J Cancer Res Clin Oncol (1992) 118:405-407
Cancer ~esearch Clinical 9 9 Springer-Verlag1992
Rapid communication Treatment results of the thioether lipid ilmofosine in patients with malignant tumours M. Winkelmann 1, K. Ebeling 1, G. Strohmeyer 1, G. Hottenrott 2, Z. Mechl 3, W. Berges 4, T. Scholten 5, M. Westerhausen 6, G. Schlimok 7, and R. Sterz 8 1 z 4 v
Medizinische Klinik und Poliklinik, Heinrich-Heine-Universit/itDiisseldorf, Chirurgische Klinik, Johann-Wolfgang-von-Goethe-Universit/itFrankfurt, a Cancer Research Institute Brfinn, CSFR, Luisenhospital Aachen, 5 Allgemeines Krankenhaus Hagen, 6 St.-Johannes-Hospital Duisburg-Hamborn, ZentralklinikumAugsburg, 8 Boehringer Mannheim, Federal Republic of Germany
Received 6 March 1992 / Accepted 10 March 1992
Summary. In a multicentre study patients with liver metastases stratified to the histology of the primary tumour were investigated. A total of 102 patients with colorectal adenocarcinoma, non-small-cell lung cancer, pancreatic cancer, primary liver carcinoma and malignant melanoma were treated with the thioether lipid ilmofosine. The drug was administered orally as a tablet at a dosage of 150-300 mg/day (75 mg/tablet). The tolerability of ilmofosine was poor. There was a dose-limiting gastrointestinal toxicity with nausea, vomiting and loss of appetite (WHO grade II-IV) in 67% of patients. During the period of therapy (1-29 weeks, 8.5 weeks mean) no complete remission and no partial response were observed. We thus conclude that treatment with oral ilmofosine is not effective in patients with liver metastases due to various malignancies. Key words: (Thio)ether lipids - Metastasized tumours Oral therapy
membrane production (Berdel et al. 1985; Munder et al.
1981). In the first phase I clinical trials reduction in size and even disappearance of liver metastases could be demonstrated (Sterz, personal communication). As a consequence of these findings a multicentre phase II study was performed in patients with malignant tumours and liver metastases. Reasons for studying patients with malignant liver tumours were the high-first-pass effect (Herrmann personal communication) of alkyllysophospholipids in the liver and the ease of measurement and documentation of malignant lesions of the liver.
Patients and methods From August 1989 to December 1990 a total of 102 patients aged between 25 and 79 years (mean age = 59 years) received outpatient treatment with the thioether lipid ilmofosine, which was kindly provided by Boehringer Mannheim. Patients were treated with two to four tablets of ilmofosine (75 rag/tablet) daily p.o. for up to 29 weeks. Progression of these disease in the last 3 months prior to
Introduction Chemotherapy in patients with metastasized tumours is still mostly palliative. Therefore it is important to find new, more effective cytostatic drugs with few side-effects. Because of their clearly demonstrated antineoplastic activity in vitro and in vivo, synthetic alkyllysophospholipids have recived some interest in clinical oncology (Berde11990; Bonjouhliem et al. 1986; Fromm et al. 1987; Herrmann et al. 1988). It has been shown that the main dose-dependent mechanism of action of these lysolecithin derivates is based on a complex interaction with the lipid metabolism of tumour cell membranes; the overall result is an inhibition of tumour cell growth due to impeded
Patients 90 8O 7O 6O 5O 40 3O 20 10 0 1 2 3 4 5 6 7 8 9 lo 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
Offprint requests to: M. Winkelmann, Medizinische Klinik und Poliklinik, Abt. H/imatologie, Onkologie u. klin. Immunologic, Heinrich-Heine-Universitfit, Moorenstrasse 5, D-4000 D/isseldorf, FRG
Weeks
Fig. 1. Treatment period. Duration of treatment, 1-29 weeks; mean value, 8.5 weeks; median, 6 weeks
406 study entry had been confirmed in all patients, who all had primary or secondary malignant liver tumours. Of the 102 cases, 89 could be evaluated as planned. Six treatment strata were defined according to the histology of the primary tumour and previous cytostatic treatment (Table 1). Treatment schedule. The treatment period was at least 12 weeks. In the case of response or stable disease, therapy was to be continued until progression. The highest tolerated oral dose was determined for each patient during the first 2 weeks (between 2 x 75 and 4 x 75 mg ilmofosine daily) and this dose was then applied continously until the end of the study. Drug application was stopped in cases of severe side-effects or demonstrable progression of the tumour. All cases treated regularly with ilmofosine for at least 6 weeksk were evaluated for its efficacy. Figure 1 shows the treatment duration for the entire series.
