II Study of Recombinant Interferon Gamma in Advanced Renal Cell Carcinoma

0022-534 7 /88/1392-0251$02.00/0

Vol. 139, February

THE JOURNAL OF UROLOGY

Copyright© 1988 by The Williams & Wilkins Co.

Printed in U.S. A.

PHASE I/II STUDY OF RECOMBINANT INTERFERON GAMMA IN ADVANCED RENAL CELL CARCINOMA MARC B. GARNICK, STEVEN D. REICH, BARBARA MAXWELL, SHERRIE COVAL-GOLDSMITH, JEROME P. RICHIE AND SETH A. RUDNICK From the Departments of Medicine and Surgery, Harvard Medical School, Division of Medicine, Dana-Farber Cancer Institute and Division of Urology, Brigham and Women's Hospital, Boston, and Biogen Research Corporation, Cambridge, Massachusetts

ABSTRACT

A phase I and II evaluation of 42 patients with advanced renal cell carcinoma treated with recombinant interferon gamma was done. Patients were treated with either a daily 2-hour infusion or 24-hour infusion for 7 days every 3 weeks for at least 2 cycles. Patients who demonstrated stable disease or improvement on therapy then were continued on a maintenance program of 5 days of recombinant interferon gamma administered every 3 to 4 weeks. The initial starting dose was 10 mcg. per m. 2 per day with escalations to 30, 100, 300, 1,000 and 3,000 mcg. per m. 2 • Dose-limiting toxicity occurred at 1,000 to 3,000 mcg. per m. 2, and included leukopenia, chills, fevers, rigors and hepatotoxicity as manifested by elevation in the transaminase and bilirubin levels. Tumor responses were seen initially at the 300 mcg. per m. 2 dose level. Over-all, of 41 patients evaluable for therapeutic effectiveness 1 demonstrated a complete response 6 months in duration and 3 demonstrated partial responses 2, 9 and 13 months in duration. However, 6 patients demonstrated organ site responsiveness, including resolution of pulmonary lesions (2 complete and 1 partial responses), lymphadenopathy (1 complete and 1 partial responses), a pleural-based lesion in 1 patient with a partial response and complete resolution of hepatic metastases in 1 patient. We conclude that recombinant interferon gamma at a dose of 1,000 to 3,000 mcg. per m. 2 for 7 days and repeated every 2 to 3 weeks had demonstrable anticancer activity in patients with metastatic renal carcinoma. (J. Ural., 139: 251-255, 1988) Interferons are a family of naturally occurring protein molecules with antiviral, antiproliferative and immunomodulating properties. Interferon-')' is a member of this family and it is available for clinical trials through recombinant deoxyribonucleic acid technology. Pre-clinical studies demonstrated that the activities of the recombinant molecule are similar to those of the naturally occurring material even though the recombinant molecule lacks the sugars that are part of the natural interferon. Interferon-')' appears to have greater antitumor effects compared to those of other interferons in pre-clinical and in vitro systems. 1• 2 In vitro studies demonstrate that the activities of interferon-')' are greatest when target cells are incubated for prolonged periods. 3 Animal studies show that the antitumor effects are mediated by a direct cytotoxic effect and an indirect, immunologically mediated effect. The direct effects are greatest as dose is increased. Interferon-')' has activity against renal cell carcinoma in model systems. 4 Approximately 19,000 cases of renal cell carcinoma will be diagnosed in the United States in 1987, with 9,000 deaths. Although radical nephrectomy is effective for cancer that is limited to the kidney parenchyma, metastatic disease is refractory to nearly all forms of systemic therapy. Consequently, centers caring for patients with metastatic renal cell cancer have focused on investigational agents and approaches. 5 •6 We determine the clinical effect of recombinant interferon'¥ in the management of patients with metastatic renal cell carcinoma. Because of the apparent need for prolonged contact of interferon-')' with target cells to reach maximal biological effects, the trial was designed to compare short-term (2-hour) daily infusions with continuous ii.fusions. Accepted for publication July 20, 1987. Supported in part by a grant from the Biogen Research Corporation. Read at annual meeting of American Urological Association, New York, New York, May 18-22, 1986.

