- Email: [email protected]
A Randomized Pilot Study of SRL172 (Mycobacterium vaccae) in Patients with Small Cell Lung Cancer (SCLC) Treated with Chemotherapy
Clinical Oncology (2002) 14: 23–27 doi:10.1053/clon.2001.0030, available online at http://www.idealibrary.com on
New Therapies A Randomized Pilot Study of SRL172 (Mycobacterium vaccae) in Patients with Small Cell Lung Cancer (SCLC) Treated with Chemotherapy L. ASSERSOHN*, B. E. SOUBERBIELLE*‡, M. E. R. O’BRIEN*†, C. D. ARCHER*, R. MENDES*, R. BASS†, K. V. BROMELOW‡, R. D. PALMER0, E. BOUILLOUX¶, D. A. KENNARD¶, I. E. SMITH* *Royal Marsden Hospital NHS Trust, Sutton, Surrey SM2 5PT; †MidKent Oncology Centre, Maidstone, Kent ME16 9QQ; ‡Department of Molecular Medicine, King’s College, London SE5 9NU; 0Department of Bacteriology, University College London Medical School, London W1P 6DB; ¶SR Pharma, 26th Floor, Centre Point, 103 New Oxford Street, London WC1A 1DD, U.K. Received: 13 August 2001
Revised: 17 October 2001
Accepted: 18 October 2001
Background: SRL172 is a suspension of heat killed Mycobacterium vaccae, that has been found to be a potent immunological adjuvant when used with autologous cells in animal models. This is a phase II study to test the clinical activity, feasibility and safety of combining SRL172 with chemotherapy to treat patients with small cell lung cancer (SCLC). Methods: Patients were randomized to receive chemotherapy with (n=14) or without (n=14) SRL172. The chemotherapy was either platinum-based (MVP, n=10) or anthracycline-based (ACE, n=18). SRL172 was given intradermally on day 0, weeks 4, 8 and then 3–6 monthly. Results: The treatment arms were well balanced for disease extent (43% with limited stage in each arm). The toxicity of chemotherapy and overall response at 12–15 weeks (57%) was the same for both treatment regimens. Median survival was 8.6 months and 12.9 for patients treated with chemotherapy alone and with the combination respectively (P=0.10). The survival trend was similar for both disease extent and chemotherapy regimen employed in favour of combination chemotherapy with SRL172. Conclusions: There is a trend to improved median survival in SCLC with the combination of chemotherapy and SRL172 with no increased toxicity and irrespective of drug regimen. A phase III study examining chemotherapy in combination with SRL172 in SCLC is now underway. Assersohn, L. et al. (2002) Clinical Oncology 14, 23–27. 2002 The Royal College of Radiologists Key words: Small cell, lung cancer, SRL172, Mycobacterium vaccae, chemotherapy
There are approximately 430 000 new cases of lung cancer in the U.S. and Western Europe, 20% of which are small cell lung cancer (SCLC). SCLC follows an aggressive course with frequent rapid growth, early dissemination and development of drug resistance. Treatment for limited and extensive SCLC is combination chemotherapy with established drugs, such as platinums, etoposide, anthracyclines, cyclophosphamide Author for correspondence: Dr M. E. R. O’Brien, Lung Unit, The Royal Marsden Hospital NHS Trust, Downs Road, Sutton, Surrey SM2 5PT, U.K. Tel: 020 8661 3280; Fax: 020 8643 0373; E-mail: [email protected] 0936–6555/02/010023+05 $35.00/0
and Vinca alkaloids, and this can offer median survival durations of 10–16 months in limited disease and 7–11 months in extensive disease [1]. To date, novel chemotherapeutic agents have not improved survival rates with established regimens [2,3]. Therefore, new treatment strategies are required, one of which is the re-exploration of immunotherapy now in combination with chemotherapy. Chemotherapeutic agents may induce in vivo release of either tumourspecific or tumour-associated antigens from the treated tumour. An ‘immunological adjuvant’ is a product that augments the immune response to an antigen. SRL172 is a non-specific immunological adjuvant that is a 2002 The Royal College of Radiologists
24
preparation of heat-killed Mycobacterium vaccae. In vitro SRL172 induces a T cell response from tumour cells (IL-2, IL-12 and -IFN) whilst in vivo, an increase in natural killer (NK) cells and a decrease in IL-4 have been reported [4]. Recently we reported the first of our series of phase II studies, in which patients with inoperable NSCLC and mesothelioma were treated with chemotherapy or chemotherapy and SRL172 [5]. A trend was seen in those patients randomized to receive the combination of chemotherapy and SRL172 with improved response rate (54% vs 33%), improved median survival (9.7 months vs 7.5 months) and improved 1 year survival (42% vs 18%). This was not confirmed in the phase III trial in NSCLC (personal communication). SCLC may be a more immunogenic tumour than NSCLC and is the subject of other vaccine studies [6]. Encouraging results with SRL172 have also been reported in melanoma [7] and prostate cancer [8]. In this SCLC study, the feasibility, safety and clinical effects of combining intradermal SRL172 with intravenous chemotherapy were assessed in a cohort of patients presenting with SCLC.
