Predictors of early mortality and validation of novel prognostic models in Asian patients on phase I trials (PIT): A single-center experience.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 6618-6618
Author(s):  
Aziah Ahmad ◽  
Whee Sze Ong ◽  
Wan-Teck Lim ◽  
Wai Meng David Tai ◽  
Cindy Lim ◽  
...  
Keyword(s):  
Phase I ◽  
Cox Model ◽  
Prognostic Score ◽  
Univariate Analysis ◽  
Prognostic Models ◽  
Molecular Profile ◽  
Cancer Center ◽  
Cancer Type ◽  
Phase I Trials ◽  
Discriminative Ability

6618 Background: Despite the growing number of clinical trials conducted in Asia and the unique pt demographic and molecular profile of endemic cancers, there is still lacking of studies examining the outcomes of pts on PIT. We examined the characteristics and outcomes of pts enrolled in phase I trials in National Cancer Center Singapore (NCCS). Methods: We reviewed 296 pts enrolled in PIT from 2004-2012 to identify factors that predicted for 90-day mortality and OS. Logistic regression model and Cox proportional hazard model assessed factors associated with 90DM and OS, respectively. The discriminative ability of the RMH prognostic score (LDH, no of met sites, albumin) and the final multivariate Cox model derived in Asian pts was evaluated using Harrell’s concordance index (c-index), and that for the logistic model was based on area under ROC curve (AUC). Internal validation was performed based on simulated data via bootstrapping. Results: Median age 60 (23-85), M:F (65/35%). The commonest cancer type thoracic (56%), GI (24%), head and neck (12%). 57% pt had comorbidities, commonest diabetes (16.6%) and hepatitis B (11.1%). Median no of lines of treatment 2. 20% of pts had known mut status. 15% pts survived less than 90 days from start of trial. Median OS was 9.6 m (95CI 7.8-11.2 m). Based on the RMH prognostic model, pts with score of 0 to 1 had a superior OS (median OS = 12.9 m) compared to those with score of 2 to 3 (OS = 5.7 m) (p < 0.001). The c-index for the RMH prognostic score was 0.64. On univariate analysis, alb<35,LDH>ULN, ≥3 met sites, low BMI, ECOG>0, Na<135,plt>440, Hb<12 and ≥3 lines of chemo were negative prognostic factors. On multivariate analysis, reduced model selection techniques identified alb<35, LDH>ULN, ≥3 met sites, and ≥ 3 prior lines of chemo as independent negative predictors of OS with a bias-corrected of 0.69. For 90DM, we developed a risk normogram based on ECOG, WBC, Na and Hb as continuous predictors with bias-corrected AUC 0.78. Conclusions: We have developed a novel NCCS normogram to predict for 90DM for PIT. The RMH prognostic score can be improved upon with the addition of number of prior lines of chemotherapy, underscoring the importance of early access to phase I trials.

Characteristics and outcomes of patients with advanced hepatocellular carcinoma treated on phase I trials.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 281-281 ◽  
Author(s):  
Ishwaria Mohan Subbiah ◽  
Filip Janku ◽  
Apostolia Maria Tsimberidou ◽  
Aung Naing ◽  
Ahmed Omar Kaseb ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Phase I ◽  
Serum Sodium ◽  
Prognostic Score ◽  
Univariate Analysis ◽  
Single Agent ◽  
Advanced Hepatocellular Carcinoma ◽  
Phase I Trials ◽  
Phase I Clinical Trials