MATERIALS AND METHODS

Lyophilized human recombinant interferon-')' containing 146 amino acids with an amino acid sequence of cysteine, tyrosine and cystine at the N-terminus was used. Material was supplied in vials of 100, 500 and 1,000 mcg. with greater than 97 per cent purity and less than 1 ng. per vial endotoxin. The specific activity was approximately 20 million antiviral units per mg. protein. The terminal half-life in normal volunteers was calculated at 6 hours.* Patient selection. A total of 42 patients with stage IV renal cell carcinoma was entered onto this phase I and II trial. Of the 42 patients 30 had undergone prior nephrectomy (table 1). All but 1 patient had either bidimensionally measurable or evaluable (for example malignant effusion or bone lesion) disease. One patient had been rendered surgically free of disease after multiple resections of pulmonary and central nervous system nodular metastases before entry into the trial. All patients were evaluated with a detailed history, physical examination and appropriate radiographic studies of sites of metastatic disease, including chest x-ray, computerized tomography of the abdomen, pelvis and head, and appropriate nuclear medicine scans. Index lesions were bidimensionally measured by 1 of us (M. B. G.). Patients were required to have a life expectancy of at least 4 months and a performance status on the Eastern Cooperative Oncology Group (ECOG) scale of Oto 2, and to be between 18 and 80 years old. All patients gave written informed consent. Patients who were on concurrent anticancer therapy were excluded. All patients were required to have a white count of greater than 4,000/mm.3, granulocytes greater than 1,500/mm.3, platelets greater than 100,000, hemoglobin greater than 10 gm./100 ml., creatinine clearance greater than 50 ml. per minute, serum creatinine less than 2

* Biogen Report C84-049R, Biogen Research Corp., Cambridge, Massachusetts. 251

252

GARNICK AND ASSOCIATES TABLE

1. Patient characteristics

No. treated: Evaluable for response, 41 Evaluable for toxicity, 42 Male/female pts. Age range Previous treatment: Nephrectomy Radiotherapy Chemotherapy Steroids Hormonal therapy Immunotherapy No previous treatment ECOG performance status Median mos. from diagnosis to metastatic disease No. cycles of recombinant interferon-y given (range/median/mean)

42

32/10

37-74 30 10 6

1 6

7 7 0-2 5

1-19/2/5.4

mg./dl., total bilirubin less than 2.5 mg./dl., or serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase and alkaline phosphatase levels of less than 2 times the upper limit of normal. The purpose of our study was to determine the maximally tolerated dose of recombinant interferon-r by 1 of 2 schedules and to assess antitumor activity once the maximally tolerated dose has been achieved. Dosage and administration schedule. All patients received an initial 7-day course of intravenous recombinant interferon-r in the hospital, followed by a 2-week break and a second 7-day course. Patients were allocated randomly to receive either a 24hour continuous infusion per day or a 2-hour infusion per day during the 7 days of administration. Patients were evaluated for response after a 28-day rest after cycle 2 (fig. 1). Patients with complete, partial or minor responses, or stabilization of disease entered a maintenance program at the same dose level consisting of a 2-hour infusion per day for 5 days every 3 to 4 weeks. Those with progressive disease received no further recombinant interferon-r. Dose levels were 10, 30, 300, 1,000 and 3,000 mcg./m. 2 per day for 7 days with no intra-patient dose escalations. Six patients were entered at each dose level (3 on the 24-hour continuous infusion schedule and 3 on the 2-hour infusion schedule), except for the 3,000 mcg./m. 2 per day level in which 6 additional patients were entered on the 2-hour schedule to define further toxicities. The protocol was modified after the entrance of patient 31 to shorten the original 4-week rest period after cycle 2 of infusions to 2 weeks so that patients could enter maintenance treatment in a more timely fashion. Patients demonstrating regression of tumor or stabilization of disease after 2 cycles of treatment were entered on the maintenance program (fig. 1;. Toxicity assessment. Toxicity was scored according to World Health Organization guidelines. 7 Treatment was discontinued at the appearance of life-threatening toxicity. The maximally tolerated dose was to be determined if one of the following occurred: 1 patient suffered severe toxicity (according to World Health Organization criteria) and 1 had moderate toxicity, 3 patients had moderate toxicity or 1 patient had dose-dependent severe toxicity that was not reversible within 3 weeks. Alternatively, a maximally tolerated dose was to be defined if 5 patients were treated in the same dose group and the addition of the last 2 patients resulted in 1 additional severe toxicity with 2 previous moderate toxicities. Evaliwtion of response. For patients with bidimensionally measurable lesions a complete response required that all lesions disappear for at least 1 month. A partial response required that the sum of the products of the diameters of each selected lesion decrease by 50 per cent or more with no lesion increasing in size. Patients were categorized as being stable if there was no progression of disease, or evidence of partial or complete response. Patients in the stable disease category are listed as

