Escalating dose regimen of intraperitoneal mitoxantrone: Phase I study—clinical and pharmacokinetic evaluation

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Escalating Dose Regimen of Intraperitoneal Mitoxantrone: Phase I Study-Clinical and Pharmacokinetic Evaluation B. BLOCHL-DAUM,* *Department

H.G. EICHLER,t H. RAWER,* R. JAKESZ,+, H. SALZER,$ G. STEGER,* J. SCHiiLLER,I E. GUNTHER,** B. PROKSCHII and G. EHNINGERll

of Chemotherapy,

University of Vienna, Austria, ?I. Department of Medicine,

tiniversi& of Vienna, Austria,

$,Department of Surgery, University of Vienna, Austria, §Z. Department of Gynecology, University of Vienna, Austria, IlDepartment of Medicine,

UniversiQ of Tiibingen, F.R.G.,

~Rudolfsstiftung,

Special Oncologic Ambulance, **Medizinische

Abstract-Mitonantrone,

a recent anthracenedione

direct intraperitoneal

(i.p.)

application

is a potentially

mg/m’)

and 7 stable

disease

(5 male,

16 female)

were given i.p. every 4 weeks. Five partial

ascites was seen in an additional patients

months) were achieved. 3 patients.

only after 35 and 40 mglm’

Phanacokinetic

with gastrointestinal

sequestered

(2-8+

toxicities

were

months)

disappearance

07

was obseroed

liquid chromatography yielded

and the mean disappearance

in the intraperitoneal

(9),

Increasing of in 4

i.p.

data: The mean ratio of area under curve peritoneal ,Juid to plasma excretion within 24 h was 0.42%

remissions

A reduction

Severe toxicity (leucopenia)

analysis using high performance

clearance rate was 680 mllmin

systemic

maximum tolerated doses as well as pharmacokinetic

in 21 patients

courses (2-6+

F.R.G.

useful drug for

ovarian (6), unknown (2) and other (4) primary cancers and peritoneal carcinomatosis. doses (10-40

Reutlingen,

because of its high tissue binding and therapeutic index.

We have carried out studies to establish studies with i.p. mitoxantrone

derivative,

Vienna, Austria and

Klinik

half lif

was 1109.

the following The peritoneal

was 13.1 h. Mean urinary

of the i.p. dose. These data indicate that mitoxantrone

tissue compartment

is

and on& slowly released.

Based on the outcome of this phase I study we recommend phase II studies at a dose of 30 mg/ m2 i.p.,

repeated every 3-4

DIRECT

INTRAPERITONEAL

weeks.

INTRODUCTION anticancer

drugs

tumouricidal systemic

drug

levels

have

mitomycin

been

C and 5-FU

Mitoxantrone,

an

has shown

cytotoxic

ing ovarian

and

locally

parable

minimizing

trone

i.p. cisplatin, derivative,

gastrointestinal with

have

shown

favourablc

cancer

[7-91,

[ 12-141.

Alberts

tumour intravenous results

lymphoma

in contrast

to i.v. administration

of com-

I trial we have administered

intraperitoneally

in

to 21 patients

testinal,

or unknown

other

carcinomatosis.

establish

cell lines

trone

on mitoxantrone

malignancies

The

and to obtain

doses

with ovarian,

toxicity

detailed

administered

of

gastroinand perito-

aim of the study

the dose-limiting

mitoxan-

mitoxan-

increasing

was

to

of i.p. mitoxan-

pharmacokinetic

data

via the i.p.route.

in patients [lo,

et al. [ 151 have

intraperitoneally

severe

10-40 mg/m2 neal

includ-

No

doses.

In a phase

clini-

effects in in vitro systems

studies

observed

[l-3].

breast

mitoxantrone

with

of

to achieve

Favourable

anthracenedione

with tered

while

reported

trone

leukemia

in order

ofcytostatics.

cal results

to 23 mg/m’.

administration

was introduced

side-effects

[4--61. Clinical

(i.p.)

