Adherence to novel oral anticancer therapies in the phase I setting: The Royal Marsden experience.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2542-2542
Author(s):  
Maxime Chenard-Poirier ◽  
Joo Ern Ang ◽  
Samuel John Harris ◽  
Alvaro Henrique Ingles Garces ◽  
Satyanarayana Seeramreddi ◽  
...  
Keyword(s):  
Phase I ◽  
Univariate Analysis ◽  
Median Number ◽  
Continuous Treatment ◽  
Adherence Rate ◽  
Published Data ◽  
Pharmacokinetic Data ◽  
Treatment Schedule ◽  
Phase I Trials ◽  
Development Unit

2542 Background: The use of oral anticancer therapies has increased substantially in recent years. Nonadherence can impair the efficacy of such therapies as well as confound the interpretation of toxicity and pharmacokinetic data in phase I trials. However, there is a paucity of data regarding adherence patterns and barriers in this specific setting. Methods: We included patients treated in Phase I trials involving oral investigational medicinal products (IMPs) in the Drug Development Unit, Royal Marsden Hospital, UK, between 2012 and 2014. Patient, disease and treatment characteristics as well as compliance data from prospectively collected trial diary cards and drug accountability were recorded. Relationships between adherence rate and other variables were explored using logistic regression. Results: We collected data for 2819 patient-weeks, pertaining to 169 patients treated on 18 different phase I trials. Median age was 61 years (range 18-79), females predominated (60%), median number of previous systemic therapy was 3 (0-12) and median time on trial was 9 weeks (0.3-212.4). Hundred-percent adherence rate was 88% in the first cycle and 79% overall. Nonadherence occurred in 83 of 2819 patient-weeks (3.0%); including 75 (2.7 %) missed doses and 8 (0.3 %) overdoses. In univariate analysis, longer time on trial and a continuous treatment schedule were associated with poorer adherence, whereas fasting requirements pre- or post-dosing was associated with improved adherence. Known intracranial metastases, number of concomitant medications and opiates or anti-emetics use were not significantly associated to adherence. In multivariate analysis, fasting requirements (OR 5.347, 95%CI : 1.443-20.019, p = 0.012) and longer time on trial (OR 0.98, 95%IC : 0.961-0.996, p = 0.017) were statistically significant. Conclusions: This is the first report on adherence rates to oral anticancer IMPs in a large phase I trial population. Our observed adherence rates are at the higher end of published data in the general cancer population. Factors influencing adherence in phase I trials appear to be distinct, with fasting requirements being a unique finding. These findings may impact future early-phase trial design and conduct.

Clinical outcomes of adolescents and young adults (AYA) with advanced solid tumors participating in phase I trials.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10536-10536 ◽  
Author(s):  
Raghav Sundar ◽  
Terri Patricia McVeigh ◽  
Ann Petruckevitch ◽  
Nikolaos Diamantis ◽  
Joo Ern Ang ◽  
...  
Keyword(s):  
Drug Development ◽  
Phase I ◽  
Solid Tumors ◽  
Clinical Outcomes ◽  
Published Data ◽  
Hereditary Cancer Syndrome ◽  
Phase I Trials ◽  
Advanced Solid Tumors ◽  
Phase I Studies ◽  
Development Unit

