combined analysis of studies of the effects of the matrix ... · vol. 4, 1101-1109, may 1998...

Vol. 4, 1101-1109, May 1998 Clinical Cancer Research 1101

Advances in Brief

Combined Analysis of Studies of the Effects of the Matrix

Metalloproteinase Inhibitor Marimastat on Serum

Tumor Markers in Advanced Cancer: Selection

of a Biologically Active and Tolerable Dose for

Longer-term Studies1

John Nemunaitis, Christopher Poole,

John Primrose, Alexander Rosemurgy,

John Malfetano, Peter Brown, Amy Berrington,

Alan Cornish, Kevin Lynch2, Henrik Rasmussen,

David Kerr, David Cox, and Andrew Millar

Texas Oncology Center, Dallas, Texas 75246 [J. NI; CRC ClinicalTrials Unit, B15 2TH Birmingham, United Kingdom [C. P., D. K.1;University Surgery Unit, SOI6 6YD Southampton, United Kingdom

[J. P.]; Tampa General Hospital, Tampa, Florida 33601 [A. R.];Albany Medical College, Albany, New York 12208 [J. M.]; BritishBiotech, OX4 SLY Oxford, United Kingdom [P. B., A. B., A. C.,K. L., H. R., A. M.]; and Nuffield College, OX! 1NF Oxford,United Kingdom [D. C.]

Abstract

This combined analysis investigated the effect of man-

mastat, a specific inhibitor of matrix metalloproteinases, onmarkers of tumor progression measured in patients withadvanced cancer. By defining the tolerability and biologicalactivity of the drug, it aimed to establish an appropriate dose

range for use in Phase III trials.Patients with advanced, serologically progressive ovar-

ian, prostatic, pancreatic, and colorectal cancer were re-

cruited into six nonrandomized, dose ranging, multicenterclinical trials in North America and Europe. The biological

activity of marimastat was assessed by serial measurementsof the serum tumor markers carcinoembryonic antigen,CA125, CA19-9, and prostate-specific antigen. Patients wererecruited with tumor markers rising by more than 25%averaged over a 4-week screening period. A biological effect

was defined as a level of tumor marker at the end of treat-ment no greater than at study entry; a partial biologicaleffect was defined as a rise in the level of tumor marker overthe treatment period of 0-25% per 4 weeks. Pharmacoki-

Received 12/22/97; revised 2/9/98; accepted 2/9/98.The costs of publication of this article were defrayed in part by thepayment of page charges. This article must therefore be hereby markedadvertisement in accordance with 1 8 U.S.C. Section 1734 solely to

indicate this fact.

I Supported by British Biotech Pharmaceuticals, Ltd. Professor Kerr has

received consultancy fees from British Biotech throughout the periodcovered by this study. All trials were sponsored by British BiotechPharmaceuticals, and all investigators received investigational grants.2 To whom requests for reprints should be addressed, at Department of

Clinical Research, British Biotech Pharmaceuticals, Ltd., WatlingtonRoad, OX4 SLY Oxford, United Kingdom. Phone: 44-1865-748747;Fax: 44-1865-781 162; E-mail: [email protected].

netic and safety data were collected and assessed as thestudies progressed. All patients were followed up for sur-

vival.A total of 415 patients were recruited, with approxi-

mately equal numbers in each of the studies. Patient char-acteristics were similar across different studies and doses.

The 1 1 different doses used in the studies were grouped

according to similar trough blood levels of marimastat, and

analysis was made looking for dose-response. Marimastat

exhibited dose-dependent biological activity as assessed bybiological effect and partial biological effect (P 0.01,Cochran-Mantel-Haenszel test for non-zero correlation).Comparison of screen and treatment rates of rise of tumormarkers indicated that total daily doses of 20 mg and higherwere associated with maximal activity. Musculoskeletal ad-

verse events emerged as the principal drug-related toxicityof marimastat. These occurred in a dose- and time-depen-dent fashion and were more severe at a dose of 50 mg twicedaily than at lower doses.

Marimastat shows biological activity in patients withadvanced malignancy, as measured by the effects on levels oftumor markers. Assessment of biological activity by dose,together with safety and pharmacokinetic data, supportdoses of between 10 and 25 mg twice daily as appropriate for

Phase III studies.

Introduction

Marimastat (BB-25 16) is an inhibitor of MMPs3 ( 1 ), a

family of enzymes responsible for the degradation of extracel-

lular matrix that occurs during tissue formation and remodeling

(2). It is a low molecular weight (Mr 33 1 ) peptide-mimetic drug

containing a hydroxamate group that binds the zinc atom in the

active site of the MMP in a stereospecific manner (3). It inhibits

all known classes of MMPs but is inactive against other met-

alloenzymes such as angiotensin-converting enzyme ( 1).