MATERIALS AND METHODS

1 l] and adminis-

in doses

Patients

of up

Twenty-one

patients

(5 male/l6

female)

with

pathologically proven advanced cancer and peritoneal carcinomatosis entered the study. The presence and extent of peritoneal carcinomatosis was diag-

Accepted 21 January 1988. Addresses for correspondence: Dr. B. Blijchl-Dawn, Prof. Dr.H. Rainer, Univ.-Klinik fiir Chemotherapie, Lazarettgasse 14, A1090 Vienna, Austria and Doz. Dr. G. Ehninger, Medizinische Klinik der Universitat, Otfried Miiller-Wane, D-7400 T6bingen 1, F.R.G.

nosed had

by laparotomy gastrointestinal

ovarian 1133

cancers

or laparoscopy. cancers.

resistant

to prior

Nine patients

Six

patients

systemic

had chemo-

1134

B. Blikhl-Daum

et al.

Table 1. Demographic data Age

Patient

Sex

WHO*

1

64

F

1

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

77 56 71 63 63 43 72 57 46 47 47 69 60 52 66 58 46 53 38 60

M F F F F M F F M F F F F M F F F M F F

2 2 0 2 0 2 2 0 0 1 0 0 1 2 1 2 0 1 1 2

*WHO performance status. tA = macroscopic disease (turnour

therapy.

Six patients

primary

cancers.

The

study

tutional Patient

was

tumourt

Carcinomatosis + distant metastases

Mitoxantrone doses (mg/m’)

Pancreas

A

Yes

Colon Gastric Ovary Gastric Colon Colon Ovary Ovary Bile duct Ovary Colon Colon Ovary Unknown NSCL Unknown Breast Mesothelioma Breast Bile duct

A A A A A A A A A A B B A B B B A B B A

Yes Yes Yes No No

10,25,30, 35,40,40 20 20,25,30,35 20,25,15 20 20,25,30 30 15 20,25 20,20,30,35 25,30,35 30,30 30 30 30 30,30 30 30,30,30,30 30,30,40,40 20 30

2 cm); B = minimal

residual

informed before

are given

con-

the study.

in Table

NO NO NO NO WO

Yes NO NO

No Yes No Yes NO

Yes No

disease.

treatment

by the insti-

Written

from all patients

characteristics

Mass

or unknown

approved

committee.

sent was obtained

OT

had other tumours

protocol

review

>

Site of primary cancer

cycle

evoked

grade

before

i.p.

effusion

Mitoxantrone

1.

entered

with

a progressive

in the study;

histologically

or

carcinomatosis. months.

they must

Life

expectancy status

or

was

bilirubin

inine

ml,

below

2 mg/lOO

3000/mm3

100,000/mm3

were

and

more than excluded.

350 mg/m2

chemo-

and plasma

white

blood

platelet

excluded.

disease

3

to WHO were

not

number

Patients

patients

doses

received

Cordis’ rM Catheter

F.R.G.)

was inserted

rect distribution

to drug

detectreceived

i.v. were also

chemotherapy

of mitoxantrone

the dose 5 mg/m’

with

(NovantronerM

F.R.G.). 1. It was

Individual intended to

every 4 weeks

Alterna-

(Cordis

GmbH,

percutaneously.

infusion

of radio-opaque

phin TM, Schering,

Berlin,

anti-

skin.

of fluid in the peritoneal

prior

small volume

(Pharmacia,

after careful

of the overlying

tively a PigTail Erkrad,

of the Port-a-cath needle

percutaneously

preparation

Cor-

cavity

by injection

substance F.R.G.)

was of a

(Angiogra-

and X-ray

study.

Clinical evaluation 1. Before

each

medical

cycle

history

function i.p.

