scholarly journals Assessment of various continual reassessment method models for dose-escalation phase 1 oncology clinical trials: using real clinical data and simulation studies

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
G. D. James ◽  
S. Symeonides ◽  
J. Marshall ◽  
J. Young ◽  
G. Clack
Keyword(s):  
Phase 1 ◽  
Clinical Trial Data ◽  
Maximum Tolerated Dose ◽  
Continual Reassessment Method ◽  
Number Of Patients ◽  
Continual Reassessment ◽  
Oncology Clinical Trials ◽  
Post Hoc ◽  
Toxicity Relationship ◽  
Dose Limiting Toxicity

Abstract Background The continual reassessment method (CRM) identifies the maximum tolerated dose (MTD) more efficiently and identifies the true MTD more frequently compared to standard methods such as the 3 + 3 method. An initial estimate of the dose-toxicity relationship (prior skeleton) is required, and there is limited guidance on how to select this. Previously, we compared the CRM with six different skeletons to the 3 + 3 method by conducting post-hoc analysis on a phase 1 oncology study (AZD3514), each CRM model reduced the number of patients allocated to suboptimal and toxic doses. This manuscript extends this work by assessing the ability of the 3 + 3 method and the CRM with different skeletons in determining the true MTD of various “true” dose-toxicity relationships. Methods One thousand studies were simulated for each “true” dose toxicity relationship considered, four were based on clinical trial data (AZD3514, AZD1208, AZD1480, AZD4877), and four were theoretical. The 3 + 3 method and 2-stage extended CRM with six skeletons were applied to identify the MTD, where the true MTD was considered as the largest dose where the probability of experiencing a dose limiting toxicity (DLT) is ≤33%. Results For every true dose-toxicity relationship, the CRM selected the MTD that matched the true MTD in a higher proportion of studies compared to the 3 + 3 method. The CRM overestimated the MTD in a higher proportion of simulations compared to the 3 + 3 method. The proportion of studies where the correct MTD was selected varied considerably between skeletons. For some true dose-toxicity relationships, some skeletons identified the true MTD in a higher proportion of scenarios compared to the skeleton that matched the true dose-toxicity relationship. Conclusion Through simulation, the CRM generally outperformed the 3 + 3 method for the clinical and theoretical true dose-toxicity relationships. It was observed that accurate estimates of the true skeleton do not always outperform a generic skeleton, therefore the application of wide confidence intervals may enable a generic skeleton to be used. Further work is needed to determine the optimum skeleton.

scholarly journals A Bayesian dose-finding design for outcomes evaluated with uncertainty

2021 ◽  
pp. 174077452110015
Author(s):  
Matthew J Schipper ◽  
Ying Yuan ◽  
Jeremy MG Taylor ◽  
Randall K Ten Haken ◽  
Christina Tsien ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Data Augmentation ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Continual Reassessment Method ◽  
Number Of Patients ◽  
Continual Reassessment ◽  
Partially Observed ◽  
Dose Limiting Toxicity

Introduction: In some phase I trial settings, there is uncertainty in assessing whether a given patient meets the criteria for dose-limiting toxicity. Methods: We present a design which accommodates dose-limiting toxicity outcomes that are assessed with uncertainty for some patients. Our approach could be utilized in many available phase I trial designs, but we focus on the continual reassessment method due to its popularity. We assume that for some patients, instead of the usual binary dose-limiting toxicity outcome, we observe a physician-assessed probability of dose-limiting toxicity specific to a given patient. Data augmentation is used to estimate the posterior probabilities of dose-limiting toxicity at each dose level based on both the fully observed and partially observed patient outcomes. A simulation study is used to assess the performance of the design relative to using the continual reassessment method on the true dose-limiting toxicity outcomes (available in simulation setting only) and relative to simple thresholding approaches. Results: Among the designs utilizing the partially observed outcomes, our proposed design has the best overall performance in terms of probability of selecting correct maximum tolerated dose and number of patients treated at the maximum tolerated dose. Conclusion: Incorporating uncertainty in dose-limiting toxicity assessment can improve the performance of the continual reassessment method design.

