A PHASE I1 STUDY OF INTRAVENOUSLY- ADMINISTERED METHYL CCNU

I N T H E T R E A T M E N T OF ADVANCED SARCOMAS PAUL CHANG, MD,* MARSHALL A. LEVINE, MD,* PETER H. WIERNIK, MD,+

AND MICHAEL D. WALKER, MD$

Thirty-two patients with advanced, inoperable nonhematologic soft-tissue and osseous sarcomas were treated with Methyl CCNU administered via controlled intravenous infusion in doses of 130-170 mg/m2 every 6 weeks in a Phase I1 trial. All 28 evaluable patients were no longer responsive to adriamycin. Greater than 50% tumor regression was seen in one of two patients with chondrosarcoma and one of five patients with rliabdomyosarcoma. Less than 50% tumor regres- sion occurred in one of five patients with rhabdomyosarcoma, one of two patients with malignant giant cell tumor, and one of three patients with malignant fibrous histiocytoma. Stabilization of previously advancing disease occurred in two of seven patients with leiomyosarcoma. The drug preparation was well tolerated. Nausea and vomiting occurring in three of 32 patients. Major toxicity was myelosuppression, characterized chiefly by thrombocytopenia with lesser de- grees of leukopenia. This drug preparation appears to have minimal activity in this group of tumors.

Cancer 37:615-619, 1976.

HE NITROSOUREA DERIVATIVES WERE FIRST T synthesized in the early 1960's. As a group they have demonstrated significant anti tumor activity against a wide variety of animal tu- mor models. I-(2-Chlorethyl)-3-(4-methyl-cyclo- hexy1)-1-nitrosourea (Methyl CCNU), more- over, has been found to be unique among the nitrosoureas and most cancer chemotherapeu- tic agents because it shows a high degree of effectiveness against the Lewis lung tumor, a slow growing, low growth fraction neoplasm

Presented in part a t the 11th Annual Meeting of the American Society of Clinical Oncology, San Diego, California, May 7, 1975.

From the Section of Medical Oncology, Baltimore Cancer Research Center, National Cancer Institute, Baltimore, Maryland.

* Senior Clinical Associate, Baltimore Cancer Re- search Center.

t Chief, Section of Medical Oncology, Baltimore Cancer Research Center.

t Chief, Baltimore Cancer Research Center. Address for reprints: Paul Chang, MD, Baltimore

Cancer Research Center, University of Maryland Hos- pital, 22 South Greene Street, Baltimore, Maryland 21201.

The authors thank Ms. Christina Strove1 for typing the manuscript and the staff of the Baltimore Cancer Research Center for providing primary care to the patients involved in this study.

with similarities to many human solid tu- mors. 3-5

Delayed bone marrow suppression, particu- larly thrombocytopenia, is the dose-limiting toxicity of orally-administered Methyl CCNU (oral Methyl CCNU).7>l1 However, consider- able variation in this toxicity is seen from patient to patient. Nausea and vomiting, seen in over half the patients taking oral Methyl CCNU7p11 as well as individual differences in drug absorption, could account for this dis- crepancy. Pharmacokinetic studies in man have also shown that virtually no intact Methyl CCNU can be identified in plasma after oral administration,6 suggesting early drug metabolism.

Intravenous administration would ensure uniformity of drug delivery and absorption, and the early hepatic degradation of the par- ent compound could also be obviated. Paren- teral administration of Methyl CCNU has been limited, however, because of its high lipid solubility and low degree of ionization.

Because of these considerations a method of intravenous administration of Methyl CCNU (i.v. Methyl CCNU) was developed at the Baltimore Cancer Research Center, utilizing a 5% ethanol in 10% fat emulsion as the car-

615

616 CANCER February 1976 Vol. 37

rier vehicle.2 Phase I investigations deter- mined an intravenous therapeutic dose a p proximately three-fourths of the equitoxic oral dose.@

Broad Phase I1 trials of oral Methyl CCNU found only five partial responses in 95 evalu- able patients with sarcomas.7~10-11 In contrast three of the seven patients with advanced sar- comas who received i.v. Methyl CCNU in therapeutic doses in the Phase I study had objective tumor shrinkage. The current re- port details these and another 25 patients with sarcoma who received i.v. Methyl CCNU in a disease-oriented Phase I1 study.