The rationale for the investigation of marimastat as a

cancer therapy is that overexpression of MMPs is implicated in

the growth, invasion, and metastasis of human malignancy (4).

In preclinical cancer models, marimastat and a closely related

inhibitor, batimastat, reduced tumor growth and metastatic

spread (5-9). Neither inhibitor exhibited direct cytotoxic activ-

ity in vitro.

3 The abbreviations used are: MMP, matrix metalloproteinase: CEA,

carcinoembryonic antigen; PSA, prostate-specific antigen: BE, biolog-ical effect: PBE, partial BE.

Research. on June 25, 2020. © 1998 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

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1102 Effects of Marimastat on Serum Tumor Markers

The first trials with a new cancer chemotherapy are usually

designed to determine a maximum tolerated single dose and

dosing schedule (10). However, the mode of action of marimas-

tat as a tumoristatic agent means that chronic administration

may be required before antitumor activity can be evaluated.

Furthermore, it was anticipated that the effects of marimastat in

patients with advanced cancer would be subtle. Specifically,

conventional reductive tumor responses were not anticipated.

Even so, it was extremely important that early clinical trials with

this novel agent define a biologically active dose range in

addition to providing data on safety and tolerability. For these

reasons, Phase I studies in healthy volunteers (1 1 ) were fol-

lowed by a series of studies using a novel clinical trial method.

This method uses the rate of rise of serum tumor markers before

and during treatment as a measure of tumor progression. The

approach was based on observations that concentrations of

tumor markers in the blood are related to stage of disease; that

rising levels indicate progression; and that falls occur during

effective treatment (12-16). The hypothesis in undertaking these

studies was that the effect of marimastat on tumor markers could

be used as a measure of biological activity and as a means of

identifying an optimum dose for future randomized studies.

Because the rate of rise of tumor markers is an unvalidated

measure of disease progression, survival data were gathered on

all patients entering these studies. These data allowed analysis

of the relationships between survival and levels of tumor mark-

ers so that this measure of biological activity might be validated

as an indicator of clinical outcome.

Patients and Methods

Patients. Six trials of similar design were conducted in

patients with advanced colorectal (two studies), ovarian (two

studies), pancreatic and prostatic cancer using the tumor mark-

ers CEA, CAI25, CA19-9 and PSA, respectively. Patients with

histologically proven (except pancreatic) cancers were selected

for these studies on the basis of serum tumor markers above

prespecified levels (>5 ng/ml CEA, >35 lU/mi CA125, >10

ng/ml PSA, and >37 lU/mi CA19-9) and values rising by 25%

or more over a 4-week period. The exception was the North

American colorectal cancer study, in which the required rate of

rise of CEA was 25% over 1 2 weeks. In all studies, an Eastern

Cooperative Oncology Group performance status of 0-2 and a

predicted survival of 3 months or more was required.

Patients had failed conventional first-line treatment where

offered, and if cytotoxic therapy had been received, this was to

have been terminated at least 4 and 8 weeks before entry to the

North American and European studies, respectively. Hormonal

therapy was to be continued in the European ovarian and North

American prostate study at a constant dose, although other

antineoplastic treatments were not allowed during the study

period. Patients were excluded from the studies if: (a) surgery

had been performed in the previous week; (b) bilirubin and liver

enzymes were greater than three times and creatinine greater

than twice the upper limit of normal; (c) albumin was <2.5

g/dL; or (d) there was evidence of weight loss > 10% in the

previous 3 months.

Patients were recruited into the study from centers in North

America and Europe. Before initiation of the individual trials,

the protocols and any protocol amendments were reviewed by

the research ethics committee or institutional review board at

each center and approved. Written informed consent was ob-

tamed from all patients, and the studies were conducted in

accordance with guidelines on good clinical practice.

Objectives. The six studies aimed to investigate the ef-

fect of marimastat on the rates of rise of the relevant serum

tumor markers and to define the safety and tolerability of the

drug. By using a similar trial design for each of the studies, it

was anticipated that a combined analysis of the results would

help determine a dose range of suitable activity and tolerability

for longer-term studies.

Treatment. Gel capsules containing 5, 10, 25, or 50 mg

of marimastat were provided by British Biotech Pharmaceuti-

cals, Ltd. (Oxford, United Kingdom). Patients were recruited in

sequential dose groups of 8-10 patients each, starting at 25 mg

twice a day with a view to dose escalation to 100 mg twice daily.