A prospective PGx and PK/PD dose-finding study of irinotecan based on UGT1A1*6 and *28 genotyping (UGT0601)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14560-e14560
Author(s):  
T. Esaki ◽  
T. Satoh ◽  
T. Ura ◽  
T. Tsujinaka ◽  
Y. Sasaki ◽  
...  
Keyword(s):  
Initial Dosage ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Hematological Toxicity ◽  
Continual Reassessment Method ◽  
Continual Reassessment ◽  
Finding Study ◽  
Dose Finding Study ◽  
Grade 3 ◽  
Dose Limiting Toxicity

e14560 Background: UGT1A1*6 as well as UGT1A1*28 polymorphisms is associated with decreased glucuronidation of SN-38, the active metabolite of irinotecan (CPT-11). Although the maximum tolerated dose (MTD) and the recommended dose (RD) in Hetero was determined 150 mg/m2 (approval dose in Japan), those of Homo were unknown. Methods: Pts received prior chemotherapies except for CPT-11 for metastatic gastrointestinal cancer were enrolled. UGT1A1 polymorphisms were categorized into Wild(*1/*1), Hetero(*1/*28, *1/*6), and Homo(*28/*28, *6/*6, *28/*6). CPT-11 was administered biweekly. Starting doses were 150 mg/m2 in Wild, 100 mg/m2 in Hetero, and 75 mg/m2 in Homo. DLT was defined as grade 4 hematological, or grade 3 non-hematological toxicity. MTD closest to dose-limiting toxicity (DLT) appearance of 30% was guided by the continual reassessment method in the cohort of Hetero and Homo. DLT and pharmacokinetic (PK) sampling was evaluated during the 1st cycle. Results: Eighty-two pts were enrolled from November 2006 to November 2008 (Wild, Hetero, Homo: 41, 20, and 21, respectively). The dose level reached at 150 mg/m2 in Homo. At 150 mg/m2, DLT was observed in six pts of Homo (grade 4 neutropenia, grade 3 diarrhea: 6 and 1, respectively). The probability of DLTs were 22.2% at 125 mg/m2, and 37.4% at 150 mg/m2. The MTD was determined 150 mg/m2 in pts with Homo group. However, the incidences of grade 3/4 neutropenia at 150 mg/m2 during the 1st cycle were 9.8% (4/41), 18.8% (3/16), and 62.5% (10/16) in Wild, Hetero, and Homo, respectively. And the second administration was delayed 7 days or more in most pts in Homo (63% at 150 mg/m2). In one pt of Homo for *28/*28 died of septic shock during the 2nd cycle. SN-38 AUC (0–24h, ng*hr/mL, median) was 239 in Wild, 237 in Hetero, and 410 in Homo. Pts with Homo showed the different trend of PK/PD compared to those with Wild and Hetero. Conclusions: The MTD was 150 mg/m2 in pts with Homo group and the most frequent DLT was grade 4 neutropenia. However, our findings suggest that 150 mg/m2 q2w is difficult to recommend and the initial dosage and administration should be considered carefully for pts with Homo. [Table: see text]

Phase I Trial Using a Time-to-Event Continual Reassessment Strategy for Dose Escalation of Cisplatin Combined With Gemcitabine and Radiation Therapy in Pancreatic Cancer

2004 ◽  
Vol 22 (2) ◽  
pp. 238-243 ◽  
Author(s):  
Jeffrey H. Muler ◽  
Cornelius J. McGinn ◽  
Daniel Normolle ◽  
Theodore Lawrence ◽  
Diane Brown ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Radiation Therapy ◽  
Phase I ◽  
Dose Level ◽  
Maximum Tolerated Dose ◽  
Time To Event ◽  
Continual Reassessment Method ◽  
Full Dose ◽  
Continual Reassessment ◽  
Dose Limiting Toxicity

