Cetuximab (Cet) clearance and survival in patients (pts) with metastatic colorectal cancer (mCRC).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 699-699
Author(s):  
Di Maria Jiang ◽  
Hao-Wen Sim ◽  
Lillian L. Siu ◽  
Jeremy David Shapiro ◽  
Geoffrey Liu ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Compartment Model ◽  
Phase Iii ◽  
Population Pharmacokinetic ◽  
Mean Values ◽  
Clinical Variables ◽  
Disease Characteristics ◽  
Exposure Response ◽  
Trough Blood ◽  
Grade 3

699 Background: Cet, a monoclonal antibody against EGFR, is a standard therapy for pts with RAS wild-type (WT) mCRC. Limited previous data suggest that Cet clearance correlates with progression-free survival (PFS). We performed a population pharmacokinetic (pop-pK) analysis of Cet in pts who participated in the randomized phase III NCIC CO.20 trial in KRAS WT mCRC patients. Methods: Standard Cet doses ± brivanib were administered. Using intermittent trough blood samples, pop-pK analysis was conducted to evaluate different models. Pts were divided into quartiles according to clearance parameters to assess the exposure-response relationship to response rate (RR), PFS and overall survival (OS). Clinical variables including demographic, laboratory, disease characteristics and co-administration of brivanib were evaluated as co-variates on Cet clearance. Results: In 701 pts, Cet elimination was best described as a one-compartment model with a non-linear saturable elimination process (defined by Vmax and Km). Mean values (± standard deviation) for pop-pk parameters were 2.7 ± 0.5 L/m2 for V, 2.5 ± 0.3 mg/h/m2 for Vmax, and 101.0 ± 0.05 mg/L/m2 for Km. Grouped into quartiles, Vmax and Km were significantly associated with OS, but not RR or PFS. The median OS for pts in the lowest quartile of Vmax was 12.0 ms versus (vs.) 6.9 ms for pts in the highest quartile ( p< 0.001), while the median OS was 11.6 ms in the highest Km quartile vs. 6.9 ms in the lowest Km quartile ( p< 0.001). When compared to the quartile with the combination of highest Vmax and lowest Km, pts in the quartile with the lowest Vmax and highest Km had longer PFS (5.0 vs. 3.7 ms, HR 0.75 (95% confidence interval (CI) 0.58-0.98, p= 0.032) and OS (11.7 vs. 6.6 ms, HR 0.59 (95% CI, 0.45-0.77, p< 0.001). Pts in the lower Vmax and higher Km quartiles also experienced less grade 3 toxicity. Neither clinical variables nor brivanib administration were associated with Cet clearance parameters. Conclusions: For KRAS WT mCRC, standard Cet dosing is not optimal for all pts. Pts with slower Cet clearance have significantly improved PFS and OS. Further studies are needed to optimize Cet doses based on individual pK assessments, and to identify novel factors associated with clearance.

Cetuximab (Cet) clearance and survival in patients (pts) with metastatic colorectal cancer (mCRC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3600-3600
Author(s):  
Di Maria Jiang ◽  
Hao-Wen Sim ◽  
Lillian L. Siu ◽  
Jeremy David Shapiro ◽  
Geoffrey Liu ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Compartment Model ◽  
Phase Iii ◽  
Population Pharmacokinetic ◽  
Limited Data ◽  
Wild Type ◽  
Free Survival ◽  
Blood Samples ◽  
Mean Values ◽  
Grade 3

