Department of Medical Oncology, University Hospital Antwerp, Edegem, Belgium; 1Department of Medical Oncology, University Hospital Groningen, Groningen; 2NDDO Oncology, Free University Hospital, Amsterdam, The Netherlands; 3European Organization for Research and Treatment of Cancer, Early Clinical Studies Group, Brussels, Belgium; 4Menarini Ricerche S.p.A, Italy
Received 19 June 2001; revised 20 August 2001; accepted 5 September 2001.
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Abstract |
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Twenty-four patients received 55 cycles. Doses of MEN-10755 were 15, 30, 40 and 45 mg/m2.
At a dose of MEN-10755 45 mg/m2, treatment could not be given as planned due to neutropenia and one patient developed a decrease in cardiac function. This dose level was considered to be the MTD. Chemotherapy-naive patients could be treated with 40 mg/m2/week, and only one DLT (grade 4 neutropenia) was observed. At that dose, three of six chemotherapy pretreated patients developed a DLT during their first treatment cycle: one patient developed a grade 4 thrombocytopenia, one patient a grade 4 neutropenia and one patient developed a grade 3 acute hypersensitivity reaction resulting in discontinuation of treatment. At this dose level, one other patient did not receive treatment on day 15 as planned due to grade 3 neutropenia. No responses were observed.
MEN-107555 at a dose of 30 mg/m2/week in pretreated patients and 40 mg/m2/week in chemotherapy-naive patients for three consecutive weeks followed by 1 week rest is recommended for phase II testing.
Key words: anthracyclines, dose-limiting toxicity, maximum tolerated dose, MEN-10755, pharmokinetics, phase I
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Introduction |
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The pharmacological activity of doxorubicin-related anthracyclines was thought to be due to structural features of the amino sugar [3]. Later studies indicated that the presence of the amino group in C-3 of the sugar was not required for pharmacologic action and that the lack of the amino group increased the drugs ability to stimulate DNA cleavage mediated by topoisomerase II [4].
MEN-10755 is a new synthetic anthracycline in which the amino group at the second sugar residue is bound in axial orientation to the first residue. In this residue the amino group is substituted by a hydroxyl group [5] (Figure 1).
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Anthracyclines act by inhibiting the nuclear enzyme DNA topoisomerase II, which relaxes DNA supercoils arising during replication and gene transcription [4]. The DNA cleavage induced by MEN-10755 shows the same sequence specificity as doxorubicin and idarubicin. The antitumour activity of MEN-10755 is likely related to its intrinsic cytotoxic potential.
This paper describes a phase I study of MEN-10755, administered as a short intravenous infusion given weekly for 3 weeks followed by 1 week rest. The objectives were to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs); to study the pharmacokinetics of MEN-10755 at the different dose levels; to document any antitumour activity; and to propose a safe dose for phase II evaluation. The pharmacokinetic data obtained in this study will be reported separately together with those obtained during the phase I study in which the drug was given once every 3 weeks.
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Patients and methods |
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Patients
All patients had a pathologically confirmed diagnosis of a solid tumour not amenable to standard treatment and had evaluable or measurable disease. They were older than 18 years, had a good performance status 2 [World Health Organization (WHO)] [8], a life expectancy of at least 3 months, and adequate renal (creatinine <1.4 mg/dl), liver (bilirubin
1.5 mg/dl, other liver function tests equal or less than twice the upper limit of normal, unless liver metastases were present), bone marrow (neutrophils
1500/mm3, platelets
100 000/mm3) and cardiac function (left ventricular ejection fraction measured by multiple gated acquisition (MUGA) scan
50%). Patients had no other significant medical conditions affecting compliance with the protocol. Prior radiotherapy, immunotherapy or chemotherapy was discontinued for at least 4 weeks prior to the start of the study, and 6 weeks in the case of extensive radiotherapy, mitomycin or nitrosourea treatment.
Patients who were pregnant, breast-feeding or fertile without adequate contraceptives were excluded, as were those who had acute infections, severe psychological disorders, or clinical signs of brain or meningeal metastases. Prior use of anthracyclines or anthracenediones was not allowed.
Treatment protocol
Menarini Ricerche (Rome, Italy) supplied MEN-10755 as a lyophilised orange coloured powder in 10 ml glass vials of 10 mg MEN-10755 hydrochloride, which was reconstituted with 550 ml sterile saline/water for injection. The finished product was administered through a sideline of a peripheral or central venous infusion of 0.9% sodium chloride as a 15 min infusion. The 15 min infusion was chosen rather than a bolus injection to improve the safety of the administration and to control for different administration durations with different doses in the two centres. MEN-10755 was given weekly for 3 weeks followed by 1 week rest. Retreatment was planned on day 29 or after full recovery from the previous cycle.
