Multi-Institutional Study of the Angiogenesis Inhibitor
`TNP-470 in Metastatic Renal Carcinoma
`
`By Walter M. Stadler, Timothy Kuzel, Charles Shapiro, Jeffery Sosman, Joseph Clark, and Nicholas J. Vogelzang
`
`Purpose: Renal cell carcinoma is resistant to most
`chemotherapy, and only a minority of patients respond
`to immunotherapy. Its highly vascular nature suggests
`that antiangiogenesis therapy might be useful. We thus
`performed a phase II study of the fumigillin analog
`TNP-470 in previously treated patients with metastatic
`renal cell carcinoma.
`Patients and Methods: Metastatic renal cell carci-
`noma patients with good organ function were entered
`onto the study through five separate institutions. There
`were no exclusion criteria for prior therapy. All patients
`were treated at a dose of 60 mg/m2 of TNP-470 infused
`over 1 hour three times per week.
`Results: Thirty-three patients were enrolled. Therapy
`was generally well tolerated, but asthenia, fatigue,
`vertigo, dizziness, sense of imbalance, and loss of con-
`
`TREATMENT OF METASTATIC renal cell carcinoma
`
`is woefully inadequate, and approximately 11,900
`Americans will die of disease in 1999.1 Although immuno-
`therapy with interleukin-2 (IL-2), interferon alfa (IFNa), or
`both is considered standard, only 15% of individuals experi-
`ence an objective response and only 5% experience a
`complete response.2-5 Renal cell cancer is also resistant to
`most chemotherapeutic agents, in part due to overexpression
`of various multidrug resistance proteins.6,7 Novel ap-
`proaches to this disease are thus needed. Because of the
`vascular nature of renal tumors, an antiangiogenesis ap-
`proach is attractive. Furthermore, experimental studies have
`suggested that such an approach may circumvent the devel-
`opment of drug resistance.8
`One of the first antiangiogenesis compounds to undergo
`clinical testing is the fumigillin analog TNP-470. Fumigillin
`was originally isolated from Aspergillus fumigatus contami-
`nating endothelial cell cultures.9 Subsequent studies re-
`vealed that fumigillin was a potent inhibitor of endothelial
`growth in vitro as well as in vivo, but that administration to
`animals led to profound weight loss.9 A number of analogs
`were then synthesized, and TNP-470 was selected as the
`least
`toxic compound with the greatest antiangiogenic
`activity.9,10 TNP-470 inhibits in vitro endothelial cell prolif-
`eration,
`including growth stimulated by basic fibroblast
`growth factor (bFGF).9-11 Additionally, it inhibits angiogen-
`esis in the chorioallantoic membrane and rat corneal as-
`says.9-11 It can also inhibit tumor growth and metastases in a
`number of rodent tumor model systems, including a rodent
`renal cell carcinoma.9,10,12-14
`
`centration were common and severe enough to lead to
`therapy discontinuation in five patients. There was only
`one partial response of short duration (response rate,
`3%, 95% confidence interval, 0% to 16%), but six
`patients (18%) remained on study for 6 or more months
`without toxicity or disease progression.
`Conclusion: Long-term therapy with TNP-470 has
`manageable toxicities and is feasible in patients with
`metastatic renal cell carcinoma but does not lead to any
`significant objective responses. Further studies in this
`population using TNP-470 schedules that produce more
`prolonged drug levels and clinical trial end points other
`than objective tumor regression may be indicated.
`J Clin Oncol 17:2541-2545. r 1999 by American
`SocietyofClinicalOncology.
`
`Animal studies have revealed that the highest doses lead
`to myelosuppression, microhemorrhages in various organs,
`and neurotoxicity consisting of seizures, tremors, and ataxia.15
`Phase I studies in humans have revealed reversible neurotox-
`icity as the major dose-limiting toxicity. These consisted of
`fatigue/asthenia, weakness, nystagmus, diplopia, vertigo,
`dysmetria, and truncal ataxia.16-18 Hemorrhage into a CNS
`lymphoma and into a cytomegalovirus retinitis lesion was
`also observed in AIDS patients with Kaposi’s sarcoma.16
`One patient with biopsy-proven metastatic cervical carci-
`noma on a phase I study experienced a complete and
`long-lasting response in her lung lesions.17
`We initiated a phase II study of TNP-470 in patients with
`refractory metastatic renal cell carcinoma using a three times
`weekly bolus infusion. We confirm previous observations of
`asthenia and cerebellar toxicities as the most significant
`adverse events. We also report one partial response and
`several patients with prolonged freedom from progression
`and suggest that this compound may be worthy of further
`study in this population.
