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`Journal of Immunotherapy
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`11:67-70 © 1992 Raven Press, Ltd., New York
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`A Phase II Study of Recombinant Tumor Necrosis Factor
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`in Renal Cell Carcinoma: A Study of the National Cancer
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`Institute of Canada Clinical Trials Group
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`Jamey Skillings, *Rafal Wierzbicki, tElizabeth Eisenhauer, :j:Peter Venner,
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`§Francois Letendre, "David Stewart, and ~Brian Weinerman
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`Department of Medical Oncology, London Regional Cancer Centre, London, Ontario, Canada; *Section of Medical
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`Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; tDirector, NCIC,
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`Investigational New Drug Program, Kingston, Ontario; :j:Department of Medicine, Cross Cancer Institute,
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`Edmonton, Alberta; §Department of Medicine, Hotel Dieu de Montreal, Montreal, Quebec; "Ottawa Regional Cancer
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`Centre, Civic Division, Ottawa, Ontario; and ~St. Boniface Hospital, Winnipeg, Manitoba, Canada
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`Summary: The National Cancer Institute (NCI) Canada Clinical Trials Group
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`conducted a phase II study of recombinant tumor necrosis factor (rTNF) given
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`intravenously daily for 5 days every other week, in measurable metastatic renal
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`cell carcinoma. Two of 26 patients responded with responses lasting >200
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`days. Toxicity was severe including rigors, fever, headache, fatigue, hypoten(cid:173)
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`sion, and localized pain. We conclude that rTNF, given as described, has only
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`modest antitumor activity in renal cell carcinoma and produces considerable
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`toxicity. We plan no further studies ofrTNF in this disease. Key Words: Phase
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`II-Renal-Tumor necrosis factor-Metastatic.
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`Treatment of metastatic renal cell carcinoma with
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`chemotherapy and progestational agents has been
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`discouraging (1). Only vinblastine sulphate seems
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`minimally effective with an objective response rate
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`of ~20% (1). Early studies of biologic agents have
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`suggested that they may be more promising. Alpha
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`interferon (IFN-alpha) is reported to produce re(cid:173)
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`sponses in 11-26% of patients (2-5). The demon(cid:173)
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`stration of in vitro synergistic effects on colony for(cid:173)
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`mation of IFN-alpha plus IFN-gamma has led to
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`studies showing objective response rates of 28 and
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`24% (complete response two of 29 and four of 29
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`patients studied) (6). Rosenberg et al. (7) docu(cid:173)
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`mented a complete plus partial response rate of 33%
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`Received March 14, 1991; accepted July 15, 1991.
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`Address correspondence and reprint requests to Dr. 1.
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`Skillings at 790 Commissioners Rd. East, London, Ontario, Can(cid:173)
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`ada N6A 4L6.
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`in patients using interleukin-2 plus lymphokine(cid:173)
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`activated killer (LAK) cells. In view of the low ob(cid:173)
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`jective response rate to IFN in the Canadian Study
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`(11 %) and the considerable reported toxicity of in(cid:173)
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`terleukin-2 plus LAK cells, it appeared reasonable
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`to study new biologic agents for renal cell carci(cid:173)
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`noma.
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`The exact mechanism of action by which tumor
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`necrosis factor (TN F) exerts its antitumor effects is
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`not known. It appears to exert its cytostatic effects
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`during the premitotic phase of the cell cycle (G2)
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`and its cytotoxic effects shortly after mitosis (8). A
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`phase I study of recombinant TNF (rTNF) admin(cid:173)
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`istered subcutaneously alternating with intrave(cid:173)
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`nously, was reported to show unacceptably severe
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`inflammation at the subcutaneous site (9). Hypoten(cid:173)
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`sion occurred but was corrected by fluid adminis(cid:173)
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`tration. Intramuscular administration caused simi(cid:173)
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`lar local problems (10). In a phase I trial of intrave-
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`67
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`Breckenridge v. Novartis, IPR 2017-01592
`Page 1 of 4
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`68
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`J. SKILLINGS ET AL.