3600 Background: Cet, a monoclonal antibody against EGFR, is a standard therapy for RAS wild-type (WT) mCRC. Limited data suggest a correlation between Cet clearance and progression-free survival (PFS). We performed a population pharmacokinetic (pop-pK) analysis of Cet in pts with KRAS WT mCRC who participated in the randomized phase III NCIC CO.20 trial. Methods: Standard Cet doses ± brivanib (Briv) were administered. Intermittent blood samples were obtained, and analyzed by ELISA for Cet. Pop-pK analysis was conducted to estimate Cet clearance. Pts were divided into quartiles according to clearance parameters to evaluate exposure-outcome with overall survival (OS), PFS, response rate (RR), and toxicity. Results: Blood samples were available from 703 pts. Cet clearance was best described as a one-compartment model with a saturable elimination (defined by Vmax and Km). Mean values (± standard deviation) were 5.6 ± 1.4 L for V, 10.5 ± 2.8 mg/h for Vmax, and 403.1 ± 2.0 mg/L for Km. Vmax and Km were significantly associated with OS, but not PFS or RR. Median OS for pts in the highest quartile of Vmax was 7.8 versus (vs.) 11.6 ms for pts in the lowest Vmax quartile (HR 1.12, 95% confidence interval (CI) 1.05-1.20, p< 0.001). In the highest Km quartile, median OS was 11.6 vs. 7.6 ms in the lowest Km quartile (HR 0.89, 95% CI 0.83-0.96, p= 0.001). Pts with the lowest clearance parameters (lowest Vmax and highest Km) had significantly longer OS (11.6 ms) compared to pts with the highest clearance (highest Vmax and lowest Km) (7.6 ms) (HR 0.67, 95% CI 0.53-0.83, p< 0.001). Overall incidences of grade 3/4 toxicity were not associated with Cet clearance. However, pts with the lowest clearance parameters had more frequent grade 3 diarrhea (OR 0.23, p= 0.005). Conclusions: For KRAS WT mCRC, standard Cet dosing is not optimal for all pts. Pts with lower Cet clearance have significantly improved OS and increased likelihood of grade 3 diarrhea. Further studies are needed to identify individual patient factors associated with Cet clearance, and to optimize Cet dosing based on individual pk assessments.

Paclitaxel/gemcitabine versus paclitaxel/vinorelbine in advanced non-small cell lung cancer (NSCLC): A phase III randomized study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8038-8038
Author(s):  
P. A. Kosmidis ◽  
E. Timotheadou ◽  
A. Koutras ◽  
G. Pentheroudakis ◽  
C. Christodoulou ◽  
...  
Keyword(s):  
Randomized Study ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Disease Characteristics ◽  
Group A ◽  
Severe Infections ◽  
Grade 3 ◽  
Intent To Treat ◽  
Group B

8038 Background: Paclitaxel and vinorelbine (PV) have shown synergism of cytotoxic effect in vitro (Cancer Invert, 2000, 18(8): 804-5). This combination was compared prospectively to the paclitaxel/gemcitabine (PG) regimen in non-operable NSCLC. Methods: 415 stage IIIb wet and IV chemotherapy-naïve for metastatic disease patients with PS 0–1 were randomized to paclitaxel 200mg/m2 on day 1 plus either gemcitabine 1gm/m2 (Group A) or vinorelbine 25mg/m2 (Group B) on days 1 and 8 every 3 wks as first line chemotherapy. Results: A total of 398 out of 415 patients were eligible for analysis on the intent to treat basis (group A: 196, group B: 202). All patient and disease characteristics were well balanced. Overall response rate (RR) was 27% for group A and 24% for group B (P=0.57). Median progression free survival (PFS) was 5.2 months (m) (95% CI, 4.4 - 5.9) and 4.7m (95% CI, 4.1 - 5.3) for groups A and B respectively (P=0.51). Median survival (OS) was 11.5m (95% CI, 9.5 - 12.6) and 9.3m (95% CI, 7.7 - 10.9) for groups A and B respectively (P=0.25). Grade 3/4 neutropenia was worse (P<0.001) in group B. Febrile neutropenia and severe infections were more prominent (P<0.001, P=0.005 respectively) in group B. Conclusions: Although RR, PFS, OS are similar in both groups, toxicity is significantly worse in group B and therefore further investigation of PV is of no value. No significant financial relationships to disclose.

scholarly journals Population pharmacokinetic and exposure–response analyses of elotuzumab plus pomalidomide and dexamethasone for relapsed and refractory multiple myeloma

