The present invention provides a method of preparation of a medicament for use in the tumour therapy in mammals, including humans, characterised in that said medicament comprises a compound of formula 1 wherein: x represents the mole. of N- (2-hydroxypropyl) methacryloylamide and is from 85 to 97; y represents the mole % of 20-0- (N-methacryloyl-glycyl-aminoacyl-glycyl-) camptothecin and is from 3 to 15; z represents the mole of of N- (2-hydroxypropyl) methacryloyl glycinamide and is from 0 to 12 and a pharmaceutically acceptable carrier or excipient, characterised in that the medicament is conveniently administered employing a particular dosage

and schedule which allow a more efficacious treatment of tumours.

The polymer-bound conjugates of formula 1 were described and claimed in our international patent application W099/17804, published on April 15,1999. The polymer- bound conjugates of formula 1 are random polymer, i. e. above formula does not indicate the exact monomer sequence, and have a molecular weight preferably in the range of from 10,000 to 45,000, more preferably from 18,000 to 35,000.

We have now found that the conjugates of formula 1 are much more efficacious when intravenously infused daily for three consecutive days every 4 weeks in an amount of from 15 to 200 mg/m~/day, weekly for two or three consecutive weeks every 4 weeks in an amount of from 20 to 250 mg/m2/week, or as single administration every 4 weeks in an amount of from 20 to 250 mg/m2 of body surface area.

Preferably, the polymeric conjugates of the formula 1 contain the N- (2-hydroxypropyl) methacryloyl amide units in a proportion of 90 % or more; more preferably x is 90%. The conjugate also contains from 3 to 10 mol% of the units with the camptothecin residue, (y), more preferably 10 mol % of such units. Preferably in the conjugate of formula (1) z is about 0. Content of active camptothecin in the conjugate of formula (1) may be from 2 to 15% (weight/weight), more preferably lOo (w/w).

More particularly, the present invention is directed to the compound of formula 1 coded MAG-CPT having Mw of about 20,000; Mw/Mn of about 1.5 and content of camptothecin, determined after alkaline hydrolysis, of about 10% w/w.

A further aspect of the present invention is to provide a method of treating a mammal, including humans, suffering from tumour, comprising administering the

polymeric conjugate of the formula 1 to said mammal by intravenous infusion daily for three consecutive days every 4 weeks in an amount of from 15 to 200 mg/m~/day, weekly for two or three consecutive weeks every 4 weeks in an amount of from 20 to 250 mg/m-/week, or as single administration every 4 weeks in an amount of from 20 to 250 mg/m. The condition of the human patient can thus be improved. Preferably, the patients to be treated according the present invention have advanced solid tumours.

The exact dosage range adopted will depend upon the age, weight and condition of the patient being treated. The polymeric conjugate of formula 1 is administered as a bolus administration or as continuous infusion over from 10 minutes to 12 hours, preferably from 10 minutes to 4 hours, still more preferably over a period of about 30', using programmable continuous infusion ambulatory pump or iv infusion bags.

The present anti-tumour agent exerts a strong anti- tumour activity on human malignant tumours, for example, on solid tumours such as gastrointestinal tumours, like colorectal cancer, gastro-esophageal cancer, cancer of liver and biliary tract, pancreatic cancer; prostatic cancer, testicular cancer, lung cancer, breast cancer, malignant melanoma, mesothelioma, brain tumours (such as glioma and astrocytomas), ovarian cancer, uterine cancer including cervical cancer, cancer of the head and neck, bladder cancer, Kaposi sarcoma, including AIDS-related Kaposi sarcoma, sarcomas and osteosarcoma, renal carcinoma; and hematopoietic malignant tumours such as leukemia and lymphoma, including AIDS-related lymphomas.

The pharmaceutical compositions of the present invention containing the polymeric conjugate 1 may be formulated together with a pharmaceutically carrier or diluent.

Typically they are formulated for parenteral

administration, for example by dissolution in water for injection or physiological saline. The compound of formula 1 is more preferably supplied as units of freeze-dried powder for injection containing 0.5 or l. Og of active ingredient, more preferably containing 0.5 or 1.0 g of MAG-CPT corresponding to 50 mg or 100 mg of camptothecin content, respectively.

The following examples illustrate the invention.

Example 1.

Vial reconstitution and drug administration Freeze-dried glass vials containing -0.5 g of compound of MAG-CPT, -lactose, -polysorbate -and 1N sodium hydroxide were reconstituted with 10 ml of 0.9% sodium chloride solution for injection and subsequently diluted with same solvent according to administration dosage. The dose to be administered to the patient was put in an infusion bag containing 100 ml saline and an equal volume was then removed from the bag so that the final volume after adding the drug was always 100 ml. The resultant solution was administered intravenously using a volumetric pump in 30'. Before and after the infusion, the vein was washed with saline, 10 ml over 5'.

Example 2 A phase I pharmacological trial to investigate the iv administration of compound of formula 1 given in a 30' minutes infusion once every 4 weeks in patients with refractory or resistant solid tumours, including lung, colorectal, gastro-oesophageal, cervix, Ewing, renal, head and neck, mesothelioma and cancer of unknown primary.

Starting dose, 30 mg/m~ (as CPT-equivalent), was escalated with an initial accelerated phase with 100c dose increments (3 patients/dose level) followed by conventional dose escalation in 3-6 patient cohorts.

