Cancer Clinical Study Group Research Articles

Phase II study of amrubicin (AMR) for patients (pts) with non-small cell lung cancer (NSCLC) as third-line or fourth-line chemotherapy: Hokkaido Lung Cancer Clinical Study Group trial (HOT) 0901.

7571 Background: Although an increasing number of NSCLC pts receive third-line chemotherapy with the established benefit of second-line chemotherapy, the role of cytotoxic agent in this setting has not yet been well defined prospectively. AMR, third-generation synthetic anthracycline agent, has found favorable clinical activity and acceptable toxicity for NSCLC as well as small cell lung cancer. This prospective trial was conducted to evaluate the efficacy and safety of AMR for NSCLC pts as third-line or fourth-line chemotherapy. Methods: Eligible pts had a performance status 0 to 2, failure of second-line or third-line chemotherapy, and adequate organ function. Pts received AMR 35 mg/m2 intravenously on days 1-3 every 3 weeks. The primary endpoint was disease control rate (DCR: CR + PR + SD). Secondary endpoints were overall survival (OS), progression-free survival (PFS), response rate (CR + PR), and toxicity profile. The estimated accrual was 37 pts to confirm a DCR of 50% as desirable target level and a DCR of 30 % as uninteresting with alpha = 0.05 and beta = 0.20. Results: From August 2009 to May 2011, 41 pts were enrolled from 10 institutions. Patient characteristics were: male/female 29/12; median age 66 (range 43–74); performance status 0/1/2 16/24/1; adenocarcinoma/squamous cell carcinoma/large cell carcinoma/not other specified 30/8/2/1; EGFR mutation positive/negative/unknown 7/26/8; treatment lines 3rd/4th 26/15. The median number of treatment cycles was 2 (range 1-9). The objective responses were CR 0, PR 4, SD 22, PD 14, and NE 1, giving a DCR of 61.0% (95% CI, 46.0-75.9%). Overall response rate was 9.8% (95% CI, 0.6-18.8%). Median PFS was 2.6 months, whereas median survival time was not reached. Grade 3/4 hematological toxicities were neutropenia (68%), anemia (12%), thrombocytopenia (12%), and febrile neutropenia (17%). Grade 3/4 non-hematological toxicities were anorexia (12%), nausea (10%), and pneumonitis (2%). No treatment-related death was observed. Conclusions: AMR shows significant clinical activity with acceptable toxicities as third-line or fourth-line chemotherapyfor advanced NSCLC.

Growth in head and neck cancer clinical research in the NCRN and NCRI: Expanding opportunities for patients across the United Kingdom.

e16007 Background: The National Institute for Health Research Cancer Research Network (NCRN) was established in 2001 to benefit patients by improving the coordination, integration and speed of cancer research. Networks were established in England (NCRN), Scotland, Wales and Northern Ireland, supporting recruitment to a national portfolio across the NHS. In a decade recruitment to cancer studies has increased five fold in England to 20% of new incident cases. Head and Neck cancers affect basic functions including breathing and eating; particularly devastating for patients. The NCRI Head and Neck Cancer Clinical Studies Group is one of 23 Groups funded by NCRI members with a UK wide remit to develop a national portfolio of clinical studies. All CSGs include patients and carers as members resulting in active patient involvement in trial design, patient information and strategic direction of the portfolio. Methods: The last decade has seen unprecedented growth in the Head and Neck portfolio, which now includes 43 studies from only three studies in 2003/4. By 2010/11, 95% of UK Cancer Local Research Networks (37 networks) were recruiting to Head and Neck studies from only 2 networks in 2001/2, expanding trial access for patients and developing Head and Neck research expertise in new sites and with new investigators. Results: Numbers of patients participating in Head and Neck studies has grown exponentially. Since 2006/7 UK patient recruitment has risen 15-fold from 126 to 1890, representing almost 25% new incident cases of Head and Neck cancer. Conclusions: Rapid portfolio growth and associated network activity has expanded opportunities for patients with Head and Neck cancer; providing access to new therapeutic agents and treatment modalities, including NIHR CRN-adopted commercial trials and studies in a surgical setting. Participation in studies demonstrating the effectiveness of Intensity Modulated Radiotherapy in reducing xerostomia (including PARSPORT), has supported integration of this technique into cancer service.

