Phase II study of iproplatin (CHIP, JM-9) in advanced testicular cancers progressing after prior chemotherapy

Phase

II Study of Iproplatin

Advanced

Tes titular

(CHIP,

Cancers

JM-9)

Progressing

in After

Prior Chemotherapy MICHEL CLAVEL,* SILVIO MONFARDINI,? SIEGENTHALER,II JOSETTE RENARD,l

‘Centre Lebn Be’rard, F-69373 Hospital,

Montebello,

hleuchatel,

patients

General Hospital,

CH 2000 Neuchatel, Switzerland,

with advanced

The most severe toxicip

cycle of 240 and 180 mg/m2

dei Tumori, I-20133

was thrombocytopenia

No antitumor activig

pylamine

with two toxic deaths after a

occurred 6 weeks after the Jirst cycle while the tumor was was observed in this heavily pretreated population

(IV), CHIP, of cisplatin,

platinum

derivative

search

for a better

to the parent activity

of

although

I studies

and in Europe ranging

from

with

index

consisting

and doses

In all the studies,

in cumulative

other

myelosuppres-

skin rashes

dose

schedule,

repeated

rate was reported

carcinoma

including

to entry

in the study.

All ofthe

tumors

which

criteria

included cells

Patients

to or recurrent

therapy

containing

cisplatin. therapy

of a member

of the

4 weeks

preceding

Trials

Group,

program

with

treated

and resistant

pmol/l.

or radiation

disease-oriented

in previously

4

S25

paper

we decided phase reports

disseminated

to

that

had primary

the

testis.

status

23.5

of

provided

patients

creatininc

therapy

on

This

(WBC)

presence

the 4 weeks prior

from

serum

1

evi-

the

within

a performance

(in

the only

such as AFP and/

for the study

rising

2 130 X log/l,

in patients

was

markers

originated

proven with

or evaluable in whom

disease

were eligible

pati-

Early Clinical iproplatin.

Patients

pretreated

EORTC

large

every

2 diameters)

histologically teratocarcinoma

the level was clearly

blood

and rarely

(in

levels of serum

bilirubin

embark

icular

[2-41

had

lesions.

of progressive

elevated or PHCG,

schedules

cnts [5]. Based on this experience

conclusions

dence

with

in the U.S.A.

toxicity,

a single

a

significant,

was thrombocytopenia,

a high response ovarian

is

patients malignant

measurable diameter)

[ 11.

[5] used various toxicity

antitumor

selection

All eligible progressive

as compared The

animals

conducted

sion, gastrointestinal renal toxicity. Using

JM-91 is a quadrideveloped in the

20 to 380 mg/m’.

dose limiting toxicities

Patient

to be cross-resistant

in L 1210 leukemia

Phase

weeks,

in

found

of patients.

MATERIALS AND METHODS

compound.

iproplatin

it was

cisplatin

therapeutic

cisplatin

at a dose

or recurred after chemotherapy

[cis-dichloro-trans-hydroxy-bis-isopro-

valent

:Det Norske Radium

IEORTC Data Center, B-1000 Bruxelles. Be&urn and **Free University Hospital, NL-1081 HVAmsterdam, The Netherlands

INTRODUCTION IPROPLATIN

Milano, Itab,

respectively. Nausea and vomiting were almost universal but

mild in intensity. One renal failure progressing.

STANLEY KAYE,$ PIERRE

Glasgow G12 OYN, United Kingdom, [[Hipitaux de la Ville de

testicular cancer received iprojdatin

mg/m’ every 4 weeks. All the patients progressed

including cisplatin. jrst

Lyon, Cedex 08, France, tlstituto Narionale

Oslo 3, Norway, SGartnavel

Cadolles Pourtales,

Abstract-Twenty-two of 180-240

STEIN GUNDERSEN,:

MARTINE VAN GLABBEKEI and HERBERT M. PINEDO** on behalf of the EORTC Early Clinical Trials Group77

Entry

of O-2, white

X lO”/l,

platelets

S 150 pmol/l

and

had to be pretreated

after a previous

chemo-

No previous

chemo-

was allowed

the administration

within

the

of iproplatin.

Drug and treatment

II

Vials

our test-

cancer.