MATERIALS AND METHODS

Drug Preparation Methyl CCNU (NSC 95441, supplied by the

Drug Evaluation Branch, National Cancer In- stitute as a sterile powder) was dissolved in an absolute ethanol. This solution was then mixed with the fat emulsion (Intralipid@*) using a mechanical stirrer as previously de- scribed.2

Study Design Thirty-two patients with histologically docu-

mented metastatic or inoperable osseous or soft tissue sarcoma were treated. All but one of these patients had previously received ad- riamycin and were no longer responsive to it. Fifteen patients also had received, and were now unresponsive to streptozotocin. Patients were not excluded because of abnormal blood counts, hepatic, or renal function tests, but were allowed to recover from prior therapy before initiation of i.v. Methyl CCNU.

Intravenous Methyl CCNU was adminis- tered in doses of 130-170 mg/m2 depending on the patients’ blood counts, extent of previ- ous therapy, and granulocyte response to etio- cholanolone stimulation.8 The single previ- ously untreated patient received i.v. Methyl CCNU at 170 mg/m2. Previously treated pa- tients with normal etiocholanolone tests re- ceived 150 mg/m2, and those with abnormal etiocholanolone tests or extensive prior therapy received 130 mg/m2. All courses were given via controlled infusions with a Harvard Pumpf through a running intravenous drip. Blood

Intralipida lo%, supplied by the Drug Evaluation Branch, Division of Cancer Treatment, NCI, through the courtesy of Cutter Laboratories, Inc., Berkeley. CA.

t Harvard Compact Infusion Pump, Model 975, Harvarcl Apparatus, Millis, MA.

pressure and pulse were monitored every 5 minutes during infusion and every 15 min- utes for at least one-half hour afterwards or until stable. Each patient’s initial infusion was over 1 hour; after this was well-tolerated, all subsequent doses were infused over 20 minutes. Doses were repeated every 6 weeks until tumor progression occurred. Signed in- formed consent was obtained prior to initia- tion of therapy.

Follow-up examination and tumor measure- ments were done at least every 3 weeks. Drug toxicity was assessed with twice-weekly CBC and platelet counts, and once-weekly blood chemistries.

Partial response was defined as greater than 50% decrease in the sum of the products of the greatest perpendicular diameters of meas- urable tumors, with subjective improvement, lasting at least 1 month. Improvement was any objective response less than a partial re- sponse. Stabilization was declared only if the patient had previously advancing disease. Pro- gression was an objective increase in tumor size or the appearance of any new lesion.

RESULTS

Tumor Response Twenty-eight of the 52 treated patients

were evaluable for response (Table 1). One patient was excluded because no change was discerned in her slowly-growing neurofibro- sarcoma prior to, during, or after therapy. Five other patients died during the first course of treatment. One of these who died without apparent response on day 21 of adriamycin cardiotoxicity, had no disease at autopsy. It was uncertain in retrospect whether his ab- normal pretreatment chest x ray was due to tumor. Two patients died of progressive dis- ease on days 8 and 9 after i.v. Methyl CCNU and were considered not evaluable because of early death. Two other patients died on days 12 and 17. These patients also had progressive disease and were evaluated as drug failures, since all responses were seen by day 9 in re- sponding patients.