Table 4. Side-effects leading to drop-out in the dose-finding phase (15 Patients)
Side-effect
WHO grades
No. patients
Nausea/vomiting Loss of appetite Diarrhoea Pain Constipation Dyspnoea on exercise Fever
3-4 2-4 1-2 2-3 2 2 2
15 12 3 2 1 1 1
o~ 60"-
50 .
Results
40
In 26 (29.2%) of the 89 patients, treatment had to be stopped during the dose-finding period (days 1-14) because of acute gastrointestinal intolerance, early pro-
30
_
.
.
.
~
~
n=14
r1=66 20 10 O
Table 1. Treatment strata
Tumour
No. patients Documented
Colorectal adencarcinoma (no pretreatment) Colorectal adenocarcinoma (pretreated) Non-small-cell lung cancer Pancreatic carcinoma Hepatic carcinoma Malignant melanoma Total
I 8 weeks
I
12 weeks
Fig. 2. Mean size of indicator lesions (liver metastases) Sufficiently treated
21
12
26
16
11 8 13 10
5 1 8 4
89
46
Loss of appetite
44
Nausea/vomiting
39
Conetipatio~ ~ ~ N ~
13
Diarrhoea CNS toxicity
a2
Allergy Skin alterations
1
Stomatitis Arrhythrnias AIIopecia
Table2. Reasons for drop-out in the dose-finding phase (days 1-14)
Reason for drop-out
No. patients
Acute gastrointestinal intolerance Early progression of the disease Insufficient patient compliance
15 7 4
Total
26
Table 3. Progression interval
Neuropathy
Fig. 3. Drug-induced side-effects, WHO grades II-IV (n = 63)
gression or insufficient compliance (Table 2). A total of 46 patients were treated for at least 6 weeks. After a maximum observation time of 29 weeks, the disease had progressed in all patients. Table 3 shows the progression intervals for the individual treatment groups. The cumula-
Treatment stratum
No. patients
Mean time to progression (weeks)
Evaluable
Progressing
Colorectal adenocarcinoma (no pretreatment) Colorectal adenocarcinoma (pretreated) Non-small-cell lung cancer Pancreatic carcinoma Hepatic carcinoma Malignant melanoma
12
12
12.2
16 5 1 8 4
16 5 1 8 4
10.8 8.0 8.0 12.8 9.0
Total
46
46
11.0
407 tive growth of liver metastases (indicator lesion) in the liver is shown in Fig. 2. The main side-effects that led to a premature termination o f therapy were nausea and vomiting (WHO grades 3-4) (Table 4). Drug-induced side-effects occurring during long-term therapy in the remaining 63 patients are listed in Fig. 3; again gastrointestinal side-effects predominated. Regular monitoring of laboratory parameters revealed no evidence of any haemato-, hepato-, nephro- or severe neurotoxicity.
Discussion
The present study of the cytostatic effect of orally administered ilmofosine did not reveal an adequate therapeutic effect on the tumour diseases investigated. The maximum tolerated dose, however, was limited by gastrointestinal side-effects. These results are almost identical with the results of the ET-18-OCH 3 study of Drings and coworkers (Drings et al. 1990; K h a n a v k a r et al. 1989) and the two ilmofosine studies of the AIO in patients with malignant melanoma and hypernephroma respectively (Berdel 1990; Heim et al. 1991). An important reason for the therapeutic failure may be that effective tissue concentrations of the drug could not be achieved at the site of the tumour. Measurement of blood levels o f ilmofosine carried out in some patients revealed in fact, values 10-100 times lower than those concentrations at which ilmofosine showed cytostatic activity in in vitro investigations (Sterz personal communication). Therefore parenteral administration of thioether lipids remains the only realistic possibility of significantly increasing the maximum tolerable dose while simultaneously reducing the local gastrointestinal toxicity. Unless sufficient blood levels of ether lipids or thioether lipids are tested in tumour patients by i.v. application, this group of cytostatic drugs should not be neglected, particularly in view o f remarkable palliative ef-
fects recently reported for topical administration in skin metastases o f mammarian cancer (Unger et al. 1988).