Cyanamid, Wolfratshausen, dosages are given in Table increase

septic

the aid

(Pharmacia,

i.p. for 24 h before

HuberT”

with each

tests,

lytes. Additional after

each

the patients

and physical

and chest X-ray. included complete

patients

increasing

to the reservoir

solution

below

with

who have

of adriamycin

creat-

cell count

Treatment and regimen All

and remained

Access Sweden)

peritoneal

with

Port-a-cath’”

Sweden)

asserted

and

able heart

least

Previous

metastases

reasons for exclusion. Patients with plasma above

at

rapidly

Uppsala,

Uppsala,

all

as possible.

in 2 1ofRinger

drainage.

level

Immediately

infusion

was diluted inserted

dose

(WHO).

as completely

was via an 1 l-gauge

peritoneal

according

extraperitoneal

were

had a diffuse

verified

[ 161 was level 2 or better.

therapy

of cancer

have

cytologically

Performance

criteria

stage

proceeding

Th e d ru g was infused

(37°C).

Inclusion and exclusion criteria

the

mitoxantrone

was drained

of a previously Patients

unless

3 or 4 toxicity

had

a complete

examination,

ECG

Pretreatment laboratory tests blood counts, liver and renal

coagulation blood counts

treatment.

profile

and

were done

Whenever

ascites

electro14 days fluid

could be drained, cytologic analyses were performed. All patients had either repeated ultrasonic or ct. scan of the abdomen.

Escalating 2. Side-effects criteria

were

graded

Dose Regimen of Intraperitoneal

according

to WHO

1135

Mitoxantrone

Table 2. Side-effects of i.p. mitoxantrone, 10-30 mg/m’

[ 161.

3. Response

definition:

Complete

remission:

cal evidence

Disappearance

of active

tumours

of all clini-

for a minimum

Partial

remission:

eters

Fifty

per

cent

or

in the sum of the products in

measured

increase

lesions.

in size of any

greater

of all diam-

No

lesion

simultaneous

or appearance

of

any new lesions. Stable

disease:

partial

Steady

remission

appearance

state or response

or less

than

of new lesions

less than

progression.

and

No

no worsening

of

the symptoms. Progression:

Unequivocal

increase

50% in the size of any measurable appearance

of at least lesion,

4

of

2 months.

decrease

38 cycles in 15 patients WHO grade 0 1 2 3 Local Nausea Diarrhoea Bilirubin Alkaline phosphatase Haemoglobin Leucocytes Platelets Pulmonar) Fever Hair loss Pain Consciousness Neurotoxicity Chcmoperitonitis

35 20 35 36

2 16 0 1

1 2 1

0 0 2

0 0 0

I

0

0

36 34 38 37 35 36 36 29 36 38 38

2 2 0

0 2 0

0 0 0

0 0 0

I

0

0

0

3 2 2 3 2 0 0

0 0 0 6 0 0 0

0 0 0 0 0 0 0

0 0 0 0 0 0 0

and/or

of new lesions. Table 3. Side-effects of i.p. mitoxantrone 35-40 mg/m’

Pharmacokinetic Blood before end

(heparinized

treatment

and

of infusion.

the access All

studies

samples

port

samples

plasma

samples

at the same

were

were

at

samples. and

-80°C

until

analysed. Total urine (24 h portions) was collected during the patients’ stay in the hospital. Two hundred and fifty millilitres to the urine

of double portions

Mitoxantrone itoneal

(HPLC).

sample

described

in detail

least-square using

ance,

regression

iterative

estimate

volume

have

curve

analysis

been

mitoxantrone

program the curve

parameters

(VD)

Local Nausea Diarrhoea Bilirubin Alkaline phosphatase Haemoglobin Leucocytes Platelets Pulmonar) Fever Hair loss Pain Consciousness Nrurotoxicity Chemoperitonitis

5 1 4 6

0 3 I 0

6 3 2 5 2 4 4 0 5 6 5

0 3 1 1 3 2 2 1

0 0 1 0 0 0 0 2

provides (AUC), and

are given

an clear-

half-life.

if the coef-

Side-effects toxicity

(Tables

were

mitoxantronc. (Patients

2,

observed There

were

(WHO

1.