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`nously-administered rTNF given daily for 5 days,
`the maximum tolerated dose (MTD) was 200 f,Lg/m2
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`with the dose-limiting toxicity being constitutional
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`symptoms and hypotension (11). Low back pain has
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`been reported in several studies in occasional pa(cid:173)
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`tients (12,13) as well as pain localized to tumor site
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`in a single patient (14). A recommended starting
`dose for phase II study was 150 f,Lg/m2 in order to
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`minimize hypotension. In June of 1988, the NCI
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`Canada Clinical Trials Group undertook a phase II
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`study of intravenous rTNF in metastatic renal cell
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`carcinoma.
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`MATERIALS AND METHODS
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`Patients with measurable metastatic renal cell
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`carcinoma who had had no prior chemotherapy,
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`hormonal therapy, or IFN were considered eligible
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`if they met the following criteria: Eastern Cooper(cid:173)
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`ative Oncology Group (ECOG) performance status
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`~2, creatinine ~ 180 micromole (f,LM)/I, bilirubin
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`~27 f,LM/l, calcium ~2.95 f,LM/l, absence of acute or
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`chronic respiratory problems (unless forced expira(cid:173)
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`tory volume in one second and diffuse capacity of
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`carbon monoxide ~70% predicted and arterial p02
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`~70 mm Hg with pC02 35-45 mm Hg), granulocyte
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`count ~ 1.5 x 109/L, platelet count ~ 100 x 109/L,
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`prothrombin time (PT) < 14 s, and partial thrombo(cid:173)
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`plastin time (PTT) <35 s. The study was reviewed
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`by the institutional review board at each participat(cid:173)
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`ing center. Informed consent was obtained from all
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`patients. Patients were excluded if actively in(cid:173)
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`fected, if they had known cardiac disease of New
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`York Heart Association class II or greater, required
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`medication for arrythmia or cardiac disease, had
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`known vascular or thrombotic disease, known
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`bleeding disorder, known lipoprotein disorder,
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`brain metastases or seizures, or Iymphangitic pul(cid:173)
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`monary metastases. Patients with evaluable but not
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`measurable disease were excluded.
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`Recombinant TNF was supplied by Genentech
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`through the Division of Cancer Treatment, National
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`Cancer Institute, Bethesda, MD, U.S.A. with an
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`endotoxin content ~ 1.0 ng of endotoxin per mg of
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`protein. It was given at a starting dose of 150 mi(cid:173)
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`crogram (f,Lg)/m2/day intravenously over 30 min
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`daily, for 5 days every other week, after prehydra(cid:173)
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`tion with 500 ml normal saline given over 60-90
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`min. Patients were observed for 2 h after the first 5
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`daily injections. Chills were managed with meperi(cid:173)
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`dine and hypotension was treated with saline. Tox(cid:173)
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`icity was graded using the common toxicity criteria.
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`J Immunother, Vol. II, No.1, 1992
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`The rTNF dose was reduced by 50% if >20% drop
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`from baseline occurred in the systolic blood pres(cid:173)
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`sure. Other toxicity greater than grade 2 was man(cid:173)
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`aged with a similar dose reduction. Dose escalation
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`was not permitted.
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`Patients were followed every 4 weeks to assess
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`tumor size clinically and/or radiographically. Gran(cid:173)
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`ulocyte and platelet counts as well as chemistries
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`were done on day 5 of the first cycle and days 1 and
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`15 thereafter. PT and PTT were done on day 1 of
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`each 28 day cycle.
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`Response criteria were as follows: complete re(cid:173)
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`sponse (CR): disappearance of all clinical evidence
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`of tumor for a minimum of 4 weeks; partial response
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`(PR): ~50% decrease in tumor size (as measured by
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`the sum of the products of tumor diameters) for a
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`minimum of 4 weeks; stable disease (SD): <50%
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`decrease or <25% increase in tumor size for at least
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`8 weeks; progressive disease (PD); at least a 25%
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`increase in the size of measurable lesions; and/or
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`the appearance of any new lesions.