Purpose The primary objective of this study was to determine the maximum-tolerated dose of cisplatin that could be added to full-dose gemcitabine and radiation therapy (RT) in patients with pancreatic cancer. Patients and Methods Nineteen patients were treated. Gemcitabine 1,000 mg/m2 was administered over 30 minutes on days 1, 8, and 15 of a 28-day cycle. Cisplatin followed gemcitabine on days 1 and 15. The initial dose level of cisplatin was 30 mg/m2, escalated to a targeted dose of 50 mg/m2 using Time-to-Event Continual Reassessment Method. RT was initiated on cycle 1, day 1, in 2.4 Gy fractions to a total dose of 36 Gy. A second cycle of chemotherapy was planned following a 1-week rest. Results Four of eight patients experienced acute dose limiting toxicity at the 50 mg/m2 cisplatin dose level. Patients treated at 30 and 40 mg/m2 cisplatin dose level tolerated therapy without dose-limiting toxicity. Median survival was 10.7 months (95% CI, 5.4 to 18.2) for all patients, and 12.9 months (95% CI, 7.4 to 21.2) for those without metastasis. Conclusion Cisplatin at doses up to 40 mg/m2 may be safely added to full-dose gemcitabine and conformal RT. The Time-to-Event Continual Reassessment Method trial design allowed rapid completion of the study and confidence in the conclusion about the maximum tolerated dose, but accrued more patients to a dose level above the maximum tolerated dose than the typical phase I design. Local and systemic disease control and survival in this study cohort supports further investigation of gemcitabine-based RT and combination chemotherapy in this disease.

scholarly journals Modeling adverse event counts in phase I clinical trials of a cytotoxic agent

2018 ◽  
Vol 15 (4) ◽  
pp. 386-397 ◽  
Author(s):  
Daniel G Muenz ◽  
Thomas M Braun ◽  
Jeremy MG Taylor
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Optimal Dose ◽  
Maximum Tolerated Dose ◽  
Cytotoxic Agents ◽  
Phase I Clinical Trials ◽  
Continual Reassessment Method ◽  
Low Level ◽  
Continual Reassessment ◽  
Dose Limiting Toxicity

Background/Aims The goal of phase I clinical trials for cytotoxic agents is to find the maximum dose with an acceptable risk of severe toxicity. The most common designs for these dose-finding trials use a binary outcome indicating whether a patient had a dose-limiting toxicity. However, a patient may experience multiple toxicities, with each toxicity assigned an ordinal severity score. The binary response is then obtained by dichotomizing a patient’s richer set of data. We contribute to the growing literature on new models to exploit this richer toxicity data, with the goal of improving the efficiency in estimating the maximum tolerated dose. Methods We develop three new, related models that make use of the total number of dose-limiting and low-level toxicities a patient experiences. We use these models to estimate the probability of having at least one dose-limiting toxicity as a function of dose. In a simulation study, we evaluate how often our models select the true maximum tolerated dose, and we compare our models with the continual reassessment method, which uses binary data. Results Across a variety of simulation settings, we find that our models compare well against the continual reassessment method in terms of selecting the true optimal dose. In particular, one of our models which uses dose-limiting and low-level toxicity counts beats or ties the other models, including the continual reassessment method, in all scenarios except the one in which the true optimal dose is the highest dose available. We also find that our models, when not selecting the true optimal dose, tend to err by picking lower, safer doses, while the continual reassessment method errs more toward toxic doses. Conclusion Using dose-limiting and low-level toxicity counts, which are easily obtained from data already routinely collected, is a promising way to improve the efficiency in finding the true maximum tolerated dose in phase I trials.

Initial phase I evaluation of the novel thymidylate synthase inhibitor, LY231514, using the modified continual reassessment method for dose escalation.