281 Background: Patients with advanced hepatocellular carcinoma (HCC) have limited effective therapies. With that purpose, we analyzed the outcomes and prognostic factors of such pts treated on phase I trials w an emphasis on locoregional and targeted agents. Methods: We reviewed the records of 100 consecutive pts referred to the Phase I Clinical Trials Program from March 2004 and assessed characteristics, types of clinical trials, progression-free survival (PFS), overall survival (OS) and oncogenic mutations. Results: Of 100 referred pts, 39 were not treated mainly due to poor performance status (n=22). Of 61 treated pts (49 male, 12 female, median age 60yrs), median # of prior therapies was 3 (range, 0-8). There were no treatment-related mortalities. One pt on a sorafenib regimen had g3 hand foot syndrome unresponsive to dose reduction. A 2nd pt developed a L-sided visual blurriness after 5 days on a sunitinib regimen; CT showed a small R parieto-occipital hemorrhage, possibly related to therapy. Of 61 treated pts, 7 (11%) had stable disease (SD) > 6 months, 4 (7%) partial response (PR), on protocols combining bevacizumab+sorafenib, pazopanib+everolimus, or single-agent novel oral multikinase inhibitor of VEGFR2-TIE2, or hepatic arterial infusion (HAI) of paclitaxel or oxaliplatin w IV bevacizumab. Median PFS on Phase I trials was 2.2 months vs. 4.4 months and 4.1 months for their 1st- and 2nd-line FDA-approved therapy (p 0.019). In univariate analysis, the presence of ascites, portal hypertension, cirrhosis, serum sodium, albumin, and poor Royal Marsden Hospital (RMH) prognostic score were associated with shorter PFS and OS (p < 0.05). On multivariate analysis, independent factors of shorter OS were Caucasian race (p = 0.031), cirrhosis (p = 0.016), serum sodium (p = 0.0013), and poor RMH prognostic score (p = 0.0015). Molecular analysis in progress will be updated. Conclusions: Phase I therapy offer a reasonable therapeutic option for patients with advanced HCC. The RMH prognostic score was validated in this population. The SD > 6 months/PR rate of 18% was observed with regimen of multikinase inhibitors with mTOR inhibitors and HAI therapy.

Use of inflammation-based scores to optimize the selection of patients with advanced cancer considered for early-phase clinical trials.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13033-e13033
Author(s):  
David James Pinato ◽  
Chara Stavraka ◽  
Sean Micheal O'Cathail ◽  
Michael Seckl ◽  
Sarah Patricia Blagden
Keyword(s):  
Phase I ◽  
Cox Model ◽  
Performance Status ◽  
Univariate Analysis ◽  
Previous Treatment ◽  
Predictive Performance ◽  
Rank Test ◽  
Discriminative Ability ◽  
Selection Of Patients ◽  
Selection Of

e13033 Background: The presence of adequate organ function, favorable performance status (PS) and exhaustion of standard treatments are the main factors guiding accrual onto Phase I trials. As inflammation is inherent to the pathogenesis and prognosis of cancer we investigated the prognostic and predictive performance of inflammation based indices including the neutrophil (NLR) and platelet to lymphocyte ratio (PLR). Methods: Unselected referrals to the Phase I unit (2007-2011) were considered. Demographic, treatment, staging data and routine blood tests were collected. Patients were defined as high risk if NLR>5 or PLR>300 respectively. Changes in the NLR (ΔNLR) were recalculated at disease reassessment. Kaplan Meier and log rank test were used to assess Progression Free (PFS) and Overall Survival (OS) with each variable. Significant factors were further tested in a multivariate Cox model. C-index was used to calculate the discriminative ability of each score and ROC curves to predict 90 days survival (90DS). Results: We included 126 patients with median age 63 years (range: 22-80); median OS 4.4 months (0.2-39), 36% male; 92% with metastases, 23% PS>1. On univariate analysis LDH>450, PS, NLR≥5, hypoalbuminaemia, NLR normalization (ΔNLR) (p<0.001), >2 previous treatment lines (p=0.01) predicted for OS. After multivariate analysis low albumin, high LDH and ΔNLR remained independent predictors (p<0.05). Shorter PFS was predicted by elevated LDH and ΔNLR (p<0.05). PS and NLR ranked as most accurate predictors of both 90DS with area under the ROC curve values of 0.66 (0.55-0.77) and 0.64 (0.54-0.75) and OS with c-index scores of 0.69 (0.56-0.82) and 0.60 (0.50-0.70). When combined to PS, the NLR improved its accuracy to 0.72 (0.59-0.83). NLR≥5 at screening was associated with advanced PS, low albumin (p<0.002), LDH>450 and >2 metastatic sites (p<0.05). Conclusions: The NLR can improve the selection of patients considered for experimental therapies, with its normalization following treatment predicting for a survival benefit of 7 months in our series.