Table 1 – Patient characteristics Chemotherapy alone
Chemotherapy and SRL172
6 (43%) 8 (57%)
9 (64%) 5 (36%)
60.5 years (48–75 years)
61.5 years (46–73 years)
Performance status 1 2 3
6 (43%) 7 (50%) 1 (7%)
6 (43%) 6 (43%) 2 (14%)
Extent of disease Limited Extensive
6 (43%) 8 (57%)
6 (43%) 8 (57%)
Weight loss in preceding 3 months <5% 6 (43%) >5% 8 (57%)
7 (50%) 7 (50%)
Number of chemotherapy courses received 1 1 (7%) 2 0 3 2 (14%) 4 2 (14%) 5 1 (7%) 6 8 (57%)
1 (7%) 2 (14%) 3 (21%) 1 (7%) 1 (7%) 6 (43%)
Sex Male Female Median age (range)
PATIENTS AND METHODS
Twenty-eight previously untreated patients with histologically or cytologically verified SCLC were randomized to receive either intradermal SRL172 given concurrently with intravenous combination chemotherapy, or chemotherapy alone. One patient had mixed histology (treated with MVP chemotherapy) and was excluded from the ‘per-protocol’ analysis. All patients had lesions evaluable by clinical or radiological examination. Other inclusion criteria were life-expectancy of 12 weeks or more, age over 18 years and satisfactory renal function. Patients whose performance status was 3 or more, or who had serious concomitant illness were excluded. The protocol was approved by the Research Ethics Committees of The Royal Marsden NHS Trust and the Kent Cancer Centre. Written informed consent was obtained from all patients. All patients underwent pre-treatment physical examination, plasma electrolytes, urea and creatinine, serum liver function tests, chest radiography and staging of disease with a thoraco-abdominal CT scan. Clinical assessment of symptoms took place at the time of randomization, monthly while receiving injections of SRL172 and thereafter at 3–6 monthly intervals. Quality of life data collection was planned at baseline and at 3 monthly intervals. At each assessment visit, patients had physical examination, full blood count and chest radiography. No nadir bloods were taken. Objective response was measured by CT scanning every two courses. This was designed as a phase II study to assess the tolerability of SRL172 and to ensure that the combination of chemotherapy and SRL172 was not inferior to
chemotherapy alone. Patients without stratification were randomized to receive chemotherapy with (n=14) or without (n=14) SRL172. The randomization was used to eliminate biases in the patient groups. The chemotherapy was either platinum-based (mitomycin C 8 mg/m2 on course 1, 2, 4 and 6, vinblastine 6 mg/m2 (maximum dose 10 mg) and cisplatin 50 mg/m2, (MVP), n=10) or anthracycline based (doxorubicin 40 mg/m2, cyclophosphamide 600 mg/m2 and etoposide 100–120 mg/m2, (ACE), n=18). Initially MVP was the regimen of choice but following reports of low progression free survival for the regimen, we returned to ACE regimen for the remaining 18 patients [9]. Chemotherapy was given at 3 weekly intervals for a maximum of six courses and SRL172 was given intradermally prior to the first chemotherapy and then at monthly intervals for the first 3 injections, then at 3–6 monthly intervals thereafter. Antiemetics were routinely prescribed but dexamethasone was omitted for the first course in those who received SRL172. Patients with limited disease who achieved a complete response (CR) or good partial response (PR) received prophylactic cranial irradiation and mediastinal radiotherapy. SRL172 was formulated as a suspension of 10 mg/ml heat killed Mycobacterium vaccae in borate buffered saline (pH 8) and provided in 3 ml glass vials at a concentration of 1 mg bacilli wet weight per 0.1 ml dose and stored refrigerated at 4C in the pharmacies of both hospitals taking part in the trial.