2021 ◽  
Author(s):  
Takafumi Ide ◽  
Mayu Osawa ◽  
Kinjal Sanghavi ◽  
Heather E. Vezina
Keyword(s):  
Multiple Myeloma ◽  
Progression Free Survival ◽  
Central Compartment ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Efficacy And Safety ◽  
Refractory Multiple Myeloma ◽  
Exposure Response ◽  
Grade 3

Abstract Purpose Elotuzumab plus pomalidomide/dexamethasone (E-Pd) demonstrated efficacy and safety in relapsed and refractory multiple myeloma (RRMM). The clinical pharmacology of elotuzumab [± lenalidomide/dexamethasone (Ld)] was characterized previously. These analyses describe elotuzumab population pharmacokinetics (PPK), the effect of Pd, and assess elotuzumab exposure–response relationships for efficacy and safety in patients with RRMM. Methods A previously established PPK model was updated with E-Pd data from the phase 2 ELOQUENT-3 study (NCT02654132). The dataset included 8180 serum concentrations from 440 patients with RRMM from 5 clinical trials. Elotuzumab PK parameter estimates were used to generate individual daily time-varying average concentrations (daily Cavg) for multi-variable time-to-event exposure–response analyses of progression-free survival (PFS) and time to the first occurrence of grade 3 + adverse events (AEs) in RRMM. Results Elotuzumab PK were well-described by a two-compartment model with parallel linear and Michaelis–Menten elimination from the central compartment (Vmax) and non-renewable target-mediated elimination from the peripheral compartment (Kint). Co-administration with Pd resulted in a 19% and 51% decrease in elotuzumab linear clearance and Kint, respectively, versus Ld; steady-state exposures were similar. Vmax increased with increasing serum M-protein. Hazard ratios (95% confidence intervals) for daily Cavg were 0.9983 (0.9969–0.9997) and 0.9981 (0.9964–0.9998) for PFS and grade 3 + AEs, respectively. Conclusions The PPK model adequately described the data and was appropriate for determining exposures for exposure–response analyses. There were no clinically relevant differences in elotuzumab exposures between Pd and Ld backbones. In ELOQUENT-3, increasing elotuzumab daily Cavg prolonged PFS without increasing grade 3 + AEs.

Clinical Outcomes and Safety of Patients Treated with NAb-Paclitaxel Plus Gemcitabine in Metastatic Pancreatic Cancer: The NAPA Study

2020 ◽  
Vol 20 (11) ◽  
pp. 887-895 ◽  
Author(s):  
Martina Catalano ◽  
Giandomenico Roviello ◽  
Raffaele Conca ◽  
Alberto D’Angelo ◽  
Valeria Emma Palmieri ◽  
...  
Keyword(s):  
Performance Status ◽  
Real Life ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Ductal Adenocarcinoma ◽  
Hematological Toxicity ◽  
Free Survival ◽  
Grade 3 ◽  
Ecog Ps ◽  
Prognostic And Predictive Markers

Background: The phase III MPACT trial demonstrated the superiority of gemcitabine (Gem) combined with Nab-paclitaxel (Nab-P) versus gemcitabine alone in previously untreated patients with metastatic pancreatic ductal adenocarcinoma (PDAC). The purpose of this study was to evaluate the effect of Gem/Nab-P in routine clinical practice. Methods: From January 2015 to December 2018, patients with metastatic PDAC receiving firstline treatment with a combination of gemcitabine and Nab-paclitaxel were included in a multicentre retrospective observational study. Exploratory analyses of efficacy, and prognostic and predictive markers, were performed. Results: The cohort comprised 115 patients (median age 65 [range 50-84] years) with good performance status (ECOG PS 0-1). The median overall survival (OS) was 11 months (95% CI; 9-13) and the median progression-free survival (PFS) was 6 months (95% CI 5-7). Partial response and stable disease were achieved in 44 and 30 patients, respectively, yielding an overall disease control rate (DCR) of 64.3%. Grade 3-4 hematological toxicity frequency was 22.61% for neutropenia, 5.22% for anemia, and 3.48% for thrombocytopenia. Grade 3 asthenia was recorded in 2.61% of patients. No grade 4 non-hematological events were reported. Dose reduction was necessary in 51.3% of the patients. Conclusions: Our results confirm the efficacy and safety of a first-line regimen comprising gemcitabine and Nab-paclitaxel in metastatic PDAC in a real-life population.