Individual

0

0

0

0

0 0 1 0 0 0 0 0

0 0 1 0 1 0 0 0

0

0

0

0 0

0 I

0 0

nadir (Patient

of up to 30 mg/m’ such as nausea

grade

the study, 47 treati.p., 44 cycles were dose schedules

are

Grades after

there

3 and

35-40

4

mg/m*

of leucopenia 800/mm”)

and

1). After

dose

were

and transient

only

mild

local pain

1, 2).

Clinical response. We observed Clinical results

for toxicity.

I 0

I

4 cases

one case of chemopcritonitis

RESULTS

in Table

0 0

0 0

3, 4). only

1, 3, 10, 1 l-lowest

regimens

evaluable

0 0

data,

side-effects

given

1 2

computer-

was BO.9.

Twenty-one patients entered ment cycles were administered

4

by nonlinear

ofall available

of distribution

of correlation

liquid

recently

[18]. This

fitting under

and perequipment

computed

program

of the area

Pharmacokinetic ficient

The method,

were

the TOPFIT

based

in plasma

[ 171. Individual

curves

was added

by high pressure

preparation

concentration

water

precipitation.

concentrations

fluid were measured

chromatography and

distilled

to prevent

0

the from

immediately

frozen

6 cycles in 4 patients WHO grade 1 2 3

taken

taken

time as blood

centrifuged

ascites

were

at 1, 2, 4, 8, 24 h after

Ascites were

and

tubes)

5 partial

remissions

(duration 2, 4+, 5, 5+, 8+ months) (see Table 5), 7 patients had stable disease (2, 3+, 4+, 4, 5+, 5, 6+ months) and 3 patients died within 2 months of entering because

the study. One patient had to bc excluded of infusion-related problems, 1 patient had

1136

B. Bliichl-Daum

Table 4. Side-effects

after i.p. mitoxantrone application

neal

Mild side-effects*

NO

G 20 mgim’ 25-30 mg/m2 35-40 mg/m’

9/11

Severe side-effects?

Initial

o/11

2111 17127 216

lo/27 O/6

fluid

showed

great

with

cisplatin

[l],

5-fluorouracil

remission

mitomycin

[20],

cavity

at levels severe

Our

present

l-3

in 5 patients

with carcinomatosis

Age

Sex

tration value

logs higher

Site of primary cancer

Duration of remission

Gastric Ovary Ovary Breast Mesothelioma

2 5 4+ 5+ 8+

mitoxantrone

F F F F M

months months months months months

that

400-1000

ng/ml

excluded

of ascites because

metastases,

of appearance

and with

continued ents

(5 months)

because

were

not

clinical ance

of ascites,

version

6 cases

the

Two patiof

favourable

of ascites

reduction,

and 4 cases from positive

1

with

weeks

after

con-

trone

Peritoneal lysed

results fluid,

plasma

in 28 treatment

pharmacokinetic

parameters

The peak concentrations from

282 to 56,800

clearance mean

rate

peak plasma drug

ng/ml.

The

680 ml/min

concentration The

the administered

mean within

were

ana-

bility

The

but

in Table

fluid ranged

mean and

usually and

urinary

6.

space.

occurred

ranged excretion

In 4 patients

peritoneal

ment

plasma

treatment

fluid to plasma concentrations

1 to of

urinary

cycles 3, where

the ml, depression.

with

were still high in some patients. the pretreatment

value

course was complicated Concentrations in plasma

prior In

was 88 ng/ by marrow and perito-

thus

account

plasma

surface

rates some

protein

content

ascites values.

may

all

arc not clear, in peritoneal

Furthermore,

(through

of absorption In addition, tumour

and different

drainage to the

3 or 4 toxicity

(WHO

m2 grade

3 or

treatment

cycles.

