Invest New Drugs (2015) 33:664–670 DOI 10.1007/s10637-015-0231-9
PHASE I STUDIES
Clinical outcomes in 66 patients with advanced gastric cancer treated in phase I trials: the NCCHE experience Akihito Kawazoe & Kohei Shitara & Shota Fukuoka & Masaaki Noguchi & Yasutoshi Kuboki & Hideaki Bando & Wataru Okamoto & Takashi Kojima & Nozomu Fuse & Takayuki Yoshino & Atsushi Ohtsu & Toshihiko Doi
Received: 11 January 2015 / Accepted: 6 March 2015 / Published online: 15 March 2015 # Springer Science+Business Media New York 2015
Summary Background Although patients with advanced gastric cancer (AGC) have a poor prognosis when conventional therapies fail, they are often candidates for phase I trials. However, there is no detailed report on clinical outcomes of patients with AGC treated in phase I trials. Methods We retrospectively reviewed the medical records of 66 consecutive patients with AGC enrolled in phase I trials between March 2008 and July 2014 at our institution in Japan. Results Median age was 66 years (range, 28–78 years) and median number of previous lines of conventional chemotherapy was 3 (range, 1– 6). Five (8.6 %) and seven (12 %) patients showed objective response and stable disease >3 months, respectively. Although the time to treatment failure (TTF) of the best phase I treatment was shorter than that of the last line of conventional chemotherapy (median 1.5 vs. 2.3 months; P=0.002), TTF of the best phase I treatment was longer than that of the last line of treatment in 21 patients (32 %). Severe adverse events and grade 3 or higher toxicities were reported in eight (12 %) and 13 patients (20 %), respectively. No treatment-related death was observed. Median survival time from the start of phase I treatment was 7.5 months, and four deaths (6 %) within 30 days after last administration were observed. Conclusion Phase I trials of patients with AGC was acceptably feasible with some efficacy signal. Our results suggest that phase I trials might be one treatment option for patients with AGC when conventional therapies fail.
A. Kawazoe : K. Shitara (*) : S. Fukuoka : M. Noguchi : Y. Kuboki : H. Bando : W. Okamoto : T. Kojima : N. Fuse : T. Yoshino : A. Ohtsu : T. Doi Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East (NCCHE), 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan e-mail: [email protected]
Keywords Gastric cancer . Chemotherapy . Phase I trial . Clinical outcome
Introduction Gastric cancer is the fifth most common malignancy and the third leading cause of cancer deaths worldwide, with estimated 952,000 new cases (6.8 % of the total cancer cases) and 723,000 deaths (8.8 % of the total) in 2012 [1]. Patients with advanced gastric cancer (AGC) have a poor prognosis and are usually treated with systematic chemotherapy, including fluoropyrimidine, platinum agents, with or without epirubicin, or taxanes [2–8]. Additionally, trastuzumab, a monoclonal antibody that targets human epidermal growth factor receptor 2 (HER2), has been shown to improve the prognosis of HER2-positive AGC patients when added to fluoropyrimidine plus cisplatin in the first line [9]. Recently, two randomized phase III trials showed that ramucirumab, a monoclonal antibody that targets vascular endothelial growth factor receptor2, prolonged the overall survival (OS) of pretreated patients with AGC as monotherapy or in combination with paclitaxel [10, 11]. However, the median OS of patients with AGC treated with a combination and sequential regimen involving these agents was still approximately 12 months [6–9]. Therefore, the development of novel anticancer agents for patients with AGC is urgently required. Recent remarkable progress in the understanding of the molecular biology of cancer has led to an increased number of early clinical trials in oncology to develop new agents, the main stream of which are molecular targeted agents. If patients with AGC have a good performance status even after the failure of standard therapies, they are often candidates for
Invest New Drugs (2015) 33:664–670
phase I trials of investigational agents. The primary objectives of phase I trials are to determine the maximum tolerated dose of a drug, to define safety profiles, and to describe its pharmacokinetics with exploratory analysis of objective tumor response [12]. According to a report from National Cancer Institute, which includes 11,935 participants from 460 phase I trials, the rates of response to treatment, toxic events corresponding to grade 4 and more and toxicity-related deaths in phase I trials were 10.6, 14.3, and 0.5 %, respectively [13]. In other studies, the overall response rates of patients with several kinds of malignancies in phase I trials ranged from 4.0 to 8.9 %, with toxicity-related deaths reported to be 0.5 % or lower [14–17]. More recent reports also focus on the clinical benefits of enrolling patients in phase I trials [18–20]. For instance, the relationship between better tumor response and favorable OS was reported [18]. In addition, it has been shown that the progression-free survival (PFS) of patients with head and neck cancer enrolled in phase I trials was similar to the PFS of their last line of standard chemotherapy [19], and those with thyroid cancer had a significantly longer time to treatment failure (TTF) compared with their last line of treatment [20]. However, the impact of phase I treatment on safety and efficacy of patients with AGC has not yet been reported in detail. Therefore, we retrospectively investigated the characteristics and clinical outcomes in patients with AGC enrolled in phase I trials at our institution.