The starting dose was selected on the basis of data from healthy

volunteer studies, which suggested that doses of 25 mg twice

daily would achieve the target trough levels of 40 p.g/L, six

times the IC50s for several of the major MMPs. This blood level

had also been identified as showing activity in animal cancer

model (data not shown). Patients were recruited at doses of 25

and 50 mg twice daily, although it became apparent that doses

beyond this level were poorly tolerated. Seventeen patients were

recruited at 75 mg twice daily in the North American ovarian

and pancreatic studies before this dose was discontinued due to

adverse events. Thereafter, doses were titrated downward, and

patients were recruited at 10 and S mg twice daily, and 25, 20,

10, and 5 mg once daily. An additional 17 patients were re-

cruited with prostatic cancer at 2 mg twice daily and 2 mg once

daily, but these doses were not continued due to low trough

levels of marimastat and reduced activity.

Patients received marimastat for 4 weeks, except in the

North American colorectal cancer study, in which treatment was

for 12 weeks. Marimastat was allowed to be continued indefi-

nitely where patients were considered to be responding to treat-

ment or where, in the opinion of the investigator, the patient was

benefiting from the drug. All patients were followed up for

adverse events and survival.

End Points. The study entry criteria required that pa-

tients have levels of tumor markers rising by 25% or more in a

4-week screening period (12 weeks in the North American

colorectal cancer study). Subsequent measures were made at

days 0 and 28. The rate of rise of tumor markers in both

screening and treatment phases were calculated as a percentage

rise in 28 days via the formula (100) X [(A2 - A1)/A1] X

[28/D], where � and A2 were the levels of marker measured D

days apart. The protocol defined a BE as a rate of rise of tumor

marker at the end of the treatment period of <0% (i.e., a tumor

marker level no greater than that at day 0). A PBE was defined

as a rate of rise of tumor marker of between 0 and 25%.

Nonresponders were defined as those patients displaying a rate

of rise of tumor marker during marimastat treatment of >25%,

or who withdrew due to disease progression, or who died within

6 weeks of starting treatment.

Because practical difficulties in observing patients with

progressive cancer meant that samples were not always taken at

scheduled times or according to the protocol, a computerized



Clinical Cancer Research 1103

Table I Patien t characteristics b y study

Total Colorectal (1 ) Colorectal (2)” Ovarian (I) Ovarian (2) Pancreatic Prostate

No. of patients

Stage III/IV

Rate of rise of tumor marker”Mean age

Median age (range)

No. not completing treatment

No. evaluable by intention to treat

No. evaluable by algorithm

415

90%

64%63

64 (31-88)

71 (17%)

312 (75%)

223 (54%)

70

83%

56%63

65 (40-87)

6

61

55

61

85%

52%62

62 (37-83)

30

43

22

66

92%

89%59

60 (34-81)

6

60

49

66

97%

60%60

61 (31-83)

8

47

26

64

88%

72%63

63 (43-84)

12

4230

88

100%58%71

71 (45-88)

9

5941

a North American colorectal cancer study; treatment period of I 2 weeks.

b Median screening rate of rise, per-algorithm.

preanalysis algorithm was devised that selected for analysis

those tumor marker measurements that adhered most closely to

the protocol (see below). These strictly per-algorithm data are

supplemented by data on patients with analyzable screening and

treatment measures in an intention-to-treat analysis. In these

patients, the rate of rise of tumor marker may have been <25%

during screening but was in all cases greater than zero (median

rate of rise for the extra patients was 1 5%). This low rate of rise

may increase the probability of the patient achieving the cate-

gorical responses of BE or PBE. However, comparison of the

screen and treatment rates of rise of tumor markers analyzes this

possible effect by measuring the difference between rates of rise

rather than the absolute values on treatment.

Blood samples were taken for pharmacokinetic evaluation

on days 0, 14, and 28, and additional samples were taken from

those patients who continued to receive marimastat beyond the

end of the study period. In calculating a mean trough level for

each patient, both day 14 and day 28 measurements were re-

quired. Clinical chemistry and hematology, urinalysis, and vital

signs were monitored throughout the study. All adverse events

were recorded, whether related or unrelated to marimastat. The

eventual date of death was recorded for all patients where

possible.

Application of Algorithm for Tumor Marker Measure-ment. The computerized algorithm was derived from the

study protocols and stipulated that patients were to have two

screening (SI and S2) and two treatment (Tl and 12) tumor

marker values determined at the same laboratory. Si was to be

measured >2 weeks before S2 but less than 13 weeks before the

start of the study. S2 must have been taken within 4 weeks of the

start of treatment and be higher than a specified minimum level

(5 ng/ml CEA, 35 lU/mI CA-125, 37 IU/ml CA19-9, and 10

ng/ml PSA). The rate of rise of tumor marker averaged over 28

days must have been �25%. Tl was required to be measured

less than 7 days before, and less than 2 days after the start of

treatment. 12 was to be measured between 22 and 34 days after

the start of treatment but no more than 2 days after the discon-

tinuation of treatment.

