scholarly journals A Bayesian Zero-Inflated Binomial Regression and Its Application in Dose-Finding Study

2019 ◽  
Author(s):  
Puntipa Wanitjirattikal ◽  
Chenyang Shi
Keyword(s):  
Drug Efficacy ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Early Phase Clinical Trial ◽  
Binomial Regression ◽  
Finding Study ◽  
Potential Possibility ◽  
Phase Clinical Trial ◽  
Dose Finding Study ◽  
Dose Limiting Toxicity

AbstractIn early phase clinical trial, finding maximum-tolerated dose (MTD) is a very important goal. Many researches show that finding a correct MTD can improve drug efficacy and safety significantly. Usually, dose-finding trials start from very low doses, so in many cases, more than 50% patients or cohorts do not have dose-limiting toxicity (DLT), but DLT may occur suddenly and increase fast along with just two or three doses. Although some fantastic models were built to find MTD, little consideration was given to those ‘0 DLTs’ and the ‘jump’ of DLTs. We developed a Bayesian zero-inflated binomial regression for dose-finding study based on Hall (2000), which analyses dose-finding data from two aspects: 1) observation of only zeros, 2) number of DLTs based on binomial distribution, so it can help us analyse if the cohorts without DLT have potential possibility to have DLT and fit the ‘jump’ of DLTs.

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]

Docetaxel and Gemcitabine in the Treatment of Metastatic Breast Carcinoma: A Dose Finding Study

2009 ◽  
Vol 95 (4) ◽  
pp. 427-431
Author(s):  
Vita Leonardi ◽  
Valentina Palmisano ◽  
Alessio Pepe ◽  
Antonella Usset ◽  
Giovanna Manuguerra ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dose Level ◽  
Metastatic Breast ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Finding Study ◽  
Previously Treated ◽  
Dose Finding Study ◽  
Level 2 ◽  
Dose Limiting Toxicity

Aims and background Patients with metastatic breast cancer previously treated with anthracyclines for advanced disease are usually refractory to any further treatment with anthracyclines and have a poor prognosis. Therefore, new drugs or new combinations of drugs are needed. One approach has been to focus on the type of chemotherapy with low toxicity that preserves quality of life during treatment, such as weekly drug administration. Study design We designed a dose-finding study to determine the maximum tolerated dose of gemcitabine plus docetaxel, given on a weekly schedule in metastatic breast cancer previously treated with anthracyclines. Three escalating doses of gemcitabine (900, 1000 and 1100 mg/m2) on days 1 and 8 in combination with a fixed dose of docetaxel, 35 mg/m2 on days 1 and 8 were planned. Dose-limiting toxicity included grade >3 hematologic toxicity, grade >2 stomatitis, asthenia, diarrhea or organ-specific toxicity (except alopecia). Dose escalation was stopped if 1 out of 3 patients at any dose level experienced dose-limiting toxicity. Results Nine patients received a mean of 5.1 (range, 1–9) cycles. Gastrointestinal and leukopenia were the main dose-limiting toxicity. No patient experienced dose-limiting toxicity at dose level 1; at dose level 2, 2 out of 3 patients had dose-limiting toxicity and 3 additional patients treated at dose level 2 confirmed that the maximum tolerated dose had been reached. Conclusions The recommended gemcitabine dose in combination with docetaxel (35 mg/m2 for a phase II study) was established at 900 mg/m2.

Safety and antitumor activity of AMG 706 in patients (pts) with thyroid cancer (TC): A subset analysis from a phase 1 dose-finding study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3030-3030 ◽  
Author(s):  
D. Boughton ◽  
L. Rosen ◽  
A. Van Vugt ◽  
R. Kurzrock ◽  
M. Eschenberg ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Stage Iv ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Finding Study ◽  
Stage Iv Disease ◽  
Modified Recist ◽  
Dose Finding Study

3030 Background: AMG 706 is an investigational, oral, small molecule multi-kinase inhibitor with both antiangiogenic and direct antitumor activity that selectively targets VEGF, PDGF, and Kit receptors. From a phase 1 study (Rosen ASCO 2005; Herbst EORTC 2005), encouraging antitumor activity was seen in pts with TC. In this analysis, we report on the TC subset from the study. Methods: Pts with refractory solid tumors received oral AMG 706 QD (50, 100, 125, 175 mg) or BID (25 mg) intermittently or continuously for 28-day cycles. Study objectives were to assess safety, establish the maximum tolerated dose (MTD), and generate pharmacokinetic profiles of AMG 706 in these pts. Tumor response (modified RECIST) was evaluated at wk 8 and Q12W thereafter. Data from Oct 2005 were analyzed. Results: In this study, 7 of 71 pts enrolled had TC. Baseline demographics for this subset were 4 W/3 M, median (range) age of 58 (41, 78) yrs, ECOG 1 (71%), and all had stage IV disease. Histologies were papillary (3: PTC), follicular (1; FTC), Hürthle cell (1), anaplastic (1), and medullary TC (1; MTC). All pts received prior external radiotherapy, radioiodine, chemotherapy, and/or surgery. Initial doses of AMG 706 were 125 mg and 175 QD and 25 mg BID. The MTD for the study was 125 mg QD. Median (range) time on treatment for the TC pts was 141 (14, 564) days. Treatment-related adverse events are summarized ( table ). Best objective responses were 3 pts with partial response (PR), 3 with stable disease (SD), and 1 with progressive disease. PR was seen in pts with MTC, PTC and FTC. Two pts with PR did not have confirmation of response (1 had a PR during the last assessment). The 3 pts with PR received AMG 706 for 338, 366, and 564 days; 2 pts are still receiving AMG 706. Time to response for these 3 pts were 210, 217, and 304 days. Conclusion: In patients with TC, AMG 706 appears to be relatively well tolerated and displays promising antitumor activity for some pts. Based on these favorable findings, a phase 2 study of AMG 706 for the treatment of advanced TC is ongoing. [Table: see text] [Table: see text]