nonresponders, since this category has little biological meaning for renal cell cancer. Patients who demonstrated a minor response, that is with tumor shrinkage but less than that for a partial response, were categorized in the stable group. Progressive disease was defined as either the appearance of new lesions or a 25 per cent or more increase in the sum of the products of the diameters for each lesion measured. For unidimensional lesions progression was considered an increase of 50 per cent or more of 1 measurement. In addition to patients being analyzed with standard criteria, all sites of metastatic disease were listed per patient and each organ specific site was analyzed separately. Therefore, a patient who had complete disappearance of pulmonary lesions but no regression of an in situ kidney lesion was described as having a complete regression in the lung but with an over-all response of stabilization of disease. Because previous data had suggested that primary kidney lesions rarely if ever respond to systemic therapy, we believed that a more detailed analysis of the biological activity could be obtained by assessing not only standard response criteria but also organ site specific responsiveness. Patient characteristics. Table 1 shows the patient characteristics. All 42 patients were evaluable for toxicity and 41 were evaluable for response. There were 32 men and 10 women between 37 and 76 years old (mean age 58 years). Sites of metastatic disease included the lung, pleura or mediastinum in 33 patients (80 per cent), lymph nodes in 9 (22 per cent), bone in 8 (20 per cent), kidney in 6 (15 per cent), liver in 3 (7 per cent) and other sites in 2 (5 per cent). Previous therapy included nephrectomy in 30 patients, radiation to either the primary anatomical location or a metastatic site in 10, previous chemotherapy in 6, steroids in 1 and prior hormonal therapy in 6.

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24° CI

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FIG. 1. Study schema. Patients were allocated randomly to receive 24-hour continuous infusion (CJ) or 2-hour infusion for 7 days (d X 7). After re-evaluation after second 7-day cycle, patients were offered maintenance therapy if they had complete regression (CR), partial regression (PR), minor response (MR) or stabilization of disease (SD). Patients who suffered progressive disease (PD) went off study. Maintenance therapy included 2-hour infusion (INF) for 5 days every 3 to 4 weeks.

253

I?~TER,FERor,lS FOR RENAL CELL CA.~'1CEH

Five ,--V"'""··v had received trial of a-interferon (reco1nbir.sant and nomecombinant), 2 had received immune ribonucleic acid therapy and 7 had received no previous therapy, The interval between diagnosis and the development of metastatic disease was O to 11 years, with a median for 5 months, All patients were O to 2 on the ECOG performance scale, The number of cycles of interferon received ranged from 1 to 19, with a median of 2 and a mean of 5,4, Statistical methods. The survival distribution was estimated with the Kaplan-Meier product-limit method. Differences between groups in survival were tested for statistical significance with the log-rank test. RESULTS

Toxicity. Side effects characteristic of other interferons were noted with the use of recombinant interferon-')'. Tables 2 and 3 demonstrate the hematological and nonhematological abnormalities. The nonhematological abnormalities are broken down by 2-hour or 24-hour infusion. World Health Organization criteria were used. Three individuals received less than 14 days of interferon treatment because of the development of lifethreatening toxicity (hepatotoxicity, acute respiratory compromise and hypotension). All clinical toxicities were reversible within 2 to 3 weeks after discontinuation of recombinant interferon-')'. Hepatotoxicity as characterized by marked abnormalities in liver function studies, especially the alkaline phosphatase and transaminase levels, took approximately 6 weeks to return to normal in 1 patient after discontinuation of the drug. This patient was treated at a dose of 3,000 mcg./m. 2 • Hepatotoxicity developed 5 days into the initial treatment cycle. Mild hyperglycemia was noted frequently on random blood glucose determinations. No patient required any hypoglycemic therapy for such elevations. When noted, proteinuria usually was mild, with 1 exception. One patient who received maintenance therapy for 1 year suffered acute interstitial nephritis and marked proteinuria, which resolved after discontinuation of the drug. Myelosuppression tended to occur usually during week 1 of interferon administration. In patients in whom the drug was discontinued because of leukopenia the white blood count returned to normal within 3 days. The maximally tolerated dose was 3,000 mcg./m. 2 intravenously on days 1 to 7 as a 2-hour continuous infusion. When given as a 24-hour continuous infusion this dose produced unacceptable toxicity in terms of myelosuppression and constitutional symptoms. However, 1 mg./m. 2 on days 1 to 7 given either as a 2-hour or a 24-hour infusion was tolerated. Response. With standard response criteria 22 patients were categorized as having stable disease, 3 had a partial response (for 2, 9 and 13 months, respectively), 1 had a complete response (6 months) and 15 had progression of disease (table 4). To date 16 patients are alive, including 15 with active disease and 1 rendered free of disease by an operation. A total of 26 patients died of metastatic renal cancer. The organ specific response criteria are demonstrated in table 5. One patient with a complete response in a supraclavicular TABLE

