II study of intraperitoneal mitoxantrone in refractory ovarian cancer

Annals of Oncology 5: 343-347, 1994. O 1994 Kluwtr Academic Publishers. Printed in the Netherlands.

Original article Phase I/Q study of intraperitoneal mitoxantrone in refractory ovarian cancer A. M. Oza,2 W. ten Bokkel Huinink,1 R. Dubbelman,1 O. Soepenberg,1 I. Mandjes,1 E. Aartsen1 & J. G. Me Vie3 l

Antoni van Leeuwenhoel Ziekenhuis, Netherlands Cancer Institute, Amsterdam, The Netherlands; ^Department of Medicine, Princess Margaret Hospital, Toronto, Canada; *CRC Cancer Research Campaign, London, U.K.

previously received systemic platinum based therapy. Five of the 14 had also previously been treated with intraperitoneal Background: Mitoxantrone has demonstrable clinical activity carboplatin. Fifty-one cycles were administered. when administered intravenously in a wide range of maligResults: The dose limiting toxicity in the phase I study was nancies. The feasibility and toxicity of intra-peritoneal ad- peritoneal irritation and pain. Leucopenia was frequent at ministration was established in a phase I study. The optimal doses equal or greater than 30 mg/m2. Three complete dose from the phase I was subsequently evaluated in a phase remissions were documented in the phase I study (2 breast II study. cancer and 1 ovarian cancer). There was no significant Patients and methods: 19 patients with refractory malig- haematologica] toxicity in the phase II assessment, though nancies and extensive abdominal disease (13 ovarian cancer, local toxicity precluded further therapy in 2 patients. No 4 breast cancer, 2 mesothelioma) were entered in a phase I objective responses were seen in the phase II evaluation. study. The dose of intraperitoneal mitoxantrone was escalatConclusions: These studies demonstrate the feasibility of ed from 10 mg/m2, administered in 21 of fluid via a Tenkhoff intra-peritoneal mitoxantrone therapy in patients with pericatheter, to 55 mg/m2, in increments of 5 mg/m2. Cycles toneal disease, but do not support its routine use in ovarian were repeated every three weeks. Sixty-seven cycles of mito- cancer. xantrone were administered, the maximum tolerable dose being 25 mg/m2. A phase II study at this dose was conducted Key words: ovarian cancer, mitoxantrone, intraperitoneal in 14 patients with refractory ovarian cancer, all of whom had therapy, phase I, phase II Summary

Introduction

Mitoxantrone has demonstrable clinical activity against a wide range of human malignancies in vivo and in vitro [1,2]. In vitro cloning assays demonstrate significant activity of mitoxantrone against ovarian cancer. Alberts et al. [3] found the mean concentration x time product achievable in the intra-peritoneal space after intra-peritoneal administration to the ID50 ratio to be most favourable with mitoxantrone, of all drugs tested, suggesting this route of administration may be therapeutically possible. Of equal importance is the lack of vesicant activity of mitoxantrone [4J. Persistent intra-peritoneal disease represents a major problem in ovarian cancer, despite high response rates following systemic platinum based therapy. In many patients, disease remains confined to the abdominal cavity and causes significant morbidity due to ascites, adhesions and bowel obstruction prior to eventual death. The possibility of intra-peritoneal therapy with a non platinum compound therefore offers the possibility of an alternative therapeutic approach in these patients and may aid palliation or in the long term control of minimal disease, to prolong disease free survival. With

this approach, it may also be possible to expose tumor cells to a higher concentration of mitoxantrone, at doses which would have significant systemic toxicity if administered intravenously. Several phase I and phase II studies of intraperitoneal mitoxantrone [5-7] have been reported, local toxicity often being dose limiting. To try and ameliorate local toxicity, peritoneal dialysate has been removed after a finite dwell time. The pharmacokinetics of intraperitoneally administered mitoxantrone would support this and have been reported by us previously [8]. This report constitutes the clinical phase I and II study of intraperitoneal mitoxantrone, with a dwell time of 4 hours. Methods Phase I Patients with advanced malignancy confined to the peritoneal cavity were eligible for the phase I study. Additional eligibility criteria included a Karnofsky performance status greater than or equal to 60%, a white cell count of at least 3.0 x lO'/l, a platelet count of at least 100 x lO'/l, serum creaunine levels of <2.0 mg/dl, serum bilirubin values of <1.5 mg/dl and a minimal life expectancy of 6 months.