The starting dose of MEN-10755 was 15 mg/m2/week, which was half that of the highest known non-toxic dose at that time in the triweekly phase I study [9]. Doses were escalated according to a Fibonacci-like scheme depending on toxicity. If no toxicity was seen in at least three patients the dose was escalated by 100%.
Prophylactic use of anti-emetics, corticosteroids or haematopoietic growth factors was not allowed. In case nausea or vomiting occurred, rescue with dopamine-antagonists and corticosteroids was allowed and they could be given prophylactically in subsequent cycles. Also, the therapeutic use of haematopoietic growth factors was not allowed.
Dose-limiting toxicities were defined as grade 4 neutropenia, febrile neutropenia (fever >38°C and neutrophils <500/mm3) requiring hospitalisation, grade 4 thrombocytopenia and a bleeding episode requiring platelet infusions for haematological toxicity and any grade 3 and 4 non-haematological toxicity according to National Cancer Institute-Common Toxicity Criteria (NCI-CTC) [10] except for fatigue, asthenia and vomiting without the use of adequate prophylactic anti-emetics. Cardiac toxicity was defined as a decrease in left ventricular ejection fraction (LVEF) <45% or with a drop of >15% below baseline, if baseline values were >60% measured by MUGA scan.
The MTD was defined as the dose with a DLT in two or more out of six patients treated at a given dose level or if the proposed schedule could not be administered according to the protocol due to toxicity.
The recommended dose for phase II testing was the dose one step below the MTD, provided that at least five patients were treated at this dose level without developing DLT.
At least three patients receiving at least one evaluable cycle were allocated to each dose level depending on toxicity. If significant toxicity, defined as DLT, was observed at a given dose level or if treatment in a patient had to be postponed for more than 2 weeks, three more patients had to be treated at that dose level. When two of six patients at a dose level required 2 weeks delay for retreatment or could not receive the full 3-week regimen every 4 weeks for other reasons, then the continuation of the protocol was discussed.
Patients were scheduled to receive at least two cycles. Treatment could be continued at the same dose, in the case of stable disease or response, provided no serious toxicity was observed. No dose escalation was allowed in the same patient. In the case of progressive disease, patients were removed from the study.
If on day 8 or day 15 the neutrophil count was <1000/mm3 these doses were omitted; no specific recommendations were applied for platelet counts in that respect. Doses on day 8 and/or day 15 were not to be postponed. If the dose on day 8 had to be omitted, the patient could be retreated on day 15 provided that the neutrophil count was >1000/mm3. The last treatment day in each cycle was day 15.
Patients could be retreated on day 28 if the following criteria were met:
Patients whose treatment had to be delayed for >2 weeks were off study.
Treatment was discontinued in cases of refusal or non-compliance of the patient to the study protocol, life threatening toxicity, cardiac toxicity or worsening of the renal or pulmonary function.
Toxicity evaluation
Patients were evaluable for toxicity after at least one drug administration. Toxicity was evaluated by the NCI-CTC [10]. Each patient was assessed clinically prior to the start of treatment and weekly thereafter. Haematological and biochemical profiles, and urinalysis were performed weekly. Creatinine clearance, electrocardiogram and chest X-ray were carried out prior to each cycle, and a computer tomography (CT) scan of the tumour was carried out every two cycles, where applicable. An assessment of left ventricular function by MUGA scan was performed at baseline and after every two cycles. All tests were repeated at the end of the study.
Tumour response
Patients were evaluable for response if disease measurements were recorded over at least an 8-week period from the first day of treatment. Tumour measurements were performed before the start of treatment, every two cycles and at the end of the study. Response evaluation was done according to WHO criteria [9]. A complete response indicated the complete resolution of all known lesions, and no appearance of new lesions, determined in two assessments no less than 4 weeks apart. A partial response showed a reduction of the sum of the products of the two longest perpendicular diameters, equal to or more than 50%, no progression in any non-measured evaluable or non-evaluable lesion, and no appearance of new lesions, determined in two assessments no less than 4 weeks apart. Patients with stable disease showed no progression of their lesions. Progressive disease was defined either by the appearance of new lesions or an increase of >25% of the sum of the products of the two longest perpendicular diameters of existing lesions. When progression was observed after one cycle, it was considered early progression.
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Results |
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At dose level II (30 mg/m2, n = 6), one patient could not be treated on day 15 due to haematological toxicity; one patient showed progressive disease after two drug administrations in cycle 1 and one patient refused treatment after one administration in cycle 1. Three patients could be given the planned treatment dose and schedule without problems. Overall, one of the five evaluable patients showed a drug-related DLT (grade 4 neutropenia) in cycle 1.