Total No. Total No. Fever Chills/rigors Nausea/vomiting Anorexia Myalgias/arthralgias Headaches Proteinuria Hyperglycemia Transient mental status changes

42 39 30 23 8 11 16 21

37 7

node withdrew because of intolerance to the after initiation of cycle 1 of recombinant ird-c,,-t",o,-CW>-M, While off therapy the patient subsequently had relapse in the original area of supraclavicular lymphadenopathy. This patient was treated with another cycle of recombinant interferon-')' and again a response in the supraclavicular lymph node was demonstrated, One patient who presented with a resected brain metastasis, advancing liver metastases and in situ kidney cancer had complete remission of the liver metastases. While on a maintenance program of recombinant interferon-,y, the kidney lesion grew and required embolization to prevent intractable hematuria. The response in the liver was continued for greater than 14 months and the patient still is receiving treatment. Table 5 outlines the individual anatomical areas that underwent disease regression and the duration of such regression. As indicated previously, patients were analyzed with classical response criteria. It is of interest that 1 patient had complete resolution of pulmonary nodules with stabilization of disease in the kidney. This patient was rendered free of disease by nephrectomy and there has been no evidence of disease for greater than 10 months. Neutralizing antibodies. Samples for neutralizing antibody were collected before treatment and again after cycle 1 of therapy. No neutralizing antibodies were induced. In several patients samples were taken after cycle 2 of treatment and no TABLE

10 Meg.

100 Meg.

300 Meg,

1,000 Meg.

3,000 Meg.

4

3 1

4 3 1

6 0 1

0 0

0 0

5 1 2 1 1

11 3 5 3 0

2 2 0 0 0

Total Mild Moderate Severe Life threatening

TABLE 4.

3. Myelosuppression

30 Meg,

5 0

Results of treatment in 41 patients Duration (mos.)

Dose (mcg./ m.')

No.(%)

Responders: Complete Partial

1

2

Median

6

2, 9, 13

6 9

1, 8

4

(2.4)

3 (7.3)

Nonresponders: Minor tumor regression Mixed regression Stable disease Progressive

Actual

(7.3)

20 (48.7) 15 (36.5)

1, 16

6

0

()

Recombinant Interferon-,) Schedule (hrs.) 3,000/2 300/2, 1,000/2 and 3,000/ 24*

* The dose level and schedule of the 3 patients with a partial response.

2. Adverse effects according to dose schedule

10 Meg.

30 Meg.

100 Meg.

300 Meg.

1,000 Meg.

3,000 Meg.

2 Hrs.

24 Hrs.

2 Hrs.

24 Hrs.

2 Hrs.

24 Hrs.

2 Hrs.

24 Hrs.

2 Hrs.

24 Hrs.

2 Hrs.

24 Hrs.

3 2 2 1 0 0 1 1 1 0

3

3 3 3 1 0 0 0 1

3 3 0 1 0 0 0 1 2 0

3 2 3 1 1 1 1 0

3

3 3 2 2 0 0 0 2 3 0

3

3

3 3 2

3

3 3

9 8 8

3

3 0

0 0 0 0 0 2 0

3 0

3 0

3 0 2 0 1 3 1

3 1

0 0 2 2 3 1

3 1 0 1 2 2

3 0

3 2 0 1 2 2 3 0

6 5

5 4 6

3 3 4 2 2 1

8

3 3

3

2

254

GARNICK AND ASSOCIATES TABLE 5.

Pt. No.

Site

27 29

Lungs Rib Periaortic lymph node Liver

31

Mediastinum Lungs

21

32 34

Complete Partial Partial Complete Stable Partial

Multiple pulmonary lesions 2X3cm. 6 x 8 cm. 1.9 X 1 cm. 2.5 X 2.3 cm.

Complete Stable Complete Complete

Followup Measurement 0 x O cm. Not done 1.4 x 1.4 cm. Scan within normal limits

\ \

~

71

I

\

14 mos. 2 mos.