1995 ◽  
Vol 13 (11) ◽  
pp. 2842-2850 ◽  
Author(s):  
D A Rinaldi ◽  
H A Burris ◽  
F A Dorr ◽  
J R Woodworth ◽  
J G Kuhn ◽  
...  
Keyword(s):  
Dose Level ◽  
Thymidylate Synthase ◽  
Dose Escalation ◽  
Pharmacokinetic Studies ◽  
Maximum Plasma ◽  
Treatment Schedule ◽  
Continual Reassessment Method ◽  
Toxic Dose ◽  
Continual Reassessment ◽  
Dose Limiting Toxicity

PURPOSE To determine the toxicities, maximal-tolerated dose (MTD), pharmacokinetic profile, and potential antitumor activity of LY231514, a novel thymidylate synthase (TS) inhibitor. PATIENTS AND METHODS Patients with advanced solid tumors were administered LY231514 intravenously over 10 minutes, weekly for 4 weeks, every 42 days. Dose escalation was based on the modified continual reassessment method (MCRM), with one patient treated at each minimally toxic dose level. Pharmacokinetic studies were performed in all patients. RESULTS Twenty-five patients were administered 58 courses of LY231514 at doses that ranged from 10 to 40 mg/m2/wk. Reversible neutropenia was the dose-limiting toxicity. Inability to maintain the weekly treatment schedule due to neutropenia limited dose escalation on this schedule. Nonhematologic toxicities observed included mild fatigue, anorexia, and nausea. At the 40-mg/m2/wk dose level, the mean harmonic half-life, maximum plasma concentration, clearance, and apparent volume of distribution at steady-state were 2.02 hours, 11.20 micrograms/mL, 52.3 mL/min/m2, and 6.64 L/m2, respectively. No major antitumor responses were observed; however, minor responses were achieved in two patients with advanced colorectal cancer. CONCLUSION The dose-limiting toxicity, MTD, and recommended phase II dose of LY231514 when administered weekly for 4 weeks every 42 days are neutropenia, 40 mg/m2, and 30 mg/m2, respectively.

Phase I trial of temsirolimus (TEM) plus sorafenib (SOR) in advanced hepatocellular carcinoma (HCC) with pharmacokinetic (PK) and biomarker correlates.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4102-4102 ◽  
Author(s):  
Robin Katie Kelley ◽  
Halla Sayed Nimeiri ◽  
Pamela N. Munster ◽  
Mary Frances Mulcahy ◽  
Maxwell Thomas Vergo ◽  
...  
Keyword(s):  
Phase 1 ◽  
Mammalian Target Of Rapamycin ◽  
Maximum Tolerated Dose ◽  
Advanced Hepatocellular Carcinoma ◽  
Best Response ◽  
Hand Foot Syndrome ◽  
Prior Systemic Therapy ◽  
Expansion Cohort ◽  
Cancer Network ◽  
Dose Limiting Toxicity

4102 Background: Mammalian target of rapamycin inhibitors added to SOR augment antitumor effect in HCC models. We developed a phase 1 trial to determine maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of TEM plus SOR in HCC patients (pts). The study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support from Pfizer, Inc., and conducted at 2 NCCN centers. Methods: Eligibility: ≥1 measurable site. No prior systemic therapy (Tx). ECOG ≤2, Child Pugh ≤7, bilirubin ≤2 mg/dL, platelets (PLT) ≥75,000/mcL. Design: 3+3 escalation. Dose-limiting toxicity (DLT) window 28 days. MTD expansion cohort of 9 pts for PK and biomarkers. Endpoints: 1°: MTD, RP2D. 2°: Safety, toxicity, PK for TEM. Exploratory: Tumor necrosis, alpha fetoprotein (AFP)-L3, des-γ-carboxyprothrombin, and circulating tumor cells (CTC) by slide-based assay. Results: 21 pts enrolled. Median age: 60 (47-77). Male/Female: 15/6. Etiology: HCV 9 (43%), HBV 4 (19%), HBV+HCV 2 (10%), ETOH 2 (10%), unknown 4 (19%). Toxicity: DL1: 1 DLT Grade (Gr) 3 PLT. All pts required reductions for adverse events (AE); de-escalated to DL-1 for intolerability. DL-1: 1 DLT Gr3 hand-foot syndrome (HFS). Most common related ≥Gr 3 AE: HypoPO4 (52%); PLT (24%); transaminitis (19%); diarrhea, fatigue, HFS (10% each). Possibly related serious AE (SAE): Gr4 tumor rupture, Gr4 urosepsis, Gr3 dental infection with Gr2 ANC, Gr2 pneumonia (1 pt, 5% each). Best response: Confirmed partial response (PR) 2/21 (10%), stable disease (SD) 11/21 (52%), progression 1/21 (5%), 7/21 (33%) not evaluable. Time on study: Range <1 to 19+ months; median 3+ months for pts who completed ≥1 cycle (16/21). 16/21 (76%) had baseline elevated AFP ≥20; 8/16 (50%) had >50% decline. CTC were detected in 5/5 of tested samples. Decreased tumor enhancement on Tx was seen. Conclusions: DL-1 is MTD and RP2D, lower than a prior trial in pts without HCC; tolerability may be impacted by cirrhosis. Encouraging durable radiographic and AFP responses occurred. [Table: see text]