Methods Patients We reviewed the electronic medical records of 66 consecutive patients with AGC who were treated in phase I trials after the failure of systemic anticancer therapies at our institution between March 2008 and July 2014. All patients had experienced failure of conventional therapy, with histologically proven gastric adenocarcinoma, as reviewed by a pathologist at our institution. The retrospective study was conducted under an institutional review board waiver in accordance with the Japanese Ethical Guidelines For Epidemiological Research. The following baseline characteristics were collected for each patient: age, gender, tumor histology, Eastern Cooperative Oncology Group (ECOG) performance status (PS), number of previous treatments, site of metastasis, and TTF of the last line of conventional chemotherapy. Safety profiles, including the incidence of dose limiting toxicity (DLT), severe adverse events (SAE), grade 3 or more toxic events, and death within 30 days after the last administration of phase I treatment were assessed according to each phase I protocol and the Common Terminology Criteria for Adverse Events version 3.0 or 4.0 as defined
665
in each protocol. Among the patients enrolled in trials with exploratory biomarker analysis and tumor biopsy, the incidence of adverse events related to biopsy procedures was also assessed. Tumor response was evaluated by each investigator based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 or 1.1 every 4 to 8 weeks as defined in each protocol, along with date of treatment discontinuation, progression, death, and last follow-up visit. Statistical analysis TTF of phase I treatment was defined as the time from the start of phase I treatment to the discontinuation of the treatment for any reason. TTF of the best phase I trials was defined as the longest TTF in patients enrolled in >1 clinical trial. TTF of the last line of conventional chemotherapy was also defined as the time from the start of the patient’s last conventional chemotherapy to the discontinuation of the treatment for any reason. Patients were censored at the time of their last follow-up if they were continuing treatment. The median TTF was estimated by the Kaplan–Meier method and compared using the logrank test. Hazard ratios (HR) with a 95 % confidence interval (CI) were calculated using a Cox regression model with a single covariate. Response rate in patients with measurable disease was evaluated according to the RECIST version 1.0 or 1.1. Disease control rate (DCR) was defined as the proportion of patients who achieved either complete response (CR), partial response (PR), or stable disease (SD). PFS was defined as the time from the start of phase I treatment to either the first objective evidence of disease progression or death from any cause. OS was defined as the time from the start of phase I treatment to death from any cause. For PFS or OS, patients were censored at the time of their last followup if they were free of disease progression or from death, respectively. Median PFS and OS were estimated by the Kaplan–Meier method, and the difference between patients with PR or SD and those with PD was evaluated using the log-rank test. Statistical analyses were performed using IBM® SPSS® Statistics version 21 (IBM Corporation, Armonk, NY, USA). All tests were two-sided, and P-values 3 months, all of whom were treated with targeted agents as monotherapy.