>50% reduction in No. and size of lesions 0 XO cm. 6 X 8cm. 0 x O cm. 0 x O cm.

6 mos. 4 mos. to nephrectomy 10+ mos.

---,, --------------.

. ______ ------------------~,..._,

- - - - - - - ~ B 0.61 A

I

I

1

'-------------------

B O .s 1 L O .4

"j

~

~

v

9mos. 3.5 wks. 13 mos. 14+ mos.

~

0.B P I R 0.

0.3

Duration of Response

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0.91

Q

Response

2.1 x 2.6 cm. Evaluable 3.0 x 1.8cm. 3 X 4 cm. scan defeet

Supraclavicular node Kidney Lungs

1.0

Organ site response

Initial Measurement

I

:::L~···························a··········~, .... ,......... . 0

100

200

300

400

500

600

700

DAYS AFTER FIRST DOSE

FIG. 2. Survival estimates as function of dose. Dotted line represents patients receiving doses of 300 mcg./m.2 or more and includes population treated at 300, 1,000 and 3,000 mcg./m.2. Solid line represents patients treated at 10, 30 or 100 mcg.jm. 2 (p not significant by log-rank test). Survival distribution was estimated using Kaplan-Meier product-limit method. Differences between groups in survival were tested for statistical significance using log-rank test.

antibodies were found. The assay to measure neutralizing antibodies measures the ability of exogeneously added recombinant interferon-"( to inhibit infection of Wistar Institute, Susan Hayflick (WISH) cells by encephalomyocarditis virus. If neutralizing antibodies are absent the recombinant interferon-"( will protect against infection of WISH cells by encephalomyocarditis virus. If neutralizing antibodies are present infection of WISH cells by encephalomyocarditis virus will occur. 8 • 9 DISCUSSION

This was the initial phase I and II study of recombinant interferon-"( for patients with metastatic renal cell cancer. Although there are dose and nondose-related toxicities, the side effect most troublesome to individuals was the onset of fever and rigors at the 3,000 mcg./m. 2 dose level. Of the patients 17 per cent had World Health Organization grade 3 fever and 50 per cent had grade 3 rigors. Isolated instances of hypotension, development of respiratory distress with a clinical situation mimicking acute pulmonary embolism and severe hepatotoxicity occurred in 3 individuals treated at the highest dose of the drug, which caused immediate discontinuation of treatment before completion of the 2 full treatment cycles. All but 1 patient in the study were evaluable for disease regression. Primary kidney lesions did not undergo any significant tumor regression even in patients whose peripheral disease, such as pulmonary parenchyma or lymphadenopathy, clearly responded. This has been noted in other studies with other interferon preparations. 10• 11 Pulmonary, lymphatic and in 1 case hepatic metastases all responded to therapy. No patient with osseous metastases or other visceral metastases outside of the lung, liver and lymphatics demonstrated any

meaningful disease regression. Likewise, patients whose tumor burden was minimal with a good performance status had a higher likelihood for a more durable response. In an earlier study with recombinant a-interferon Quesada and associates noted that a higher degree of complete or partial remission was seen in individuals with disease limited to the lung and these patients may indeed fare more favorably than those with extrathoracic metastases. 11 We could not determine whether prior nephrectomy enhances the likelihood of obtaining tumor response. Although we cannot make any definite conclusions relating to the impact of treatment on over-all survival, the median duration of survival for patients treated at the higher dose levels (greater than 300 mcg./m. 2 ) has not been reached, compared to a median duration of survival of 1 year for patients treated at the lower dose level (less than 300 mcg./m. 2 ). Survival estimates by dose received are shown in figure 2. The distinction between doses of less than 300 and 300 or greater mcg./ m. 2 was made since the first clinical response in this study was noted at the 300 mcg./m. 2 dose. Our results differ from those of Vadhan-Raj and associates 12•13 in terms of maximally tolerated dose. In a recently reported phase I trial of recombinant interferon-"( that used a different preparation of the interferon a maximally tolerated dose of 500 mcg./m. 2 per day for 5 days given for 2 weeks was noted. 12 Although we gave a 7-day course the doses of interferon were substantially higher with our maximally tolerated dose of 3,000 mcg./m. 2 • However, the quantitative and qualitative side effect profile reported in the studies of VadhanRaj and associates was similar to our own. In summary, recombinant interferon-"( can be administered safely to individuals with metastatic renal cancer, with a max-