scholarly journals Reduced-Dose Radiation Therapy for HPV-Associated Oropharyngeal Carcinoma (NRG Oncology HN002)

2021 ◽  
pp. JCO.20.03128
Author(s):  
Sue S. Yom ◽  
Pedro Torres-Saavedra ◽  
Jimmy J. Caudell ◽  
John N. Waldron ◽  
Maura L. Gillison ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Radiation Treatment ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Oropharyngeal Carcinoma ◽  
Reduced Dose ◽  
Phase Iii Study ◽  
Grade 3 ◽  
Dose Radiation

PURPOSE Reducing radiation treatment dose could improve the quality of life (QOL) of patients with good-risk human papillomavirus–associated oropharyngeal squamous cell carcinoma (OPSCC). Whether reduced-dose radiation produces disease control and QOL equivalent to standard chemoradiation is not proven. PATIENTS AND METHODS In this randomized, phase II trial, patients with p16-positive, T1-T2 N1-N2b M0, or T3 N0-N2b M0 OPSCC (7th edition staging) with ≤ 10 pack-years of smoking received 60 Gy of intensity-modulated radiation therapy (IMRT) over 6 weeks with concurrent weekly cisplatin (C) or 60 Gy IMRT over 5 weeks. To be considered for a phase III study, an arm had to achieve a 2-year progression-free survival (PFS) rate superior to a historical control rate of 85% and a 1-year mean composite score ≥ 60 on the MD Anderson Dysphagia Inventory (MDADI). RESULTS Three hundred six patients were randomly assigned and eligible. Two-year PFS for IMRT + C was 90.5% rejecting the null hypothesis of 2-year PFS ≤ 85% ( P = .04). For IMRT, 2-year PFS was 87.6% ( P = .23). One-year MDADI mean scores were 85.30 and 81.76 for IMRT + C and IMRT, respectively. Two-year overall survival rates were 96.7% for IMRT + C and 97.3% for IMRT. Acute adverse events (AEs) were defined as those occurring within 180 days from the end of treatment. There were more grade 3-4 acute AEs for IMRT + C (79.6% v 52.4%; P < .001). Rates of grade 3-4 late AEs were 21.3% and 18.1% ( P = .56). CONCLUSION The IMRT + C arm met both prespecified end points justifying advancement to a phase III study. Higher rates of grade ≥ 3 acute AEs were reported in the IMRT + C arm.

Olaparib maintenance monotherapy for non-germline BRCA1/2-mutated (non-gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC) patients (pts): Phase IIIb OPINION primary analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5545-5545
Author(s):  
Andres Poveda ◽  
Stephanie Lheureux ◽  
Nicoletta Colombo ◽  
David Cibula ◽  
Kristina Lindemann ◽  
...  
Keyword(s):  
Brca Mutation ◽  
Progression Free Survival ◽  
Complete Response ◽  
Subsequent Treatment ◽  
Phase Iii ◽  
Primary Analysis ◽  
Platinum Sensitive ◽  
Platinum Based Chemotherapy ◽  
Phase Iiib ◽  
Grade 3