172 Table 2 – Response rate at 12–15 weeks
Overall response Complete response (CR) Partial response (PR) Stable disease (SD) Progressive disease (PD) Non-evaluable (NE)
Chemotherapy alone number, n=14
Chemotherapy and SRL172 number, n=14
8 (57%) 1 (7%) 7 (50%) 2 (14%) 2 (14%) 2 (14%)
8 (57%) 2 (14%) 6 (43%) 0 5 (36%) 1 (7%)
RESULTS
Patient characteristics are shown in Table 1. The two groups were well balanced with regard to performance status, age, sex and extent of disease. Three patients were of WHO performance status (PS) 3 at the time treatment was commenced and are included in the analysis. In both treatment arms 43% of patients had limited SCLC whilst 57% had extensive disease. Median age was 60.5 and 61.5 years in the chemotherapy alone and combined chemotherapy and SRL172 groups, respectively. Fifty-seven per cent of patients in the chemotherapy alone and 50% of patients in the combined cohort had had more than 5% weight loss in the preceding 3 months. Eight patients in the chemotherapy alone and six patients in the combined group, each out of a total 14 patients in each arm, received six courses of chemotherapy. Following injection of SRL172, there was no treatment related toxicity, except for some induration at the
25
injection site. An overall response rate of 57% was seen in both treatment arms (Table 2). This was seen in 37.5% of those with extensive disease and 83% of those with limited disease. In the group treated with chemotherapy plus SRL172, on the intention to treat analysis (ITT), a trend towards improved survival was seen with median survival in the combination arm of 12.9 months vs 8.6 months (P=0.10) (Fig. 1). On the ‘per-protocol’ analysis, in which one patient was excluded due to mixed histology, the median survival time for all patients with limited disease was 11.0 months compared with 9.3 months for those with extensive disease in this cohort (P=0.22). Median survival time for all patients receiving MVP chemotherapy was 8.7 months (n=9) compared with 11.0 months with ACE chemotherapy (n=18) (P=0.53). The survival in patients in the combination arm compared with chemotherapy alone was 14.1 months vs 9.2 months (P=0.42) for limited disease, 11.2 months vs 6.0 months (P=0.19) for extensive disease, 14.4 months vs 9.7 months (P=0.34) for those treated with ACE chemotherapy and 12.0 months vs 6.8 months (P=0.22) for those treated with MVP chemotherapy (Table 3). For those treated with chemotherapy alone, the median survival time for patients with limited disease was 9.2 months compared with 6.0 months for those with extensive disease. For patients treated with chemotherapy and SRL172, the median survival time was 14.1 months for those with limited disease and 11.2 months for those with extensive disease. Haematological and non-haematological toxicities were similar in both treatment arms (Tables 4 and 5). Full quality of life assessment was not analysed as the number of patients returning repeat questionnaires was small.
Fig. 1 – Overall survival for patients treated with chemotherapy with and without SRL172.