At dose level III (45 mg/m2, n = 2 of whom one chemotherapy-naive), day 15 could not be administered in five out of six cycles (two of two in cycle 1) due to haematological toxicity (grade 3 neutropenia) and this level was for that reason considered the MTD.
In pretreated patients (n = 6), the administration of MEN-10755 40 mg/m2 did lead to discontinuation after one administration in one patient due to progressive disease. In two cycles, day 15 could not be given due to haematological toxicity (1x grade 3 and 1x grade 4 neutropenia) and six cycles were given as planned. Two patients clearly showed drug-related DLTs in cycle 1 (grade 4 neutropenia, grade 3 hypersensitivity reaction).
Of the seven patients without previous chemotherapeutic treatment who received MEN-10755 40 mg/m2, one patient showed progressive disease after two drug administrations in cycle 1 but could have received MEN-10755 on day 15. Two cycles could not be given due to haematological toxicity (grade 3 and 4 neutropenia), while nine cycles were given as planned. One patient refused treatment after the first administration of cycle 4. Only one patient showed a drug-related DLT (grade 4 neutropenia).
Toxicity results
There were no deaths due to toxicity in the study.
Haematological toxicity.
Haematological toxicity is reported in Table 2. One patient treated with MEN-10755 30 mg/m2 developed a grade 4 anaemia, considered to be possibly related to the study medication during cycle 1. He was treated for one more cycle without developing anaemia.
Dose-limiting neutropenia (grade 4) was observed in level II (30 mg/m2) and IV (40 mg/m2) in one and two patients, respectively, and dose-limiting thrombocytopenia in one pretreated patient at level IV. The latter toxicity may have been disease related.
Non-haematological toxicity.
Non-haematological toxicity is reported in Table 3. Thirteen of 24 patients developed grade 1 or grade 2 alopecia. One patient treated with MEN-10755 40 mg/m2 developed an acute dyspnea (grade 3) and flushing after the start of the second infusion of the first cycle. The infusion was stopped and the patient was treated with methylprednisolone 40 mg intravenously. After 30 min the infusion was restarted and the dyspnea reoccurred. Treatment was discontinued and the patient went off protocol. Three other patients experienced a mild allergic reaction. One patient, treated at a dose of 45 mg/m2, developed a grade 2 flushing and grade 1 sweating during the infusion, which resolved spontaneously. In this patient, five of seven administrations were accompanied with these symptoms. Flushing also occurred in three other patients, twice during the first cycle, i.e. on day 1 and 8, in one patient, once during the first administration in the second cycle of the second patient and during the first administration in cycles 6 and 8 in the third patient.
Fever occurred in two patients treated with 30 mg/m2 (two of 20 cycles) and was observed in two pretreated (two of nine cycles) and in three chemotherapy-naive patients treated at 40 mg/m2. It occurred in one patient (1 cycle) at the 45 mg/m2 dose level.
Gastrointestinal toxicity.
Seventeen patients developed nausea, which was grade 3 in only two patients. Treatment with anti-emetics could control the nausea in most of the patients. Ten patients were complaining of vomiting but no grade 3 or 4 vomiting was observed. Eleven patients reported anorexia which was severe (grade 3) in four patients.
Diarrhoea grade 2 was seen in one patient treated at dose level II (30 mg/m2).
One patient developed a grade 4 bilirubinaemia, which was considered not related to the study drug and another patient showed a grade 3 increase of -glutamyl transferase. No grade 3 or 4 increases of alkaline phosphatase, alanine or aspartate amino transferases were observed.
Cardiovascular toxicity.
In 13 patients treated with two or more cycles, the cardiac function was evaluated both at the start and end of treatment (Table 4). Two patients showed a decrease in LVEF to 45%. The first patient received 11 cycles (i.e. 33 administrations) of 30 mg/m2 (total dose 1667 mg). The second patient received only three cycles of 45 mg/m2 (total dose 540 mg). None of these patients showed any clinical signs of congestive heart failure. None of the other patients showed a significant impairment in their cardiac function. One patient developed a right bundle branch block during the first course of treatment which was considered possibly related to the study medication. No other ECG changes were observed.
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Discussion |
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In this phase I study, grade 3 neutropenia prevented the administration of MEN-10755 in the proposed schedule in both patients treated at 45 mg/m2. Moreover, in one patient treated at this dose level, there was a decrease of the LVEF from 54% at baseline to 45% after the administration of MEN-10755 540 mg. Both observations made us decide to consider the 45 mg/m2 to be the MTD of MEN-755 for this schedule. As MEN-10755 45 mg/m2 was delivered to only two patients, of whom one was chemotherapy-naive, a further refinement of tolerance for pretreated and untreated patients was needed.