10536 Background: AYA cancer patients are relatively under-represented in clinical trials, with no published data regarding their outcomes in phase I studies. Trials utilizing novel therapeutic agents are often considered in these patients, due to their tendency to have good organ reserve, and ability to tolerate additional lines of therapy. This study describes the experience of AYA patients with advanced solid tumors treated in a specialized drug development unit. Methods: Patient characteristics and clinical outcomes of AYA patients (defined as age 15 to 39 years at time of initial cancer diagnosis) treated at the Drug Development Unit, Royal Marsden Hospital, United Kingdom, between 2002 and 2016, were captured and analyzed from case and trial records. Results: From a database of 2631 patients treated on phase I trials, 219 AYA patients (8%) were identified. Major tumor types included gynaecological cancer (24%), sarcoma (18%), gastrointestinal (16%) and breast cancer (11%). Patients had a median of 3 previous lines of systemic chemotherapy (range 0 – 6), and 19% participated in 2 or more phase I studies. Twenty (9%) had a known hereditary cancer syndrome (most commonly BRCA), 27% had a family history (FH) of cancer, 15% no FH and 49% no FH documented. Molecular characterization of tumors (n = 45) identified mutations most commonly in p53 (33%) , PI3KCA (18%) and KRAS (9%) . Major trial categories included DNA damage repair (16%), PI3K (16%) and anti-angiogenesis (15%) agents. Grade 3/4 toxicities were experienced in 25% of patients (10% hematological). Of the 214 evaluable patients, objective response rate was 12%, with clinical benefit rate at 6 months of 22%. Median progression free survival was 2.3 months (95% CI: 1.9 to 2.8), median OS was 7.6 months (95% CI: 6.3 to 9.5), and 2-year OS was 11%. Of patients with responses, 35% were matched to phase I trials based on germline or somatic genetic aberrations. Conclusions: A sub-group of AYA patients with advanced solid tumors derive considerable benefit from participating in trials involving novel therapeutics. Future research must focus on predictive biomarkers and molecular profiling to identify those that would benefit from novel therapies.

scholarly journals A phase I/II trial to treat massive Africanized honeybee (Apis mellifera) stings using the new apilic antivenom

2021 ◽  
Author(s):  
Alexandre Naime Barbosa ◽  
Rui Seabra Ferreira ◽  
Francilene Capel Tavares de Carvalho ◽  
Fabiana Schuelter-Trevisol ◽  
Mônica Bannwart Mendes ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Apis Mellifera ◽  
Adverse Events ◽  
Phase I ◽  
Adverse Reactions ◽  
Median Number ◽  
Treatment Schedule ◽  
Africanized Honeybee ◽  
Hospitalization Period ◽  
Safety Endpoint

ABSTRACTSafety, optimal minimum dose, and, preliminary effectiveness of a new generation Africanized honeybees (Apis mellifera) antivenom (AAV) were evaluated. A phase I/II, multicenter, non- randomized, single-arm clinical trial involving 20 participants showing multiple stings were studied. Participants have received either 2 to 10 vials of AAV based on the stings number together with a predefined adjuvant, symptomatic, and complementary treatment schedule. The primary safety endpoint was the presence of early adverse reactions within the first 24 hours after treatment. Preliminary efficacy through clinical evolution, including laboratory tests, was assessed at baseline and over the following four weeks. ELISA assays and mass spectrometry estimated the venom pharmacokinetics before, during, and after treatment. Twenty adult participants, 13 (65%) males, and 7 (35%) females, with a median age of 44 years and a mean body surface of 1.92 m2 (median = 1.93 m2) were recruited. The median number of stings was 52.5 ranging from 7 to more than 2,000. Envenoming severity was classified as 80% mild, 15% moderate, and 5% severe. According to the protocol, 16 (80%) participants received two AAV vials, 3 (15%) six vials, and one (5%) 10 vials. There was no discontinuation of the treatment due to acute adverse events and there were no late adverse reactions. Two patients showed mild adverse events with only transient itchy skin and erythroderma. All participants completed the infusion within two hours and there was no loss of follow-up after discharge. ELISA assays showed venom concentrations varying between 0.25 ng/mL and 1.479 ng/mL prior to treatment. Venom levels decreased in all cases during the hospitalization period. Surprisingly, in nine cases (45%), despite clinical recovery and without symptoms, the venom levels increased again during outpatient care 10 days after discharge. Mass spectrometry showed melittin in eight participants 30 days after the treatment. Considering the promising safety results of the investigational product for the treatment of massive Africanized honeybee attacks, added to efficacy in clinical improvement and immediate decrease in blood venom level, the AAV has shown to be safe for human use.Trial registrationUniversal Trial Number (UTN): U1111-1160-7011, Register Number: RBR-3fthf8 (http://www.ensaiosclinicos.gov.br/rg/RBR-3fthf8/).