26 Table 3 – Median survival time (months)
Chemotherapy alone
Chemotherapy and SRL172
P value
Intent-to-treat population
8.6 months (n=14)
12.9 months (n=14)
0.10
Per-protocol population Limited disease Extensive disease ACE chemotherapy MVP chemotherapy
9.2 6.0 9.7 6.8
14.1 11.2 14.4 12.0
0.42 0.19 0.34 0.22
months (n=8) months (n=5) months (n=9) months (n=4)
Table 4 – Haematological toxicity (Grade 2 and 3, total number on any cycle)
Toxicity
CTC grade
Chemotherapy alone
Anaemia
2 3 2 3 2 3 2 3
6 1 11 0 2 2 1 0
Lymphopenia Neutropenia Thrombocytopenia
Chemotherapy and SRL172 6 1 5 3 2 1 0 2
Table 5 – Non-haematological toxicity (Grade 3 or 4, total number of events on any cycle)
Infection Nausea and vomiting Mucositis Diarrhoea Alopecia Malaise
Chemotherapy
Chemotherapy and SRL172
4 6 2 2 18 3
5 2 0 0 19 2
DISCUSSION
This pilot study examining the feasibility, toxicity and clinical efficacy of administering SRL172 in combination with chemotherapy to SCLC patients was a component of a larger phase II study that employed the same design for symptomatic and inoperable NSCLC and mesothelioma patients who were treated with chemotherapy or chemotherapy and SRL172 (29 patients) [5]. Despite similar response rates in the two treatment arms of this study, a trend in improved median survival is seen for the combination of chemotherapy and SRL172 in patients with SCLC. Median survival was slightly higher with ACE chemotherapy compared with MVP chemotherapy although separate analyses show that, irrespective of the chemotherapy regimen
months (n=8) months (n=6) months (n=9) months (n=5)
employed, median survival time was increased when chemotherapy was used in combination with SRL172. The toxicities seen in the combination arm were comparable to those seen in patients treated with chemotherapy alone. Little progress has been made in the treatment of SCLC in recent years despite the development of new chemotherapy agents although irinotecan (CPT-11) appears to be promising, as recently reported in a phase III study [10]. Although caution needs to be exercised when interpreting the data, in view of the small number of patients involved in each group/subgroup comparison, there is an encouraging trend for improvement in survival seen in patients receiving chemotherapy and SRL172 compared with chemotherapy alone. The results of this pilot study have encouraged a phase III randomized trial involving 600 patients to test the hypothesis of a clinical interaction between SRL172 and combination chemotherapy in patients with small cell lung cancer. This will provide the power to detect a 10% survival difference between chemotherapy and the combination of chemotherapy and SRL172. SRL172 is a promising agent that appears to be an easily administered and well-tolerated non-toxic, non-specific immunological adjuvant. Acknowledgement. We are grateful to SR Pharma plc for support.
REFERENCES 1 Zochbauer-Muller S, Pirker R, Huber H. Treatment of small cell lung cancer patients. Ann Oncol 1999;10(6):83–91. 2 Kelly K. New chemotherapy agents for small cell lung cancer. Cancer 2000;117(4):156S–162S. 3 Ardizzoni A, Grossi F. Update on the treatment of small cell lung cancer (SCLC). Ann Oncol 2000;11(3):101–108. 4 Mendes R, O’Brien M, Bromelow K, et al. A highly active regimen for malignant mesothelioma with new biological data. Br J Cancer 2000;83(Supp 1):7.8. 5 O’Brien M, Saini A, Smith I, et al. A randomized phase II study of SRL172 (Mycobacterium vaccae) combined with chemotherapy in patients with advanced inoperable non-small-cell lung cancer and mesothelioma. Br J Cancer 2000;83(7):853–857. 6 Grant SC, Kris MG, Miller V, Yao TJ, Houghton AN, Chapman PB. Long survival in 15 patients with small cell lung cancer (SCLC) immunized with BEC2 plus BCG after initial therapy: An update. Proc ASCO 1997;16:1630. 7 Maraveyas A, Baban B, Kennard D, et al. Possible improved survival of patients with stage IVAJCC melanoma receiving
172 SRL172 immunotherapy: correlation with induction of increased levels of intracellular interleukin-2 in peripheral blood lymphocytes. Ann Oncol 1999;10(7):817–824. 8 Hrouda D, Baban B, Dunsmuir W, Kirby R, Dalgleish A. Immunotherapy of advanced prostate cancer: a phase I/II trial using Mycobacterium vaccae (SRL172). Br J Urol 1998;82(4):568– 573.
27
9 Hickish T, Smith I, Nicolson M, et al. A pilot study of MVP (mitomycin-C, vinblastine and cisplatin) chemotherapy in smallcell lung cancer. Br J Cancer 1998;77(11):1966–1970. 10 Noda K, Nishiwaki Y, Kawahara M, et al. Randomized Phase III study or irinotecan (CPT-11) and cisplatin versus etoposide and cisplatin in extensive disease small cell lung cancer: Japan Clinical Oncology Group study (JCOG9511). Proc ASCO 2000;19:1887.