344 Nineteen patients were entered, of whom 13 had epitheliaJ ovarian cancer, 4 had breast cancer and 2 had intraperitoneal mesothelioma. All patients with ovarian cancer had previously been extensively treated with platinum based systemic chemotherapy. Patients with reast caner hd received prior systemic chemotherapy and hormonal therapy. The patients with intraperitoneal mesothelioma had not received prior therapy. No patient had received prior treatment with systemic or intraperiotneal mitoxantrone. All patients had a Tenckhoff catheter surgically placed. Mitoxantrone was administered in 21 of dialysis fluid, with a 4 hour dwell time. The dose was escalated from 10 mg/m2 to 55 mg/m2 (Table 1). Doses were not escalated in the same patient. It was planned to administer at least 3 cycles of intraperitoneal mitoxantrone at each level and then progress on to the next step, provided there was no evidence of dose limity toxicity. Additional patients were entered at dose levels less than the maximum tolerated dose to try and define a potential therapeutic level for phase II assessment. Cycles were planned at 3 weekly intervals and administered on time, unless there was excessive toxicity or severe cytopenia (platelet count <100 x 1071; WBC <3.0 x 1071) at the time of therapy. Antiemetics, analgesics and intravenous fluids were given as necessary. Treatment was discontinued in the event of progressive disease or excessive toxicity. Six cycles of intraperitoneal therapy were planned, with restaging investigations, including laparoscopy, after the sixth cycle. Laparoscopy was not mandated in patients who had clearly defined progressive disease (radiologically). Clinical assessment was performed prior to each cycle. Haematological and biochemical evaluations were performed weekly.

Table 2. Patient populations for phase II assessment. 14

Patients with ovarian cancer Previous therapy Cisplatin CHAC/CHAP Other Previous intraperitoneal carboplatin Mean age Median age Number of prior chemotherapy regimes 1 2 3+ Volume of disease Minimal residual disease Carcinomatosis Post secondary debulking

8 4 2 5 55 years 55 years 7 3 4 8 3 1

mitoxantrone were administered, the doses ranging from 10 to 55 mg/m2. The number of cycles at each dose and the delays incurred are shown in Table 1. Toxicity Non-haematological

Phase II The maximally tolerated dose of intraperitoneal mitoxantrone, 25 mg/m2 with a 4 hour dwell time was chosen for further evaluation in a phase II trial in 14 patients with recurrent and refractory ovarian cancer, with lesions less than 1 cm in size. All patients had previously been treated with platinum based therapy. Details of the patient population are given in Table 2. Six cycles were scheduled at 3 weekly intervals, mitoxantrone being administered intraperitoneally through the Tenchkoff catheter in 21 of dialysis fluid. Treatment was discontinued in the event of disease progression or excessive toxicity. Investigations before, during and after therapy were as in the phase I trial.

Results Phase 1 Nineteen patients were entered in the phase I study and are evaluable. Sixty-seven cycles of intraperitoneal Table ]. Number of cycles of intraperitoneal mitoxantrone at each dose level. Dose mg/m

10 15 20 25 30 35 40 45 50 55

2

Number of cycles 1 7 6 25 11 3 1 4 7 1

Delays

The non-haematological toxicities observed following intra-peritoneal administration of mitoxantrone were abdominal pain, chemical peritonitis, nausea and vomiting. Pain started in the abdominal wall progressively became more diffuse. It was excerbated by movement and when mild, relieved by simple analgesics. Peritonitis was the major dose limiting non haematological toxicity, manifest with severe pain and guarding and required intravenous fluids and analgesics. There was no clinical or laboratory data to suggest bacterial infection. Patients were not treated with systemic antibiotics. The onset of symptoms in relation to mitoxantrone administration suggested a chemical peritonitis. Peritonitis was increasingly frequent above a dose of 25 mg/m2 (Table 3, Fig. 1). At doses of 30 mg/m2 or above, 23 of 28 cycles were associated with chemical peritonitis, WHO grade 2 or above, compared with 12/39 cycles at Table 3. Clinical toxicity in phase I assessment. Dose mg/m2

