 2 failed unrelated donor SCT. Median age: 58 yrs (23–78). Three dose levels were evaluated. At C 22.5mg/m2 i.v. daily x 5d, I 8mg/m2 i.v. daily x 3d, A 1g/m2 i.v. daily x 5d, 2 of 3 pts developed ≥ gr.3 toxicities (↑ bili, diarrhea) necessitating dose de-escalation. Subsequent levels included C at 15mg/m2 x 5d, I at 6mg/m2 x 3d, A at 0.75g/m2 x 5d (6 pts, 1 with ≥ gr. 3 rash, ↑ bili), and C at 22.5mg/m2 x 5d, I at 6mg/m2 x 3d, and A at 0.75g/m2 x 5d (6 pts, 1 with ≥ gr. 3 ↑ bili). Nine (60%) responses (8 CR, 1 CRp) occurred. Further dose escalation of clofarabine is planned in both trials. The preliminary results indicate feasibility of the combinations. The higher response rates with CIA need to be evaluated in view of different pt. characteristics between the two trials.

A phase I trial of the proteosome inhibitor PS-341 in combination with carboplatin in platinum and taxane resistant ovarian cancer patinets

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5558-5558
Author(s):  
C. N. Landen ◽  
R. Coleman ◽  
M. R. Milam ◽  
T. Johnston ◽  
R. Iyer ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Stable Disease ◽  
Performance Status ◽  
Single Agent ◽  
Optimal Dose ◽  
Recurrent Ovarian Cancer ◽  
Cytotoxic Agents ◽  
Pharmacokinetic Data ◽  
Resistant Disease

5558 Background. PS-341 (Millenium Pharmaceuticals, Inc.), a proteosome inhibitor, affects p53, NFκB, cell adhesion molecules, and sensitivity to cytotoxic agents to promote apoptosis and inhibit metastasis in cancer cells. PS-341 alone rarely causes myelosupression or renal toxicity, and therefore is an attractive agent to use in combination with cytotoxic chemotherapy. This phase I study evaluates the safety, dose-limiting toxicities (DLTs), and optimal dose of PS-341 when combined with carboplatin in ovarian cancer patients with recurrent, platinum- and taxane-resistant disease. Methods: After IRB approval, patients with recurrent ovarian cancer, platinum and taxane resistant (progression on platinum and/or taxane therapy or recurrence within 6 months of completing platinum and/or taxane therapy), measurable disease, and performance status 0–2 were eligible and enrolled after giving informed consent. As guided by toxicity and pharmacokinetic data from single-agent phase I trials, PS-341 was administered on days 1, 4, 8, and 11 by IV push every 28 days with carboplatin (AUC 5) on day 1. Four dose levels were evaluated: 0.8, 1.0, 1.3, and 1.5 mg/m2. Dose was escalated if 0 of 3 or 1 of 6 patients had a DLT. The MTD was defined as 2 or more patients out of 6 with a DLT. Results: 21 women (median age 63, range 43–83), were treated with carboplatin and PS-341 at 0.8mg/ m2 (n=6), 1.0 mg/m2 (n=3), 1.3 mg/m2 (n=6), or 1.5 mg/m2. (n=6). At each level, respectively, there were 1, 0, 1, and 3 DLT’s attributable to PS- 341; all were grade 3, consisting of fatigue (n=3), nausea/vomiting/dehydration (n=1), and anorexia/dehydration/syncope (n=1). There were no Grade 4 toxicities. Common grade 2 toxicities included fatigue (n=12), nausea (n=10), anorexia, anemia, and dyspnea (n=7 each). 18 patients evaluable for response had stable disease (SD) or progression of disease (PD): at 0.8 mg/m2, SD=2, PD=3; at 1.0 mg/m2, PD=3; at 1.3 mg/m2, SD=3, PD=3; at 1.5 mg/m2, SD=3, PD=1. Median duration of stable disease was 4 months (range 3–10). Conclusions: The recommended dose of PS-341 in combination is 1.3 mg/m2. Treatment was well-tolerated with reversible side effects and no grade 4 toxicities, and at the optimal dose, there was a 50% rate of stable disease. No significant financial relationships to disclose.

scholarly journals A web application for evaluating Phase I methods using a non-parametric optimal benchmark

2017 ◽  
Vol 14 (5) ◽  
pp. 553-557 ◽  
Author(s):  
Nolan A Wages ◽  
Nikole Varhegyi
Keyword(s):  
Phase I ◽  
Web Application ◽  
Evaluation Process ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Correct Selection ◽  
Evaluation Tool ◽  
Operating Characteristics ◽  
Dose Selection ◽  
Non Parametric

