Clinical safety and tolerance of mitoxantrone (Novantrone)

Cancer Treatment

Reviews (1983)

10 (Su&huxt

B),

29-36

Clinical safety and tolerance (Novantrone*) Roger

of mitoxantrone

J. Crossley

Medical Research Division, Clinical Research Department, Pearl River, KY 10965, U.S.A.

American Cyanamid Company,

The American Cyanamid Company is aware of more than 3000 patients who have been exposed to mitoxantrone (Novantrone*) in one clinical trial or another. From the data that can be suitably pooled, key questions of some of the reported safety and tolerance issues regarding mitoxantrone have been examined.

Patient

population

The total number of patients known to have been exposed to mitoxantrone is 3360. From this population, those patients treated with the most common dose regimen (once every 3 weeks) and those for whom comprehensive reports are available have been analysed. Of the total of 3360 patients, 1800 were eligible on the basis of the dose regimen criterion and 877 because of the availability of detailed reports. The patient population available for analysis was divided into three groups based upon the extent of prior chemotherapy. There were 120 patients who had not received prior chemotherapy (Group A). Eighty-four patients had received treatment with either one single agent or one combination regimen (Group B). Patients in Groups A (first-line) and B (second-line) are from Phase II and Phase III clinical trials, most of whom were treated with mitoxantrone for metastatic breast cancer. The remainder (673) of the patients, had been exposed to more than one prior single agent or combination chemotherapy regimen (Group C). They were considered to be heavily pretreated and were from Phase I and II clinical trials. They were treated with mitoxantrone for a variety of neoplastic conditions. Three groups of patients were therefore identified, and since dose level regimens differed it seemed appropriate not to pool together such data for an analysis of safety and tolerance considerations.

*Trademark

American

0305%7372/83/10B0029+08

Cyanamid

Company 0

$03.00/O 29

1983 Academic

Press Inc.

(London)

Limited

30

R. J. CROSSLEY

Dose

levels

Figure 1 presents the mean mitoxantrone dose as a function ofcourse number, i.e., time, for each of the three Groups. The starting dose for both the first-line Group A and second-line Group B was 14 or 12 mg/mg’; the figure indicates an average initial dose of 13 to 13.5 mg/m’. In contrast, the heavily pretreated Group C patients received an initial dose of 10 to 12 mg/m*, averaging to about 11 mg/m*. The figure clearly shows a slow, but steady decline in average dose with time. This is true of all three groups. While there is undoubtedly some effect of a changing patient population with time, this decreasing trend of change reflects a real event. If treatment is initiated at the higher dose levels, the average dose drifts downwards with time reaching a level of 10 to 11 mg/m* as an average dose beginning at course 5 or 6 and is then sustained thereafter.

Myelosuppression The explanation for the declining mean dose over time appears to be myelosuppression. This is the principal dose limiting toxicity of mitoxantrone and is predominantly due to granulocytopenia. Pretreatment white blood cell counts as a function of course number for each of the three Groups are presented in Figure 2 (a). The corresponding white blood cell nadirs are shown in Figure 2(b). Both pretreatment and nadir values follow the same pattern: they tend to fall up to the fifth or sixth course and then stabilize. There is clearly a degree ofbone marrow depletion taking place during the first few courses of treatment. This is probably the reason for the dose level reductions and ensuing stabilization as shown in Figure 1. Some patients have had severe granulocytopenia with superimposing infection that have resulted in some deaths. Myelosuppression is a definite toxicity, is definitely dose-limiting, and requires the usual careful clinical management adjusted to the individual patient. For the most part, however, these problems occur during the beginning of therapy, rather than as a sudden and unexpected event once the patient has been moderately well stabilized. Other hematologic parameters are not affected to the same extent as are those of the white cell series. Platelet values drift slightly downwards with, again, a tendency to stabilize after the fifth or sixth course. Dramatic drops in platelet counts have not been observed,

I 0

I

2

3

4

5

6

7

8

9

IO

Course Figure

2. Mean

dose of mitoxantrone

per course. ~, first-line (group pretreated (group C).

A);

., second

line (group

B); ---,

heavily

CLINICAL

SAFETY

AND

TOLERANCE

OF

MITOXANTRONE

31

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(b) 3.c 2.5

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2

3

4

5 Course

-

7

6

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9

of therapy

Figure 2. Mean white blood cell count values per course. (a) -Pretreatment above the bars represent the numbers of patients within each group. treated.

values. (b) -Nadir line; 0, second

n , first

values. The numbers line; q , heavily pre-

although a few very low values have been reported. No serious clinical sequela from low platelet counts have been reported. There is no apparent effect on the red cell series, measured by either hemoglobin or hematocrit.