Commentary on “International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: Long-term results of the BA06 30894 trial.” Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK, and the International Collaboration of Trialists; Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group); European

Commentary on “International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: Long-term results of the BA06 30894 trial.” Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK, and the International Collaboration of Trialists; Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group); European

Phase II Study of Irinotecan plus S-1 Combination for Previously Untreated Advanced Non-Small Cell Lung Cancer: Hokkaido Lung Cancer Clinical Study Group Trial (HOT) 0601

Objective: Platinum-free regimens can represent an alternative for advanced non-small cell lung cancer (NSCLC) if similar efficacy is provided with better tolerability. This study evaluated the efficacy and safety of combined irinotecan and S-1 for chemotherapy-naïve advanced NSCLC. Methods: Chemotherapy consisted of 4-week cycles of intravenous irinotecan (100 mg/m², days 1 and 15) and oral S-1 (80 mg/m², days 1–14). The primary endpoint was response rate, while secondary endpoints were overall survival, progression-free survival (PFS), and safety. Results: A total of 112 cycles was administered to 40 patients (median 3 cycles; range 1–6 cycles). Twelve patients showed partial response and 17 patients had stable disease, representing a response rate of 30% and a disease control rate of 72.5%. Median survival time and median PFS were 16.1 and 4.8 months, respectively. Hematological toxicities of grade 3 or 4 were neutropenia (32.5%) and anemia (5.0%). The most common nonhematological toxicities of grade 3 or 4 included diarrhea (15.0%) and anorexia (17.5%). Patients homo- or heterozygous for UGTA1A*6 tended to show a higher incidence of grade 3 diarrhea (p = 0.055). Conclusion: The combination of irinotecan and S-1 offers good efficacy and tolerability for previously untreated advanced NSCLC.

Introduction: are current drug development programmes realising the full potential of new agents?

Introduction: are current drug development programmes realising the full potential of new agents?

Deciding priorities in a clinical studies group

A Breast Clinical Studies Group seeks to support the initiation, development, recruitment to and reporting of clinical studies and randomised controlled trials. In the United Kingdom, the National Cancer Research Institute (NCRI) Breast Cancer Clinical Studies Group serves these functions (Figure ​(Figure11). Figure 1 Structure and interaction of the National Cancer Research Institute (NCRI) Breast Clinical Studies Group. BIDD, Biomarkers and Imaging Discovery and Development Committee; CTACC, Clinical Trials Advisory and Awards Committee; EORTC, European Organisation ... Trials utilising drugs, radiation and/or surgery are usually conceptualised, discussed and developed or adopted from other (international) trials organisations via the three subgroups: the UK breast intergroup for adjuvant and perioperative studies (usually the development of later phase trials), the advanced disease subgroup or the translational and imaging subgroup. Individuals with good ideas, sometimes with links to industry, will engage with Clinical Trials Units and other external organisations. In addition, there is an adoption panel for early phase drug trials led by Industry. Industry-trialist interactions include identifying individuals with an interest in the pathway/compound, early discussion with interested parties and an approach to the Breast Clinical Studies Group. The challenges of such interactions include the time taken to go through both the company and legislation required processes, the need for biological samples (which may be particularly problematic for metastatic breast cancer), how to reach 'new' investigators and how to compete with processes in the US and elsewhere. There is a continuing need for prompt and open communication between all parties, and adherence to the formal processes with properly recorded discussions and decisions. Work behind the scenes may significantly speed the process along, but occasionally can be disruptive. Additional considerations include the potential for competing trials in the UK (for example HER2 therapies in advanced disease) and particularly the delivery of accrual to trials and where trials fail to achieve recruitment targets, termination of the trial. The success of the Breast Clinical Studies Group is reflected in the 16,108 patients entered into trials/observational studies in 2009/2010, of whom 4,121 patients were entered into randomised controlled trials. These totals represent 30 to 45% of UK cancer patients in trials. Perhaps more importantly, through plenary and poster presentations at international cancer meetings and through peer reviewer publications, significant changes in clinical practice have been achieved. While the processes of trial development and implementation may be complex, but can successfully involve Industry, the independent NCRI Breast Clinical Studies Group seeks to improve the prevention, diagnosis, treatment and prognosis of patients with breast cancer.

Phase II study of irinotecan plus S-1 combination for previously untreated advanced non-small cell lung cancer: Hokkaido Lung Cancer Clinical Study Group 0601