`
`From the University of Chicago, Northwestern University, and
`Loyola University of Illinois, Chicago; Loyola University Medical
`Center, Maywood, IL; and Dana Farber Cancer Institute, Boston, MA.
`Submitted November 4, 1998; accepted March 18, 1999.
`Supported in part by TAP Pharmaceuticals.
`Address reprint requests to Walter M. Stadler, MD, University of
`Chicago, Section Hematology-Oncology, 5841 S Maryland, MC2115,
`Chicago, IL 60637; email wmstadle@mcis.bsd.uchicago.edu.
`r 1999 by American Society of Clinical Oncology.
`0732-183X/99/1708-2541
`
`JournalofClinicalOncology, Vol 17, No 8 (August), 1999: pp 2541-2545
`
`2541
`
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`
`Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
`
`NOVARTIS EXHIBIT 2073
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`Page 1 of 5
`
`

`

`2542
`
`Patients
`
`PATIENTS AND METHODS
`
`Patients were required to have recurrent or inoperable renal cell
`carcinoma, a World Health Organization performance status of 0 to 2,
`and no history of other invasive cancers in the previous 5 years. There
`were no exclusions for prior therapy, but at least 3 weeks had to have
`elapsed since the last dose of the prior drug (6 weeks for nitrosoureas
`and 4 weeks for any investigational agent). At least 4 weeks had to have
`elapsed since any prior surgery or radiotherapy, and any previously
`irradiated lesions could not be used for response evaluation. Patients
`were required to have adequate organ function defined by serum
`creatinine # 2.0 mg/dL; total bilirubin, ALT, and alkaline phosphatase #
`2 times the upper limit of normal; hemoglobin $ 9.0 g/dL; platelet
`count greater than 100,000/µL; WBC count greater than 3,000/µL; and
`absolute neutrophil count greater than 1,500/µL. In addition, patients
`were required to have a normal prothrombin time and partial thrombo-
`plastin time, no history of bleeding diathesis, and could not receive
`concomitant anticoagulation except for maintenance of central-line
`patency. Finally, all patients provided written informed consent before
`participating. Thirty-three patients were enrolled between January and
`June 1997 at five separate institutions: University of Chicago, Chicago,
`IL (eight patients); Northwestern University, Chicago, IL (nine pa-
`tients); Dana Farber Cancer Institute, Boston, MA (nine patients);
`University of Illinois, Chicago, IL (six patients), and Loyola University,
`Chicago, IL (one patient).
`
`Therapy and Dose Modifications
`
`TNP-470 (60 mg/m2) was administered by intravenous infusion over
`1 hour three times per week. The first week of therapy was administered
`in the outpatient area of the parent institution. If no significant toxicities
`were encountered, subsequent infusions could be administered at the
`patient’s home with the use of a home nursing service. Any grade 3 or 4
`toxicity led to therapy discontinuation until toxicity resolved to patient’s
`baseline or # grade 1. Therapy could then be reinitiated at a dose of 45
`mg/m2 three times per week. Recurrent grade 3 or 4 toxicity required
`therapy discontinuation.
`
`Patient Follow-up and Study End Points
`
`The primary end points for this study were objective tumor response
`rate and toxicity assessment. Response evaluations were performed
`after an initial 12 weeks of therapy and every 8 weeks thereafter.
`Toxicity evaluations were performed every 2 weeks for the first 8 weeks
`and then every 4 weeks thereafter. Interim evaluations were performed
`in patients who experienced clinical signs or symptoms of toxicity or
`disease. Partial response was defined as a 50% or greater decrease in the
`sum of the products of diameters of all measurable lesions persisting for
`at least 4 weeks without the development of any new lesions. Complete
`response was defined as disappearance of evidence of tumor persisting
`for at least 4 weeks. Progressive disease was defined as a 25% or greater
`increase in the sum of the products of diameters of all measurable
`lesions or the appearance of any new lesion. All other situations were
`defined as stable disease. Toxicity grading was by the National Cancer
`Institute common toxicity criteria.