Accepted 5 April 1988.

containing

50 mg of iproplatin

to1 were solution

reconstituted with and then further

isotonic 60 min.

saline for intravenous No further hydration

and manni-

50 ml of isotonic saline diluted in 1000 ml of administration was administered.

over

At the start of the study, the dose of iproplatin given was 240 mg/m2 but this was subsequently

ttOthcr participants (in orderofparticipation): Win’l‘en Bokkel Huinink, Amsterdam, ‘I‘he Netherlands; Rem Abeie, Geneva, Switzerland; Franc0 Cavalli, Bellinzona, Switzerland; Eduard Holdcner, St Gallen. Switzerland; Olhjorn Klepp, Trondheim, Norway.

reduced suppression 1345

to

180 mg/m’

because

in the first

14 patients

of severe

myelo-

treated.

Treat-

M. Clavel et al.

1346 ment

courses

case

of myelosuppression

were

rescheduled

repeated

treatment

maximum

(WHO)

occurred.

when

unless

of new lesions

gressive

disease),

iproplatin

stopped.

Otherwise,

qualify

and partial

standard

criteria.

eligible

the study

from

Table

1 shows

patients. progressive

were

entered

ofall the eligible patient

prior

Seven

received

majority

nantly

embryonal

carcinoma

five a raised

received two The

and

three first

starting

the

eight

considered

a definite

tumor,

three a raised

alone.

Fourteen

AFP

patients

three

received severe

of

the

not

patients,

a clear

definite

progression

cycle was completed.

2 shows

the lowest

blood

patients

penia;

suffered

toxicity

was observed, a first

dose

four evaluable

patients

were

for

tumor

2 (2-2.9)

degree

WBC

count

and

1 (1-1.9).

was much

more

severe.

count

higher

100 X lo”/1 after the first course

than

while four had the lowest 99 X log/l, two below patient

of

value:

four between

had a platelet

between

50 X 10’1

20 and

49 X log/1

20 X log/l. died.

men containing

He was a 29-year-old treated

240 mg/m2,

After

he

toxicity

with a nadir

pneumonia.

Leucopenia

developed and

platelet

0: 10 1: 7 2: 5

*All patients were previously treated by chemotherapy cisplatin [median number of drugs: 6 (4-g)].

regi-

the first iproplatin a

grade

delayed count

3

thrombo-

of 9 X log/l,3 he started broncho-

was not observed

amongst

the eight patients who receiued a starting dose of 180 mg/

another

(20-5;

Prior surgery curative palliative

patient,

by a chemotherapy

six drugs.

nausea-vomiting

year-old index

Among

only four patients

however,

was

still

a sig-

problem.

a life threatening

Performance

3 and

However,

A nadir platelet count between 50 and 99 was observed in two patients after the first cycle, while

22

Number

of leuco-

between

14 patients,

nificant

Table 1. Characteristics of eligible patient?

for white

with the day

these

dose of

a modest

five had a lowest

One

as a

values

together

In 14 patients receiving 240 mg/m’ as a starting dose, six patients had no evidence of leucopenia while

m2. Thrombocytopenia,

Median age in years Range

4

of nadir.

and

patients

240 mg/m2

received

being

second

in progression.

showed

Antitumor response as

as

and were

cytopenia

22 eligible

during

the treatment

weeks after the treatment. At that stage, gastro-intestinal bleeding and fatal

Among

a

tumor

out of the study.

180 mg/m’.

considered

after

were considered during

stopped

as being

patient

Table

1 and

five received

remaining

patients

4

was

received

progression

and dropped

PS = 1, previously

dose; because

next

then

evidence

of treatment

thrombocytopenia

cycles. 14 patients

any

progressed

interval,

3.9 X log/l,

predomi-

of the primary

+ AFP,

HCG

patients

?? one

eight 15

intention.

(16) had

only one cycle of iproplatin,

cycles,

received

the

HCG

contain-

radiotherapy.

of the patients

seven had a raised alone,

previous

had

surgery,

aim, seven with palliative

patients

(WHO

a prior regimen

undergone

with a curative The

into

All of the patients

despite

and

blood cells and thrombocytes,

non-eligible

All had

with

after the third

the characteristics

disease

ing cisplatin.

first this

Toxicip

patients

iproplatin.

?? five

change

11 institutions.

PS 3) received

without

10 patients

weeks

response.