------

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INTERFERONS FOR RENAL CELL CANCER

imally tolerated dose of 3,000 mcg./m. 2 on days 1 to 7 given as a 2-hour infusion. The antitumor responses in this disease definitely indicate clinical activity of recombinant interferon-y. Individuals with pulmonary, lymphatic and in 1 case hepatic metastases characterized our population of responding patients. Osseous and primary renal lesions were refractory to disease treatment. These results extend the spectrum of activity for interferons in renal cancer, clearly demonstrating anti-tumor activity with the use of recombinant interferon--y. Areas for future investigation should expand the dose and schedule of various interferons, as well as possibly combining recombinant interferon--y with other biological response modifiers. 14• 15 REFERENCES

1. Rubin, B. Y. and Gupta, S. L.: Differential efficacies of human type I and type II interferons as antiviral and antiproliferative agents. Proc. Natl. Acad. Sci., 77: 5928, 1980. 2. Talmadge, J. E., Tribble, H. R., Pennington, R. W., Phillips, H. and Wiltrout, R. H.: Immunomodulatory and immunotherapeutic properties of recombinant y-interferon and recombinant tumor necrosis factor in mice. Cancer Res., 47: 2563, 1987. 3. Dianz~ni, F., Salter, L., Fleischmann, W. R., Jr. and Zucca, M.: Immune interferon activates cells more slowly than does virusinduced interferon. Proc. Soc. Exp. Biol. Med., 159: 94, 1978. 4. Otto, U., Huland, H. and Zschaber, R.: Recombinant interferon gamma: first results of a clinical phase II study in patients with metastatic renal cell carcinoma and experimental studies of human renal cell carcinoma transplanted into nude mice. J. Urol., part 2, 133: 155A, abstract 168, 1985. 5. Richie, J.P. and Garnick, M. B.: Primary renal and ureteral cancer. In: Cancer and the Kidney. Edited by R. E. Rieselbach and M. B. Garnick. Philadelphia: Lea & Febiger, chapt. 17, pp. 662-706,

1982. 6. Garnick, M. B. and Brenner, B. M.: Tumors of the urinary tract. In: Harrison's Principles of Internal Medicine, 11th ed. Edited by E. Braunwald, K. J. Isselbacher, R. G. Petersdorf, J. B. Wilson, J.B. Martin and A. S. Fauci. New York: McGraw-Hill Book Co., sect. 2, part 6, chapt. 231, pp. 1218-1221, 1987. 7. WHO Handbook for Reporting Results of Cancer Treatment. WHO Offset Publication No. 48. World Health Organization, Geneva, Switzerland, 1979. 8. Green, J. A., Yeh, T.-J. and Overall, J.C., Jr.: Rapid, quantitative, and semiautomated assay for virus-induced and immune human interferons. J. Clin. Microbiol., 12: 433, 1980. 9. Yeh, T.-J., McBride, P. T., Overall J. C., Jr. and Green, J. A.: Automated, quantitative cytopathic effect reduction assay for interferon. J. Clin. Microbiol., 16: 413, 1982. 10. Quesada, J. R., Swanson, D. A., Trindade, A. and Gutterman, J. U.: Renal cell carcinoma: antitumor effects of leukocyte interferon. Cancer Res., 43: 940, 1983. 11. Quesada, J. R., Rios, A., Swanson, D., Trown, P. and Gutterman, J. U.: Antitumor activity of recombinant-derived interferon alpha in metastatic renal cell carcinoma. J. Clin. Oncol., 3: 1522, 1985. 12. Vadhan-Raj, S., Al-Katib, A., Bhalla, R., Pelus, L., Nathan, C. F., Sherwin, S. A., Oettgen, H. F. and Krown, S. E.: Phase I trial of recombinant interferon gamma in cancer patients. J. Clin. Oncol., 4: 137, 1986. 13. Vadhan-Raj, S., Nathan, C. F., Sherwin, S. A., Oettgen H. F. and Krown, S. E.: Phase I trial of recombinant interferon gamma by 1-hour LV. infusion. Cancer Treat. Rep., 70: 609, 1986. 14. Neidhart, J. A.: Interferon therapy for the treatment of renal cancer. Cancer, 57: 1696, 1986. 15. Fossa, S. D., de Garis, S. T., Heier, M. S., Flokkmann, A., Lien, H. H., Salveson, A. and Moe, B.: Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma. Cancer, 57: 1700, 1986.