No. of cycles

10 15 20 25 30 35 40 45 50 55

1 7 6 25 11 3 2 4 7 1

WHO 2 0 1 1 1 2 1 1 0 1 0

Peritonitis

Pain

0 0 0 1 5 2 1 1 1 0

Nausea/ vomiting

3

4

2

3

3

2

3

4

0 0 0 1 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 1

0 1 1 1 4 0 2 0 0 0

0 2 1 6 4 3 0 3 4 0

0 0 0 0 0 0 0 0 2 1

0 0 0 3 3 1 1 1 1 0

0 0 0 0 0 0 0 0 1 0

0 0 0 0 0 0 0 0 0 0

345 120

Abdominal pain, %

Peritonitis, %

100

-

80

120

60

40

40

20

20

10

15

20

25

30 35 40 DOSE mg/m2

45

50

55

Frequency of nadir WBC <3.0 x 1071

15 20 25 30 35 40 45 50 55

7 6 25 11 3 2 4 7 1

1 0 2 2 2 1 0 4 1

Frequency of nadir WBC <2.0 x 1071

Frequency of nadir platelets <100x 1071

0

2 0 0 0 0

Q

0 1 1

0

0 1 1

0 1 0

Dose reduction/delay

PERITONITIS

Fig. 1. Clinical toxicity of intraperitoneal mitoxantrone in phase I asessment: x axis: Dose of mitoxantrone mg/m2; y axis: Percentage of cycles associated with pain or peritonitis.

lower doses. Seven cycles of intraperitoneal mitoxantrone were administered at a dose of 50 mg/m2 and one at 55 mg/m2; of these, chemical peritonitis was documented in all 7, being grade 3/4 in all. In the single patient treated at the dose of 55 mg/m2, severe pain and peritonitis were apparent soon after the infusion and in view of this, the final dose was not escalated. Nausea and vomiting were infrequent and relieved with simple anti-emetics. There was no diarrhoea, haemorrhage or allergic reactions. No patient required steroids or antibiotics following intra-peritoneal administration. Haematological toxicity Leucopenia was increasingly common at doses above 30 mg/m2 (Tables 4 and 5). Platelet toxicity was not Table 4. Haematological toxicity. Dose mg/m2

No. of Median cycles nadir WBC count x 1071

Range nadir WBC

Median nadir platelet count x 1071

Range nadir platelets

10 IS 20 25 30 35 40-45 50-55

1 7 6 25 11 3 6 8

3.8 2.8-9.9 3.8-5.5 2.6-5.7 2.1-6.9 1.9-5.3 2.5-4.5 0.9-4.0

200 130 255 299 186 203 111 178

200 85-241 145-397 145-466 152-341 179-288 212-265 98-259

3.8 4.4 4.3 4.9 3.9 2.9 3.7 2.4

Number of cycles

severe and only in 2 cycles did the level fall below 100 x 109/l. In both these cycles, the patient had received a dose of 15 mg/m2. The summary data on nadir white cell counts shows increasing frequency of leucopenia when the dose was 30 mg/m2 or higher.

CLINICAL TOXICITY WM PAIN

Dose mg/m2 100

80

60

Table 5. Frequency of haematological toxicity.

Day of nadir

13 13 14 14 14 13 14

Dose delays were infrequent and there were no dose reductions. Seven patients had further therapy discontinued before completion of 6 cycles because of excessive toxicity. Six of these were at the dose of 30 mg/m2 or higher and 1 patient was at a dose of 25 mg/m2 (Table 6). Pharmacokinetics Clinical pharmacokinetics of intraperitoneal mitoxantrone were studied in detail in five patients and have been described elsewhere [8]. After the overall time of Table 6. Reasons for stopping treatment in phase I study. Patient

Dose mg/m2

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

15 15 20 25 25 25 25 25 25 25 30 30 30 30 35 45 45 50 50

17 18 19

Number of cycles

Reason for stopping

Response

Other P.D. End protocol Other P.D. Other Toxicity P.D. End protocol End protocol Toxicity Toxicity P.D. P.D. Toxicity End protocol Toxicity Toxicity Toxicity

N.E, P.D. C.R. Fail P.D. N.E. C.R. P.D. Fail Fail N.E. NJE, P.D. P.D. N.E. Fail Fail C.R. N.E.

N.E. — not evaluable; C.R. — complete remission; P.D. — progressive disease.

346 4 hours, 7.1%-29.2% of the delivered drug was removed, in a sample 5 patients who had pharmacokinetic evaluation. The maximal drug concentrations in peritoneal dialysate were achieved directly after the end of the infusion, the concentration declining to 10% of the maximal value at 24 hours. The median values for distribution and elimination were 56.4 minutes and 128 h respectively, the maximal plasma concentrations being achieved within one hour of the end of the infusion [8]. After 4 hours, there was no sudden change in the slope of the concentration-time curve, suggesting the distribution of mitoxantrone in the peritoneal cavity was almost completed within this period.