One additional

cycle

early progression

RESULTS Twenty-two

of iproplatin

as pro-

to

the

case,

reduction. ??

responses No

were considered

courses

the first 4 weeks

that was insufficient

within

In one

as no change

two

lesions was

death

treatment.

disease. ?? two patients

pati-

administration

shrinkage

for a 50% partial

(defined

to early

because of severe with progressive

third

In the

of the indicator

complete

with

a tumor

These

due following

considered to be a toxic death myelosuppresion in association

courses

progressions.

or the appearance

response weeks

of progressive

after one course. of 25%

defined

Organiz-

iproplatin

as early

a

myelosuppression

case of an increase

were

for

to 80% or

Health

4

clear evidence

considered

indicated

was

World

of two

was apparent

were

In the

postponed

3 or

A minimum

disease

4 weeks. retreatment

Dose adjustments

grade

were intended, ents

was

of 2 weeks.

60% were performed ation

every when

22 15 7 including

previously

patient

thrombocytopenia

occurred

receiving

180 mg/m*.

with

a PS of 1, who

patient treated

with

six different

in

He was a 48had

drugs.

been After

2

weeks of treatment with a dose of 180 mg/m* he developed thrombocytopenia with a nadir platelet count of 20, inducing a fatal upper gastro-intestinal bleeding despite intensive platelet transfusion. The non-hematological observed are listed in Table occurred almost universally

toxicities which were 3. Nausea and vomiting after iproplatin admin-

1347

Iproplatin in Advanced Testicular Cancers Table 2. Hematological

toxicity Nadir values

WBC x lo”/1 240 mg/m’ starting

X lo”/1

dose

1st course Median Range Day of nadir

4.2 (6.2-1.8) 20 (534)

Overall Median Range

3.1 (5.1-1.8)

180 mg/n?

Platelets

starting

(2K9, 20 (7-31)

dose

1st course Median Range Day of nadir

3.9 (2.4-9.5) 13 (G-21)

Overall Median Range

(2.4-9.5)

(31Y75, 13 (12-14)

54* (175-16)

3.9

*Two toxic deaths from thrombocytopenia. Table 3. Non-hematological

20 9 1 1 1

Nausea-vomiting Diarrhea Mucositis Drug fever Renal failure

istration,

of mild

or moderate

was observed

in almost

mildly.

grade

Other

intensity.

1 and 2 toxicities

1

prior m2

drug

patient,

renal

toxicity

previously

Bleomycin (240 mg/m’),

After

he

treatment. clear

At that

progression.

the fatal sidered

a fatal

cisplatin,

developed

toxicity;

VP 16,

During

after

from

grade

3 *weeks,

renal

failure

time tumor Although

indicators it is not clear

grade

4 renal

3 and

3

dose

the platebleeding. he

penia reported

the

of short

after showed

a

whether

and death.

in one case Thus

to 180 mg/m’.

by the vast majority duration

the

In spite

this

initial of this

of patients

and qualitatively

but were

less severe

than

with cisplatin. With

weekly

this case was contoxicity.

failure

occurred

was not proven

Phase II trials of new drugs in testicular cancer are difficult to accomplish because of the extent of

was

thrombocytopenia

a second toxic death due to thrombocytoNausea and vomiting were was noted.

any renal function

DISCUSSION

without

myelosuppression

developed

patient’s

reduced

dose was 240 mg/

intravenously

4, respectively,

to the

was

reduction

toxicity,

6 weeks

graded

given

Two patients

persisted

treatment

a

hematological

issue was drug-related, as a WHO

4 weeks

all of the patients. starting

Drug-induced

marked.

in a 30-year-old

was 2.7 X lo’/1 and he started

recovering

developed

with

Ifosfamide.

nausea-vomiting lets count

occurred

treated

and

every

in virtually

the iproplatin

hydration.

fever and mucositis. A severe

treatment

Initially

but only

included

90 41 5 5 5

7 0

Diarrhea

half of the patients

Percentage of total patients

Number of patients with grade 3-4 toxicities

Number of patients

Type

toxicities

creatinine

we did not demonstrate

impairment. 6 weeks

after

The only fatal renal the

to be drug-related.

treatment

and

No antitumor

activity was detected in this trial concerning patients pretreated with cisplatin. We conclude that iproplatin given at a dose of 180-240 mg/m’ is not active in this patient population.

M. Clavel et al.

1348

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2. 3.

4.

5.

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