Cardiotoxicity A total of 128 reports on cardiac events have been received. These reports include incidents ranging from minor and transient electrocardiogram variations to congestive heart failure and myocardial infarction. Sufficiently detailed data on 88 episodes have been received to permit some estimates of possible predictive factors which influence these cardiac events to be made. Table 1 shows the breakdown of these 88 episodes (cases) by type ofevent. The group ‘all other’ comprises a wide variety of cardiac incidents. These vary not only in type and

32

R. J. CROSSLEY Table

1.

SubclassiCcation

Type Congestive Decreased ejection AU others

of cardiac

of event

Number

heart failure left ventricular fraction (3 10%)

events

of patients 29 25 34

Total

88

severity, but lack any apparent relationship to therapy. They were mostly only of minimal clinical significance. Table 2 shows the association of various factors with the development of congestive cardiac failure and a decrease of the ejection fraction. Clearly prior anthracycline therapy dominates. Since more than half the patients who developed these side effects had previously had anthracyclines, prior anthracycline exposure appears to be a clear predisposing factor. Nevertheless, there appears to be one case that followed the characteristic pattern described for the anthracyclines. When cardiac biopsies from this patient were examined histologically, the sections were rated as normal at baseline, Grade 1 at 120 mg/m’ and Grade 2 at 208 mg/m’ cumulative dose mitoxantrone. Three months later this patient developed congestive heart failure and ultimately died following poor response to therapy. There have been several elective cardiac biopsies and some of them were described as Grade l/2, Grade 1 and one Grade 2. None of them had any clinical or left ventricular ejection fraction changes. Similarly some of the congestive failure patients have had cardiac biopsies and have revealed no specific or unusual histological features, certainly not of the characteristic anthracycline type. Since prior anthracycline therapy appears to be a likely predisposing cardiotoxicity factor, further analyses were done. Of the 877 patients for which data are available for other analyses presented here, there was information on 774 of the exact nature of their prior therapy (Table 3). There were 358 patients who had had prior anthracycline therapy and 416 who did not. The numbers of patients who were recorded to have had up to a cumulative dose of 260 mg/m’ mitoxantrone, decreased as time increased. As noted in Table 3, very little information is available for patients beyond 12@140 mg/m2 in the prior anthracycline group and beyond 14&160 mg/m2 in the no prior anthracycline group.

Table

2. Association of predisposing factors with cardiac failure and decreased ejection numbers of patients

Factor

Congestive failure

congestive fraction by

D.XIKWd ejection fraction

Prior anthracyclines Mediastinal radiation Prior cardiovascular disease No predisposing factors

20 4 4 1

14 3 4 4

Total

29

25

CLINICAL

SAFETY Table

3.

Total (mdm2)

AND

TOLERANCE

Number diotoxic

of patients events

Prior anthracyclines

G20 21-40 41-60 61-80

OF at

No prior anthracyclines

358 214 66 34 23

81-100 101-120 121-140 141-160 161-180 181-200

16 10 2

-

201-220 221-240 241-260

risk

-

33

MITOXANTRONE for

car-

Total

416 323 162 106 61 38 26 15

774 537 228

9

9

5 3

2

5 3 2

1

I

140 84 54 36 17

These data serve as the basis for standard life-table analysis. Life-table curves (Fig. 3) were constructed for both groups. They are shown for all patients receiving more than 160 mg/m2 included as one data point rather than stretching out the very small numbers. Up to 120 mg/m2 cumulative dose in the prior anthracycline group and up to 160 mg/m2 in the no prior anthracycline group few congestive heart failures (CHF) occur (Fig. 3a). It

E 2 .G 3 2

80 (b) 60-

40

201 I

I 0

_20

40

60 Cumulative

Figure 3. Life-table (b)-Left ventricular

T

T

80

+ 100

-+/+--f---y + 120

dose of mitoxantrone

f + 140

h 160

I >I60

(mg/m’)

analyses of cardiotoxic events by prior anthracydine use. (a)-congestive heart failure. ejection fraction decreases greater than 10%. The vertical bars are the standard deviations. ---, prior anthracyclines; p, no prior anthracyclines.

34

R. J.

CROSSLEY

is necessary to emphasize however that these are cumulative numbers and not the incidence rate at each dose level. Beyond these two points ( 120 and 160 mg/m2) there is an increase in CHF, but numbers are small, and the exact pattern of this profile is yet to be determined. With four of the nine patients exposed to doses of mitoxantrone in excess of 160 mg/m2 there is evidence of cardiotoxic potential and congestive cardiac failure. A pattern similar to that seen in CHF patients is seen in the group of patients who had a greater than 10% decrease in left ventricular ejection fraction (Fig. 3b). A few cases occurred at low doses in patients who had prior anthracyclines. For the most part, cumulative doses of 120 and 160 mg/m2 are the points at which most problems are seen. Nevertheless, the overall pattern is still of a relatively low incidence. It appears then that there is a tendency for mitoxantrone to produce some cardiac toxicity particularly if patients had prior anthracycline therapy. At this time therefore, it would seem prudent that at cumulative dose levels of 100-120 mg/m2 of mitoxantrone in patients previously exposed to anthracyclines or 14CL160 mg/m2 in those not previously treated with these drugs, caution is exercised and the benefit to risk ratio is carefully weighed.

