Early human trials with anticancer agents

J. &on.

Dis. Vol. 15, pp. 229-236.

EARLY HUMAN

Pergamon Press Ltd. Printed in Great Britain

TRIALS WITH ANTICANCER

DOSAGE SCHEDULES

AGENTS

AND ROUTES OF ADMINISTRATION*

BRUCE I. SHNIDER, M.D.? Georgetown

University,

(Received

Washington

14 November

D.C.

1961)

INTRODUCTION

I and II studies represent the most frequent type of evaluation utilized in the search for new antitumor agents in the clinic. Simple as they would appear to be, they present a great variety of problems, few of which have been satisfactorily solved or even clearly defined. In general, a Phase I study is considered to include only an evaluation of the pharmacology of a new drug to estimate what will be a safe dose and a satisfactory route of administration for a therapeutic trial. In Phase II, the therapeutic response in a variety of tumors is determined in an effort to uncover those that are truly responsive. If activity is of a high order it is then envisioned that a Phase III comparison with a standard form of therapy or placebo will be made in those tumors shown to be responsive by the Phase II trial. In an evaluation of such studies of chemotherapeutic drugs in man one cannot help but be struck by the divergent results reported with the same agent despite careful clinical evaluation by experienced observers. Human nature seems to prevent the separation of pharmacologic observations from therapeutic results so that Phase I studies blend into or become Phase II studies without appropriate design or intent on the part of the investigators involved. The initial data desired may therefore become obscured by the search for therapeutic activity. The basic issues in any clinical evaluation of drug activity are the identihcation and control of all factors that interfere with or assist in making the observations and the collection and evaluation of data. The factors that concern us in this discussion are those of dosage schedules and routes of administration. In discussing this, I have drawn on some of the experiences of the Eastern Cooperative Chemotherapy Group to illustrate what may be encountered in such studies. PHASE

DOSAGE

SCHEDULES

In the preparation of a protocol for preliminary pharmacological studies, the investigator utilizes the best available animal data to establish an initial dose for the investigation and determination of a satisfactory dosage schedule for therapeutic *Supported in part by Research Grant CYP 2824, Cancer Chemotherapy National Service Center, National Cancer Institute, Public Health Service. TAssociate Professor of Medicine, Director Tumor Service, Georgetown University Medical Division, D. C. General Hospital, Chairman, Pastern Cooperative Solid Group for Cancer Chemotherapy. 229

230

BRUCE

I.

SENDER

trials [2]. An example of the problems one may encounter can be demonstrated by the experiences of some of our members with 6-Azauracil [3]. Pharmacological studies had indicated that this drug was well tolerated in mice, rats, cats, dogs, were noted in adult animals with doses and monkeys. No definite toxic manifestations Cats were able to tolerate 2000 mg intraperitoneally in as high as 90 mg/kg/day. acute studies with no toxic manifestations. Preliminary animal studies revealed the drug to be completely absorbed from the gastrointestinal tract and almost completely eliminated in the urine in 6 to 8 hours. Table 1 illustrates the toxicity which occurred when 6-Azauracil was given to man in an ascending dose schedule. The drug was continued until toxicity developed, which in most instances consisted of central nervous system manifestations. The median duration of drug administration to toxicity was 11 days or, in terms of total dose, 144 mg/kg. The chronic toxicity studies are illustrated in Table 2. A dose-response relationship is demonstrated in that the median duration to significant toxicity at 15 and 4.5 mg/kg/day was 21 and 49 days respectively. It quickly became evident that the dose for human trial was decidedly smaller than the tolerated dose in animals, and that the neurotoxicity that necessitated this low dose for therapeutic studies was not predicted by the animal toxicity studies. The reason for this difference between man and animal is unknown. The occurrence of neurotoxicity in man at a fraction of the dose toIerated in animals precluded therapeutic trials in man at anywhere near the dosage that was necessary to produce antitumor effects in animals. Early in the formative days of the Eastern Cooperative Cancer Chemotherapy group, a study was undertaken to evaluate the feasibility and usefulness of cooperative clinical research in cancer chemotherapy and to apply the principles of the therapeutic trial to clinical cancer chemotherapy. The drugs used in this study were two alkylating agents, triethylenethiophosphoramide and mechlorethamine. The specifics of this study have already been reported [4], but certain features of the study indicate another difficulty in developing satisfactory drug dosages for chemotherapeutic studies in man. TABLE

1.

6-AZAURACIL.