Phase I Study of Triciribine Phosphate Monohydrate, a Specific Inhibitor of AKt Phosphorylation, in Adult Patients with Advanced Hematologic Malignancies.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 913-913
Author(s):  
Farhad Ravandi ◽  
Jeffrey Lancet ◽  
Francis Giles ◽  
William Plunkett ◽  
Betsy Williams ◽  
...  
Keyword(s):  
Platelet Count ◽  
Phase I ◽  
Phase I Study ◽  
Specific Inhibitor ◽  
Hematologic Malignancies ◽  
Median Number ◽  
Pharmacokinetic Data ◽  
Akt Phosphorylation ◽  
Akt Activation ◽  
Prior Therapy

Abstract Activation of Akt, a serine/thronine protein kinase downstream of PI3 kinase, promotes cell survival through phosphorylation of Bad as well as activation of IKKa-NFkB pathway. Aberrant activation of Akt, by its amplification and overexpression, as well as through the loss of the upstream tumor suppressor PTEN, has been reported in many human cancers and is associated with poor prognosis, resistance to chemotherapy and shortened survival; disruption of Akt pathways inhibits tumor cell growth, angiogenesis and metastasis, and induces apoptosis. Through high through put screening of a library of small molecules, it has been determined that Triciribine Phosphate Monohydrate (TCN-PM), a nucleoside analog, is an inhibitor of Akt activation, and inhibition of Akt activation may be one of its antiproliferative mechanisms. We have conducted a phase I study of TCN-PM in patients with advanced hematological malignancies. Cohorts of 3 patients receive escalating doses of TCN-PM at 15, 25, 35, and 45 mg/m2 administered IV on days 1, 8, and 15 of a 28 day cycle. Twenty four (19M, 5F) patients have been enrolled in 2 institutions and have received a median of 1 cycle (range, 1 – 3) of TCN-PM including 4 in cohort I, 4 in cohort II and 16 in cohort III. Median age of the patients is 60 (range, 30 – 79). Twenty two patients had AML, 1 CLL, and 1 MDS. Median number of prior therapy before inclusion in the study was 3 (range, 1 – 7). Ten patients were inevaluable including 1 in cohort I, 1 in cohort II, and 8 in cohort III due to disease progression (in 7) and other (in 3). Dose limiting toxicity of mucositis was observed in a patient on the third cohort resulting in expansion of that cohort. No further incidences of mucositis were seen in the expanded cohort. No other severe adverse events related to treatment have been observed. 2 patients have achieved major improvements in platelet count lasting 7 and 36 days. One patient achieved a minor improvement in platelet count. Four patients have achieved major improvements in neutrophil count lasting a median of 19 (range, 8 – 40) days while on therapy. Cell death, measured by annexin-5 staining was examined in pre and post treatment samples in 14 patients; in 2 patients there was a significant increase in apoptosis to 25% and 27% after TCN-PM but this did not correlate with response. Pharmacodynamic studies evaluating inhibition of Akt phosphorylation as well as pharmacokinetic data will be presented. Accrual to higher dose levels is continuing.