References
Berdel WE (1990) Ether lipids and derivatives as investigational anticancer drugs. Onkologie 13:245-250 Berdel WE, Andreesen R, Munder PG (1985). Synthetic alkylphospholipid analogs: a new class of antitumor agents. In: Kuo JF (ed) Phospholipids and cellular regulation. CRC Press Boca Raton Florida, USA 2:41-73 Bonjouhliem R, Phillips ML, Kuhler KM, Grindey GB, Poore GA, Schultz RW, Altom MG (1986) Studies on the antitumor activity of (2-alkoxyalkyl)- and (2-alkoxyalkanyl)-phosphocholines. J Med Chem 29:2472-2477 Drings P, Gfinther I, Khanavkar B (1990) Is stable disease a success of antineoplastic therapy? Alkyllysophospholipid - Edelfosinestudy results in non small cell lung cancer (NSCLC) patients. Cancer Res Clin Oncol 116 [Suppl I]:127 Fromm M, Berdel WE, Schick HD, Fink U, Pahlke O, Bicker U, Reichert A, Rastetter J (1987) Antineoplastic activity of the thioether lysophospholipid derivative BM 41.440 in vitro. Lipids 22:916-918 Heim ME, Kleeberg UR, Winkelmann Met al. (1991) Phase II trial of the thioether phospholipid analogue Ilmofosine in advanced malignant melanoma. Eur J Cancer 27 [Suppl 2]: 158 Herrmann DBJ, Pahlke W, Munder PG, Bicker U (1988) Antineoplastic and antimetastatic activity of the thioether phospholipid ilmofosine (BM 41.440) in vivo. 79th Annual Meeting of the American Association of Cancer Research, May 25-28, New Orleans, USA Khanavkar B, Ulbrich F, Gatzemeier U, Meyer-Schwickerath E, Lorenz J, Schreml WK, Brugger R, Schick HD, von Pawel J, Nordstrtm R, Drings P (1989) Treatment &non-small cell lung cancer with the alkyllysophospholipid Edelfosine. Contrib Oncol 37:224-235 Munder PG, ModoM1 M, Bausert W, Oettgen HF, Westphal O (1981) Alkyllysophospholipids in cancer therapy. In: Hersh EM, Chirigos MA, Mastrangelo MD (eds) Augmenting agents in cancer therapy. Raven, New York, pp 441-457 Unger C, Eibl H, Breiser A, et al. (1988) Phase I study with daily hexadecylphosophocholine in patients with malignant diseases. Onkologie 11:285-286
Cancer ~esearch Clinical 9 9 Springer-Verlag1992
Rapid communication Treatment results of the thioether lipid ilmofosine in patients with malignant tumours M. Winkelmann 1, K. Ebeling 1, G. Strohmeyer 1, G. Hottenrott 2, Z. Mechl 3, W. Berges 4, T. Scholten 5, M. Westerhausen 6, G. Schlimok 7, and R. Sterz 8 1 z 4 v
Medizinische Klinik und Poliklinik, Heinrich-Heine-Universit/itDiisseldorf, Chirurgische Klinik, Johann-Wolfgang-von-Goethe-Universit/itFrankfurt, a Cancer Research Institute Brfinn, CSFR, Luisenhospital Aachen, 5 Allgemeines Krankenhaus Hagen, 6 St.-Johannes-Hospital Duisburg-Hamborn, ZentralklinikumAugsburg, 8 Boehringer Mannheim, Federal Republic of Germany
Received 6 March 1992 / Accepted 10 March 1992
Summary. In a multicentre study patients with liver metastases stratified to the histology of the primary tumour were investigated. A total of 102 patients with colorectal adenocarcinoma, non-small-cell lung cancer, pancreatic cancer, primary liver carcinoma and malignant melanoma were treated with the thioether lipid ilmofosine. The drug was administered orally as a tablet at a dosage of 150-300 mg/day (75 mg/tablet). The tolerability of ilmofosine was poor. There was a dose-limiting gastrointestinal toxicity with nausea, vomiting and loss of appetite (WHO grade II-IV) in 67% of patients. During the period of therapy (1-29 weeks, 8.5 weeks mean) no complete remission and no partial response were observed. We thus conclude that treatment with oral ilmofosine is not effective in patients with liver metastases due to various malignancies. Key words: (Thio)ether lipids - Metastasized tumours Oral therapy
membrane production (Berdel et al. 1985; Munder et al.
1981). In the first phase I clinical trials reduction in size and even disappearance of liver metastases could be demonstrated (Sterz, personal communication). As a consequence of these findings a multicentre phase II study was performed in patients with malignant tumours and liver metastases. Reasons for studying patients with malignant liver tumours were the high-first-pass effect (Herrmann personal communication) of alkyllysophospholipids in the liver and the ease of measurement and documentation of malignant lesions of the liver.