Prognostic factors for cancer patients with good performance status considered for inclusion in phase I clinical trials

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2568-2568
Author(s):  
M. Bonneterre ◽  
N. Penel ◽  
M. Vanseymortier ◽  
E. Dansin ◽  
S. Clisant ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Prognostic Factors ◽  
Serum Albumin ◽  
Phase I ◽  
Cancer Patients ◽  
Cox Model ◽  
Performance Status ◽  
Univariate Analysis ◽  
Rank Test ◽  
Phase I Clinical Trials

2568 Background: For investigators, the selection of patients to be considered for phase I clinical trials is difficult, because of the lack of objective criteria for a rational decision-making process. From October 1997 to October 2002, we retrospectively assessed prognostic factors for cancer patients considered for Phase 1 trials. Methods: 148 consecutive patients who had been screened for inclusion in 6 different phase I trials were included in the present study. 70 out of them actually received the phase I treatment. Univariate (Log-Rank test) and multivariate analysis (Cox proportional hazard ratio model) were performed to determine the prognostic factors related to overall survival (OS) after screening. Results: The study comprised 63 men and 85 women, with a median age of 54 (range 23–79). The most frequent primary cancer sites were: breast (38 cases), head and neck (28 cases), lung (18 cases) and colorectal (17 cases). 91 out of them had a performance status PS = 0. The median OS of the 148 patients was 5.7 months (173 days, range 1–2,421). Univariate analysis identified PS = 1, Body Mass Index < 20, liver and visceral metastasis, serum albumin < 38 g/L, lymphocytes count < 0.7 x 109/L and granulocytes count > 7.5 x 109/L as poor prognostic factors. The Cox model identified serum albumin < 38 g/L (HR 2.51 [1.51–4.18], p=0.0001) and lymphocyte count < 0.7 x 109/L (HR 2.27 [1.13–4.62], p=0.024) as independent prognostic variables for OS. All patients presenting with both prognostic factors died within 90 days. Conclusion: We propose a simple model, easily obtained at the patient bedside, which can discriminate patients who have a life expectancy of over 3 months and thus could be enrolled in phase-I anti-cancer trials. No significant financial relationships to disclose.

Mortality within 30 days of immunotherapy (checkpoint inhibitors) in metastatic cancer patients treated at Australian tertiary cancer center.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 6600-6600
Author(s):  
Hiren A. Mandaliya ◽  
Sang Kim ◽  
Gaik Tin Quah ◽  
Sandy Tun Min ◽  
James Carlton ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Advanced Cancer ◽  
Checkpoint Inhibitors ◽  
Metastatic Cancer ◽  
Univariate Analysis ◽  
Cell Cancer ◽  
Small Sample ◽  
Cancer Center ◽  
Published Data ◽  
Cancer Type

6600 Background: Cancer treatment has evolved rapidly since the advent of immunotherapy (checkpoint inhibitors). As compared to chemotherapy, immunotherapy is associated with a more favourable but distinct side effect profile. Mortality within 30 days of chemotherapy in cancer patients has been accepted as a clinical indicator of preventable harm and used as an auditing tool for clinical practice and improving quality of life. This should be investigated in the current era of immunotherapy, as it has been the standard treatment for advanced melanoma, lung cancer, renal cell cancer and others. Methods: We conducted a retrospective study on patients with advanced cancer treated with immunotherapy and died within 30 days of treatment. Clinical data on patients treated with immunotherapy at Calvary Mater Newcastle between 2006 and 2018 was collected. Data were compared with 30-day mortality statistics of chemotherapy. Results: A total of 601 metastatic cancer patients received immunotherapy agents (Pembrolizumab, Nivolumab, Ipilimumab, Atezolizumab, Tislelizumab and MSB0011359C) on 5022 occasions. Seventy-six (12.6%) patients died within 30 days of receiving immunotherapy. Median age was 68 years (35-90). Melanoma was the most prevalent cancer type (63%) followed by lung (20%). Forty-seven (47%) of patients received immunotherapy as first-line treatment and 39% as second-line. Patients died within 30 days received an average 2 (1-16) immunotherapy doses. A quarter of patients had ECOG 3 and ECOG 4 before last dose. Majority of deaths were related to disease (86%). Nearly 80% of patients died in hospital. One patient died due to treatment-related pneumonitis. In univariate analysis, there was no association between mortality and patients’ demographic variables such as age, sex, BMI, cancer type, ECOG performance status, immunotherapy agent and prior treatment. Conclusions: To our knowledge, this is the first ever real-world data on 30-day mortality after immunotherapy in advanced cancer. Thirty-day mortality rates were comparable to published data on patients treated with chemotherapy. Results emphasise significance of careful selection of advanced cancer patient for immunotherapy. Due to small sample size, the power to detect a significant association between patients demographics and survival is reduced.