New Therapies A Randomized Pilot Study of SRL172 (Mycobacterium vaccae) in Patients with Small Cell Lung Cancer (SCLC) Treated with Chemotherapy L. ASSERSOHN*, B. E. SOUBERBIELLE*‡, M. E. R. O’BRIEN*†, C. D. ARCHER*, R. MENDES*, R. BASS†, K. V. BROMELOW‡, R. D. PALMER0, E. BOUILLOUX¶, D. A. KENNARD¶, I. E. SMITH* *Royal Marsden Hospital NHS Trust, Sutton, Surrey SM2 5PT; †MidKent Oncology Centre, Maidstone, Kent ME16 9QQ; ‡Department of Molecular Medicine, King’s College, London SE5 9NU; 0Department of Bacteriology, University College London Medical School, London W1P 6DB; ¶SR Pharma, 26th Floor, Centre Point, 103 New Oxford Street, London WC1A 1DD, U.K. Received: 13 August 2001
Revised: 17 October 2001
Accepted: 18 October 2001
Background: SRL172 is a suspension of heat killed Mycobacterium vaccae, that has been found to be a potent immunological adjuvant when used with autologous cells in animal models. This is a phase II study to test the clinical activity, feasibility and safety of combining SRL172 with chemotherapy to treat patients with small cell lung cancer (SCLC). Methods: Patients were randomized to receive chemotherapy with (n=14) or without (n=14) SRL172. The chemotherapy was either platinum-based (MVP, n=10) or anthracycline-based (ACE, n=18). SRL172 was given intradermally on day 0, weeks 4, 8 and then 3–6 monthly. Results: The treatment arms were well balanced for disease extent (43% with limited stage in each arm). The toxicity of chemotherapy and overall response at 12–15 weeks (57%) was the same for both treatment regimens. Median survival was 8.6 months and 12.9 for patients treated with chemotherapy alone and with the combination respectively (P=0.10). The survival trend was similar for both disease extent and chemotherapy regimen employed in favour of combination chemotherapy with SRL172. Conclusions: There is a trend to improved median survival in SCLC with the combination of chemotherapy and SRL172 with no increased toxicity and irrespective of drug regimen. A phase III study examining chemotherapy in combination with SRL172 in SCLC is now underway. Assersohn, L. et al. (2002) Clinical Oncology 14, 23–27. 2002 The Royal College of Radiologists Key words: Small cell, lung cancer, SRL172, Mycobacterium vaccae, chemotherapy
There are approximately 430 000 new cases of lung cancer in the U.S. and Western Europe, 20% of which are small cell lung cancer (SCLC). SCLC follows an aggressive course with frequent rapid growth, early dissemination and development of drug resistance. Treatment for limited and extensive SCLC is combination chemotherapy with established drugs, such as platinums, etoposide, anthracyclines, cyclophosphamide Author for correspondence: Dr M. E. R. O’Brien, Lung Unit, The Royal Marsden Hospital NHS Trust, Downs Road, Sutton, Surrey SM2 5PT, U.K. Tel: 020 8661 3280; Fax: 020 8643 0373; E-mail: [email protected] 0936–6555/02/010023+05 $35.00/0
and Vinca alkaloids, and this can offer median survival durations of 10–16 months in limited disease and 7–11 months in extensive disease [1]. To date, novel chemotherapeutic agents have not improved survival rates with established regimens [2,3]. Therefore, new treatment strategies are required, one of which is the re-exploration of immunotherapy now in combination with chemotherapy. Chemotherapeutic agents may induce in vivo release of either tumourspecific or tumour-associated antigens from the treated tumour. An ‘immunological adjuvant’ is a product that augments the immune response to an antigen. SRL172 is a non-specific immunological adjuvant that is a 2002 The Royal College of Radiologists
24
preparation of heat-killed Mycobacterium vaccae. In vitro SRL172 induces a T cell response from tumour cells (IL-2, IL-12 and -IFN) whilst in vivo, an increase in natural killer (NK) cells and a decrease in IL-4 have been reported [4]. Recently we reported the first of our series of phase II studies, in which patients with inoperable NSCLC and mesothelioma were treated with chemotherapy or chemotherapy and SRL172 [5]. A trend was seen in those patients randomized to receive the combination of chemotherapy and SRL172 with improved response rate (54% vs 33%), improved median survival (9.7 months vs 7.5 months) and improved 1 year survival (42% vs 18%). This was not confirmed in the phase III trial in NSCLC (personal communication). SCLC may be a more immunogenic tumour than NSCLC and is the subject of other vaccine studies [6]. Encouraging results with SRL172 have also been reported in melanoma [7] and prostate cancer [8]. In this SCLC study, the feasibility, safety and clinical effects of combining intradermal SRL172 with intravenous chemotherapy were assessed in a cohort of patients presenting with SCLC.