ACUTE

TOXICITY STUDIES

Total Cases 15 Total drug trials 17 No. of

Dose (mgkgky)

trials

Days on drug

No. showing EEG changes

No. showing neurotoxicity

Other toxicity

9

17

3-16

10

6

18

11

2-10.5

10

8

27

6

3-14.5

6

5

36

4

&lo.5

4

4

Toxic psychosis (1) Thrombocytopenia-(1) 400,000 -+ 48,000 ?Cardiac arrhythmia

2

5+ days after drug discontinued Toxic psychosis

45

2

5-14

2

(1)

Early Human Trials with Anticancer TABLET.

231

Agents

6-AZALJRACXL. CHRONICTOXICITYSTUDIE~

Total cases 28 Total drug trials 31 Dose (mg/kgWy)

Days on drug

Trials

Abnormal EEG (day)

18

3-120

3143

18

9

4

4-70

3131

4

15

7

1I-45

10145

7

27

2

4.5

TABLE 3.

Drug

3842

11

(6-40) Thrombocytopenia (2) 160,000 + 39,000 215,000 +4,000 1 Bleeding Jaundice (1) Toxic psychosis (1) (8-41) (3-20) Thrombocytopenia (1) 350,000 + 60,000 Leukopenia (3) 4-8 +2.6 4.2 j1.8 5.2 +2.0+4.6 while on drug 2

(9-20)

GRADEDMUWRES OFRFSPONSEFORHODGKIN'SDISEASE Patients showing positive response

TSPA

Mean duration of responses (days) 44*7*3

8/11 (73%) 9/9 (100%)

[4]

Mean reduction in measured tumors 36+6%

S.D.f

N.S.D.* HNz

Other toxicity

Neurotoxicity (no.) WY)

81k5.6

S.D.t 70&6%

*No significant difference tsignificant difference (P=O.Ol)

In previously untreated Hodgkin’s disease (Table 3) there was no significant difference in the number of patients with objective responses to the two drugs. The median duration of remission for the thiotepa (TSPA) treated cases was 44 + 7.3 days, and for nitrogen mustard cases 81? 5.6 days. The median reduction in tumor size was 36 f 6 per cent for the thiotepa patients and 70 + 6 per cent for those on nitrogen mustard. Both of these differences are significant at the O-01 level. It appeared evident that at the dose studied, thiotepa was less active than nitrogen mustard in Hodgkin’s disease. There were however two disturbing features. The survival time data suggested that patients with thiotepa had a better survival time than those treated with nitrogen mustard, possibly due to earlier disease, and an examination of the maximum white blood cell count changes (Table 4) indicated that although the white counts at the start were essentially the same, the amount of depression was greater for those patients receiving nitrogen mustard than for those receiving thiotepa. Accordingly a second

232

BRUCE

TABLET.

MAXIMUMWHITEBLOOD

I. SENDER

[4]

CELLCOLJNTCHANGES,HODGKIN'SDISEASE

(Medians in thousands) Drug

Number of patients At start

TSPA HN2

11 8*

Count Low

7.6 8.1

Change

4.1 2.9

3.5 5.2

*Data incomplete in one patient.

series of patients was studied in an attempt to obtain a dose-response curve. Patients received a high and low dose of nitrogen mustard or of thiotepa. The high dose of nitrogen mustard was the “standard dose” (0 *4 mg/kg) utilised in our initial study while the low dose was one half this amount. For thiotepa the high dose was twice (0.4 mg/kg/wk) that of the dose used in the initial study (0.2 mg/kg/wk). It was quickly found that this type of design was far superior to the rigid one-dose system. A preliminary evaluation of our results indicates that there is little difference between TABLE 5. ___-.. Lowest WBC (x 1000) dose

rhn.-i*.ln

\F

,

n

,

7

3

. ,

i9/-

..

j

I n

/ -_-_ m

211

Lowest count

...

. .

I/

platelet

( x1000)

,150 100 50 0

Stomatitis, nausea and/or vomiting

I... ~J _~~.._.~L .* . ... = "k... . .&:. . ..I

0 I

... .. ..

0

..

0

.. . .. . 30-min infusions

/ /

per day

I

7

.. / .

/

It

‘j :

.

IT

I

/

.,... . .. q /* . . .\ -c

:!

)

y-x& ..

6-hr

l

!

. .

0

.