Table 7. Haematological toxicity in phase II study.

Leucocyte Platelet

Initial count x 1071

Nadir count x 10Y1

Day nadir

4.7 (2.5-14.3) 238 (109-945)

3.0 (1.5-6.3) 187 (109-604)

13 12

Discussion

The phase I/n studies have demonstrated the safety and feasibility of intraperitoneal administration of mitoxantrone, the maximal clinically tolerable dose being 25 mg/m2, with a 4 hour dwell time. In the phase I study, the maximum treatment dose was 55 mg/m2, Response in phase I peritonitis being dose limiting. A previously reported Two patients with breast cancer primaries and one pa- pharmacokinetic study from the same patient populatient with ovarian cancer achieved complete remission, tion has shown that mitoxantrone binds extensively to at doses of 25, 50 and 20 mg/m2 respectively. Re- the peritoneal tissues and drug distribution in a deep sponses were assessed clinically and radiologically with tissue compartment from which it is slowly released. CT scans and ultrasonography. Ten patients had docu- The distribution of mitoxantrone in the peritoneal cavmented failure or progressive disease. Six patients were ity was almost completed within a dwell time of 4 hours not evaluable for response because further therapy was (Nageletal. 1992). discontinued (Table 6). One patient with breast cancer The phase I study was encouraging with 3 laparohad therapy discontinued because of excessive toxicity scopically documented complete remissions from a after 4 cycles was in complete remission at termination group of patients with advanced peritoneal malignancy. of therapy. However, in the phase II evaluation, no significant activity of mitoxantrone against ovarian cancer was seen. This was disappointing and in contrast to the Results in phase II findings of Markman et al. [7], who documented comFourteen patients with ovarian cancer, with a median plete remissions in 6/18 patients whose largest tumour age of 55 years (mean 55) were entered in the phase II diameter was <1 cm pre treatment. However, their reevaluation of intraperitoneal Mitoxantrone 25 mg/m2. sponse rates in patients with tumours larger than 1 cm All had been previously treated with platinum based were only 9% (1/11). The discrepency with our study is therapy (Cisplatin 8, CHAC/CHAP 4, other 2) and 5 difficult to explain as patients in the phase II evaluation had also received previous intraperitoneal carboplatin. all had disease <1 cm in maximal diameter. Markman Fifty-one cycles of chemotherapy were administered to et al. do not report removal of the dialysate after a finite these patients. Only 2 patients completed 6 cycles of dwell time, and this may explain their higher reported therapy, treatment being discontinued early because of toxicity and perhaps response, though the pharmacokinetic data would make this unlikely. progressive disease or toxicity. Toxicity of intraperitoneal mitoxantrone is signifiResponse cant at doses above 25 mg/m2, clinically, with chemical peritonitis as well as haematologically. Even at the dose No responses were documented. Progressive disease/ of 25 mg/m2, 2 patients had to discontinue further failure of therapy was documented clinically in 11 pa- treatment as a direct consequence. Administering the tients. Three patients were not evaluable for response intraperitoneal mitoxantrone for a finite dwell time may because of early discontinuation of treatment because have reduced toxicity, compared with other series. There was no evidence of bowel obstruction in any of of excessive toxicity (2) or Tenchkoff complication (1). our patients. The studies demonstrate the feasibility of intraperiToxicity toneal mitoxantrone therapy in patients with extensive peritoneal disease, but do not support its routine use in Haematological toxicity was not significant, nadir being patients with ovarian cancer. recorded at days 10-13 (Table 7). The major clinical toxicity was chemical peritonitis and pain, necessitating early discontinuation of therapy in 2 patients. Two References cycles of therapy were associated with infection due to 1. Shekenberg TD, Von Hoff DD. Mitoxantrone: A new anticancer the Tenchkoff catheter and there was leakage in a furdrug with significant clinical activity. Ann Intern Med 1986; 105: ther 2 cycles. 67-81.

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Received 19 May 1993; accepted 5 January 1994. Correspondence to: Dr. W. ten Bokkel Huinink Antoni van Leeuwenhoek Ziekenhuis Netherlands Cancer Institute Plesmanlaan 121 1066 CX Amsterdam The Netherlands