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`J.P. Donnelly et al.
`
`norfloxacin for selective decontamination in patients with severe
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`Infect Dis 1990, 3, 197-202.
`15. Pizzo PA, Hathorn JW, Hiemenz J, et al. A randomized trials
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`in cancer patients with fever and neutropenia. N Eng[J Med 1986,
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`Microbiol Rev 1989, 2, 329-353.
`17. Weightman NC, Simpson EM, Speller DCE, Mott MG, Oakhill
`A. Bacteraemia related to indwelling central venous catheters:
`prevention, diagnosis and treatment. Eur J Clin Microbiol Infect
`Dis 1988, 7, 125-129.
`18. EORTC International Antimicrobial Therapy Project Group.
`Gram-positive bacteraemia in granulocytopenic cancer patients. Eur
`J Cancer 1990, 26, 569-574.
`19. Press OW, Ramsey PG, Lasrson EB, Fefer A, Hickman RO.
`Hickman catheter infections in patients with malignancies. Medicine
`1984, 63, 189-200.
`20. Weisman SJ, Scoopo FJ, Johnston GM, Altman AJ, Quinn JJ.
`Septicemia in pediatric oncology patients: the significance of virid(cid:173)
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`21. Kern W, Kurrie E, Schmeiser T. Streptococcal bacteremia in adult
`patients with leukemia undergoing aggressive chemotherapy: a
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`
`22. Cohen J, Donnelly JP, Worsley AM, Catovsky D, Goldman JM,
`Galton DAG. Septicaemia caused by viridans streptococci in neu(cid:173)
`tropenic patients with leukaemia. Lancet 1983, ii, 1452-1454.
`23. Furneri PM, Tempera G, Caccamo F, Speciale AM. In vitro activity
`of ciprofloxacin against clinical isolates and standard strains of
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`24. Verhagen C, Stalpers LJ, De Pauw BE, Haanen C. Drug-induced
`skin reactions in patients with acute non-lymphocytic leukaemia.
`Eur J Haematol 1987, 38, 225-230.
`25. Pizzo PA. After empiric therapy: what to do until the granulocyte
`comes back. Rev Infect Dis 1987, 9, 214-219.
`26. De Pauw BE. Antibacterial therapy in the immunocompromised
`host. Cu"Opinion Infect Dis 1989, 2, 561-567.
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`crobial strategy in febrile neutropenic patients. Results of a multi(cid:173)
`center study in 1260 patients with hematological malignancies.
`Onkologie 1990, 13, 38-42.
`
`Acknowledgements-The authors would like to thank the patients and
`clinical and laboratory staff in each of the hospitals for their cooperation.
`We are indebted to Bayer and their representatives, Dr J Branholte
`(The Netherlands) and to Dr J.W. Busch (Germany) for their active
`participation and to Dr P.J. Heidt, secretary to the EORTC Gnotobiotic
`Project Group, who undertook the major part of organising and adminis(cid:173)
`trating the groups activities.
`
`Eur]Cancer, Vol. 28A,No. 415,pp. 878-880, /992.
`Printed in Great Bruain
`
`0964-/947192 $5.00 + 0.00
`© /992 Pergamon Press Ltd
`
`Vinblastine in Metastatic Renal Cell Carcinoma:
`EORTC Phase II Trial 30882
`Sophie D. Fossa, Jean-Pierre Droz, Michele M. Pavone-Macaluso,
`Frans J.J. Debruyne, Karine Vermeylen, Richard Sylvester and the
`members of the EORTC Genitourinary Group.
`
`32 patients with metastatic renal cell carcinoma (MRCC) who had had no prior chemotherapy received vinblastine
`0.15 mg/kg intravenously once weekly for 6 weeks, thereafter every second week, provided no major toxicity.
`Dose modifications were based on haematological and neurological side-effects. Only one complete response
`was observed among 26 evaluable patients (response rate: 4%; 95% confidence interval: 0-20%). 4 out of 29
`patients developed grade 3 leukopenia. Grade 3 peripheral neurotoxicity was recorded in 2 patients. 2 patients
`had grade 3 alopecia. Vinblastine has no major significance on the clinical management of MRCC.
`Eur J Cancer, Vol. 28A, No. 4/5, pp. 878-880, 1992.