Survival analysis Median PFS and OS for the overall population were 1.6 months (95 % CI, 1.4–1.8 months) and 7.5 months (95 % CI, 5.7–9.3 months), respectively (Fig. 3). Among 58 patients with measurable lesions, the median PFS of patients with PR or SD (n=28; 2.7 months; 95 % CI, 2.4–3.0 months) was significantly longer than that of patients with PD (n=30; 1.3 months; 95 % CI, 1.1–1.5 months) (HR, 0.08; 95 % CI, 0.04–0.19; P
PHASE I STUDIES
Clinical outcomes in 66 patients with advanced gastric cancer treated in phase I trials: the NCCHE experience Akihito Kawazoe & Kohei Shitara & Shota Fukuoka & Masaaki Noguchi & Yasutoshi Kuboki & Hideaki Bando & Wataru Okamoto & Takashi Kojima & Nozomu Fuse & Takayuki Yoshino & Atsushi Ohtsu & Toshihiko Doi
Received: 11 January 2015 / Accepted: 6 March 2015 / Published online: 15 March 2015 # Springer Science+Business Media New York 2015
Summary Background Although patients with advanced gastric cancer (AGC) have a poor prognosis when conventional therapies fail, they are often candidates for phase I trials. However, there is no detailed report on clinical outcomes of patients with AGC treated in phase I trials. Methods We retrospectively reviewed the medical records of 66 consecutive patients with AGC enrolled in phase I trials between March 2008 and July 2014 at our institution in Japan. Results Median age was 66 years (range, 28–78 years) and median number of previous lines of conventional chemotherapy was 3 (range, 1– 6). Five (8.6 %) and seven (12 %) patients showed objective response and stable disease >3 months, respectively. Although the time to treatment failure (TTF) of the best phase I treatment was shorter than that of the last line of conventional chemotherapy (median 1.5 vs. 2.3 months; P=0.002), TTF of the best phase I treatment was longer than that of the last line of treatment in 21 patients (32 %). Severe adverse events and grade 3 or higher toxicities were reported in eight (12 %) and 13 patients (20 %), respectively. No treatment-related death was observed. Median survival time from the start of phase I treatment was 7.5 months, and four deaths (6 %) within 30 days after last administration were observed. Conclusion Phase I trials of patients with AGC was acceptably feasible with some efficacy signal. Our results suggest that phase I trials might be one treatment option for patients with AGC when conventional therapies fail.
A. Kawazoe : K. Shitara (*) : S. Fukuoka : M. Noguchi : Y. Kuboki : H. Bando : W. Okamoto : T. Kojima : N. Fuse : T. Yoshino : A. Ohtsu : T. Doi Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East (NCCHE), 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan e-mail: [email protected]
Keywords Gastric cancer . Chemotherapy . Phase I trial . Clinical outcome
Introduction Gastric cancer is the fifth most common malignancy and the third leading cause of cancer deaths worldwide, with estimated 952,000 new cases (6.8 % of the total cancer cases) and 723,000 deaths (8.8 % of the total) in 2012 [1]. Patients with advanced gastric cancer (AGC) have a poor prognosis and are usually treated with systematic chemotherapy, including fluoropyrimidine, platinum agents, with or without epirubicin, or taxanes [2–8]. Additionally, trastuzumab, a monoclonal antibody that targets human epidermal growth factor receptor 2 (HER2), has been shown to improve the prognosis of HER2-positive AGC patients when added to fluoropyrimidine plus cisplatin in the first line [9]. Recently, two randomized phase III trials showed that ramucirumab, a monoclonal antibody that targets vascular endothelial growth factor receptor2, prolonged the overall survival (OS) of pretreated patients with AGC as monotherapy or in combination with paclitaxel [10, 11]. However, the median OS of patients with AGC treated with a combination and sequential regimen involving these agents was still approximately 12 months [6–9]. Therefore, the development of novel anticancer agents for patients with AGC is urgently required. Recent remarkable progress in the understanding of the molecular biology of cancer has led to an increased number of early clinical trials in oncology to develop new agents, the main stream of which are molecular targeted agents. If patients with AGC have a good performance status even after the failure of standard therapies, they are often candidates for
Invest New Drugs (2015) 33:664–670
phase I trials of investigational agents. The primary objectives of phase I trials are to determine the maximum tolerated dose of a drug, to define safety profiles, and to describe its pharmacokinetics with exploratory analysis of objective tumor response [12]. According to a report from National Cancer Institute, which includes 11,935 participants from 460 phase I trials, the rates of response to treatment, toxic events corresponding to grade 4 and more and toxicity-related deaths in phase I trials were 10.6, 14.3, and 0.5 %, respectively [13]. In other studies, the overall response rates of patients with several kinds of malignancies in phase I trials ranged from 4.0 to 8.9 %, with toxicity-related deaths reported to be 0.5 % or lower [14–17]. More recent reports also focus on the clinical benefits of enrolling patients in phase I trials [18–20]. For instance, the relationship between better tumor response and favorable OS was reported [18]. In addition, it has been shown that the progression-free survival (PFS) of patients with head and neck cancer enrolled in phase I trials was similar to the PFS of their last line of standard chemotherapy [19], and those with thyroid cancer had a significantly longer time to treatment failure (TTF) compared with their last line of treatment [20]. However, the impact of phase I treatment on safety and efficacy of patients with AGC has not yet been reported in detail. Therefore, we retrospectively investigated the characteristics and clinical outcomes in patients with AGC enrolled in phase I trials at our institution.