Background/aims: In evaluating the performance of Phase I dose-finding designs, simulation studies are typically conducted to assess how often a method correctly selects the true maximum tolerated dose under a set of assumed dose–toxicity curves. A necessary component of the evaluation process is to have some concept for how well a design can possibly perform. The notion of an upper bound on the accuracy of maximum tolerated dose selection is often omitted from the simulation study, and the aim of this work is to provide researchers with accessible software to quickly evaluate the operating characteristics of Phase I methods using a benchmark. Methods: The non-parametric optimal benchmark is a useful theoretical tool for simulations that can serve as an upper limit for the accuracy of maximum tolerated dose identification based on a binary toxicity endpoint. It offers researchers a sense of the plausibility of a Phase I method’s operating characteristics in simulation. We have developed an R shiny web application for simulating the benchmark. Results: The web application has the ability to quickly provide simulation results for the benchmark and requires no programming knowledge. The application is free to access and use on any device with an Internet browser. Conclusion: The application provides the percentage of correct selection of the maximum tolerated dose and an accuracy index, operating characteristics typically used in evaluating the accuracy of dose-finding designs. We hope this software will facilitate the use of the non-parametric optimal benchmark as an evaluation tool in dose-finding simulation.

An adaptive design for the identification of the optimal dose using joint modeling of continuous repeated biomarker measurements and time-to-toxicity in phase I/II clinical trials in oncology

2019 ◽  
Vol 29 (2) ◽  
pp. 508-521 ◽  
Author(s):  
Maria-Athina Altzerinakou ◽  
Xavier Paoletti
Keyword(s):  
Phase I ◽  
Adaptive Design ◽  
Random Effect ◽  
Joint Modeling ◽  
Maximum Tolerated Dose ◽  
Small Sample ◽  
Dose Finding ◽  
Operating Characteristics ◽  
Activity Measurements ◽  
Dose Limiting Toxicity

We present a new adaptive dose-finding method, based on a joint modeling of longitudinal continuous biomarker activity measurements and time to first dose limiting toxicity, with a shared random effect. Estimation relies on likelihood that does not require approximation, an important property in the context of small sample sizes, typical of phase I/II trials. We address the important case of missing at random data that stem from unacceptable toxicity, lack of activity and rapid deterioration of phase I patients. The objective is to determine the lowest dose within a range of highly active doses, under the constraint of not exceeding the maximum tolerated dose. The maximum tolerated dose is associated to some cumulative risk of dose limiting toxicity over a predefined number of treatment cycles. Operating characteristics are explored via simulations in various scenarios.

scholarly journals On the coherence of model-based dose-finding designs for drug combination trials

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0242561
Author(s):  
Yeonhee Park ◽  
Suyu Liu
Keyword(s):  
Phase I ◽  
Drug Combination ◽  
Treated Patient ◽  
Single Agent ◽  
Sufficient Conditions ◽  
Dose Finding ◽  
Phase I Clinical Trials ◽  
Model Based ◽  
Dose Combination ◽  
Theoretical Results

The concept of coherence was proposed for single-agent phase I clinical trials to describe the property that a design never escalates the dose when the most recently treated patient has toxicity and never de-escalates the dose when the most recently treated patient has no toxicity. It provides a useful theoretical tool for investigating the properties of phase I trial designs. In this paper, we generalize the concept of coherence to drug combination trials, which are substantially different and more challenging than single-agent trials. For example, in the dose-combination matrix, each dose has up to 8 neighboring doses as candidates for dose escalation and de-escalation, and the toxicity orders of these doses are only partially known. We derive sufficient conditions for a model-based drug combination trial design to be coherent. Our results are more general and relaxed than the existing results and are applicable to both single-agent and drug combination trials. We illustrate the application of our theoretical results with a number of drug combination dose-finding designs in the literature.

scholarly journals Adapting isotonic dose-finding to a dynamic set of drug combinations with application to a phase I leukemia trial

2021 ◽  
pp. 174077452098348
Author(s):  
Nolan A Wages ◽  
Daniel R Reed ◽  
Michael K Keng ◽  
Mark R Conaway ◽  
Gina R Petroni
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Drug Combination ◽  
Myeloid Leukemia ◽  
Dose Finding ◽  
Design Stage ◽  
Operating Characteristics ◽  
Current Form ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid

Background/aims This article describes the proposed design of a phase I study evaluating the safety of ceramide nanoliposome and vinblastine among an initial set of 19 possible dose combinations in patients with relapsed/refractory acute myeloid leukemia and patients with untreated acute myeloid leukemia who are not candidates for intensive induction chemotherapy. Methods Extensive collaboration between statisticians and clinical investigators revealed the need to incorporate several adaptive features into the design, including the flexibility of adding or eliminating certain dose combinations based on safety criteria applied to multiple dose pairs. During the design stage, additional dose levels of vinblastine were added, increasing the dimension of the drug combination space and thus the complexity of the problem. Increased complexity made application of existing drug combination dose-finding methods unsuitable in their current form. Results Our solution to these challenges was to adapt a method based on isotonic regression to meet the research objectives of the study. Application of this adapted method is described herein, and a simulation study of the design’s operating characteristics is conducted. Conclusion The aim of this article is to bring to light examples of novel design applications as a means of augmenting the implementation of innovative designs in the future and to demonstrate the flexibility of adaptive designs in satisfying changing design conditions.