Table 1 – Patient characteristics Chemotherapy alone
Chemotherapy and SRL172
6 (43%) 8 (57%)
9 (64%) 5 (36%)
60.5 years (48–75 years)
61.5 years (46–73 years)
Performance status 1 2 3
6 (43%) 7 (50%) 1 (7%)
6 (43%) 6 (43%) 2 (14%)
Extent of disease Limited Extensive
6 (43%) 8 (57%)
6 (43%) 8 (57%)
Weight loss in preceding 3 months <5% 6 (43%) >5% 8 (57%)
7 (50%) 7 (50%)
Number of chemotherapy courses received 1 1 (7%) 2 0 3 2 (14%) 4 2 (14%) 5 1 (7%) 6 8 (57%)
1 (7%) 2 (14%) 3 (21%) 1 (7%) 1 (7%) 6 (43%)
Sex Male Female Median age (range)
PATIENTS AND METHODS
Twenty-eight previously untreated patients with histologically or cytologically verified SCLC were randomized to receive either intradermal SRL172 given concurrently with intravenous combination chemotherapy, or chemotherapy alone. One patient had mixed histology (treated with MVP chemotherapy) and was excluded from the ‘per-protocol’ analysis. All patients had lesions evaluable by clinical or radiological examination. Other inclusion criteria were life-expectancy of 12 weeks or more, age over 18 years and satisfactory renal function. Patients whose performance status was 3 or more, or who had serious concomitant illness were excluded. The protocol was approved by the Research Ethics Committees of The Royal Marsden NHS Trust and the Kent Cancer Centre. Written informed consent was obtained from all patients. All patients underwent pre-treatment physical examination, plasma electrolytes, urea and creatinine, serum liver function tests, chest radiography and staging of disease with a thoraco-abdominal CT scan. Clinical assessment of symptoms took place at the time of randomization, monthly while receiving injections of SRL172 and thereafter at 3–6 monthly intervals. Quality of life data collection was planned at baseline and at 3 monthly intervals. At each assessment visit, patients had physical examination, full blood count and chest radiography. No nadir bloods were taken. Objective response was measured by CT scanning every two courses. This was designed as a phase II study to assess the tolerability of SRL172 and to ensure that the combination of chemotherapy and SRL172 was not inferior to
chemotherapy alone. Patients without stratification were randomized to receive chemotherapy with (n=14) or without (n=14) SRL172. The randomization was used to eliminate biases in the patient groups. The chemotherapy was either platinum-based (mitomycin C 8 mg/m2 on course 1, 2, 4 and 6, vinblastine 6 mg/m2 (maximum dose 10 mg) and cisplatin 50 mg/m2, (MVP), n=10) or anthracycline based (doxorubicin 40 mg/m2, cyclophosphamide 600 mg/m2 and etoposide 100–120 mg/m2, (ACE), n=18). Initially MVP was the regimen of choice but following reports of low progression free survival for the regimen, we returned to ACE regimen for the remaining 18 patients [9]. Chemotherapy was given at 3 weekly intervals for a maximum of six courses and SRL172 was given intradermally prior to the first chemotherapy and then at monthly intervals for the first 3 injections, then at 3–6 monthly intervals thereafter. Antiemetics were routinely prescribed but dexamethasone was omitted for the first course in those who received SRL172. Patients with limited disease who achieved a complete response (CR) or good partial response (PR) received prophylactic cranial irradiation and mediastinal radiotherapy. SRL172 was formulated as a suspension of 10 mg/ml heat killed Mycobacterium vaccae in borate buffered saline (pH 8) and provided in 3 ml glass vials at a concentration of 1 mg bacilli wet weight per 0.1 ml dose and stored refrigerated at 4C in the pharmacies of both hospitals taking part in the trial.