First line treatment of HER-2/neu positive advanced breast cancer patients with liposomal doxorubicin (Myocet), docetaxel and trastuzumab. A phase I-II study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10744-10744 ◽  
Author(s):  
D. Amadori ◽  
G. Gasparini ◽  
M. O. Vannozzi ◽  
C. Milandri ◽  
P. Serra ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Dose Level ◽  
Liposomal Doxorubicin ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Data ◽  
Treatment Schedule ◽  
Weekly Dose ◽  
Who Grade ◽  
Her 2

10744 Background: Our preclinical data showed synergic effect of Adriamicyn followed by Taxotere in BC cell lines. The combination of anthracyclines, taxanes and trastuzumab could potentially obtain a high number of objective responses and a consistent impact on the time to progression and on the overall survival. The aim of this phase I-II study was to assess the maximum tolerated dose (MTD) of liposomal doxorubicin (Myocet-M) and Taxotere (T) in combination with Herceptin (H). A reduction of cardiotoxicity risk without reducing chemotherapy activity was supposed. Methods: Locally advanced or metastatic her-2/neu positive BC patients (pts) with LVEF ≥ 60% were enrolled in an open, single arm, non-randomized phase I-II escalation trial in 3 to 6 pts/cohorts. The treatment schedule was: M 50 mg/m2 (or 60, depending on dose level assignment) on day 1, T 30 mg/m2 on day 2 and 9, H 4 mg/kg on day 2 followed by weekly dose of 2 mg/kg, every three weeks. MTD dose was identified on the basis of DLT defined according to WHO grade classification of toxicity or specific conditions of LVEF decrease. A pharmacokinetic (PK) analysis of doxorubicin until 72 hours after M administration was planned. Results: Seven pts, median age 63 yrs, were enrolled. Four pts were allocated to dose level 50/30 (M/T) and other 3 pts to dose level 60/30. At the dose level 60/30 febrile neutropenia (DLT) occurred in 2 pts. Other 2 pts experienced febrile neutropenia (no DLT). One event of tachicardia (WHO grade 1) at maximum tolerated dose level was completely recovered without treatment. LVEF values were unmodified. Six patients were enrolled in the PK analysis. T pharmacokinetic data obtained on day 2 and on day 9 were not statistically different. Conclusions: The MTD was defined at M 50 mg/m2 in combination with T 30 mg/m2. The cardiac tolerability was good, with no significant change in LVEF values from baseline to the end of therapy. PK data indicated that the residual concentration of M found on day 2 was did not influence T pharmacokinetics, according to literature data. A phase II study is ongoing to assess activity and PK interactions between drugs. Till now 25 patients have been enrolled, the planned sample size is 45. No significant financial relationships to disclose.

Clinical outcome and prognosis of metastatic colorectal cancer (mCRC) patients (pts) on phase 1 trials: A single institution experience from 1999 to 2016.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 828-828
Author(s):  
Audrey E. Kam ◽  
Gopichand Pendurti ◽  
Umang H. Shah ◽  
Mohammad Haroon Ghalib ◽  
Imran Chaudhary ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Phase I ◽  
Risk Score ◽  
Phase 1 ◽  
Median Number ◽  
Direct Bilirubin ◽  
P Value ◽  
Phase I Trials ◽  
Phase 1 Trials ◽  
Valuable Treatment