5545 Background: In the Phase II Study 19 trial (NCT00753545; Ledermann et al Lancet Oncol 2014), maintenance olaparib improved progression-free survival (PFS) vs placebo in PSR OC pts, including non-BRCAm pts. A significant PFS benefit was also seen with maintenance olaparib vs placebo in gBRCAm PSR OC pts in the Phase III SOLO2 trial (NCT01874353; Pujade-Lauraine et al Lancet Oncol 2017). To investigate olaparib maintenance monotherapy in non-gBRCAm PSR OC pts who had received ≥2 prior lines of platinum-based chemotherapy (PBC), we performed the Phase IIIb, single-arm, OPINION study (NCT03402841). Methods: Pts had high-grade serous or endometrioid OC and were in complete response (CR) or partial response (PR) to PBC. Pts received maintenance olaparib (tablets; 300 mg bid) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed PFS (modified RECIST v1.1). Secondary endpoints included PFS by homologous recombination deficiency (HRD) and somatic BRCA mutation (sBRCAm) status determined by central Myriad tumor and germline testing; and time to first subsequent treatment (TFST). The primary analysis was planned for 18 months (mo) after the last patient was enrolled. Results: 279 pts were enrolled from 17 countries (mean age: 64 years); 253 pts (90.7%) were confirmed non-gBRCAm. At data cut-off (Oct 2, 2020), median PFS was 9.2 mo (95% CI 7.6–10.9), with 210 PFS events (75.3% maturity). 65.3%, 38.5% and 24.3% of pts were progression-free (PF) at 6, 12 and 18 mo, respectively. The Table shows PFS in key subgroups. Median TFST was 13.9 mo (95% CI 11.5–16.4). Median exposure to olaparib was 9.4 mo (range 0.0–31.9). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 29.0% of pts and serious TEAEs in 19.7% of pts. TEAEs led to dose interruption, dose reduction and treatment discontinuation in 47.0%, 22.6% and 7.5% of pts, respectively. Conclusions: Our findings support the use of olaparib maintenance therapy in non-gBRCAm PSR OC pts, consistent with our interim analysis and previous trials in this setting. Clinical trial information: NCT03402841. [Table: see text]

JUPITER-02: Randomized, double-blind, phase III study of toripalimab or placebo plus gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (NPC).

2021 ◽  
Vol 39 (18_suppl) ◽  
pp. LBA2-LBA2
Author(s):  
Rui-hua Xu ◽  
Hai-Qiang Mai ◽  
Qiu-Yan Chen ◽  
Dongping Chen ◽  
Chaosu Hu ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Double Blind ◽  
Grade 3 ◽  
First Line Treatment

LBA2 Background: Gemcitabine-cisplatin (GP) chemotherapy is the standard 1st line treatment for locally advanced, recurrent or metastatic (r/m) NPC. Toripalimab, a humanized IgG4K monoclonal antibody specific for PD-1, provided durable responses in patients (pts) with r/m NPC as monotherapy in the ≥2nd line setting (POLARIS-02 study). The results of JUPITER-02, a randomized, placebo-controlled, double-blinded Phase III trial of toripalimab in combination with GP chemotherapy as first-line treatment for r/m NPC are summarized. Methods: Pts with advanced NPC with no prior chemotherapy in the r/m setting were randomized (1:1) to receive toripalimab 240 mg or placebo d1 in combination with gemcitabine 1000 mg/m2 d1, d8 and cisplatin 80 mg/m2 d1 every 3 weeks (Q3W) for up to 6 cycles, followed by monotherapy with toripalimab or placebo Q3W until disease progression, intolerable toxicity, or completion of 2 years of treatment. Stratification factors were ECOG PS (0 vs. 1) and extent of disease (recurrent vs. primary metastatic) at enrollment. Progression-free survival (PFS) and response were assessed by independent review committee (IRC) per RECIST v1.1. The primary endpoint was PFS by IRC in the ITT population. Secondary end points included ORR, DOR and OS. There was one prespecified interim analysis of PFS at 130 PFS events with a planned final analysis at 200 PFS events. Results: 289 pts were randomized: 146 to the toripalimab arm and 143 to the placebo arm. By May 30, 2020 as the interim analysis cutoff date, the median treatment duration was 39 weeks in the toripalimab arm and 36 weeks in the placebo arm. A significant improvement in PFS was detected for the toripalimab arm compared to the placebo arm (HR = 0.52 [95% CI: 0.36-0.74] two-sided p = 0.0003), with median PFS of 11.7 vs. 8.0 months. The 1-year PFS rates were 49% and 28% respectively. An improvement in PFS was observed across relevant subgroups, including all PD-L1 subgroups. The ORR was 77.4% vs. 66.4% (P = 0.033) and the median DOR was 10.0 vs. 5.7 months (HR = 0.50 [95% CI: 0.33-0.78]). As of Jan 15, 2021, OS was not mature, with 25 deaths in the toripalimab arm and 35 in the placebo arm (HR = 0.68 [95% CI: 0.41-1.14], P = 0.14). The incidence of Grade ≥3 adverse events (AEs) (89.0% vs 89.5%); AEs leading to discontinuation of toripalimab/placebo (7.5% vs 4.9%); and fatal AEs (2.7% vs 2.8%) were similar between two arms; however, immune-related (irAEs) (39.7% vs. 18.9%) and Grade ≥3 irAEs (7.5% vs. 0.7%) were more frequent in the toripalimab arm. Conclusions: The addition of toripalimab to GP chemotherapy as 1st-line treatment for pts with advanced NPC provided superior PFS and ORR and longer DOR than GP alone with a manageable safety profile. These results support the use of toripalimab with GP chemotherapy as the new standard care for this population. Clinical trial information: NCT03581786.