The rules of this algorithm were relaxed for the intention-

to-treat analysis, whereby those patients who entered the study

with a rate of rise of tumor marker >0% but <25% were

included. Patients were also included in the intention-to-treat

analysis if Sl and S2 values were measured more than 13 weeks

and more than 4 weeks before the start of treatment, respec-

tively, provided that the two values remained more than 2 weeks

apart.

All patients who failed to meet one or more of these

inclusion criteria were excluded from the analyses. The baseline

characteristics of these patients were assessed to ensure that

their exclusion would not confound the analyses.

Statistical Analysis. The data were entered on a Clintrial

database and independently verified. The database was then

quality assured against original source documents. To ensure

that cell sizes were large enough for analysis of BE and PBE, the

primary end points of the study, dose groups were combined

according to trough levels of marimastat. Categorical data were

analyzed using the Cochran-Mantel-Haenszel test for non-zero

correlation using rank scores for row and column variables (17).

Study effect was accounted for in this analysis. Ratios of screen-

ing and treatment rates of rise of tumor markers were compared

within dose grouping using the Wilcoxon signed rank test.

Survival curves were derived using the Kaplan-Meier method,

and differences were analyzed by the log-rank test. Survival data

were also analyzed using a proportional hazards model, taking

into account those recorded factors with possible prognostic

significance.

Results

Patients. A total of 415 patients were recruited into the

six studies. Baseline characteristics, including tumor stage, age,

and screening rate of rise of tumor marker, are presented in

Table I . Approximately equal numbers were recruited to each of

the six studies. Patient numbers and characteristics according to

dose group are presented in Table 2. No potentially confounding

factors are identified between groups of patients according to

cancer type or dose group.

Assessment of Biological Activity. Of 415 patients re-

cruited, 223 (54%) were eligible for analysis of tumor marker

response according to the strict rules of the algorithm. This

number includes 15 patients who died or withdrew due to

disease progression before the end of treatment and who were

categorized as nonresponders. An intention-to-treat analysis in-

corporated data from 3 12 (75%) patients with evaluable screen-

ing and treatment measurements. A total of 103 patients (25%)

were excluded from either analysis. These comprised 27 (6%)

patients who failed to complete the study for reasons other than

early death or disease progression (included above as nonre-

sponders). An additional 50 (12%) patients were excluded on

the basis of having invalid or absent screening or treatment data,

19 (5%) where the screening rate of rise of tumor marker was

<0%, and 7 (2%) who had no treatment data in the 22-34-day




Table 2 Patient characteristics by dose group

5 mg once 10 mg once 5 mg twice 25 mg once 10 mg twice 25 mg twice 50 mg twice Abandoneddaily daily daily daily” daily daily daily doses”

No. of patients 50 60 35 61 59 57 59 34

Tumor

Colorectal 21 21 8 22 20 20 19 0

Ovarian 21 18 8 19 19 18 21 8

Prostatic 8 12 9 1 1 10 10 1 1 17

Pancreatic 0 9 10 9 10 9 8 9

Rate of rise of tumor marke?� 50% 69% 47% 88% 62% 61% 55% 68%No. not completing treatment 15 10 5 8 6 1 1 10 6

No. evaluable by intention to treat 41 46 24 53 45 43 40 20

No. evaluable by algorithm 32 35 12 41 31 29 29 14

a Includes 29 patients treated at 20 mg once daily.

h Includes 9 patients treated at 2 mg once daily, 8 patients treated at 2 mg twice daily, and I 7 patients treated at 75 mg twice daily.C Median screening rate of rise, per-algorithm.

Table 3 Biological responses observed for patients with evaluable screening and treatment levels of tumor markers

Per-algorithm analysis Intention-to-treat analysis

Dose BE (%) PBE (%) NR” (%) Total BE (%) PBE (%) NR (%) Total NE

2 mg once daily 0 (0.0) 2 (33.3) 4 (66.7) 6 0 (0.0) 2 (33.3) 4 (66.7) 6 32 mg twice daily 0 (0.0) 0 (0.0) 3 (100.0) 3 0 (0.0) 1 (20.0) 4 (80.0) 5 3

5 mg once daily 4 (12.5) 10 (31.3) 18 (56.3) 32 4 (9.8) 13 (31.7) 24 (58.5) 41 9

5 mg twice daily I (8.3) 5 (41.7) 6 (50.0) 12 4 (16.7) 9 (37.5) 1 1 (45.8) 24 1110 mg once daily 5 (14.3) 4 (1 1.4) 26 (74.3) 35 5 (10.9) 8 (17.4) 33 (71.7) 46 1410 mg twice daily 6 (19.4) 12 (38.7) 13 (41.9) 31 10 (22.2) 16 (35.6) 19 (42.2) 45 1420 mg once daily 5 (25.0) 2 (10.0) 13 (65.0) 20 5 (20.8) 4 (16.7) 15 (62.5) 24 5