`
`INTRODUCTION
`THE EFFICACY of chemotherapy in metastatic renal cell carci(cid:173)
`noma (MRCC) has been limited [l, 2]. Vinblastine has been
`reported to be the most active drug [3] with claimed response
`rates up to 25% [4]. However, not all older trials meet the strict
`criteria of a phase II study. Therefore the EORTC Genitourinary
`Group decided to re-evaluate the efficacy of weekly bolus
`injections of vinblastine in MRCC.
`
`PATIENTS AND METHODS
`From 1988 to 1990 eight institutions entered 32 patients with
`measurable MRCC into the EORTC phase II trial 30882 (Table
`1).
`
`Patients were eligible for the trial if they had shown pro(cid:173)
`gression of bidimensionally measurable metastases from renal
`cell carcinoma during the 2 months preceding the trial entry,
`Other eligibility criteria were: age below 65 years, performance
`status (WHO): 0 or 1, adequate renal and liver function, no
`previous chemotherapy, whereas prior hormone treatment and
`immuno-modulating therapy was allowed provided that all
`treatment had been stopped for at least 4 weeks before trial
`entry. Informed consent was obtained from all the patients.
`
`Treatment
`Vinblastine 0.15 mg/kg was injected into a line of a running
`normal saline infusion, once every week for 6 weeks. Thereafter
`
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`Vinblastine in Metastatic Renal Cell Carcinoma
`
`879
`
`Table 1. Patients' characteristics
`
`No. of eligible patients
`No. of patients evaluable for response
`Male/female
`Age (years)
`Performance status (WHO)
`0
`
`Weight loss prior to trial entry
`~ 5%
`6---10%
`11-20%
`unknown
`Time from initial diagnosis to
`treatment start (weeks)
`
`Pre-trial treatment
`Surgery
`Radiotherapy
`Hormone treatment
`Interferon
`
`Sites of indicator lesions
`Lung
`Lymph nodes
`Liver
`Skin
`Other
`
`• Median, t range.
`
`31
`26
`23/8
`53* (37-64)1
`
`10
`21
`
`21
`4
`3
`3
`
`51' (0--513)t
`
`28
`7
`4
`9
`
`17
`11
`5
`2
`3
`
`treatment was continued by one intravenous injection of vinblas(cid:173)
`tine 0.15 mg/kg given every second week until development of
`progressive disease or unacceptable toxicity.
`
`Dose modification
`The weekly vinblastine injections were postponed for 1 week
`if the leucocyte count fell below 3.0 x 109/1 or platelets below
`120 x 109/1. In such cases the subsequent vinblastine dose was
`to be reduced by 25%. If no haematological recovery was
`observed after 1 week's postponement, treatment was to be
`delayed for a further week. If treatment had to be delayed for
`more than 2 weeks, the patient went off study. A 25% reduction
`of the single dose was also recommended in case of grade II
`peripheral neurotoxicity. Treatment had to be discontinued in
`case of grade III peripheral neurotoxicity, but could ( on the
`discretion of the investigator) be restarted with a 25% dose
`reduction after improvement of the neurological symptoms.
`
`Response evaluation
`The response rate was evaluated according to the WHO
`criteria [5] after a minimum treatment time of 6 weeks. Patients
`progressing before the end of the 6 weeks' treatment were
`included in the category 'progressive disease'.
`
`RESULTS
`I of the 32 patients entered was subsequently deemed to be
`ineligible. Of the remaining 31 patients 2 were not evaluable for
`response or toxicity (incomplete data: 1; treatment not given
`according to the protocol: 1) and 3 patients were only evaluable
`for toxicity, leaving 26 completely evaluable patients.
`A median of 5.5 cycles (range: 1-9) was given to the 29
`evaluable patients. All treatment was given on an out-patient
`basis.
`Only 1 complete response (liver metastases evaluated by
`ultrasound) was seen in the 26 completely evaluable patients.
`(response duration: 28+ months). 8 patients had stable disease
`and 17 patients had progressed at the first response evaluation.
`The main toxicities were leukopenia (grade 1: 8; grade 2: 8;
`grade 3: 4), nausea/vomiting (grade 1: 2; grade 2: 4; grade 3: 1)
`and peripheral neuropathy (grade 1: 3; grade 2: l; grade 3: 2). 5
`patients developed alopecia (grade 1: 2; grade 2: l; grade 3: 2).
`The vinblastine dose was reduced at least once in 9 patients and
`delayed in 10, mainly due to leukopenia and/or peripheral
`neuropathy.