Phase I/II dose-finding study of crizotinib (CRIZ) in combination with erlotinib (E) in patients (pts) with advanced non-small cell lung cancer (NSCLC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2610-2610 ◽  
Author(s):  
Sai-Hong Ignatius Ou ◽  
Ramaswamy Govindan ◽  
Keith D. Eaton ◽  
Gregory Alan Otterson ◽  
Martin Gutierrez ◽  
...  
Keyword(s):  
Phase I ◽  
Advanced Nsclc ◽  
Kinase Inhibitor ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Dry Eyes ◽  
Egfr Inhibition ◽  
Development Of Resistance ◽  
Finding Study ◽  
Dose Finding Study

2610 Background: c Met expression is common in NSCLC tumors and has been implicated in the development of resistance to EGFR inhibitors. CRIZ is an ALK and MET/HGF receptor tyrosine kinase inhibitor (TKI). In pre-clinical studies, combining CRIZ with an EGFR inhibitor enhanced anti-tumor activity in NSCLC cell lines that were either sensitive or resistant to EGFR inhibition. The phase I portion of a phase I/II study (A8081002; NCT00965731) investigated the combination of E (EGFR TKI) and CRIZ in pts with advanced NSCLC. Methods: Pts had advanced NSCLC, 1 or 2 prior chemotherapy regimens, and no previous MET-directed therapy. Endpoints included maximum tolerated dose (MTD) determination, safety, and pharmacokinetics (PK). Pts received CRIZ 150 or 200 mg BID combined with E 100 mg QD (150/100 and 200/100, respectively). Results: Twenty-five pts have been treated to date. Median duration of combination therapy in 150/100 (n=18) was 6.6 weeks (0.1–25.3); for 200/100 (n=7) was 6.9 weeks (3.0–64.7). Five pts had dose-limiting toxicities (grade [G] 2 and unable to receive at least 80% of the planned dose or ≥G3), all of which resolved: 3 pts at 150/100, G2 vomiting, G2 esophagitis and dysphagia, G3 diarrhea and dehydration; and at 200/100, G3 dry eye (1 pt) and G3 esophagitis (1 pt). Most pts (92%) experienced treatment-related adverse events (TRAEs), mainly of G1 or 2 severity. Common TRAEs were diarrhea (72%), rash (56%) and fatigue (44%). Six pts discontinued therapy due to TRAEs (150/100: G3 diarrhea, G3 dehydration, and G2 rash in 1 pt, G2 asthenia, G2 vomiting, G2 esophagitis, n=1 each; 200/100: G3 dry eyes, G1 esophagitis, n=1 each). One partial response (200/100; duration 61 weeks) and 9 stable diseases (n=7 150/100, n=2 200/100; duration 7–54 weeks) were observed overall. Co-administration of both doses of CRIZ with E increased E AUC by 1.8 fold, while CRIZ PK parameters appeared to be unaffected. Plasma exposure to E 100 mg QD with CRIZ was comparable to that of 150 mg QD from historical data. Conclusions: E plus CRIZ at the MTD was well tolerated, with no unexpected AEs, and showed signs of activity in a pre-treated population. E 100 mg QD plus CRIZ 150 mg BID was defined as MTD.