A phase I, dose-escalation, multicenter study of ACT-PFK-158, 2HCl in patients with advanced solid malignancies explores a first-in-human inhibitor of glycolysis.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. TPS494-TPS494 ◽  
Author(s):  
Rebecca Ann Redman ◽  
Paula Raffin Pohlmann ◽  
Michael R. Kurman ◽  
Gilles Tapolsky ◽  
Jason Chesney
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Phase 1 ◽  
Hypoxia Inducible Factor ◽  
Therapeutic Index ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Peripheral Blood Mononuclear ◽  
Activating Mutations ◽  
Dose Limiting Toxicity

TPS494 Background: In human cancers, loss of PTEN, stabilization of hypoxia inducible factor-1α, and activation of Ras and AKT converge to increase the activity of a regulator of glycolysis, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3). This enzyme synthesizes fructose-2,6-bisphosphate (F2,6BP), which is an activator of 6-phosphofructo-1-kinase, a crucial step of glycolysis that is tightly controlled by multiple metabolic feedback mechanisms and dictates the rate of glycolytic flow. The vast majority of pancreatic ductal adenocarcinomas and approximately 50% of colon adenocarcinomas harbor activating mutations in Ras and these tumors have been reported to be highly glycolytic. PFK158 is a potent small molecule inhibitor of PFKFB3 that is selectively cytotoxic to Ras-transformed epithelial cells and displays broad anti-tumor activity causing ~80% growth inhibition in several mouse models of human-derived tumors and syngeneic murine models of colon cancer. Importantly, IND-enabling safety and toxicity studies have demonstrated that PFK158 is well tolerated in rats and dogs with an expected good therapeutic index, lending support for a phase 1 trial that is now underway. Methods: The primary objective of the study is to describe the dose limiting toxicity and to determine either the maximum tolerated dose or biological effective dose of PFK-158 in a “3+3” cohort-based dose escalation design that follows a modified Fibonacci scheme. Multiple secondary endpoints have been incorporated to assess the effects of PFK-158 on peripheral blood mononuclear cell F2,6BP activity and on glucose uptake using FDG-PET imaging. This trial is currently enrolling at two US sites; Cohort 1 has been completed without dose-limiting toxicity and Cohort 2 is enrolling with two subjects under treatment as of September 2014. In conclusion, PFK158 is the first-in-man and first-in-class PFKFB3 inhibitor to be examined in a phase I trial and may have significant clinical utility either as a monotherapy or when combined with other targeted agents. Clinical trial information: NCT02044861.

Phase 1/2 study of safety/efficacy using trabectedin, ipilimumab, and nivolumab as first-line treatment of advanced soft tissue sarcoma (STS).

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. TPS46-TPS46 ◽  
Author(s):  
Erlinda Maria Gordon ◽  
Victoria S. Chua-Alcala ◽  
Katherine Kim ◽  
William W. Tseng ◽  
Doris M Quon ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Categorical Variables ◽  
Phase 2 ◽  
First Line ◽  
First Line Therapy ◽  
Number Of Patients