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`RESULTS AND DISCUSSION
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`Twenty-six patients from seven cancer centers
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`were entered on study. Of these, four were ineval(cid:173)
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`uable for response due to early interruption of ther(cid:173)
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`apy for toxicity for the following reasons: develop(cid:173)
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`ment of symptomatic hypotension with a >40% de(cid:173)
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`crease in systolic blood pressure after initial dose
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`(one patient), grade 4 rigors requiring hospitaliza(cid:173)
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`tion after initial dose (one patient), grade 3 rigors
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`and dyspnea requiring complete bed rest after sec(cid:173)
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`ond dose (one patient), and grade 3 hallucination
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`after fifth dose (one patient).
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`The median age for all patients was 59 years
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`(range 26-75 years). Most patients had a good per(cid:173)
`formance status of EeOG grade 0 (n = 11) and 1 (n
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`= 11). Four patients were entered with a perfor(cid:173)
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`mance status of ECOG grade 2. Eighteen patients
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`were men and eight were women. Radiotherapy had
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`been administered to four patients. Twelve patients
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`had undergone nephrectomy. The location of dis(cid:173)
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`ease commonest was lung (n = 19). Other common
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`sites of tumor included kidney (n = 15), soft tissue
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`(n = 8), bone (n = 6), and abdomen (n = 2). One
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`patient had a pleural effusion and two patients had
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`ascites, but all patients had measurable tumor else(cid:173)
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`where.
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`Ten patients received 10 doses (one cycle), dis(cid:173)
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`continuing therapy due to disease progression. Five
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`patients received 20 doses (two cycles) prior to dis-
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`NOVARTIS EXHIBIT 2091
`Breckenridge v. Novartis, IPR 2017-01592
`Page 2 of 4
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`TNF IN RENAL CELL CARCINOMA
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`69
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`TABLE 1. Phase II study of recombinant tumor
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`necrosis factor in renal cell carcinoma. Most severe
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`toxicityO by patient (n = 26)
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`Arthralgia/myalgia
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`Chest pain
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`Constipation
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`Cardiac dysrhythmias
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`Fever
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`Hypertension
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`Hematuria
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`Hypotension
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`Fatigue/lethargy
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`Localized pain
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`Reaction to i.v. site
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`Nausea
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`Vomiting
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`Confusion/hallucinations
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`Headache
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`Pulmonary
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`Rigors/chills
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`None
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`I
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`0
`I
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`1
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`1
`2
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`0
`8
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`8
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`3
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`0
`8
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`6
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`I
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`7
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`0
`5
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`Grade
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`2
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`1
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`1
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`0
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`0
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`20
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`1
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`0
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`4
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`3
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`4
`I
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`5
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`6
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`0
`8
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`0
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`16
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`2
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`0
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`0
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`1
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`0
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`2
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`1
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`1
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`2
`2
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`0
`I
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`0
`1
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`2
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`1
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`4
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`4
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`0
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`0
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`0
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`0
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`0
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`0
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`0
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`1
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`0
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`0
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`0
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`0
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`0
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`0
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`0
`1
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`I
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`
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`0
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`0
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`0
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`0
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`0
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`0
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`0
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`0
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`0
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`0
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`0
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`0
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`0
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`0
`
`0
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`0
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`0
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`Total
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`4
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`1
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`1
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`2
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`21
`5
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`1
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`14
`13
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`9
`I
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`14
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`12
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`2
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`17
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`2
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`26
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`0
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`a Includes toxicities considered to be "possibly", "prob-
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`ably", or "definitely" related to the drug.
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`ease progression. Five other patients received six,
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`eight, nine, 15, and 23 doses, respectively, before
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`documented progression. The two responding pa(cid:173)
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`tients received 70 and 101 doses, respectively.
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`Hematologic toxicity was minimal with granulo(cid:173)
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`cytopenia occurring in two patients (one with grade
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`1 and one with grade 3). Grade 1 thrombocytopenia
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`occurred in three patients.
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`Nonhematologic toxicity is shown in Table 1.