--

I

5

5 median * Vertical bar indicates TLoading dose: given in two equal intervals at 7 to 14-doy

doses

24hours

apart

lOllawed

by half

the

loading

dose

Early Human Trials with Anticancer Agents

233

nitrogen mustard at “standard dose” and thiotepa at the higher dose in regard to number of responders, duration of remission and degree of remission [5]. Interestingly, the response rate for the low dose of nitrogen mustard was the same as for the highdosage schedule. We thus have here an example of how the failure to establish a proper dose-response relationship in preliminary studies may affect the resultant clinical evaluation of therapeutic activity. A Phase I study which blended into a Phase II study but which nonetheless served as an adequate basis for the establishment of drug dosage for use in a broad-scale clinical trial might be reflected in the presentation of our experiences with Vinblastine sulfate (Table 5). For all of the schedules, the toxicity of this drug appeared to be dose related. The daily doses in the range of 0 -05 mg/kg produced toxicity comparable to a dose of 0.3 mg/kg/wk. Thus the tolerated dose per unit time was relatively independent of the schedule, being 0 *3 mg/wk on the weekly schedule and 0 *35 mg/kg/wk for the daily schedule. For the loading dose schedule, an initial course of O-3 to 0.4 mg/kg produced toxicity comparable to those already mentioned. There was no evidence of a particular dose schedule being associated with a large proportion of favorable responses. From this study we could establish that a safe but effective dose to be utilized in clinical therapeutic trials was 0 *2-O*3 mg/kg/wk or between 0.02 and 0.05 mg/kg daily. In view of the greater suitability of a single weekly dose schedule for chemotherapeutic trials it was chosen for continuation of our Phase II investigation in preference to a daily dose schedule. ROUTES

OF

ADMINISTRATION

In addition to determining the dosage, the investigator must also determine an effective route of administration. Should a new drug always be given intravenously, or is it feasible to infer from animal data that an oral or intramuscular route may be equally satisfactory? The problem of routes of administration and effective dose level can be appropriately defined as part of the initial pharmacological evaluation of a new agent. In our preliminary studies of cyclophosphamide, the drug was administed orally, intravenously, intramuscuIarly and into body cavities in a variety of dosages and a variety of schedules varying from daily to weekly injections [7]. Tables 6, 7 and 8 indicate dosage schedules and the major routes of administration studied. In evaluating these results, it was evident that the drug produced toxic manifestations by all three routes, oral, intravenous and intramuscular. Up to 9 mg/kg/day were tolerated orally without excessive toxicity. Rather marked nausea and vomiting developed as higher oral dose levels were reached. Three mg/kg intravenously per day appeared to be satisfactorily tolerated without severe toxicity. One could produce mild to moderate toxicity when intravenous doses of 15 to 18 mg/kg were given once weekly. Beyond this, rather marked nausea and vomiting and moderately severe leucopenia or thrombocytopenia occurred. As the study progressed, a pattern of difference between the routes of administration became evident. Approximately 8 per cent objective responses were noted in the patients receiving oral therapy as contrasted with a 25 per cent objective response rate by the intravenous route. No objective responses were seen in the patients receiving drug intramuscularly or by the loading dose schedule. The final analysis of the preliminary data provided a satisfactory dosage schedule and route of administration for the final comparative study of this compound.

234

BRUCE

I. SHNIDER

TABLE 6. EFFECTSOFINTRAVENOUS

DOSES [i']--CYCLOPHOSPHAMDE

Daily doses mg/kg/day 1.5

Days 1842

No. pts.

WBC <3000

7

1

WBC t2000

2.0

5-62

7

1

2

3.0 4.0 6.0 8.0

7-62 4-18 613 3

6 3 2 1

4

26

6

5

1

Pits. < 75,000

1

1 1 1

WBC < 2000 and pits. < 75,000 1 (prior Rx with mitomycin) 1 (prior Rx with myelosuppressive drugs)

Nausea and vomiting 1

1

1

2 2 2

3

6

2 2

1

6

Alopecia

Weekly doses

mzlk

No. doses

3.0

6

6

6.0

3-11

26

3

8.0 9.0

l-6 3-12

4 30

2

12.0

2-7

9

1

14.0

1-6

3

15.0

1-13

18

2

6

16.0 18.0

3-6 1-12

2 13

1 4

1 6

20.0

3-14

9

1

3

21.0

l-11

8

4

3

22.0 24.0 25.0 27.0

2 1-9 l-5 4

2 3 9 3 145

3

1

1 4

1

1

4

1 4

2

2

1

20

25

16

2

2 3

1 3

1

8

3

1

6

5

2 2 3 3

2 3 4 3

3 4 3

12

48

27

235

Early Human Trials with Anticancer Agents DOSES [7]-CYCLOPHOSPHAMIDE

TABLE 7. EFFECIX OF INTRAMUSCULAR

Dose

No. pts.