Efficacy of Melphalan and Prednisone Plus Thalidomide in Patients Older Than 75 Years With Newly Diagnosed Multiple Myeloma: IFM 01/01 Trial

2009 ◽  
Vol 27 (22) ◽  
pp. 3664-3670 ◽  
Author(s):  
Cyrille Hulin ◽  
Thierry Facon ◽  
Philippe Rodon ◽  
Brigitte Pegourie ◽  
Lotfi Benboubker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Elderly Patients ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Standards Of Care ◽  
Newly Diagnosed ◽  
Grade 3 ◽  
To Receive

Purpose Until recently, melphalan and prednisone were the standards of care in elderly patients with multiple myeloma. The addition of thalidomide to this combination demonstrated a survival benefit for patients age 65 to 75 years. This randomized, placebo-controlled, phase III trial investigated the efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed myeloma. Patients and Methods Between April 2002 and December 2006, 232 previously untreated patients with myeloma, age 75 years or older, were enrolled and 229 were randomly assigned to treatment. All patients received melphalan (0.2 mg/kg/d) plus prednisone (2 mg/kg/d) for 12 courses (day 1 to 4) every 6 weeks. Patients were randomly assigned to receive 100 mg/d of oral thalidomide (n = 113) or placebo (n = 116), continuously for 72 weeks. The primary end point was overall survival. Results After a median follow-up of 47.5 months, overall survival was significantly longer in patients who received melphalan and prednisone plus thalidomide compared with those who received melphalan and prednisone plus placebo (median, 44.0 v 29.1 months; P = .028). Progression-free survival was significantly prolonged in the melphalan and prednisone plus thalidomide group (median, 24.1 v 18.5 months; P = .001). Two adverse events were significantly increased in the melphalan and prednisone plus thalidomide group: grade 2 to 4 peripheral neuropathy (20% v 5% in the melphalan and prednisone plus placebo group; P < .001) and grade 3 to 4 neutropenia (23% v 9%; P = .003). Conclusion This trial confirms the superiority of the combination melphalan and prednisone plus thalidomide over melphalan and prednisone alone for prolonging survival in very elderly patients with newly diagnosed myeloma. Toxicity was acceptable.

Phase III Trial of Infusional Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan (FOLFOXIRI) Compared With Infusional Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) As First-Line Treatment for Metastatic Colorectal Cancer: The Gruppo Oncologico Nord Ovest

2007 ◽  
Vol 25 (13) ◽  
pp. 1670-1676 ◽  
Author(s):  
Alfredo Falcone ◽  
Sergio Ricci ◽  
Isa Brunetti ◽  
Elisabetta Pfanner ◽  
Giacomo Allegrini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Peripheral Neurotoxicity ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Secondary Resection ◽  
Phase Iii Study ◽  
Grade 3