`
`DISCUSSION
`Our series comprises mainly 'good risk' patients (good per(cid:173)
`formance status, lung metastases only in 12 patients), who
`received relatively high doses of vinblastine. However, 9 patients
`had progressed on prior interferon therapy, which might rep(cid:173)
`resent a negative selection criterion.
`Our response rate of only 4% [95% confidence interval (Cl):
`0-20%] is in disagreement with results from older in vitro [3]
`and clinical [4] studies. The present results compare, however,
`favourably with recent studies demonstrating a ,::: 10% response
`rate when using intravenous continuous 5 days infusions of
`vinblastine [6, 7], and support observations on inefficacy of
`combination treatment containing vinblastine [8].
`Though the overall toxicity of vinblastine is mild, certain
`safety rules should be considered when vinblastine is given to
`patients with MRCC: The white blood cells must be monitored
`regularly and vinblastine doses have to be delayed and/or reduced
`according to leucopenia. Peripheral neuropathy represents the
`most important non-haematological toxicity and may necessitate
`discontinuation of the drug.
`Patients with measurable MRCC should principally be entered
`into clinical trials evaluating experimental treatment. The most
`actual therapeutic approaches today comprise immunomodulat(cid:173)
`ing therapies with interferon [9] and/or interleukin-2 [10],
`achieving a 15-30% response rate. If this is not possible and the
`patient and/or the doctor considers systemic treatment, a 6--8
`week trial with weekly intravenous vinblastine does not seem to
`be a completely unreasonable therapeutic alternative, not at
`least on the background of the inefficacy and toxicity of other
`cytostatics in MRCC [8]. In spite of occasionally impressive
`responses during treatment with vinblastine, the drug, however,
`has no major significance in the clinical management of MRCC.
`
`Correspondence to S.D. Fossa.
`S. D. Fossa is at the Department of Medical Oncology and Radiotherapy,
`The Norwegian Radium Hospital, Montebello 0310, Oslo 3, Norway;
`J-P. Droz is at the Institut Gustave Roussy, Villejuif, France; M.M.
`Pavone-Macaluso is at the Department of Urology, University Hospital,
`Palermo, Italy; F.J.J. Debruyne is at the Department of Urology,
`University Hospital Nijmegen, The Netherlands; and K. Vermeylen
`and R. Sylvester are at the EORTC Data Center, Brussels, Belgium.
`Revised 28 Oct. 1991; accepted 11 Nov. 1991.
`
`1. Stoter G, Williams SD, Einhorn LH. Genitourinary tumors. In:
`Pinedo H. ed. Cancer Chemotherapy Annual II. Amsterdam,
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`2. Marsoni S, Hoth D, Simon R, Leyland-Jones B, De Rosa M, Wittes
`RE. Clinical drug development: An analysis of phase II trials,
`1970-1985.
`3. Hrushesky W, Murphy GP. Evaluation of chemotherapeutic agents
`in a new murine renal carcinoma model. J Natl Cancer Inst 1974,
`52, 1117-1122.
`
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`

`880
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`S.D. Fossa et al.
`
`4. Hrushesky WJ, Murphy GP. Current status of the therapy of
`advanced renal carcinoma.] Surg Oncol 1977, 9. 277.
`5. Miller AB, Hoogstraten B, Staquet M, Winkler, A. Reporting
`results of cancer treatment. Cancer l 981, 47, 207-214.
`6. Tannock IF, Evans WK. Failure of 5-day Vinblastine infusion in
`the treatment of patients with renal cell carcinoma. Cancer Treat
`Rep 1985, 69,227.
`7. Crivellari D, Tumolo S, Frustaci S, et al. Phase II Study of five-day
`continuous infusion of Vinblastine in patients with metastatic renal
`cell carcinoma. Am] Clin Oncol l 987, 10, 231.
`8. Sommer HH, Fossa SD, Lien HH. Combination chemotherapy of
`advanced renal cell cancer with CCNU and Vinblastine. Cancer
`Chemother Pharmacol 1985, 14,277.
`
`9. Fossa SD, Stenwig AE, Lien HH. Long-term results in patients
`with metastatic renal cell carcinoma treated with interferon with or
`without vinblastine. World] Urol (in press).
`10. Rosenberg SA, Lotze MT, Muul LW, et al. A progress report
`on the treatment of 157 patients with advanced cancer using
`lymphokine-activated killer cells and interleukin-2 or high dose
`interleukin-2 alone. N Engl] Med 1987, 316, 889-897.