WBC <3OOO

1

mg/kg

Days

Daily 0.02 0.1 0.5

22 83 39-63

1 1 3

3x/Wk 0.1 0.5 2.5 5.0

40 61-154 56 29-57

1 3 2 4

Weekly 1.0 5-o 10.0 12.0

29-42 49-98 1l-62 35

2 3 2 1

WBC <2OOO

1

mg/kg@y 0.75 1.5 3.0 9.0 18.0 21 .o 27.0

1 1

42 13-42

1 16

7-62 7-21 2 l-3 l-3

9 4 2 2 2

1 1

36

3

2 3 2 2 2

1

1

1

1 3

3

1

1

[7]-CYCLOPHOSPHAMIDE

WBC <2OOO and plts. < 75,000

Nausea and vomiting

1

1

1

3 1 1

1

6

2

Phs. WBC WBC <3OOO <2OOO < 75,000

Days

Alopecia

1

TABLE 8. EFFECTSOF ORALDOSES

No. pts.

Nausea and vomiting

1

23

Daily doses

Pits. < 75,000

2 4 2* 2* 2* 13

Alopecia

4 2 1 1 1 9

Weekly doses No.

=w/k

doses

10.0 15.0 21.0 24.0 27.0

8 4-7 6 4 4

11

1 2

1

1

1

;; 2$ 2$

1 1 2 2

2

9

6

*Nausea and vomiting severe and uncontrolled by antiemetics at doses of 18.0 mg/kg and above. tModerate nausea and vomiting with doses of 15 mg/kg. $Severenausea and vomiting with doses of 21 mg/kg or higher.

236

BRUCE I.

SHNIDER

SUMMARY

The proper measurement of drug action requires the use of the proper dosage of drug. If it is too low, little therapeutic benefit may be seen between the drug and its control in the final comparative study. If the dose is too high, therapeutic effect can be obscured by toxicity. Such toxicity in Phase I studies may prevent subsequent clinical evaluation. A dose-response curve should be established wherever feasible and should encompass the “sensitive” portion of the curve. The route of administration may also affect the therapeutic activity of a compound and should be clearly established as one in which true therapeutic activity can be seen. Proper utilization of these factors is essential to the development of adequate Phase I and Phase II studies of chemotherapeutic compounds in man. Acknowledgement-I wish to acknowledge the important role of the member institutions of the Eastern Cooperative Solid Tumor Group for Cancer Chemotherapy in compiling the data for the studies and articles from which the material this discussion was gathered.

REFERENCES 1. 2.

4.

5. 6.

7.

8.

MODELL, W.: Problems in the Evaluation of Drugs in Man, J. Pharm., Land. 11, 577, 1959. LITCHFIELD, J. T.: Forecasting Drug Effects in Man from Studies in Laboratory Animals, J. Amer. med. Ass. 177, 34, 1961. Clements, J.: Clinical Studies of 6-Azauracil, Cancer Rex 20, 28, 1960. ZUBROD, C. G., SCHNEIDERMAN,M., FREI, E., BRINDLEY, C., GOLD, G. L., SCHNIDER, B. I., OVIEDO, R., GORMAN, J., JONES, R., JONSSON, U., COLSKY, J., CHALMERS, T., FERGUSON, B., DEDERICK. M.. HOLLAND. J.. SELAWRY. 0.. REGELSON. W.. LASAGNA. L. and OWENS. A. H.: Appraisal’of Methods forth; Study of Chemotherapy of Cancer in Man, J. chron. Dk 11, 7, 1960. BRINDLEY, C. 0.: Personal Communication. FREI, E., FRANZINO, A., SHNIDER, B. I., GIOVANNI, C., COLSKY, J., BRINDLEY, C. O., HOSLEY, H., HOLLAND, J. F., GOLD, G. L. and JONSSON, U.: Clinical Studies of Vinblastine, Cancer Chemotherapy Reports, No. 12, 125, 1961. SHNIDER, B. I., GOLD, G. L., HALL, T., DEDERICK, M., NEVINNY, H. B., POTEE, K., LASAGNA, L., OWENS, A. H., HRESCHYSHYN, M., SELAWRY, O., HOLLAND, J. F., JONES, R., COLSKY, J., FRANZINO, A., ZUBROD, C. G., FREI, E. and BRINDLEY, C.: Preliminary Studies with Cyclophosphamide, Cancer Chemotherapy Reports, No. 8, 106, 1960. MODELL, W. and HOUDE, R. W.: Factors Influencing the Clinical Evaluation of Drugs, J. Amer. med. Ass. 167, 2190, 1958.