25 mg once daily 2 (9.5) 3 (14.3) 16 (76.2) 21 3 (10.3) 4 (13.8) 22 (75.9) 29 3

25 mg twice daily 7 (24.1) 8 (27.6) 14 (48.3) 29 12 (27.9) 12 (27.9) 19 (44.2) 43 14

50 mg twice daily 13 (44.8) 5 (17.2) 1 1 (37.9) 29 15 (37.5) 7 (17.5) 18 (45.0) 40 19

75 mg twice daily 1 (20.0) 0 (0.0) 4 (80.0) 5 2 (22.2) 2 (22.2) 5 (55.6) 9 8Total 223 312 103

a NR, nonresponder; NE, nonevaluable by algorithm or on intention-to-treat basis.

window. Some of these patients were excluded for more than

one of these reasons. The baseline characteristics of excluded

patients was not found to be different from those included in the

analyses (data not shown).

The results categorized by BE (�0% rise in tumor marker)

and PBE (between 0 and 25% rise) are shown by individual dose

group in Table 3 and after grouping doses according to trough

plasma level (Table 4) in Figs. 1 and 2. Testing these data for

dose-response indicates that the proportion of patients showing

a BE or PBE increased as dose increased, both in the per-

algorithm and intention-to-treat analyses (P = 0.01 for both,

Cochran-Mantel-Haenszel test; test values 6.0 and 6.7, respec-

tively).

The medians and quartiles of percentage rates of rise of

tumor markers during screening and treatment are shown in

Figs. 3 (per-algorithm) and 4 (intention-to-treat). Falls were

apparent in all dose groups, although the differences in the rates

of rise of tumor markers were more substantial at higher doses;

differences between treatment and screening rate of rise (when

analyzed as a ratio) were significant at the 5% level for both

per-algorithm and intention-to-treat analyses only in patients

receiving total daily doses of 20 mg or higher (Wilcoxon signed

rank test).

Trough plasma levels of marimastat are presented by dose

in Table 4. For a given dose, trough levels were substantially

Table 4 Trough plasma levels (p.g/L) by dose

Group Dose n” Range Mean (SE)

1 2 mg once daily

2 mg twice daily5 mg once daily

3

413

3.5-7.4

4.0-17.43.3-27.5

5.1 (1.2)

10.6 (3.1)

14.8 (2.1)

2 5 mg twice daily10 mg once daily

2232

5.4-78.56.5-249.9

29.1 (4.5)38.7 (8.2)

3 10 mg twice daily

20 mg once daily25 mg once daily

44

2020

12.8-277.5

8.2-229. 116.8-164.3

70.0 (8.2)

53.5 (11.4)54.3 (9.5)

4 25 mg twice daily 42 19.0-756.1 166.2 (21.5)

5 50 mg twice daily75 mg twice daily

51

827.7-1050.6

88.8-676.2224.2 (25.9)

410.9 (68.8)a Number of patients with recorded trough plasma levels.

higher than those observed in healthy volunteers (1 1), and mean

trough levels greater than 40 p.g/L (-6 times IC50s) were

observed in patients treated with total daily doses of 20 mg and

above. The increased drug concentrations seen in patients with

cancer compared with healthy volunteers is probably related to

pharmacokinetic differences between young healthy males and

older patients with advanced malignancy, including increased

plasma protein binding, reduced liver and renal function, and

lower body weight. Considerable intersubject variability is ev-



70

60

50

40

30

20

10

0

Fig. I Percentage of BE and PBE by dose

group, where BE is defined as a level of

tumor marker on treatment no greater thanthat on day 0, and PBE is defined as a rise intumor marker of <25% over a 28-day period(per-algorithm analysis). od, once daily; bd,

twice daily.

70

60

50U,

C

a,a �a,

.0

CO

Co> 30a,

0

20

10

0

2mgod 5nigW lOmgbd 25mgbd Somgbd

2mgbd lOmgod 2omgod 75mgbd

5mgod 25mgod

Manmastat dose group

Fig. 2 Percentage of BE and PBE by dose

group, intention-to-treat analysis. od, oncedaily; bd, twice daily.

2mgod lOmgbd

2mgbd 2Omgod

5mgod 25mgod

Marimastat dose group


U,

Ca,

.�Co0.a,

Co

Co>w0

ident within dose groups, although an approximately linear

relationship is observed between dose and mean trough level.

There was no significant correlation between trough levels of

marimastat and BE or PBE.