scholarly journals Syntactic Analysis for Single Agent Phase I Trials in Japan, From National Cancer Center Hospital (Ncch) Experience

2014 ◽  
Vol 25 ◽  
pp. v50
Author(s):  
Hidenori Mizugaki ◽  
Noboru Yamamoto ◽  
Yutaka Fujiwara ◽  
Hiroshi Nokihara ◽  
Yasuhide Yamada ◽  
...  
Keyword(s):  
Phase I ◽  
Single Agent ◽  
National Cancer Center Hospital ◽  
Syntactic Analysis ◽  
Cancer Center ◽  
Phase I Trials ◽  
Center Hospital

Personalized medicine in a phase I clinical trials program: The M. D. Anderson Cancer Center Initiative.

2011 ◽  
Vol 29 (18_suppl) ◽  
pp. CRA2500-CRA2500 ◽  
Author(s):  
A. M. Tsimberidou ◽  
N. G. Iskander ◽  
D. S. Hong ◽  
J. J. Wheler ◽  
S. Fu ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Personalized Medicine ◽  
Phase I ◽  
Molecular Analysis ◽  
Pik3ca Mutation ◽  
Molecular Profile ◽  
Cancer Center ◽  
Molecular Testing ◽  
Phase I Clinical Trials

CRA2500 Background: We initiated a personalized medicine program hypothesizing that tumor molecular analysis and use of targeted therapy to counteract the effects of specific aberrations would improve the outcomes of affected patients. Methods: Molecular analysis was performed in the M. D. Anderson CLIA-certified pathology laboratory. Patients whose tumors had an aberration were treated in the Phase I Program with a matched targeted agent, when available. Results: Tumor molecular analysis was feasible in 852 (89%) of 955 consecutive patients with advanced cancer. Of 852 patients (median, age 56 yrs; prior therapies 4), 354 (41.5%) had ≥ 1 aberration: 10% of patients had a PIK3CA mutation; 19% KRAS; 8% NRAS; 19% BRAF; 3% EGFR; and 2% had a CKIT mutation; 21% had PTEN loss. Results are shown in the table. Median time to treatment failure (TTF) in 161 patients with 1 aberration treated with matched targeted therapy was 5.3 months (95%CI: 4.1, 6.6) vs 3.2 months (95%CI: 2.9 – 4.0) for their prior systemic antitumor therapy (prior to referral to phase I) (p= .0003). For patients with 1 aberration, the CR+PR rate was 29% with matched targeted therapy vs. 8% without matching (p = .0001). The CR+PR rate was 6% in 438 patients without molecular testing treated on the same studies. Conclusions: Preliminary results suggest that in early clinical trials matching patients with targeted drugs based on their molecular profile results in (a) longer TTF compared to their prior therapy and (b) higher rates of response, survival and TTF compared to those seen in patients treated without molecular matching. Support: 3UL1 RR024148 04 S1 and IPCT. [Table: see text]

Early-phase trials compared to first- and second-line FDA-approved treatments in patients with advanced gallbladder cancer and cholangiocarcinoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13020-e13020
Author(s):  
Ishwaria Mohan Subbiah ◽  
Apostolia Maria Tsimberidou ◽  
Aung Naing ◽  
Vivek Subbiah ◽  
Ahmed Omar Kaseb ◽  
...  
Keyword(s):  
Phase I ◽  
Drug Administration ◽  
Univariate Analysis ◽  
Hepatic Arterial Infusion ◽  
Progression Free Survival ◽  
Mek Inhibitor ◽  
Phase I Trials ◽  
Second Line ◽  
Prior Therapy ◽  
Metastatic Setting