Two of the 28 evaluable patients attained a partial response lasting 84+ weeks in a man with a slowly progressive pelvic myxoid chon- drosarcoma and 14 weeks in a man with rap- idly-growing embryonal rhabdomyosarcoma. Three patients, one each with alveolar rhab- domyosarcoma, malignant giant cell tumor, and malignant fibrous histiocytoma, had tu-

No. 2 I.V. METHYL CCNU FOR SARCOMAS * Chang et al. 617

TABLE 1. Type of Sarcoma Treated and Response to i.v. Methyl CCNU

No. Patients Response (Duration in weeks) Type of Sarcoma Treated Evaluable PR* Improved Stabilized No Response

Leiom yosarcoma 7 7 2 (17, 22) 5 Rhabdomyosarcoma 5 5 1 (14) 1(34) 3 Osteogenic 4 4 4

histiocytoma 4 3 1 ( 8 ) 2 Chondrosarcoma - 2 1 (849 1 Giant cell of bone 2 2 1(12) 1 Liposarcoma 2 2 2 Synovial 1 1 1

Malignant fibrous

7

Other 5 2: 2 TOTAL 32 28 2 3 2 21

* Partial response. + Response continues. * Other = one each: myxofihrosarcoma, mesothelioma.

mor improvement lasting 34, 12, and 8 weeks, respectively. Two other patients (both with leiomyosarcoma) had stabilization of disease.

Favorable effects occurred rather promptly in the responding patients, noted by 4 to 9 days after initiation of treatment in four pa- tients who had objective shFinkage. (The fifth such patient was not seen until the end of his first course of drug and was not evaluable from this aspect.) Although formal perform- ance status was not prospectively recorded, clinical beneficial improvement in patients’ performance was noted only in the two pa- tients who had partial responses. One of these patients was bedridden and the other limited to mobility in a wheelchair because of tumor prior to treatment. With the onset of drug- induced tumor regression, both became fully ambulatory.

All seven patients who had favorable altera- tion of disease progression were previously un- responsive to adriamycin. Three of the seven had also failed streptozotocin. This indicates lack of cross-resistance between i.v. Methyl CCNU and these agents. One other patient with a malignant giant cell tumor whose dis- ease improved with < 50% tumor decrease and pain relief on i.v. Methyl CCNU had had only a transient decrease in pain after a single oral dose of Methyl CCNU 200 mg/m* sev- eral months previously.

Toxicity Acute toxicity was limited to mild to mod-

erate nausea and vomiting in three of the 32 treated patients. This began 4-12 hours after

drug administration, lasted less than 24 hours, and required antiemetics in only one case. One additional patient complained of tran- sient “pins and needles” dysesthesias in the arms and inner thighs a few minutes after injection of the drug had ended. There was no associated dyspnea, chest pain, tetany, or perioral numbness with this symptom, which spontaneously resolved after 15 minutes. No acute blood pressure or pulse changes were noted in any patient.

Myelosuppression was the most serious tox- icity. This necessitated reduction of dosage or delay of a subsequent course of therapy in 6 of 14 patients receiving more than one course. Forty-nine courses of therapy in 25 patients were evaluable for hematologic toxicity (Ta- ble 2). Seven patients’ courses were not evalu- able for toxicity because of early patient death or failure of patients to obtain blood counts.

The median WBC nadir was 2,6OO/pl oc- curring on median day 38 with recovery (>1500 WBC/pl) by median day 42. Two patients developed infections during periods

TABLE 2. Myelmuppression of 49 Courses of i.v. Methyl CCNll (130-170 mg/ma)

Median Range

WBC nadir 2,600,lpI 500-7,600/pl Nadir day 38 8-57 Days to recovery 4 1-24

Platelet nadir 66,0OO/gl 12,000-356,000/pl Nadir day 29 19-53 Days to recovery 9 1-30

618 CANCER February 1976 Vol. 37

TABLE 3. Intravenous Methvl CCNU Myelosuppression by Course

Course No. 1 No. 2 No. 3 No. 4 No. 5

No. of evaluable patients 25 12 7 3 2 WBC nadir't 2,400 2,400 3,600 3,400 3.100

Nadir day* 38 39 38 32 57 Days to recovery* 5 3 4 8 12

Platelet nadir*t 54,000 89,000 82,000 66,000 5 7,000 Nadir day* 28 29 33 3 1 36 Days to recover-y* 9 8 12 9 14

* Median. t Per microliter.

of drug-induced leukopenia. The median platelet nadir was 66,00O/p1 occurring on median day 29 with recovery (>lOO,OOO/pl) by median day 38. Five patients had hemor- rhagic complications secondary to thrombo- cytopenia. These were the only patients who required platelet transfusions.