172 Table 2 – Response rate at 12–15 weeks
Overall response Complete response (CR) Partial response (PR) Stable disease (SD) Progressive disease (PD) Non-evaluable (NE)
Chemotherapy alone number, n=14
Chemotherapy and SRL172 number, n=14
8 (57%) 1 (7%) 7 (50%) 2 (14%) 2 (14%) 2 (14%)
8 (57%) 2 (14%) 6 (43%) 0 5 (36%) 1 (7%)
RESULTS
Patient characteristics are shown in Table 1. The two groups were well balanced with regard to performance status, age, sex and extent of disease. Three patients were of WHO performance status (PS) 3 at the time treatment was commenced and are included in the analysis. In both treatment arms 43% of patients had limited SCLC whilst 57% had extensive disease. Median age was 60.5 and 61.5 years in the chemotherapy alone and combined chemotherapy and SRL172 groups, respectively. Fifty-seven per cent of patients in the chemotherapy alone and 50% of patients in the combined cohort had had more than 5% weight loss in the preceding 3 months. Eight patients in the chemotherapy alone and six patients in the combined group, each out of a total 14 patients in each arm, received six courses of chemotherapy. Following injection of SRL172, there was no treatment related toxicity, except for some induration at the
25
injection site. An overall response rate of 57% was seen in both treatment arms (Table 2). This was seen in 37.5% of those with extensive disease and 83% of those with limited disease. In the group treated with chemotherapy plus SRL172, on the intention to treat analysis (ITT), a trend towards improved survival was seen with median survival in the combination arm of 12.9 months vs 8.6 months (P=0.10) (Fig. 1). On the ‘per-protocol’ analysis, in which one patient was excluded due to mixed histology, the median survival time for all patients with limited disease was 11.0 months compared with 9.3 months for those with extensive disease in this cohort (P=0.22). Median survival time for all patients receiving MVP chemotherapy was 8.7 months (n=9) compared with 11.0 months with ACE chemotherapy (n=18) (P=0.53). The survival in patients in the combination arm compared with chemotherapy alone was 14.1 months vs 9.2 months (P=0.42) for limited disease, 11.2 months vs 6.0 months (P=0.19) for extensive disease, 14.4 months vs 9.7 months (P=0.34) for those treated with ACE chemotherapy and 12.0 months vs 6.8 months (P=0.22) for those treated with MVP chemotherapy (Table 3). For those treated with chemotherapy alone, the median survival time for patients with limited disease was 9.2 months compared with 6.0 months for those with extensive disease. For patients treated with chemotherapy and SRL172, the median survival time was 14.1 months for those with limited disease and 11.2 months for those with extensive disease. Haematological and non-haematological toxicities were similar in both treatment arms (Tables 4 and 5). Full quality of life assessment was not analysed as the number of patients returning repeat questionnaires was small.
Fig. 1 – Overall survival for patients treated with chemotherapy with and without SRL172.