`
`Acknowledgements-Other participants in the study included: A.
`Alzdas, Marmara University Hospital, Istanbul, Turkey; A.V. Bono,
`Osp. Di Circolo e Fondazione E.S. Macchi Varese, Italy; T.A. Boon,
`Academic Hospital, Utrecht, The Netherlands; and K.H. Kurth,
`Academic Medical Center, Amsterdam, The Netherlands.
`
`Eur]Cancer, Vol. 28A,No. 415.pp. 880-884, 1992.
`Pn·nzed in Great Britain
`
`0964-1947192 $5.00 + 0.00
`© 1992 Pergamon Press Ltd
`
`Prolonged Chemotherapy for Localised Squamous
`Carcinoma of the Oesophagus
`Jaffer A. Ajani, Bernadette Ryan, Tyvin A. Rich, Marion McMurtrey,
`Jack A. Roth, Louis DeCaro, Bernard Levin and Clifton Mountain
`
`We evaluated the feasibility of six courses of chemotherapy in 34 consecutive patients with localised squamous
`cell carcinoma of the oesophagus. All 32 evaluable patients first received at least two courses of chemotherapy.
`There were 18 patients with resectable carcinomas who underwent surgery and 14 patients with unresectable
`carcinomas who received definitive chemoradiotherapy. After two courses of5-fluorouracil and cisplatin 21 (66%)
`of 32 patients had either a complete or major response. A median of five courses (range, 1-6 courses) was
`administered. 17 out of 18 (94%) patients with resectable carcinoma had a 'curative' resection (negative proximal,
`distal, and radial margins by histopathology in an en-block resection specimen) and 2 patients had a complete
`pathological response. The median survival duration of all patients was 28 months (range, 2-46+ months). The
`median survival duration of 14 patients with unresectable carcinoma was 23 months (range, 8-36+ months), and
`the median survival duration of 18 patients with resectable carcinoma has not been reached at a median follow(cid:173)
`up of 24+ months (range, 10+ to 46+ months). No deaths occurred because of chemotherapy or chemoradiation
`therapy. Our data suggest that prolonged chemotherapy is feasible in patients with locoregional squamous
`carcinoma of the oesophagus. An ongoing controlled trial will determine the contribution of chemotherapy to
`patients' survival.
`Eur J Cancer, Vol. 28A, No. 4/5, pp. 880-884, 1992.
`
`INTRODUCTION
`CARCINOMA OF the oesophagus results in 5-year survival rates
`less than 6% which have not changed over the past 4 decades
`[ 1]. At the time of diagnosis, only 48% of patients have carcinoma
`confined to the oesophagus or regional lymph nodes [l]. Unless
`adequately controlled, the primary carcinoma is the common
`cause of morbidity and mortality.
`The results of treatments to control the primary carcinoma
`have been dismal producing median survival rates well below
`
`Correspondence to J .A. Ajani.
`J.A. Ajani is at the UT M.D. Anderson Cancer Center, 1515 Holcombe
`Blvd; Box 78, Houston, Texas 77030-4096; and B. Ryan, T.A. Rich,
`M. McMurtrey, J.A. Roth, L. DeCaro, B. Levin and C. Mountain are
`at the Department of Medical Oncology, Thoracic Surgery, Clinical
`Radiotherapy, The University of Texas M.D. Anderson Cancer Center,
`Houston, Texas, U.S.A.
`Revised 28 Sep. 1991; accepted 7 Oct. 1991.
`
`18 months [2, 3]. The 5-year survival rates following surgery
`have ranged from 1 % to less than 20%, and the median survival
`duration has been 12 months or less [2, 4-6]. Similarly,
`treatments with definitive or palliative radiotherapy have
`resulted in poor 5-year survival rates as well [3, 7, 8]. The
`increased sensitivity with potential radiocurability of squamous
`cell carcinoma of the oesophagus to radiotherapy has long been
`known [9]; similarly, its sensitivity to many chemotherapy
`agents has been noted [10, 11]. More recently, the introduction
`of chemotherapy in the treatment of localised carcinoma has led
`to several newer approaches.
`Chemotherapy has been employed in two common strategies.
`First, one or two courses of combination chemotherapy have
`been administered before surgery (12-14]. Second, combination
`chemotherapy and concurrent radiotherapy ( chemoradiation
`therapy) have been administered [15-19] prior to surgery or
`chemoradiation therapy has been used as a definite method to
`eradicate localised carcinoma [20-22].
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