Although survival was not a primary end point of these

studies, survival analysis was performed to assess whether

changes in the rate of rise of tumor markers were a valid marker

of disease outcome. A survival curve is shown in Fig. 5, with

patients separated according to whether they were categorized

as a BE or PBE or as nonresponders. Patients suffering early

deaths are excluded from the nonresponders to avoid an exag-

geration of the poorer survival curve. Survival in the two groups

was significantly different in favor of those patients showing a

BE or PBE, both in the per-algorithm protocol and intention-

to-treat analyses (P 0.0003 and P 0.0001, respectively,

log-rank test). Both are “responder analyses,” and their results

must be interpreted with caution. No significant difference was

observed in the survival curves of patients with a BE compared

with those with a PBE. Proportional hazards analysis revealed

baseline lactate dehydrogenase and albumin to be highly signif-

icant factors in determining survival (P < 0.005). Falls in tumor

markers remained a significant factor in determining survival



a,0,.� �

Cot

Co�

.-

E�-CO

0.0

I--.-

180 -

150

120

90

60

30

0

-30

I-

[

0 Screen

I Treatment

I.�.II II. � - � - � -� - -I � �-1- -C- ‘

5mgod 5mgbd lOmgod 25mgod lOmgbd 25mg

-r

i SOmgbd

Dose of marimastat

Fig. 4 Median percentage rate of rise of

tumor marker during screening and treat-

ment with marimastat, by dose group

with upper and lower quartiles, intention-

to-treat analysis. od, once daily; bd, twice

daily. Bars represent upper and lower

quartiles.

Dose of marimastat


.� �

a,t

‘- 0#{149}

E��Co0E

Fig. 3 Median percentage rate of rise oftumor marker during screening and treat-ment with marimastat, by dose group withupper and lower quartiles, per-algorithmanalysis. od, once daily; bd, twice daily.

Bars represent upper and lower quartiles.

when adjusting for baseline covariates in the per-algorithm

analysis (P = 0.05) but not in the intention-to treat analysis

(P = 0.16).

Safety Assessments. The most commonly reported ad-

verse events, whether thought to be related to marimastat or not,

are presented in Table S. Most subjects reported at least one

adverse event. Musculoskeletal events, particularly arthralgia,

myalgia, and back pain, occurred frequently and seemed to be

dose related. Symptoms attributable to the gastrointestinal sys-

tem were also common, as one would expect in this population

with advanced malignancy, although no dose relationship was

observed. Fatigue, fever, rash, dyspnea, and disseminated car-

cinoma were all reported in considerable numbers, although a

possible dose-relationship was observed with rash only.

When considering events reported to be possibly related to

marimastat, the principal toxicity of the drug was revealed to be

musculoskeletal side effects. These were described commonly

as myalgia, arthralgia, and tendinitis, occurring predominantly

in the upper limbs. The symptoms appeared reversible and arose

in a dose- and time-dependent fashion. Doses of 75 mg twice

daily and higher were abandoned because of the frequency and

severity of musculoskeletal symptoms observed. Table 6 mdi-

cates that few patients reported musculoskeletal problems in the

first month of treatment severe enough to result in dose modi-

fication or withdrawal. Beyond 28 days of treatment, however,

the need to reduce the dose or withdraw the patient due to these

side effects become more frequent, particularly at doses of 25

mg twice daily and higher.



Fig. 5 Kaplan-Meier survival analysisof patients exhibiting BEs and PBEs,compared with nonresponders (NR) cx-cluding early deaths (ED), per-algorithmanalysis.

0 200 400 600

Survival Time (days)


2’.0

Co

a-Co

.?

0)

Table 5 Most common a dverse events, all causalities”

2 mg once daily 10 mg twice daily2 mg twice daily 10 mg once daily 20 mg once daily 50 mg twice daily

5 mg once daily 5 mg twice daily 25 mg once daily 25 mg twice daily 75 mg twice daily

Number recruited 67 95 120 57 76

Arthralgia 18(2) 22(3) 46(8) 21 (7) 33(13)Myalgia 9(1) 9(0) 28(8) 9(1) 20(8)Backpain 16(2) 12(0) 22(3) 9(2) 11 (3)Abdominal pain 20 (7) 26 (5) 42 (9) 14 (4) 18 (4)

Fatigue 12(3) 23(0) 28(4) 16(0) 20(1)Nausea 21 (4) 28 (4) 33 (3) 16 (2) 20 (3)Vomiting 16 (3) 21 (5) 26 (4) 1 1 (0) 15 (0)

Constipation 14(2) 23(3) 15(2) 7(1) 12(0)Diarrhea 13(1) 10(2) 20(1) 5(1) 9(0)

Anorexia 11 (1) 12(2) 17(3) 12(1) 11 (2)

Fever 12 (0) 19 (0) 1 1 (I) 8 (1) 8 (0)

Rash 3 (0) 8 (0) 8 (0) 7 (0) 1 1 (0)Dyspnea 6(2) 12(2) 14(2) 7(0) 14(4)

Carcinoma 7 (7) 14 ( 10) 10 (9) 7 (5) 8 (7)

Ascites 9(2) 11 (5) 12(3) 6(2) 12(2)

a Numbers in parentheses, severe events.