e19012 Background: Platinum-containing therapy is a standard first-line treatment for advanced non-small cell lung cancer (NSCLC). Platinum-free regimens can be alternative if they can provide similar efficacy with better tolerability. This study evaluated the efficacy and safety for combination of irinotecan and S-1, a newly developed oral 5-fluorouracil derivative, for chemotherapy-naïve advanced NSCLC. Methods: In this multicenter phase II trial, we initially planned to enroll 40 patients. Chemotherapy consisted of 4-week cycles of irinotecan (100 mg/m2 IV, day 1 and 15) and S-1 (80 mg/m2 orally, day 1–14). Primary end point was response rate; secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. Association of UGT1A1 genotypes (*6 and *28) with frequency of severe toxicity was also examined. Results: A total of 112 cycles was administered into 40 patients (median, 3 cycles: range, 1–6). Median age was 64 years (range, 42–75); 29 patients (73%) had adenocarcinoma, and 8 patients (20%) had squamous cell carcinoma. Majority of the patients (32 cases, 80%) had stage IV disease. Twelve patients exhibited partial response (PR), and 17 patients exhibited stable disease (SD), resulting in response rate of 30% [95% confidence interval (95% CI), 16.6–46.5] and disease control rate of 72.5% (95% CI, 56.1–85.4). Median OS and PFS were 13.8 months (95% CI, 10.7–16.9) and 4.7 months (95% CI, 3.4–6.0), respectively. Hematological toxicities of grade 3 or 4 were neutropenia (32.5%) and anemia (5.0%). The most common non-hematologic toxicities of grade 3 or 4 included diarrhea (15.0%) and anorexia (17.5%). There were no treatment-related deaths. Among the 40 patients, there were 1 homozygous and 8 heterozygous for UGT1A1*6, whereas 7 heterozygous for UGT1A1*28; none of the patients had both genotypes. Patients with homozygous or heterozygous for UGT1A1*6 showed a trend for high incidence of grade 3 diarrhea (p = 0.055). No association of UGT1A1*28 with severe toxicity was observed in this study. Conclusions: Irinotecan and S-1 combination is an alternative treatment with tolerable toxicity for previously untreated advanced NSCLC. No significant financial relationships to disclose.

Randomized Trial of Two or Five Computed Tomography Scans in the Surveillance of Patients With Stage I Nonseminomatous Germ Cell Tumors of the Testis: Medical Research Council Trial TE08, ISRCTN56475197—The National Cancer Research Institute Testis Cancer Clinical Studies Group

Surveillance is a standard management approach for stage I nonseminomatous germ cell tumors (NSGCT). A randomized trial of two versus five computed tomography (CT) scans was performed to determine whether the number of scans influenced the proportion of patients relapsing with intermediate- or poor-prognosis disease at relapse. Patients with clinical stage I NSGCT opting for surveillance were randomly assigned to chest and abdominal CT scans at either 3 and 12 or 3, 6, 9, 12, and 24 months, with all other investigations identical in the two arms. Three of five patients were allocated to the two-scan schedule. Four hundred patients were required. Two hundred forty-seven patients were allocated to a two-scan and 167 to five-scan policy. With a median follow-up of 40 months, 37 relapses (15%) have occurred in the two-scan arm and 33 (20%) in the five-scan arm. No patients had poor prognosis at relapse, but two (0.8%) of those relapsing in the two-scan arm had intermediate prognosis compared with 1 (0.6%) in the five-scan arm, a difference of 0.2% (90% CI, -1.2% to 1.6%). No deaths have been reported. This study can rule out with 95% probability an increase in the proportion of patients relapsing with intermediate- or poor-prognosis disease of more than 1.6% if they have two rather than five CT scans as part of their surveillance protocol. CT scans at 3 and 12 months after orchidectomy should be considered a reasonable option in low-risk patients.

Multicenter phase II trial of neoadjuvant exemestane for postmenopausal patients with hormone receptor-positive, operable breast cancer: Saitama Breast Cancer Clinical Study Group (SBCCSG-03)

This multicenter phase II trial evaluated the efficacy and tolerability of 4 months of neoadjuvant exemestane in 44 postmenopausal patients with estrogen receptor (ER)-positive and/or progesterone receptor-positive, stage II to IIIB breast cancer measuring >or=3 cm. Pathological response was assessed by a central review board using response criteria proposed by the Japanese Breast Cancer Society. Clinical response [complete or partial response (PR)] was assessed by caliper, mammography, or ultrasound. Rates of breast-conserving surgery (BCS) and adverse events were also evaluated. A pathological response was observed in 13 (43%) of 30 patients who underwent surgery at 4 months. Fourteen patients were excluded from the pathological analysis: eight continued exemestane because of PR or stable disease (SD) at 4 months, three underwent chemotherapy because of progressive disease, and three underwent surgery within 2 months because of adverse events. A clinical response was seen in 27 (66%) of 41 evaluable patients. BCS was performed in 27 (90%) of 30 patients who underwent surgery at 4 months. Of the ten patients eligible for mastectomy at baseline, six chose to continue exemestane treatment without surgery because of a PR or SD at 4 months. Adverse events, most of which were grade 1, occurred in <or=10% of patients. These results suggest that neoadjuvant exemestane treatment is effective and well tolerated in postmenopausal women with ER-positive breast cancer. Further studies are required to determine the optimal duration of neoadjuvant treatment and to identify response criteria that can more accurately predict long-term outcomes.

Multicenter phase II trial of neoadjuvant exemestane for postmenopausal patients with hormone-sensitive, operable breast cancer: Saitama Breast Cancer Clinical Study Group (SBCCSG-03)

Multicenter phase II trial of neoadjuvant exemestane for postmenopausal patients with hormone-sensitive, operable breast cancer: Saitama Breast Cancer Clinical Study Group (SBCCSG-03)