A phase I dose escalation study of sunitinib in combination with gemcitabine + cisplatin for advanced non-small cell lung cancer (NSCLC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18057-18057 ◽  
Author(s):  
M. Reck ◽  
N. Frickhofen ◽  
U. Gatzemeier ◽  
H. Fuhr ◽  
S. Lanzalone ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Dose Escalation Study ◽  
Finding Study ◽  
Grade 3 ◽  
Multitargeted Tyrosine Kinase Inhibitor

18057 Background: Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3, approved internationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. SU has also shown single- agent activity in NSCLC. In this study we assess the safety, tolerability, and pharmacokinetics (PK) of SU in combination with gemcitabine (G) and cisplatin (C). Methods: This is a phase I, dose-finding study in pts with untreated, stage IIIB/IV NSCLC not amenable to curative treatment. Planned dose levels include: oral SU (37.5 or 50 mg/day for 2 wks followed by 1 wk off treatment [2/1 schedule]) plus G (1000 or 1250 mg/m2 iv on days 1 and 8 of a 21-day cycle) and C (80 mg/m2 iv on day 1 of each cycle). SU doses are escalated in serial pt cohorts to determine the maximum tolerated dose (MTD) for both schedules. SU continuous dosing (CD) schedule will also be tested. PK and antitumor efficacy are also assessed. Results: As of Oct 2006, 13 pts were treated on the 2/1 schedule: 6 pts with SU 37.5 mg + G 1000 mg/m2 + C 80 mg/m2, and 7 pts with SU 50 mg + G 1000 mg/m2 + C 80 mg/m2. No dose-limiting toxicities (DLTs) were observed with SU 37.5 mg, while 2 pts experienced neutropenia and infection as DLTs with SU 50 mg. Grade 3/4 hematological AEs included neutropenia (n=3 at dose level 1 and n=5 at dose level 2), thrombocytopenia (n=1 and 5) and anemia (n=2 and 0). 3 pts achieved a partial tumor response at the SU 50 mg/day dose level. There were no apparent drug-drug interactions between SU in combination with G and C based on their systemic exposures in this study. Conclusions: The combination of SU (37.5 mg) on schedule 2/1 with G (1000 mg/m2) and C (80 mg/m2) in advanced NSCLC appears safe and tolerable in this pt population. Testing with G escalated to 1250 mg/m2 or with SU administered on a CD schedule is ongoing. No significant financial relationships to disclose.

scholarly journals Pediatric Phase I and Pharmacokinetic Study of Erlotinib Followed by the Combination of Erlotinib and Temozolomide: A Children's Oncology Group Phase I Consortium Study

2008 ◽  
Vol 26 (30) ◽  
pp. 4921-4927 ◽  
Author(s):  
Regina I. Jakacki ◽  
Marta Hamilton ◽  
Richard J. Gilbertson ◽  
Susan M. Blaney ◽  
Jean Tersak ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Pharmacokinetic Study ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Maximum Tolerated Dose ◽  
Receptor Expression ◽  
Dose Finding ◽  
Pharmacokinetic Studies ◽  
Mixed Response

Purpose We conducted a phase I and pharmacokinetic study of the epidermal growth factor receptor (EGFR) inhibitor erlotinib as a single agent and in combination with temozolomide in children with refractory solid tumors. Patients and Methods Erlotinib was administered orally once daily to cohorts of three to six children for a single 28-day course. Patients then received the combination of daily erlotinib and temozolomide daily for 5 days for all subsequent 28-day courses. An oral erlotinib solution was administered during the dose-finding phase and a tablet formulation was subsequently studied at the maximum-tolerated dose (MTD). Pharmacokinetic studies and ERBB-receptor expression and signaling studies were performed. Results Forty-six patients, median age 11.5 years, received erlotinib at doses of 35, 50, 65, 85, or 110 mg/m2/d. At 110 mg/m2/d, two of four patients had dose-limiting toxicity (DLT) consisting of rash and hyperbilirubinemia, whereas one of six patients developed dose-limiting rash at 85 mg/m2/d. The most frequent non-DLTs included diarrhea, rash, and hyperbilirubinemia. The combination of erlotinib and temozolomide was well tolerated. The median apparent erlotinib clearance was 3.1 L/h/m2 and the median terminal half-life was 8.7 hours. One patient with a neurocytoma had stable disease for 19 months, two patients with neuroblastoma remained on study for 23 and 24 months, and one patient with myoepithelioma had a mixed response. Conclusion The recommended phase II dose of erlotinib in recurrent pediatric solid tumors is 85 mg/m2/d, either alone or in combination with temozolomide.

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