Overall, twenty pre-treated patients were entered (median age 62 years; ECOG PS 0-1) and 31 cycles were evaluated for non-haematological and haematology toxicity. Dose levels studied were 30,60,120,170,200 and 240 mg/m2 (as CPT-equivalent). Non-haematological toxicities mainly consisted of mild and rare nausea/vomiting and diarrhoea. NCI-CTC Gr. 1-2 anaemia scatterenly occurred during treatment. At the highest dose of 240 mg/m2 (as CPT-equivalent), dose limiting toxicities were observed with NCI-CTC Grade 4 neutropenia (2 patients), NCI-CTC Grade 4 thrombocytopenia (1 patient) and NCI-CTC Grade 3 diarrhoea (2 patients). One of these patients (M, 69y, metastatic rectal ca) admitted at day +12 of course 1 with NCI-CTC grade 2 diarrhoea, grade 4 febrile neutropenia and thrombocytopenia, died of multi-organ failure caused by sepsis.

A patient (M, 55y, squamous cell laryngeal carcinoma) reported a symptomatic improvement of his neck tumour with 30% tumour mass shrinkage to be considered as disease stabilisation. The patient was treated for two courses at the dose level of 170 mg/m2 (as CPT- equivalent) before having new metastases in the lung diagnosed by CT scan. One year before entering the study the patient had tracheotomy followed by two cycles of chemotherapy with cisplatin and'5-FU. Best response to the treatment was partial response. Soon after the patient received radiotherapy to the larynx (best response was no change) Few months later, a second chemotherapy with carboplatin (AUC=5) and 5-FU was

administered for two cycles with no change of the tumour mass.

Considering the unresponsiveness of recurrent head & neck cancer, the symptomatic, though short-lasting, benefit experienced by this heavily pre-treated patient from the treatment with compound of formula 1 could not be considered any worse than the one reported with previous chemotherapies.

Example 3 A phase I pharmacological study to investigate the iv administration of compound of formula 1 given daily in a 30'intravenous infusion for three consecutive days every 4 weeks in patients with refractory or resistant solid tumours, including colorectal, gastro-oesophageal, cervix, ovarian and head and neck cancer.

Starting dose, 17 mg/m2/day (as CPT-equivalent), was escalated with an initial accelerated phase (1 patient/ dose level) followed by conventional dose escalation in 3-6 patient cohorts. Overall, twelve patients were entered [median age 55 years; ECOG PS 0-1 (data from 9 patients)] and 28 cycles were evaluated for non- haematological and haematological toxicity. Dose levels studied were 17,34,57,68,85 and 100 mg/m~/day x 3 q 4wks (total doses of 51,102,171,204,255 and 300 mg/m2/cycle, respectively as CPT-equivalent). Non- haematological toxicities mainly consisted of mild nausea and vomiting occurring across all tested dose levels and mild bladder complaints at the dose levels of 68,85 and 100 mg/m/day (as CPT-equivalent).

Haematology toxicity consisted of NCI-CTC Grade 1-2 anaemia scatterenly occurring during treatment. NCI-CTC Grade 3 anaemia was observed in one patient during the third cycle of treatment at 68 mg/m/day (as CPT-

equivalent). At the dose level of 85 mg/m-/day (as CPT- equivalent) an NCI-CTC grade 3 leucopenia and grade 4 neutropenia were reported in one patient during the second cycle of treatment. At the dose level of 100 mg/m-/day (as CPT-equivalent) an NCI-CTC Grade 2 leukopenia occurred in one patient during the first treatment course. The study continues to recruit patients, as the MTD has not been reached.

One patient with advanced colon cancer, treated at 57 mg/m2/day (171 mg/m2/course as CPT-equivalent), reported a disease stabilisation for five months. The patient (F, 54y, advanced colon adenocarcinoma) had low anterior resection of the tumour one year before entering the above study. She received adjuvant radiotherapy and chemotherapy with 5-FU/Leucovorin lasting for six cycles. One month later she was treated with an investigational agent for one treatment cycle (response to this treatment not available). Soon after she entered the above study with multiple liver metastases and received five courses of the compound of formula 1 before progressing in a supraclavicular lymphonode.

One patient (F, 59 Y, advanced ovarian carcinoma) received five cycles of compound of formula 1 at 68 mg/m'/day (204 mg/m-/course as CPT-equivalent) with stabilisation of the disease (patient on trial at the time of present report). The patient had a long history of recurrent ovarian cancer sensitive to platinum and taxanes based regimens. Six years before entering the present study, she presented with stage III ovarian carcinoma. Laparatomy was followed by six cycles of carboplatin and taxol. Second look laparatomy confirmed a complete response. One year after the patient received five cycles of carboplatin and endoxan (best response was complete response). Laparatomy was performed few months later followed by two cycles of carboplatin,

endoxan and then cisplatin (not evaluable for response) and subsequently by tamoxifen (six cycles and no change as best response). The last therapy before entering the study was taxol (six cycles and partial response as best response). At entry into the study with compound of formula 1, the patient presented with ascites and a large tumoral involvement of the liver and cecum.

Example 4 A phase I pharmacological study to investigate the iv administration of compound of formula 1 given once weekly in a 30'intravenous infusion for three consecutive weeks every 4 weeks in patients with a variety of refractory or resistant solid tumours, including colorectal, gastro-oesophageal, melanoma, cervix, ovarian, lung, head and neck and renal cancer.

Starting dose, 80 mg/m-/week (as CPT-equivalent), is escalated with an initial accelerated phase (3 patient/ dose level) followed by conventional dose escalation in 3-6 patient cohorts.