Examining the overall thrombocytopenia and leukopenia by course (Table 3), there was no discernible pattern of cumulative suppres- sion. Ten patients received two or more drug courses at the same dose and were evaluable for cumulative myelosuppression. Examining the myelosuppression of these patients indi- vidually by course showed that only two had cumulatively greater thrombocytopenia with repeated doses. Cumulative greater leukopenia was seen in only one of these patients-the only patient in this study to show this effect on white cells.

DISCUSSION

The results of this Phase I1 study do not confirm the initially encouraging results of treating advanced sarcomas with i.v. Methyl

TAMX 4. Intravenous Methyl CCNU Hematologic Toxicity by Course and Dose

Course # I # 2 Dose (mg/m*) 150 130 150 130

No. patients 1 1 14 4 6 WRC nadir*t 2,400 2,400 2,500 2,700

Nadir day' 42 3 6 45 31

Platelet nadir*t 41,000 65,000 72,000 71,000 Nadir day* 27 29 31 31 Recovery day* 36 37 3 3 40

* Median. t Per microliter.

Recovery day* 47 43 47 33

CCNU. Of 28 patients, seven had responses. Only the two patients with partial responses showed improvement of their clinical status after therapy. T h e other five patients with lesser responses showed no significant clinical improvement. Several broad Phase I1 studies with oral Methyl CCNU have shown > 50% tumor regression in five of 95 evaluable sar- coma patient~.~JoJl The response rate of sar- comas to IV Methyl CCNU appears to be quite similar.

It is noteworthy that the longest partial re- sponse was in a patient with a chondrosar- coma. While chondrosarcomas generally are slow-growing tumors associated with long sur- vival, they are also characterized by being quite refractory to chemotherapy. The partial response of one of two patients with chon- drosarcoma treated with i.v. Methyl CCNU in this study suggests that i.v. Methyl CCNU may be of some value in treating inoperable or metastatic chondrosarcoma. A further trial of this agent in chondrosarcoma may be war- ranted. It is important to note, however, that the responding tumor was a myxoid chondro- sarcoma, probably of extraskeletal origin, as opposed to the classical chondrosarcoma of the other nonresponding patient. Extraskele- tal myxoid chondrosarcomas have been re- ported to have more benign clinical courses, although their relative responsiveness to chemotherapy has not been analyzed.'

Table 2 shows considerable variability of myelosuppression after i.v. Methyl . CCNU. This occurred despite the alteration of drug dose according to the patient's extent of prior therapy and marrow granulocyte reserves. Fur- thermore, examination of the myelosuppres- sion seen in the 11 patients who received all doses at 130 mg/m2 and the 14 patients who received doses only at 150 mg/m2 shows no difference in the average degree or duration

No. 2 I.V. METHYL CCNU FOR SARCOMAS Chang et al. 619

of this toxicity (Table 4). It thus appears that variation in toxicity among individuals is probably due to differences in cell uptake, drug metabolism, or drug excretion.

Despite this variability, the hematologic toxicity of i.v. Methyl CCNU was acceptable. Additionally, the nausea and vomiting, which occur frequently with oral Methyl CCNU,’Jl were markedly decreased, occurring in only three of 32 treated patients. Delayed bone marrow suppression, the most significant side effect, was similar to that of oral Methyl CCNU and other nitrosoureas,ll with throm- bocytopenia being more severe than leuko- penia, which was more severe than anemia. Thrombocytopenia appeared earlier and lasted

longer than leukopenia. Anemia was fre- quently corrected by transfusions, making quantitation of severity inaccurate. Cumula- tive toxicity which occurs in up to 40% of patients with oral Methyl CCNUll may be less common with i.v. Methyl CCNU, appear- ing in only two of ten patients in this study.