Patients and methods From August 1989 to December 1990 a total of 102 patients aged between 25 and 79 years (mean age = 59 years) received outpatient treatment with the thioether lipid ilmofosine, which was kindly provided by Boehringer Mannheim. Patients were treated with two to four tablets of ilmofosine (75 rag/tablet) daily p.o. for up to 29 weeks. Progression of these disease in the last 3 months prior to
Introduction Chemotherapy in patients with metastasized tumours is still mostly palliative. Therefore it is important to find new, more effective cytostatic drugs with few side-effects. Because of their clearly demonstrated antineoplastic activity in vitro and in vivo, synthetic alkyllysophospholipids have recived some interest in clinical oncology (Berde11990; Bonjouhliem et al. 1986; Fromm et al. 1987; Herrmann et al. 1988). It has been shown that the main dose-dependent mechanism of action of these lysolecithin derivates is based on a complex interaction with the lipid metabolism of tumour cell membranes; the overall result is an inhibition of tumour cell growth due to impeded
Patients 90 8O 7O 6O 5O 40 3O 20 10 0 1 2 3 4 5 6 7 8 9 lo 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
Offprint requests to: M. Winkelmann, Medizinische Klinik und Poliklinik, Abt. H/imatologie, Onkologie u. klin. Immunologic, Heinrich-Heine-Universitfit, Moorenstrasse 5, D-4000 D/isseldorf, FRG
Weeks
Fig. 1. Treatment period. Duration of treatment, 1-29 weeks; mean value, 8.5 weeks; median, 6 weeks
406 study entry had been confirmed in all patients, who all had primary or secondary malignant liver tumours. Of the 102 cases, 89 could be evaluated as planned. Six treatment strata were defined according to the histology of the primary tumour and previous cytostatic treatment (Table 1). Treatment schedule. The treatment period was at least 12 weeks. In the case of response or stable disease, therapy was to be continued until progression. The highest tolerated oral dose was determined for each patient during the first 2 weeks (between 2 x 75 and 4 x 75 mg ilmofosine daily) and this dose was then applied continously until the end of the study. Drug application was stopped in cases of severe side-effects or demonstrable progression of the tumour. All cases treated regularly with ilmofosine for at least 6 weeksk were evaluated for its efficacy. Figure 1 shows the treatment duration for the entire series.
Table 4. Side-effects leading to drop-out in the dose-finding phase (15 Patients)
Side-effect
WHO grades
No. patients
Nausea/vomiting Loss of appetite Diarrhoea Pain Constipation Dyspnoea on exercise Fever
3-4 2-4 1-2 2-3 2 2 2
15 12 3 2 1 1 1
o~ 60"-
50 .
Results
40
In 26 (29.2%) of the 89 patients, treatment had to be stopped during the dose-finding period (days 1-14) because of acute gastrointestinal intolerance, early pro-
30
_
.
.
.
~
~
n=14
r1=66 20 10 O
Table 1. Treatment strata
Tumour
No. patients Documented
Colorectal adencarcinoma (no pretreatment) Colorectal adenocarcinoma (pretreated) Non-small-cell lung cancer Pancreatic carcinoma Hepatic carcinoma Malignant melanoma Total
I 8 weeks
I
12 weeks
Fig. 2. Mean size of indicator lesions (liver metastases) Sufficiently treated
21
12
26
16
11 8 13 10
5 1 8 4
89
46
Loss of appetite
44
Nausea/vomiting
39
Conetipatio~ ~ ~ N ~
13
Diarrhoea CNS toxicity
a2
Allergy Skin alterations
1
Stomatitis Arrhythrnias AIIopecia
Table2. Reasons for drop-out in the dose-finding phase (days 1-14)
Reason for drop-out
No. patients
Acute gastrointestinal intolerance Early progression of the disease Insufficient patient compliance
15 7 4
Total
26
Table 3. Progression interval
Neuropathy
Fig. 3. Drug-induced side-effects, WHO grades II-IV (n = 63)
gression or insufficient compliance (Table 2). A total of 46 patients were treated for at least 6 weeks. After a maximum observation time of 29 weeks, the disease had progressed in all patients. Table 3 shows the progression intervals for the individual treatment groups. The cumula-
Treatment stratum
No. patients
Mean time to progression (weeks)
Evaluable
Progressing
Colorectal adenocarcinoma (no pretreatment) Colorectal adenocarcinoma (pretreated) Non-small-cell lung cancer Pancreatic carcinoma Hepatic carcinoma Malignant melanoma
12
12
12.2
16 5 1 8 4
16 5 1 8 4
10.8 8.0 8.0 12.8 9.0
Total
46
46
11.0
407 tive growth of liver metastases (indicator lesion) in the liver is shown in Fig. 2. The main side-effects that led to a premature termination o f therapy were nausea and vomiting (WHO grades 3-4) (Table 4). Drug-induced side-effects occurring during long-term therapy in the remaining 63 patients are listed in Fig. 3; again gastrointestinal side-effects predominated. Regular monitoring of laboratory parameters revealed no evidence of any haemato-, hepato-, nephro- or severe neurotoxicity.