Six patients previously treated with chemotherapy were given MEN-10755 40 mg/m2. Three of them developed a DLT during their first treatment cycle: one patient developed a grade 4 thrombocytopenia, which may have been disease-related, one a grade 4 neutropenia and one patient developed a grade 3 acute hypersensitivity reaction resulting in the discontinuation of treatment. At this dose level, one other patient could not receive MEN-10755 on day 15 as planned due to grade 3 neutropenia. This dose level was considered to be the MTD for pretreated patients and for phase II testing, a dose of 30 mg/m2/week for 3 consecutive weeks followed by 1 week rest is recommended in this patient population.
In chemotherapy-naive patients, one of seven patients developed a dose-limiting grade 4 neutropenia during the first cycle at MEN-10755 40 mg/m2. A second patient developed grade 3 neutropenia on day 15, which precluded the administration of the drug as planned. However, all other patients received the treatment without problems during the first cycle. Therefore, the recommended dose for chemotherapy-naive patients is 40 mg/m2/week ¥ 3 every 4 weeks.
Another group tested the same drug in a 3-weekly schedule. The MTD in this study was 100 mg/m2. This schedule seemed to cause more nausea and vomiting (controllable with anti-emetics) and four patients experienced a significant reduction in LVEF [9].
The pharmacokinetics in both studies indicated linear kinetics and that the plasma half-life, plasma clearance and volume of distribution at steady state were not dose-dependent. The pharmacokinetic parameters were not influenced by the administration schedule [11].
In this phase I study, we were able to detect the DLT and MTD in chemotherapy pretreated and chemotherapy-naive patients. As mentioned earlier, one patient showed a decrease in LVEF after already three cycles at MEN-10755 45 mg/m2 and there was a second patient who showed a similar decrease after a prolonged exposure to MEN-10755 (11 cycles at 30 mg/m2). In the other three patients, treated with more than MEN-10755 500 mg this was not observed. However, this phase I study treated only one patient for more than four cycles, so definite conclusions on the cardiotoxicity of MEN-10755 can not be drawn.
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Acknowledgements |
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Footnotes |
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References |
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2. Suarato A, Angelucci F, Geroni C. Ring-B modified anthracyclines. Curr Pharm Des 1999; 5: 217227.[ISI][Medline]
3. Di Marco A, Casazza A, Gambetta R et al. Relationship between activity and amino sugar stereochemistry of daunorubicin and adriamycin derivatives. Cancer Res 1976; 36: 19621966.[Abstract]
4. Capranico G, Supino R, Binaschi M et al. Influence of structural modifications at the 3' and 4' positions of doxorubicin on the drug ability to trap topoisomerase II and to overcome multidrug resistance. Mol Pharmacol 1994; 45: 908915.[Abstract]
5.
Animati F, Berettoni M, Cipollone A et al. New anthracycline disaccharides synthesis of L-daunosaminyl-(1
4)-2-deoxy-L-rhamnosyl and of L-daunosaminyl-
(1
4)-2-deoxy-L-fucosyl daunorubicin analogues. J Chem Soc Perkin Trans 1996; 1: 13271329.
6.
Arcamone F, Animati F, Berettoni M et al. Doxorubicin disaccharide analogue: apoptosis-related improvement of efficacy in vivo. J Natl Cancer Inst 1997; 89: 12171223.
7. Pratesi G, De Cesare M, Caserini C et al. Improved efficacy and enlarged spectrum of activity of a novel anthracycline disaccharide analogue of doxorubicin against human tumor xenografts. Clin Cancer Res 1998; 4: 28332839.[Abstract]
8. World Health Organisation. WHO Handbook for Reporting Results of Cancer Treatment. Geneva: WHO Offset Publication 1979.
9. Roelvink M, Dombernowsky P, Aamdal S et al. Phase I study to determine the safety of MEN-10755 in patients with a solid tumor on a short iv infusion given every 3 weeks. Eur J Cancer 1999; 35 (Suppl 4): 289 (Abstr 1161).[ISI][Medline]
10. Investigators Handbook: a Manual for Participants in Clinical Trials of Investigational Agents. National Cancer Institute 1986.
11. Bos AME, Seegers M, Roelvink M et al. Phase I pharmacokinetic study of MEN-10755 in solid tumors. Eur J Cancer 1999; 35 (Suppl 4): 291 (Abstr 1170).