4 toxicity Also,

criteria

In contrast, was

abdominal

the may

and

variability

could in the

factors

such

burden

and

pathways high

In the present study, mitoxantrone 30 mg/m2 were well tolerated without ofgrade

which

circulation)

peritoneal

safely be administered.

of the

for at least part of

of the

contribute

by

for the wide varia-

into the systemic

status,

intrapatient

was also reported

in i.p. concentrations.

for

up to mitoxan-

compartmentalization

concentrations.

as patient

and

to differences

in peritoneal

give rise to different

Four

of pharmacokinetic

could be responsible

drug is absorbed

was 586. Pretreat-

in patients

which

The

in 12 patithe

cavity

that

concentrations

and/or

differences

24 h was 0.42 + 0.51%

dose.

volume

in a l-4 h

from

cavity

that

form.

inter-

reasons

be attributed

route

concentrations

range

in mitoxantrone may

i.p.

suggest released.

indicating

in an active

[24]. The

the variability

peritoneal

resulted

was measured between 24 and 48 h and for 0.12 * 0.11%. The mean ratio of

AUC

Patient

are listed

of 13.1 h in the peritoneal

(18 cycles)

excretion accounted

urine

in 14 patients.

in peritoneal

administration

488 ng/ml. ents

was

half-life

after

and/or

cycles

of the

plasma

A similar

after

in the intraperitoneal

considerable

et al.

Alberts

the The

demonstrate

also

in our observations

parameters. Pharmacokinetic

when [23].

to 3.64% data

results

measured,

was

were were

of only 0.42%

compared

and only slowly

is still released

There variability

to negative.

excretion

advantage

treatment

were

plasma

14 mg/m2

is sequestered

compartment

of

after i.p. administration

The

tissue

88 ng/ml

the

1231. These

pharmacokinetic

plasma

previously

intravenously

24 h after dosing,

mitoxantrone

peak

concentrations

only

by a renal

i.v. administration

in the plasma

have

in

AUC

in the range

we

availability

of administration.

was dis-

4 cases of disappear-

of hydronephrosis results

to be

because

Further

included

ofcytologic

disease.

for response lesions.

observations

reduction

treatment

of progressive

the lack of measurable

had

were

values

after

lower systemic

of extraperitoneal

2 patients

evaluable

but

AUC

(305 ng.h/ml),

administered

is also reflected a reduction

in the perito-

and peak plasma

was

within

a mean

was obtained

contrast,

AUC

are in agree-

mitoxantrone

concentrations

1450 ngh/ml drug

data

6): After i.p. adminis-

the average

In

in the plasma

toxicity.

(Table

lower

ng/ml.

reported 56 71 47 46 53

3 4 II 18 19

whereas

was 2 log cycles l-488

than

pharmacokinetic

of 2@40 mg/m2

neal cavity,

in the peritoneal

local or systemic

of 33 675 ng.h/ml

[21, 221

the possibility

drug concentrations

without

in [ 191,

cytarabine

C [2] demonstrated

ofmaintaining

peritonei Patient

intrapatient

[3], doxorubicin

melphalan

ment with these results 5. Partial

and

DISCUSSION studies of i.p. chemotherapy

feasibility

humans and

O/27 4/6

*WHO grade 1 and 2: pain and nausea. tWH0 grade 3 and 4: leukopenia and chemoperitonitis.

Table

inter-

variability.

44 cycles in 19 patients

side-elects

et al.

of

range

of

doses up to appearance [IS])

and can

after 35-40 observed pain

mg/

in 4/6 occurred

Escalating

Dose Regimen

of Intraperitoneal

Table 6. Pharmacokinetic Patient

Cycle

AIJC(pt) (ngh/ml)

Dose (mg/ m’)

I I I 2 3 3 3 3 4 5 6 6 6 9 9 IO I5 I6 I7 I8 I8 I8 I8 19 I9 I9 I9 21

35 40 40 20 25 30 35 20 20 20 20 25 30 20 25 20 30 30 30 20 20 20 20 30 30 40 40 20

IV

v VI I II III IV \ I I I II III I II I I I I I II III IV I II III IV I

AUC (p) (ngh/ml)