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`Rigors, fevers, hypotension, nausea, vomiting, and
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`headache were frequently noted. Minor toxicities
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`A
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`occurring in one patient each included grade 1 al(cid:173)
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`lergy, diaphoresis, weakness, and numbness, and
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`grade 2 diarrhea and heartburn. Atrial fibrillation,
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`thought to be drug-related, occurred in a patient
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`leading to withdrawal from study. This arrhythmia
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`resolved with digoxin.
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`Pain occurred in nine patients, most requiring
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`narcotics. Sites of pain included the back most com(cid:173)
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`monly, as well as hips, chest, ribs, and pelvis. In
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`four of the patients, the pain represented an exac(cid:173)
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`erbation of pre-existing pain.
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`Of 10 patients with a normal alkaline phosphatase
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`at baseline, nine developed increases to 2-5 times
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`normal (grade 1), while one developed an increase
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`between 2.6 and 5 times normal (grade 2). An ele(cid:173)
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`vated serum glutamic oxaloacetic transaminase
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`(SGOT) occurred in 10 of21 patients who were nor(cid:173)
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`mal at baseline with three of those having a grade 2
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`elevation. A grade 1 elevation of creatinine oc(cid:173)
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`curred in three of 17 patients , all normal at baseline.
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`Of patients entering the study with biochemical ab(cid:173)
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`normalities, there was one patient who developed a
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`grade 3 (5.1-10 times normal) elevation of alkaline
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`phosphatase and one who developed a grade 3 ele(cid:173)
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`vation of SGOT. No patient demonstrated hyper(cid:173)
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`bilirubinemia.
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`Of 22 evaluable patients, there was a response
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`rate of 8%. One patient with one lung lesion and a
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`metastasis in the contralateral kidney after nephrec(cid:173)
`tomy had a CR lasting 204 days (Fig. O. He re(cid:173)
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`lapsed in the left lung at a site previously unin(cid:173)
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`volved without relapse at the initial sites of disease.
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`Most of his treatment was given at 25% of the initial
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`dose because of the severity of the pain occurring
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`just after the rTNF infusion. A second patient had
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`FIG. 1. A: CT abdomen prior to therapy with tumor in the remaining kidney. B: CT after completion of therapy showing complete
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`response in the right kidney.
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`J Immunother, Vol. 11, No.1, 1992
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`NOVARTIS EXHIBIT 2091
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`70
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`J. SKILLINGS ET AL.
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`B
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`FIG. 2. A: CT abdomen prior to therapy showing a large tumor in the right kidney. B: CT abdomen after rTNF therapy prior to
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`resection.
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`an objective PR in the primary kidney lesion (Fig. 2)
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`with near complete regression of lung nodules and
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`an "improved" bone scan. His primary tumor was
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`resected and showed extensively necrotic, moder(cid:173)
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`ately-to-poorly differentiated renal cell carcinoma
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`with extensive areas of fibrosis and hemosiderin
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`formation at the margins of the tumor. He continues
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`in remission after >2 years.
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`CONCLUSION
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`Recombinant TNF caused moderate to severe
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`toxicity, and produced a low response rate. It is
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`noteworthy, however, that both responses occurred
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`in patients with significant renal masses and were
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`quite durable. We conclude that single agent rTNF,
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`given as described in this study, has only limited
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`activity in renal cell carcinoma. We have no plans
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`to study this agent further in this disease.
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`Acknowledgment: This research was supported by a
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`grant from the NCI of Canada. We thank the following
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`individuals who, in addition to the authors, contributed
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`patients to the study: Dr. Susan Aitken, Ottawa Regional
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`Cancer Centre, Civic Division, Ottawa, Ontario; Dr. Li(cid:173)
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`onel Israels, Manitoba Cancer Treatment and Research
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`Foundation, Winnipeg, Manitoba; Dr. Ronald MacCor(cid:173)
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`mick, Nova Scotia Cancer Treatment and Research
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`Foundation, Halifax, Nova Scotia; and Dr. Michael Thirl(cid:173)
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`will, Montreal General Hospital, Montreal, Quebec. We
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`thank the NCI (U.S.A.) and Genentech for provision of
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`the drug, and Maggi Stawarski for secretarial assistance.
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`NOVARTIS EXHIBIT 2091
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