Acute

toxicity

Mitoxantrone seems on the whole to be very well tolerated. To obtain incidence levels of acute side effects that are not confounded by dose and by prior chemotherapy, patient data was separated into Groups A, B, and C. The standard World Health Organization criteria were used to grade severity. Ungraded side-effects are also included, these are usually mild, although it has not yet been possible to fully confirm this. The incidence of nausea and vomiting for each of the three groups by course number is shown in Figure 4. The profile is dominated by Grade 1 (nausea only) and by Grade 2 (transient vomiting) to a lesser extent. There are occasional reports of Grade 3 (vomiting

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Course

2

Course

3

b Course

7

Course

4

b Course

8

g 40 30 20 IO a

c

a

b Course

c 6

a

c

a

c

Figure 4. Incidence of nausea and vomiting. Figures 4-7 give stacked bar charts of the incidence of the toxicity by course and by extent of prior chemotherapy. Toxicity grades are according to the World Health Organization criteria. The numbers above the bars represent the numbers of patients within each group. q , grade 4,0, grade 3; q , grade 2; a, grade 1; n , ungraded. a, first-line; b, second-line; c, heavily pre-treated.

CLINICAL

SAFETY

G

5

Figure

5. Incidence

14 12

of diarrhea.

AND

TOLERANCE

Course

I

Course

Course

4

Course

0,

OF

MITOXANTRONE

2

5

Course

3

Course

6

IEI,grade 1; n , ungraded. a, first-line;

grade 4; 0, grade 3; Q, grade 2; b, second-line; c, heavily treated.

requiring therapy) and very few of Grade 4 (intractable vomiting). The apparent difference between Group C and the other groups may be partially due to the fact that they had lower initial doses; however, since they were heavily pretreated with drugs which produce nausea and vomiting, this may have been a relative effect. Diarrhea occurs more frequently than expected (Fig. 5). There appears to be something of a dose-response effect. Most of the reports are of Grade 1 diarrhea,(transient) and of Grade 2 (tolerable), with only a small incidence of Grade 3 (intolerable). None of the patients experienced diarrhea leading to hemorrhagic dehydration (Grade 4). The incidence of stomatitis and mucositis are given in Figure 6. Again, the pattern is dominated by Grade 1 (soreness/erythema) and by Grade 2 (erythema and ulcers) severity ratings. There are only a few reports of Grade 3 (ulcers, requiring a liquid diet) toxicity. None of the patients experienced Grade 4 oral toxicity (alimentation not possible). These

25 ,

I

Course

5

Figure 6. Incidence

Course

6

of stomatitis/mucositis.

Course Key

7

Course as Fig. 5.

8

R. J. CROSSLEY

36 75 ,

I

60 45 30 ‘ij 2

15 0

8

Course

I

Course

2

Course

3

Course

4

Course

5

Course

6

Course

7

Course

8

Figrrrc 7. Incidence of alopecia. Bars showing incidence for Group C patients are horizontal incidence was d 1.3% for each of grades 1 to 3 and ungraded; there were no grade 4 reports.

lines since the Key as Fig. 5.

findings were seen only in patients receiving mitoxantrone once every three weeks with 12-14 mg/m’ as an initial dose. When the dose is increased and the drug is administered more frequently, as for leukemia patients, stomatitis becomes the dose-limiting toxicity. Alopecia is usually very mild (Fig. 7). The picture is clearly dominated by Grade 1 (minimal hair loss). There are a few patients with mild hair loss not requiring a wig, Grade 2. There are even fewer reports of patients with Grade 3 (moderate and requiring a wig), and still fewer Grade 4 (complete hair loss). As was noted for the other toxicities, again there appears to be a minor dose-response effect. But, the increases are in Grade 1 reports, most notably in the Course 7 and 8 data. Many of the patients reappear at subsequent courses with the same problem minimal alopecia.

Conclusiohs The data on clinical safety and tolerance and discussed here leads to the following

of mitoxantrone conclusions:

administered

1. Hematological effects are dose-limiting. 2. Cardiotoxicity can occur, but is relatively mild and is likely therapy and previous or existing cardiovascular disease. 3. Acute toxicity is relatively infrequent and mild in severity.

once every 3 weeks

to be affected

by prior

Acknowledgements I wish to thank the mitoxantrone with this drug.

the staff of the American Cyanamid Company who have been involved in project and the numerous oncologists who have conducted clinical trials