Methods Patients We reviewed the electronic medical records of 66 consecutive patients with AGC who were treated in phase I trials after the failure of systemic anticancer therapies at our institution between March 2008 and July 2014. All patients had experienced failure of conventional therapy, with histologically proven gastric adenocarcinoma, as reviewed by a pathologist at our institution. The retrospective study was conducted under an institutional review board waiver in accordance with the Japanese Ethical Guidelines For Epidemiological Research. The following baseline characteristics were collected for each patient: age, gender, tumor histology, Eastern Cooperative Oncology Group (ECOG) performance status (PS), number of previous treatments, site of metastasis, and TTF of the last line of conventional chemotherapy. Safety profiles, including the incidence of dose limiting toxicity (DLT), severe adverse events (SAE), grade 3 or more toxic events, and death within 30 days after the last administration of phase I treatment were assessed according to each phase I protocol and the Common Terminology Criteria for Adverse Events version 3.0 or 4.0 as defined
665
in each protocol. Among the patients enrolled in trials with exploratory biomarker analysis and tumor biopsy, the incidence of adverse events related to biopsy procedures was also assessed. Tumor response was evaluated by each investigator based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 or 1.1 every 4 to 8 weeks as defined in each protocol, along with date of treatment discontinuation, progression, death, and last follow-up visit. Statistical analysis TTF of phase I treatment was defined as the time from the start of phase I treatment to the discontinuation of the treatment for any reason. TTF of the best phase I trials was defined as the longest TTF in patients enrolled in >1 clinical trial. TTF of the last line of conventional chemotherapy was also defined as the time from the start of the patient’s last conventional chemotherapy to the discontinuation of the treatment for any reason. Patients were censored at the time of their last follow-up if they were continuing treatment. The median TTF was estimated by the Kaplan–Meier method and compared using the logrank test. Hazard ratios (HR) with a 95 % confidence interval (CI) were calculated using a Cox regression model with a single covariate. Response rate in patients with measurable disease was evaluated according to the RECIST version 1.0 or 1.1. Disease control rate (DCR) was defined as the proportion of patients who achieved either complete response (CR), partial response (PR), or stable disease (SD). PFS was defined as the time from the start of phase I treatment to either the first objective evidence of disease progression or death from any cause. OS was defined as the time from the start of phase I treatment to death from any cause. For PFS or OS, patients were censored at the time of their last followup if they were free of disease progression or from death, respectively. Median PFS and OS were estimated by the Kaplan–Meier method, and the difference between patients with PR or SD and those with PD was evaluated using the log-rank test. Statistical analyses were performed using IBM® SPSS® Statistics version 21 (IBM Corporation, Armonk, NY, USA). All tests were two-sided, and P-values 3 months, all of whom were treated with targeted agents as monotherapy.
Survival analysis Median PFS and OS for the overall population were 1.6 months (95 % CI, 1.4–1.8 months) and 7.5 months (95 % CI, 5.7–9.3 months), respectively (Fig. 3). Among 58 patients with measurable lesions, the median PFS of patients with PR or SD (n=28; 2.7 months; 95 % CI, 2.4–3.0 months) was significantly longer than that of patients with PD (n=30; 1.3 months; 95 % CI, 1.1–1.5 months) (HR, 0.08; 95 % CI, 0.04–0.19; P