In view of the low response rate of sarcomas to i.v. Methyl CCNU, further trials of this agent in this group of tumors do not appear warranted except perhaps for chondrosar- coma. The low response rate plus the signifi- cant, variable, delayed myelosuppression also make it unlikely that the drug can be success- fully employed in combination chemotherapy of these neoplasms.

REFERENCES

1 . Enzinger, F. M., and Shiraki, M.: Extraskeletal myxoid chondrosarcoma. Hum. Pathol. 3:421-435, 1972.

2. Fortner, C. L., Grove, W. G., Bowie, D., and Walker, M. D.: Fat emulsion vehicle for intravenous administration of an aqueous insoluble drug. Am. /. Hosp. Pharm. 32:582-584, 1975.

3. Johnston, T. P., McCaleb, G. S., Opliger, P. S., and Montgomery, J. A.: The synthesis of potential anti- cancer agents. XXXVI N-nitrosoureas. 11. Haloalkyl derivatives. /. M e d . Chem. 9:892-911, 1966.

4. Johnston, T. P., McCaleb, G. S., Opliger, P. S., Laster, W. R., Jr., and Montgomery, J. A.: Synthesis of potential anti-cancer agents. XXXVIII N-nitro- soureas. IV. Further synthesis and evaluation of halo- ethyl derivatives. /. M e d . Chem. 14:600-614, 1971.

5. Mayo, I. G., Laster, W. P., Jr., Andrews, C. M., et al.: Success and failure in the treatment of solid tumors. 111. “Cure” of metastatic Lewis Lung car- cinoma with Methyl CCNU (NSC 95441) Cancer Chemother. Rep. 56: 183-195, 1972.

6. Sponzo, R. W., DeVita, V. T., and Oliverio, V. T.: Physiologic disposition of I-(2 chlorethyl)-3-cyclohexyl- I-nitrosourea (CCNU) and l-(2-chlorethyl)-3-(4-methyl

cyclohexy1)-1 -nitrosourea (MeCCNU) in man. Cancer 31:1154-1159, 1973.

7. Tranum, B. P., Haut, A., Rivkin, S., et al.: A Phase I1 Study of Methyl CCNU in the treatment of solid tumors and lymphomas-..\ Southwest Oncology Group Study. Cancer 35:1148-1153, 1975.

8 . Vogel, J. M., Kimball, H. R., Wolff, S. M., and Perry, S.: Etiocholanolone in the evaluation of marrow reserves in patients receiving cytotoxic agents. Ann. Intern. Med. 67:1226-1238, 1967.

9. Walker, M. D., Mann-Kaplan, R. S., Sklansky, B. D., Levine, M. A., Weiss, H. D., and Wiernik, P. H.: Toxicity and pharmacology of intravenous Methyl CCNU (I.V. MeCCNU) in man (Phase I). Proceedings of the American Society for Clinical Oncology 14:39, May, 1973 (Abstract).

10. Wassermann, T. H., Comis, R. L., Broder, L. E., Slavik, M., and Carter, S. K.: 1-(2-chlorethyl)-3-(4-methyl cyclohexy1)-I-nitrosourea (MeCCNU), NSC-95441. Clin- ical Brochure (1974).

11. Young, R. C., Walker, M. D., Canellos, G. P., Schein, P. S., Chabner, B. A., and DeVita, V. T.: Initial clinical trials with Methyl CCNU, 1-(2-chlorethyl)-3- (4-methyl cyclohexy1)-1 -nitrosourea (MeCCNU). Cancer 3 1 : 1 164-1 169, 1973.