Purpose The Gruppo Oncologico Nord Ovest (GONO) conducted a phase III study comparing fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI [irinotecan 165 mg/m2 day 1, oxaliplatin 85 mg/m2 day 1, leucovorin 200 mg/m2 day 1, fluorouracil 3,200 mg/m2 48-hour continuous infusion starting on day 1, every 2 weeks]) with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI). Methods Selection criteria included unresectable metastatic colorectal cancer, age 18 to 75 years, and no prior chemotherapy for advanced disease. The primary end point was response rate (RR). Results A total of 244 patients were randomly assigned. An increase of grade 2 to 3 peripheral neurotoxicity (0% v 19%; P < .001), and grade 3 to 4 neutropenia (28% v 50%; P < .001) were observed in the FOLFOXIRI arm. The incidence of febrile neutropenia (3% v 5%) and grade 3 to 4 diarrhea (12% v 20%) were not significantly different. Responses, as assessed by investigators, were, for FOLFIRI and FOLFOXIRI, respectively, complete, 6% and 8%; and partial, 35% and 58%, (RR, 41% v 66%; P = .0002). RR confirmed by an external panel was 34% versus 60% (P < .0001). The R0 secondary resection rate of metastases was greater in the FOLFOXIRI arm (6% v 15%; P = .033, among all 244 patients; and 12% v 36%; P = .017 among patients with liver metastases only). Progression-free survival (PFS) and overall survival (OS) were both significantly improved in the FOLFOXIRI arm (median PFS, 6.9 v 9.8 months; hazard ratio [HR], 0.63; P = .0006; median OS, 16.7 v 22.6 months; HR, 0.70; P = .032). Conclusion The FOLFOXIRI regimen improves RR, PFS, and OS compared with FOLFIRI, with an increased, but manageable, toxicity in patients with metastatic colorectal cancer with favorable prognostic characteristics. Further studies of FOLFOXIRI in combination with targeted agents and in the neoadjuvant setting are warranted.

Phase III Study Comparing Amrubicin Plus Cisplatin With Irinotecan Plus Cisplatin in the Treatment of Extensive-Disease Small-Cell Lung Cancer: JCOG 0509

2014 ◽  
Vol 32 (12) ◽  
pp. 1262-1268 ◽  
Author(s):  
Miyako Satouchi ◽  
Yoshikazu Kotani ◽  
Taro Shibata ◽  
Masahiko Ando ◽  
Kazuhiko Nakagawa ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Progression Free Survival ◽  
Small Cell ◽  
Phase Iii ◽  
Point Estimate ◽  
Small Cell Lung ◽  
Extensive Disease ◽  
Grade 3

Purpose This randomized phase III trial was conducted to confirm noninferiority of amrubicin plus cisplatin (AP) compared with irinotecan plus cisplatin (IP) in terms of overall survival (OS) in chemotherapy-naive patients with extensive-disease (ED) small-cell lung cancer (SCLC). Patients and Methods Chemotherapy-naive patients with ED-SCLC were randomly assigned to receive IP, composed of irinotecan 60 mg/m2 on days 1, 8, and 15 and cisplatin 60 mg/m2 on day 1 every 4 weeks, or AP, composed of amrubicin 40 mg/m2 on days 1, 2, and 3 and cisplatin 60 mg/m2 on day 1 every 3 weeks. Results A total of 284 patients were randomly assigned to IP (n = 142) and AP (n = 142) arms. The point estimate of OS hazard ratio (HR) for AP to IP in the second interim analysis exceeded the noninferior margin (HR, 1.31), resulting in early publication because of futility. In updated analysis, median survival time was 17.7 (IP) versus 15.0 months (AP; HR, 1.43; 95% CI, 1.10 to 1.85), median progression-free survival was 5.6 (IP) versus 5.1 months (AP; HR, 1.42; 95% CI, 1.16 to 1.73), and response rate was 72.3% (IP) versus 77.9% (AP; P = .33). Adverse events observed in IP and AP arms were grade 4 neutropenia (22.5% v 79.3%), grade 3 to 4 febrile neutropenia (10.6% v 32.1%), and grade 3 to 4 diarrhea (7.7% v 1.4%). Conclusion AP proved inferior to IP in this trial, perhaps because the efficacy of amrubicin as a salvage therapy was differentially beneficial to IP. IP remains the standard treatment for extensive-stage SCLC in Japan.

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