A total of 350 serious adverse events were reported, of

which 39 (1 1.1%) were thought to be possibly related to mari-

mastat. Events included cases related to the musculoskeletal (7

cases) and gastrointestinal (12) systems, and cases of liver

dysfunction (4), dehydration (3), fever (2), and thrombophlebitis

(2). Other individual events included hematoma, hypotension,

anemia, renal insufficiency, pain, hernaturia, disseminated car-

cinoma, asthenia, and edema. Many out-of-range laboratory

values were recorded in this group of patients with progressive

cancer and a high frequency of hepatic metastases, although the

only trend observed was a small rise in mean liver transaminases

and bilirubin levels.

Discussion

The use of tumor markers as a measure of disease progression

has not been common in the evaluation of new cancer treat-

ments, and this novel approach has been the subject of some

controversy (18, 19). However, the predominantly tumoristatic

activity of marimastat would be difficult to detect by conven-

tional techniques in early-stage studies. The clinical trials re-

ported here show changes in the rates of rise of tumor markers,

indicative of a dose-related biological effect. A relationship was

also observed between the changes in the rates of rise of tumor

markers and clinical outcome, indicating that these changes may

be a valid surrogate end point.

A combined analysis of studies of different tumor type is

unusual. However, the approach was thought reasonable when

considering the mechanism of action of this novel agent and

after transformation of absolute values of tumor markers into a

rate of rise. Furthermore, statistical analysis indicated that the

same general trend was observed in each of the studies, and no

differences were observed in patient characteristics between



1 108 Effects of Marimastat on Serum Tumor Markers

4 5. Watson, personal communication.

Table 6 Analysis of the occurrence of muscul oskeletal events by d ose group

2 mg once daily 10 mg twice daily2 mg twice daily 5 mg twice daily 20 mg once daily 50 mg twice daily�- 5 mg once daily 10 mg once daily 25 mg once daily 25 mg twice daily 75 mg twice daily

Number recruited 67 95 1 20 57 76Withdrawn or dose modified 2 (3%) 3 (3%) 1 (1%) 0 (0%) 3 (4%)

due to event by day 28Completed at day 28 with moderate 7 (10%) 3 (3%) 16 (13%) 5 (9%) 12 (16%)

or severe event

Continuing beyond day 28 (at risk) 35 47 65 31 30

Withdrawn or dose modified due 0 (0%) 2 (4%) 8 (12%) 7 (23%) 14 (47%)

to event between days 28 and 84

cancer types or between dose groups that could potentially

confound these results.

We note that the practicalities of conducting these studies

was more difficult than anticipated. Obtaining screening tumor

marker readings from patients with advanced cancer who had

not yet consented for a clinical study presented specific prob-

lems. Equally, the patients’ illnesses frequently impacted on

their ability to attend study visits according to the protocol. Such

difficulties meant that only 54% of patients were analyzable

according to a strict algorithm, although these results were

essentially the same as those seen in the 75% of the patients

meeting more relaxed inclusion criteria. Twenty-five % of pa-

tients were ineligible for either analysis, mainly because of

noncompletion of the main study or invalid tumor marker data.

The similarity of baseline characteristics of these patients to

those included in the analyses did not suggest that their exclu-

sion might introduce some selection bias.

Analysis for dose-response indicated that patients treated

with higher doses of marimastat more frequently displayed

categorical responses (BE and PBE) after 28 days of treatment.

The combination of dose groups used for the analysis was based

on a good pharmacokinetic rationale and ensured large enough

cell sizes, particularly when some doses were not used in all

studies. Moreover, it is only in patients receiving total daily

doses of 20 mg and above that mean trough levels of marimastat

exceeded the desired levels specified in the study protocols (40

�xg/L). The relative falls in rates of rise of tumor markers were

more significant at higher doses, particularly in those patients

receiving daily doses above 20 mg. For those considering sim-

ilar trials in the future, we recommend writing into their proto-

cols assessment of tumor markers in the period beyond 28 days

so that the duration of marker response might also be better

characterized.

Observation of a cohort of patients with rapidly rising

levels of tumor markers might reveal falls in these levels in the

absence of any treatment. Such regression toward a mean value

probably contributed to the falls in rates of rise of tumor markers

seen in the lower doses, although the more substantial reduc-

tions in the higher dose groups is most probably the result of

treatment. It is also possible that the effect of marimastat on

cancer antigens could be unrelated to tumor progression; for

example, the compound might suppress cancer antigen produc-

tion. This seems unlikely when one considers that in vitro

studies show minimal effect of marimastat on shedding of tumor

markers (data not shown), and animal model studies show a

reduction in the rate of rise of CEA associated with directly

measured inhibition of tumor growth by marimastat.4 The bio-

logical effects of marimastat on these markers seem consistent

with an effect on tumor progression.