25,570 8580 220 60,140 45, I78 55,400 29,860 5474 506 5171 16,315 75,970 2140 1239 17,984 2396 7226 94,000 84,489 128,039 22,976 39.09 I 11,619 7130 10.639 12,300 139,569 33,675 38,761

MtXiIl S.D.

after only 6/38 treatments compared could

to 6/6

always

after

734 410 60

75.4 72.8 90.8

104 293 901

49.6 55.6 84.3

256 8 79 6 519 378 240 173 222 380 612 536 I8

70.3 284.6 92.0 15,692.8 162.8 330.9 95.7 225.6 52.5 18.8 17.4 22.9 7753.8

305 260

1108.5 3479.6

with

These

maximal

i.p. dose at 30 mg/m’.

Histological 5 out

of

therapeutic namely

observations diagnoses Partial

14 patients effects

disappearance

the lower doses.

suggest

and

were

data

Clearance (ml/min)

26.5 121.9 66.9 8.9 II.7 10.6 9.8 98.9 106.1 61.0 36.7

7.9

39

28.9 0.6 14.5 7.1 9.4 6.5 27.7 9.8 6.9 21.4

49

7 I9 I3 I7 41 I25 102 20

161.3 144.0 19.7

15.5 8.4 4.8

I20 197 47

849.0 5.8 4.3

1.0 14.6 22.2

9617 5 2

13.3

28.6

5

97.6 189. I

13.1 8.9

680

doses, Pain

as

relief

analgesic setting

Range (pt)

Blank(p)

Range (p)

(ng/ml)

(ng/ml)

(ng/ml)

800-2400 280-640 13-304 107&6510 53&5220 70&4500 420-3200 I 12-586 7s650 54-717 25&1460 I28&4400 64-380 I 02-420 64-2560 30-282 151-570 10~56,800 267&7000 4’L70-8960 422-1540 30&2840 173-1260 2-17 72-1373 l&810 17&4170

88.0 34.7

12.6128.0 7.4-64.0 17.e23.5 1.o 23.!%34.2 5.s37.3 29.MO.O I a3.4 3.9 8.iL25.3 I J-3.2 2.s30.9 2.s4.4 11.7-41.6 16.8-488 1.8-22.9 2.1-21.7 2.0-55.6 3.1-93.3 6.0--100.9 8.s72.4 2.LGll.O

0 0 0 0 2.0 1.0 0 0 2.6 0 0 0

5.

6.

7.

8.

35.2 50.0 24.9 650.0 21.0 39. I 55.0 I I I.4 107.7 101.2 89.2 18.4 12,909. I 168.3 18.4 61.2 130.9 22.7 4.5 13.6 11.2 379.1

fluid.

pared

with

example

other

cisplatin

local

drugs

response

side-cffccts

used for i.p. treatment,

[ 151, mitoxantrone rate with

at the

seems

for

to have

less systemic

recommended

and

dosage

patient

status

were

were observed cvaluable.

noticed

or reduction

in

in

Further 7 patients,

ofascites.

Com-

In conclusion, the

demonstrated

i.p. administration the recommended

the efficacy,

low grade

pharmacokinetic warrant

phase

dose of 30 mg/m2

toxicity advantage

II studies i.p. every

weeks.

REFERENCES

4.

32.2 63.0 IO.1 110.3

586.3 2468.2

a comparable

the

2.1-7.2 4.s74.2 2.4-10.2 13.2-30.0 16Js59.0

0 0

ratio

(pf$)

7.7 12.8 3.4 0

0 0 5.3

Conc.(max)

of

30 mg/m’.

remissions so far

(h)

p: plasma, pf: peritoneal

by systemic

therapy.

heterogeneous.

(1)

88.8 84.4 26 72.2

the high

be achieved

VD

(PflP)

67 288 102 85 833

AUC: Area under curve, VD: volume ofdistribution,

Half-life

AUC ratio

I137

Mitoxantrone

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