TPS46 Background: Sarcoma cells are most immunogenic at the onset of cancer when the immune system can recognize and destroy them. Hence, immune checkpoint inhibitors would be most effective when given as first line therapy. Objectives: (1) To investigate the maximum tolerated dose of trabectedin, an alkylating agent, when given sequentially with ipilimumab, a CTLA4 inhibitor, and nivolumab, a PD-1 inhibitor, in advanced STS, (2) To investigate the objective response rate (ORR), progression free survival (PFS) and overall survival (OS) , and (3) To correlate PFS with PD-L1 and other biomarker expression in patients’ tumors. Methods: Forty patients ≥18 years of age with advanced STS will be enrolled. This is a phase 1/2 study using a defined dose of ipilimumab (1 mg/kg i.v. q 12 weeks), nivolumab (3 mg/kg i.v. q 2 weeks), and escalating doses of trabectedin (1.0, 1.3, 1.5 mg/m2 i.v. q 3 weeks). I. Dose Escalation Phase 1 (previously treated patients): The study will employ the standard “cohort of three” design. The maximum tolerated dose is defined as the highest safely tolerated dose, where not more than one patient experienced DLT, with the next higher dose level having at least two patients who experienced DLT. II. Expansion Phase 2 (previously untreated patients): An additional 22-28 patients will receive trabectedin at the MTD and defined doses of ipilimumab and nivolumab to assess overall safety and potential efficacy in a greater number of patients. Patients may continue treatment until significant disease progression or unacceptable toxicity occurs. Statistical Considerations: NIH CTCAE v4.03 and RECIST v1.1 will be used. Categorical variables will be summarized by the n and percent in each category. Point estimates for efficacy endpoint incidences will be accompanied by a 2-sided 95% exact binomial CI. Time to event endpoints will be summarized descriptively using the KM method. The analyses of all study objectives will be descriptive and hypothesis generating, for planning Phase 2/3 studies. Clinical trial information: NCT 03138161.

scholarly journals Would the Recommended Dose Have Been Different Using Novel Dose-Finding Designs? Comparing Dose-Finding Designs in Published Trials

2021 ◽  
pp. 1024-1034
Author(s):  
Rebecca B. Silva ◽  
Christina Yap ◽  
Richard Carvajal ◽  
Shing M. Lee
Keyword(s):  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Simulation Studies ◽  
Toxicity Data ◽  
Continual Reassessment Method ◽  
Optimal Interval ◽  
Patient Allocation ◽  
Continual Reassessment ◽  
Continuous Use ◽  
Dose Levels

PURPOSE Simulation studies have shown that novel designs such as the continual reassessment method and the Bayesian optimal interval (BOIN) design outperform the 3 + 3 design by recommending the maximum tolerated dose (MTD) more often, using less patients, and allotting more patients to the MTD. However, it is not clear whether these novel designs would have yielded different results in the context of real-world dose-finding trials. This is a commonly mentioned reason for the continuous use of 3 + 3 designs for oncology trials, with investigators considering simulation studies not sufficiently convincing to warrant the additional design complexity of novel designs. METHODS We randomly sampled 60 published dose-finding trials to obtain 22 that used the 3 + 3 design, identified an MTD, published toxicity data, and had more than two dose levels. We compared the published MTD with the estimated MTD using the continual reassessment method and BOIN using target toxicity rates of 25% and 30% and toxicity data from the trial. Moreover, we compared patient allocation and sample size assuming that these novel designs had been implemented. RESULTS Model-based designs chose dose levels higher than the published MTD in about 40% of the trials, with estimated and observed toxicity rates closer to the target toxicity rates of 25% and 30%. They also assigned less patients to suboptimal doses and permitted faster dose escalation. CONCLUSION This study using published dose-finding trials shows that novel designs would recommend different MTDs and confirms the advantages of these designs compared with the 3 + 3 design, which were demonstrated by simulation studies.

A Phase 1 Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel using a novel Randomized Continual Reassessment Method for Dose Escalation

2021 ◽  
pp. clincanres.4185.2020
Author(s):  
Florence Atrafi ◽  
Oliver Boix ◽  
Vivek Subbiah ◽  
Jennifer R. Diamond ◽  
Sant P Chawla ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Phase 1 ◽  
Continual Reassessment Method ◽  
Phase 1 Study ◽  
Continual Reassessment
Sign in / Sign up

Export Citation Format

Share Document