Dose-finding study of NKTR-102 in combination with cetuximab

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13503-e13503
Author(s):  
J. T. Hamm ◽  
D. Richards ◽  
R. K. Ramanathan ◽  
C. Becerra ◽  
G. Jameson ◽  
...  
Keyword(s):  
Active Metabolite ◽  
Single Agent ◽  
Safety Data ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Polymer Conjugate ◽  
Finding Study ◽  
Dose Finding Study ◽  
Tumor Types ◽  
Symptomatic Benefit

e13503 Background: NKTR-102 is an advanced polymer conjugate of irinotecan with broad single agent activity and a unique pharmacokinetic (pk) profile. The apparent half-life of the active metabolite SN-38 in patients (pts) administered NKTR-102 is approximately 50 days. NKTR-102 in combination with cetuximab was evaluated in pts with refractory solid tumors to define the maximum tolerated dose (MTD). Methods: NKTR-102 was infused over 90 minutes every 3 weeks per cycle. Cetuximab was infused over 2 hours at 400mg/m2 on day 1 followed by a weekly 1 hour infusion at 250mg/m2. Cohorts of 3 -12 pts were treated with escalating doses of NKTR- 102. MTD was established based on the dose limiting toxicities observed in cycle 1 and safety data from subsequent cycles. Serial plasma samples were collected throughout the study for PK analysis. Results: Eighteen pts were enrolled: main tumor types include colon (5), pancreas (4), rectal (2), breast (2), gastric (1), other (4). Pts received 100 mg/m2 (12) or 125 mg/m2 (6) of NKTR-102 for a median of 2.5 cycles (range 1 to 11+). At 125 mg/m2, 3 pts had G3 diarrhea, 1 in cycle 1; 2 in cycle 2. At 100mg/m2, 1 pt had G3 diarrhea in cycle 1 and a further pt had G4 fatigue in cycle 2. Other G3 toxicities for all patients in both dose groups include nausea (3), vomiting (3) and neutropenia (2). No G3 rash was reported. Partial responses (PR) were observed in 3 pts at 100 mg/m2: confirmed (rectal, colorectal) and unconfirmed (gastric). Another pt with pancreatic cancer had a decrease in CA19–9 from 2000 at baseline to 157 U/ml with associated symptomatic benefit. NKTR-102 resulted in sustained exposure to SN-38 with no evidence of PK drug interactions between NKTR-102 and cetuximab. Conclusions: NKTR-102 shows evidence of clinical antitumor activity in combination with cetuximab. Toxicity is manageable; diarrhea and neutropenia are dose limiting. The recommended dose of NKTR-102 with cetuximab is 100mg/m2 every three weeks. Data support further evaluation of this combination in appropriate tumor types. [Table: see text]

CTNI-51. ADJUVANT TROTABRESIB, A REVERSIBLE POTENT BROMODOMAIN AND EXTRATERMINAL INHIBITOR, PLUS TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA: INTERIM RESULTS FROM A PHASE 1B DOSE-FINDING STUDY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi71-vi72
Author(s):  
Maria Vieito ◽  
Matteo Simonelli ◽  
Filip de Vos ◽  
Victor Moreno ◽  
Marjolein Geurts ◽  
...  
Keyword(s):  
Standard Of Care ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Newly Diagnosed ◽  
Post Dose ◽  
Finding Study ◽  
Newly Diagnosed Glioblastoma ◽  
Phase 1B ◽  
Dose Finding Study

Abstract Trotabresib (CC-90010) demonstrated antitumor activity as monotherapy in patients with advanced malignancies (Moreno et al. ESMO 2020. Abstract 5270) and enhanced the antiproliferative effects of temozolomide in preclinical studies. CC-90010-GBM-002 (NCT04324840) is a phase 1B dose-finding study investigating standard-of-care temozolomide + radiotherapy followed by adjuvant trotabresib + temozolomide or concomitant trotabresib + temozolomide + radiotherapy followed by adjuvant trotabresib + temozolomide, post-resection, in patients with newly diagnosed glioblastoma. We present interim results for adjuvant trotabresib + temozolomide. Patients received trotabresib 15, 30, or 45 mg daily (4 days on/24 days off) + temozolomide administered per label for 6 cycles, followed by trotabresib 45 mg monotherapy daily (4 days on/24 days off). Primary objectives are to establish the safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of trotabresib. Preliminary efficacy, pharmacokinetics, and pharmacodynamics are also being investigated. Of 13 patients enrolled, 5, 6, and 2 received trotabresib 15, 30, and 45 mg, respectively, plus temozolomide. Grade 3/4 treatment-related adverse events were reported in 2, 4, and 1 patients receiving trotabresib 15, 30, and 45 mg, respectively. MTD and RP2D are not yet reached; dose limiting toxicity (grade 4 thrombocytopenia) was reported in 1 patient in the 30-mg group. Of 10 evaluable patients, 1 had complete response and 7 had stable disease per RANO criteria. Trotabresib exposure increased proportionally with dose. Day 4 time to peak trotabresib concentration was 0.5–2.0 hours; mean terminal half life was 60–70 hours. Day 4 blood CCR1 RNA 2–4 hours post-dose was downregulated below baseline in the 15-mg group and ≥ 50% in the 30-mg group. Adjuvant trotabresib + temozolomide appears well tolerated, with promising preliminary efficacy. Treatment was ongoing at data cutoff in 9 patients in the adjuvant cohort; enrollment is continuing in the adjuvant and concomitant therapy dose-escalation cohorts.

Sign in / Sign up

Export Citation Format

Share Document