26 Table 3 – Median survival time (months)
Chemotherapy alone
Chemotherapy and SRL172
P value
Intent-to-treat population
8.6 months (n=14)
12.9 months (n=14)
0.10
Per-protocol population Limited disease Extensive disease ACE chemotherapy MVP chemotherapy
9.2 6.0 9.7 6.8
14.1 11.2 14.4 12.0
0.42 0.19 0.34 0.22
months (n=8) months (n=5) months (n=9) months (n=4)
Table 4 – Haematological toxicity (Grade 2 and 3, total number on any cycle)
Toxicity
CTC grade
Chemotherapy alone
Anaemia
2 3 2 3 2 3 2 3
6 1 11 0 2 2 1 0
Lymphopenia Neutropenia Thrombocytopenia
Chemotherapy and SRL172 6 1 5 3 2 1 0 2
Table 5 – Non-haematological toxicity (Grade 3 or 4, total number of events on any cycle)
Infection Nausea and vomiting Mucositis Diarrhoea Alopecia Malaise
Chemotherapy
Chemotherapy and SRL172
4 6 2 2 18 3
5 2 0 0 19 2
DISCUSSION
This pilot study examining the feasibility, toxicity and clinical efficacy of administering SRL172 in combination with chemotherapy to SCLC patients was a component of a larger phase II study that employed the same design for symptomatic and inoperable NSCLC and mesothelioma patients who were treated with chemotherapy or chemotherapy and SRL172 (29 patients) [5]. Despite similar response rates in the two treatment arms of this study, a trend in improved median survival is seen for the combination of chemotherapy and SRL172 in patients with SCLC. Median survival was slightly higher with ACE chemotherapy compared with MVP chemotherapy although separate analyses show that, irrespective of the chemotherapy regimen
months (n=8) months (n=6) months (n=9) months (n=5)
employed, median survival time was increased when chemotherapy was used in combination with SRL172. The toxicities seen in the combination arm were comparable to those seen in patients treated with chemotherapy alone. Little progress has been made in the treatment of SCLC in recent years despite the development of new chemotherapy agents although irinotecan (CPT-11) appears to be promising, as recently reported in a phase III study [10]. Although caution needs to be exercised when interpreting the data, in view of the small number of patients involved in each group/subgroup comparison, there is an encouraging trend for improvement in survival seen in patients receiving chemotherapy and SRL172 compared with chemotherapy alone. The results of this pilot study have encouraged a phase III randomized trial involving 600 patients to test the hypothesis of a clinical interaction between SRL172 and combination chemotherapy in patients with small cell lung cancer. This will provide the power to detect a 10% survival difference between chemotherapy and the combination of chemotherapy and SRL172. SRL172 is a promising agent that appears to be an easily administered and well-tolerated non-toxic, non-specific immunological adjuvant. Acknowledgement. We are grateful to SR Pharma plc for support.
REFERENCES 1 Zochbauer-Muller S, Pirker R, Huber H. Treatment of small cell lung cancer patients. Ann Oncol 1999;10(6):83–91. 2 Kelly K. New chemotherapy agents for small cell lung cancer. Cancer 2000;117(4):156S–162S. 3 Ardizzoni A, Grossi F. Update on the treatment of small cell lung cancer (SCLC). Ann Oncol 2000;11(3):101–108. 4 Mendes R, O’Brien M, Bromelow K, et al. A highly active regimen for malignant mesothelioma with new biological data. Br J Cancer 2000;83(Supp 1):7.8. 5 O’Brien M, Saini A, Smith I, et al. A randomized phase II study of SRL172 (Mycobacterium vaccae) combined with chemotherapy in patients with advanced inoperable non-small-cell lung cancer and mesothelioma. Br J Cancer 2000;83(7):853–857. 6 Grant SC, Kris MG, Miller V, Yao TJ, Houghton AN, Chapman PB. Long survival in 15 patients with small cell lung cancer (SCLC) immunized with BEC2 plus BCG after initial therapy: An update. Proc ASCO 1997;16:1630. 7 Maraveyas A, Baban B, Kennard D, et al. Possible improved survival of patients with stage IVAJCC melanoma receiving
172 SRL172 immunotherapy: correlation with induction of increased levels of intracellular interleukin-2 in peripheral blood lymphocytes. Ann Oncol 1999;10(7):817–824. 8 Hrouda D, Baban B, Dunsmuir W, Kirby R, Dalgleish A. Immunotherapy of advanced prostate cancer: a phase I/II trial using Mycobacterium vaccae (SRL172). Br J Urol 1998;82(4):568– 573.
27
9 Hickish T, Smith I, Nicolson M, et al. A pilot study of MVP (mitomycin-C, vinblastine and cisplatin) chemotherapy in smallcell lung cancer. Br J Cancer 1998;77(11):1966–1970. 10 Noda K, Nishiwaki Y, Kawahara M, et al. Randomized Phase III study or irinotecan (CPT-11) and cisplatin versus etoposide and cisplatin in extensive disease small cell lung cancer: Japan Clinical Oncology Group study (JCOG9511). Proc ASCO 2000;19:1887.