828 Background: Pts with mCRC who progress on all standard therapies have a poor prognosis and limited therapy options. Phase 1 trials represent a valuable treatment option. Herein we report the characteristics and outcomes of mCRC patients treated at our institution. Methods: We reviewed records of pts with mCRC enrolled on phase I trials at our institution from January 1999 to December 2016. Treatment-related response, toxicity, and deaths were recorded. Prognostic factors for overall survival (OS) were calculated using univariate (UVA) and multivariable Cox PH analysis (MVA). Results: We observed 187 enrollments with 152 unique patients accrued on 37 phase I trials. Median age was 59 years (range 29-83) and median number of prior therapies was 3 (range 0-8). 144 patients were evaluable for response. The clinical benefit rate (SD+response, CBR) was 33.2% and the ORR was 4.3%. Grade 3/4 non-hematological and hematological AE were seen in 25.5% and 17.3% of patients, respectively. Treatment-related mortality was 0.5%. Median PFS was 1.7 mos and OS was 8.2 mos. In UVA, the following variables predicted a shorter OS: age (p = 0.049); PS > 1 (p < 0.01); sites of metastases > 2 (p = 0.04); LDH > ULN (p < 0.001); albumin < 3.5 (p < 0.001); direct bilirubin > ULN (p = 0.02); WBC > 5.2 (p = 0.001); anemia (p = 0.046). In MVA, age > 60 (HR 1.63, p < 0.004), albumin < 3.5 (HR 3.69, p < 0.001), direct bilirubin > ULN (HR1.69, p < 0.01), and WBC > 5.2 (HR 1.97, p < 0.001) were negative prognostic factors for OS, adjusted for race and sex. A risk score based on MVA revealed that patients with a score of 0-1 had an improved OS (12.5mos) compared to a score of 2 (9.1mos, p-value < 0.005) and 3 (3.2 mos, p-value < 0.001). Conclusions: Patients with mCRC enrolled on phase 1 trials had a CBR of 33.2% and median OS of 8.2 mos, which exceeds third line therapies including regorafenib and trifluridine/tipiracil. Negative prognostic factors for OS were: age > 60, albumin < 3.5, direct bilirubin > ULN, and WBC > 5.2. A risk score based on these parameters showed that patients with a higher score had a significantly shorter OS, which may be useful in selecting patients for phase 1 trials.

Characteristics and outcome of patients (pts) enrolled on phase I trials: A report from the Pediatric Oncology Branch, NCI

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9550-9550
Author(s):  
A. Kim ◽  
E. Fox ◽  
K. Warren ◽  
S. Blaney ◽  
S. Berg ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Phase I ◽  
Performance Status ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Drug Dose ◽  
Cell Transplant ◽  
Phase I Trials ◽  
Eligibility Criteria ◽  
Increased Risk

9550 Background: Knowledge of the characteristics and outcomes of pts enrolled on pediatric phase I trials may aid in the design of future phase I trials and selection of pts. Methods: Pre-enrollment characteristics and treatment outcomes (toxicity, response, survival) were retrospectively analyzed from pts with refractory solid tumors enrolled in 16 phase I trials with similar eligibility criteria from 1992 to 2005. The relationship between patient characteristics and dose-limiting toxicity (DLT) was evaluated using multivariate analysis. Results: Of 262 pts (62% M, 38% F) eligible for analysis, 147 were on trials of myelosuppressive drugs (MS) and 115 were enrolled on trials of non-MS. 50 pts (19%) participated in =2 separate trials. Median (range) or (frequency) entry characteristics were: age 13.5 yrs (1–24); ECOG performance score 0 (30%), 1 (50%), 2 (19%); prior regimens 2 (0–9); prior stem cell transplant (20%); prior radiation (66%); concomitant medications 1 (0–12); and presence of metastatic disease (65%). 94% of pts were evaluable for the primary trial outcome, and 92% participated in pharmacokinetic (PK) studies. 17% of pts had grade 3 as their highest-grade toxicity. 22% of pts had grade 4 as their highest-grade toxicity, of which 91% were hematological. DLT rate was 18%. 5% of pts came off study due to toxicity, and treatment related death occurred in 0.3%. Age, prior radiation, medications, prior regimens, performance status, gender, transplant history, and drug dose expressed as a fraction of the maximum tolerated dose were included in the multivariate analysis. Only drug dose (OR 14.2, 95% CI 3.0–67.8) and prior radiation (OR 3.4, 95% CI 1.1–10.7) were statistically significantly associated with increased risk of developing DLT after adjusting for all other variables. The median number of cycles was 1 (range 0–31). Complete and partial response rate was 3%, however, 18% of pts had stable disease (received = 3 cycles). The median survival (Kaplan Meier analysis) from time of enrollment was 5 months. Conclusion: Standard phase I eligibility criteria selected a population of pts who tolerated the investigational agents well and >90% were evaluable for the toxicity and PK endpoints. Prior radiation was associated with a greater risk for DLT. No significant financial relationships to disclose.

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.

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.

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.

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.

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