e13020 Background: Patients with advanced cholangiocarcinoma (CC) and gallbladder carcinoma (GC) have few effective therapeutic options. We compared prognostic factors and clinical outcomes of CC/GC pts treated on phase I trials with that of their first-, second-line and last Food and Drug Administration (FDA)-approved therapy given in setting of metastatic disease. Methods: We retrospectively reviewed electronic medical records of patients with GC and CC evaluated in the phase I program clinic from November 2004 to March 2011. Results: Of the 72 patients with CC or GC, 32 (44%) were not enrolled on a trial mainly due to clinical deterioration (n=25). Of 40 treated patients (GC=6; CC=34; median age 60 years; median prior systemic therapies = 3), 8 (20%) had stable disease (SD) > 6 months; 3 (8%) achieved a partial response (PR); SD > 6 months/PR was observed mainly on protocols with hepatic arterial infusion drug administration and/or angiogenic inhibitors, anti-her2/neu agents or a novel MAPK/ERK kinase (MEK) inhibitor. Median progression-free survival (PFS) on phase I trials was 2.0 months (95% CI 1.7, 2.8) versus 3.0 months (95% CI 2.4, 5.0; p=0.95), 3.0 months (95% CI 2.3, 4.6; p=0.98), and 3.0 months (95% CI 2.4, 3.9; p=0.79) for their first-, second-, and last systemic therapy with FDA-approved agents given in the metastatic setting, respectively. In univariate analysis, factors associated with a shorter Phase I PFS were > 3 metastatic sites, elevated ALT (>56 IU/L), serum creatinine (>1.6mg/dL), and CA19-9 (>35U/mL). Conclusions: In heavily pretreated patients, PFS in the clinical trials setting remained poor but did not differ significantly from that of their first-line, second-line, and last prior therapy with FDA-approved agents. Response rate (SD >6 months/PR) of 28% was seen in trials with locoregional treatment or inhibitors of angiogenesis, her2/neu or MEK.

Clinical outcome for patients with metastatic colorectal cancer (mCRC) enrolled in phase I clinical trials: Single institution experience.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13550-e13550
Author(s):  
Umang Shah ◽  
Gopichand Pendurti ◽  
Umang Swami ◽  
Yijuan Hou ◽  
Mohammad Haroon Ghalib ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Phase I ◽  
Meta Analysis ◽  
Univariate Analysis ◽  
Phase Iii ◽  
Cancer Drug ◽  
Phase I Trials ◽  
Survival Times ◽  
Phase I Clinical Trials ◽  
Phase I Studies

e13550 Background: Phase I studies are a fundamental step in anti-cancer drug development. Prior meta-analysis looking at phase I studies showed an overall response rate (ORR) of 10.6 % and grade 4 toxicity rate of 14.3 %, and specifically, patients (pts) with mCRC enrolled in phase I trials had an ORR of 1.3 %. Herein, we report the results of a 12-year experience from our institution. Methods: Records from pts with metastatic colorectal adenocarcinoma enrolled in phase I studies at our institution from January 1999 to December 2010 were reviewed. Recorded data included treatment related responses, survival times and adverse events (AE). Kaplan-Meier analysis, t-test and X2 tests were used to analyze data. A Cox proportional-hazard model using clinical parameters at enrolment was used to predict survival. Results: Our cohort included 141 pts with mCRC (83% colon and 17% rectum) enrolled in 25 unique phase I trials. Median patient age at enrolment was 59 years, 66% were female and 81% had an ECOG PS of 0-1. Pts received a median of 3 lines of chemotherapy prior to enrolment. The median overall survival (OS) was 8.9 months. The ORR was 4.2%. The clinical benefit rate (ORR or stable disease for ≥ 4 months) was 22%. Univariate analysis showed that being female (P=0.02), Hb <12 g/dL (P=0.01), Alb < 4 g/dL (P=<0.001), Alkaline phosphatase > 150 U/L (P=<0.001) and LDH ≥ 300 U/L (P=<0.001) were independently associated with shorter survival. Multivariate analysis showed that females (HR of 2.81 95% CI 1.71-4.59, p= <0.001), Hb ≥ 12 g/dL (1.67, 95%CI 1.03-1.71, p=0.04), Alb < 4 g/dL (HR 2.51, 95% CI 1.59-3.98, p= <0.001) and LDH ≥300 U/L (HR 2.59, 95% CI 1.65-4.03, p= <0.001) were associated with shorter survival. Grade 3/4 non-hematological and hematological AE were seen in 25% and 45% of patients, respectively. Conclusions: This cohort of pts that received a median of 3 prior lines of therapy had a median OS and ORR of 8.9 months and 4.2%, respectively. These findings are similar to the ones reported in the recent phase III trial using regorafenib. Interestingly, multivariate analysis showed that a Hb of ≥ 12g/dL was associated with worse survival, in agreement with prior reports in which red cell growth factors were used.

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