Discussion
The present study of the cytostatic effect of orally administered ilmofosine did not reveal an adequate therapeutic effect on the tumour diseases investigated. The maximum tolerated dose, however, was limited by gastrointestinal side-effects. These results are almost identical with the results of the ET-18-OCH 3 study of Drings and coworkers (Drings et al. 1990; K h a n a v k a r et al. 1989) and the two ilmofosine studies of the AIO in patients with malignant melanoma and hypernephroma respectively (Berdel 1990; Heim et al. 1991). An important reason for the therapeutic failure may be that effective tissue concentrations of the drug could not be achieved at the site of the tumour. Measurement of blood levels o f ilmofosine carried out in some patients revealed in fact, values 10-100 times lower than those concentrations at which ilmofosine showed cytostatic activity in in vitro investigations (Sterz personal communication). Therefore parenteral administration of thioether lipids remains the only realistic possibility of significantly increasing the maximum tolerable dose while simultaneously reducing the local gastrointestinal toxicity. Unless sufficient blood levels of ether lipids or thioether lipids are tested in tumour patients by i.v. application, this group of cytostatic drugs should not be neglected, particularly in view o f remarkable palliative ef-
fects recently reported for topical administration in skin metastases o f mammarian cancer (Unger et al. 1988).
References
Berdel WE (1990) Ether lipids and derivatives as investigational anticancer drugs. Onkologie 13:245-250 Berdel WE, Andreesen R, Munder PG (1985). Synthetic alkylphospholipid analogs: a new class of antitumor agents. In: Kuo JF (ed) Phospholipids and cellular regulation. CRC Press Boca Raton Florida, USA 2:41-73 Bonjouhliem R, Phillips ML, Kuhler KM, Grindey GB, Poore GA, Schultz RW, Altom MG (1986) Studies on the antitumor activity of (2-alkoxyalkyl)- and (2-alkoxyalkanyl)-phosphocholines. J Med Chem 29:2472-2477 Drings P, Gfinther I, Khanavkar B (1990) Is stable disease a success of antineoplastic therapy? Alkyllysophospholipid - Edelfosinestudy results in non small cell lung cancer (NSCLC) patients. Cancer Res Clin Oncol 116 [Suppl I]:127 Fromm M, Berdel WE, Schick HD, Fink U, Pahlke O, Bicker U, Reichert A, Rastetter J (1987) Antineoplastic activity of the thioether lysophospholipid derivative BM 41.440 in vitro. Lipids 22:916-918 Heim ME, Kleeberg UR, Winkelmann Met al. (1991) Phase II trial of the thioether phospholipid analogue Ilmofosine in advanced malignant melanoma. Eur J Cancer 27 [Suppl 2]: 158 Herrmann DBJ, Pahlke W, Munder PG, Bicker U (1988) Antineoplastic and antimetastatic activity of the thioether phospholipid ilmofosine (BM 41.440) in vivo. 79th Annual Meeting of the American Association of Cancer Research, May 25-28, New Orleans, USA Khanavkar B, Ulbrich F, Gatzemeier U, Meyer-Schwickerath E, Lorenz J, Schreml WK, Brugger R, Schick HD, von Pawel J, Nordstrtm R, Drings P (1989) Treatment &non-small cell lung cancer with the alkyllysophospholipid Edelfosine. Contrib Oncol 37:224-235 Munder PG, ModoM1 M, Bausert W, Oettgen HF, Westphal O (1981) Alkyllysophospholipids in cancer therapy. In: Hersh EM, Chirigos MA, Mastrangelo MD (eds) Augmenting agents in cancer therapy. Raven, New York, pp 441-457 Unger C, Eibl H, Breiser A, et al. (1988) Phase I study with daily hexadecylphosophocholine in patients with malignant diseases. Onkologie 11:285-286