Trough plasma levels of marimastat were found to be very

variable, and no significant correlation was observed between

trough levels and BE or PBE. Full pharmacokinetic profiles and

estimates of free drug would have provided more information,

but such measurements were impractical in the context of these

studies.

Most patients tolerated marimastat well. Safety assessment

reveals that the principal drug-related toxicities were events of

the musculoskeletal system. These side effects occurred more

commonly, were generally more severe, and developed more

rapidly at higher doses of marimastat. Musculoskeletal events

precluded further evaluation of doses of marimastat beyond 50

mg twice daily. Other commonly encountered adverse events

such as abdominal pain, fatigue, nausea, and vomiting predom-

inantly reflected the nature of the underlying disease processes,

although confirmation of this will rely on evaluation of placebo-

controlled data from Phase IH studies. Likewise, a small trend to

increasing liver transaminases and bilirubin may reflect the

development of hepatic metastases in a large proportion of

patients. The small number of cases ofjaundice possibly related

to marimastat dictate that liver function is appropriately moni-

tored in controlled studies.

The observed biological activity of marimastat on tumor

markers is encouraging and has allowed a dose range of 10-25

mg twice daily to be identified for further studies. This dose has

been selected on the basis of the combined analysis of biological

activity described, pharmacokinetic data, and the observation of

dose-related musculoskeletal pain. Prospective randomized din-

ical trials are now underway to evaluate the effect of marimastat

on clinical outcome and to define the long-term tolerability of

the drug.

Acknowledgments

We thank the following clinicians who recruited the patients into

these studies: Dr. M. Adams, Velindre Hospital, Cardiff, United King-dom; Dr. F. Ahmann, Arizona Cancer Center, Tuscon, AZ; Dr. D.

Alberts, Arizona Cancer Center, Tuscon, AZ; Dr. V. Barley, Bristol




Oncology Centre, Bristol, United Kingdom; Dr. J. Barter, Lombardi

Cancer Center, Washington, DC; Dr. H. Bleiberg, Institut Jules Bordet,Brussels, Belgium; Dr. P. Boasberg, John Wayne Cancer Institute, Santa

Monica, CA; Dr. Bordelon, Texas Oncology, PA., Dallas, TX; Dr. E.

Casper, Memorial Sloan Kettering Cancer Center, New York, NY; Dr.

Cox, Texas Oncology, PA., Dallas, TX; Dr. F. Daniel, Freedom Fields,Plymouth, United Kingdom; Dr. Eisenberger, Johns Hopkins Univer-

sity, Baltimore, MD; Dr. B. Harbaugh, Texas Oncology, PA., Dallas.

TX; Dr. J. Harris, RUSH Presbyterian Hospital, Chicago, IL; Dr. P.Johnson, St. James’s University Hospital, Leeds, United Kingdom; Dr.

P. Kantoff, Dana Farber Cancer Institute, Boston, MA; Dr. A. Langle-

ben, Royal Victoria Hospital, Montreal, Quebec, Canada; Dr. J. Mansi,St. George’s Hospital, London, United Kingdom; Dr. J. Marshall, Geor-

getown University Hospital, Washington, DC; Dr. D. Moore, Indiana

University, Indianapolis, IN; Dr. J. Neoptolemos, Queen Elizabeth Hos-

pita!, Birmingham, United Kingdom; Dr. T. Perren, St. James’s Univer-

sity Hospital, Leeds, United Kingdom; Dr. M. Piccart, Institut Jules

Bordet, Brussels, Belgium; Dr. B. Roth, Indiana University Medical

Center, Indianapolis, IN; Dr. J. Schink, University of Wisconsin Mcd-

ical Center, Madison, WI; Dr. M. Seymour, Cookridge Hospital, Leeds,

United Kingdom; Dr. N. Teng, Stanford University, Stanford, CA; Dr.

H. Thomas, Hammersmith Hospital, London, United Kingdom; Prof. S.Van Belle, Universitair Ziekenhuis, Gent, Belgium; Dr. J. Vermorken,

Free University Hospital, Amsterdam, the Netherlands; Dr. R. Wolff,

Duke University Medical Center, Durham, NC; and Dr. S. Zahnoen,

University of Cincinnati, Cincinnati, OH.

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1998;4:1101-1109. Clin Cancer Res J Nemunaitis, C Poole, J Primrose, et al. tolerable dose for longer-term studies.in advanced cancer: selection of a biologically active and

markersmetalloproteinase inhibitor marimastat on serum tumor Combined analysis of studies of the effects of the matrix

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