`
`Statistical Considerations
`
`Patient accrual was performed with a two-step mechanism. An initial
`19 patients were accrued, with at least one response needing to be
`observed to proceed to the second accrual stage. The null hypothesis to
`be tested in the first stage was that the response rate was 15% or greater.
`
`STADLER ET AL
`
`If no patients responded then the null hypothesis could be rejected with
`a confidence of greater than 95%. The second stage was designed to
`accrue a cumulative total of 30 patients such that the SE on the response
`rate would be # 0.09. To maintain simultaneous commitments made to
`patients at the various participating institutions, the total accrual was 33
`patients. All patients were deemed assessable for response, survival, and
`toxicity. Event-free survival was defined as the time from the start of
`therapy until discontinuation as a result of either progressive disease or
`a toxic event. Overall survival was defined as the time from the start of
`therapy until death. All survival estimates were censured as of August 1,
`1998, and calculated by the Kaplan-Meier method.
`
`RESULTS
`Table 1 depicts baseline characteristics of all patients.
`Because there was no exclusion criteria for prior therapy, a
`heavily pretreated group was enrolled. In fact, 30 (91%) of
`33 patients had received at least one prior therapy, and in all
`cases this included IL-2 and/or IFNa. Twenty-seven percent of
`patients also underwent prior chemotherapy, usually in the
`
`Table 1. Baseline Characteristics of All Enrolled Patients
`
`Characteristic
`
`No. of Patients
`
`Total enrolled
`Sex (M/F)
`Age, years
`Median
`Range
`Performance status (World Health Organization)
`0
`1
`2
`Number of metastatic sites
`1
`2
`$ 3
`Sites of metastatic disease
`Lung only
`Lymph node only
`Liver (with or without other sites)
`Bone (with or without other sites)
`Prior nephrectomy
`Interval, nephrectomy to therapy, months
`Median
`Range
`Interval, metastatic disease diagnosis to therapy, months
`Median
`Range
`Prior therapy for metastatic disease
`Immunotherapy
`Chemotherapy
`Radiation
`Surgery
`Other
`Number of prior regimens
`Median
`Range
`
`33
`25/8
`
`58
`40-81
`
`11
`17
`5
`
`7
`16
`10
`
`4
`1
`6
`10
`24
`
`30
`8
`10
`3
`4
`
`41
`7-277
`
`14
`2-84
`
`2
`0-7
`
`NOTE. Metastatic sites are defined as the number of organs involved.
`Multiple enlarged lymph nodes were still considered one site of disease.
`
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`Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
`
`NOVARTIS EXHIBIT 2073
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`Page 2 of 5
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`

`

`TNP-470 IN METASTATIC RENAL CARCINOMA
`
`context of a clinical trial. This selection bias favored the accrual
`of patients with indolent disease, and the median interval from
`diagnosis of metastatic disease to study initiation was 14 months.
`The median interval between nephrectomy, in those patients who
`underwent this procedure, and study initiation was even longer at
`41 months. Nevertheless, patients had a significant disease
`burden and 30% had three or more metastatic sites. In addition,
`only 33% of patients had no disease symptoms and a normal
`performance status.
`The primary study end point was response rate. There was
`one response among the first 19 patients, and, therefore, the
`study proceeded to the second stage, in which no additional
`responses were observed. The overall response rate was thus
`3% (95% confidence interval, 0% to 16%). The lone
`responder had a 1.4 3 1.4 cm paratracheal lymph node and
`two approximately 1.0-cm lung nodules, which regressed at
`the initial 12-week evaluation. He was, however, removed
`from the study at that time due to the development of
`asthenia and neurocortical toxicity and subsequently pro-
`gressed and died 8 months after study discontinuation as a
`result of progressive metastatic renal cancer. Figure 1
`depicts event-free survival, with events being defined as
`progressive disease or toxicity requiring study discontinua-
`tion. The median event-free survival was 12 weeks (Fig 1).
`Six patients (18%) remained on study without toxicity or
`progressive disease for 6 months or more. Five of these six
`patients had progressive disease on prior therapy, and one
`had recurrent disease after adjuvant IFNa therapy. As of this
`report, three patients remain on study at 591, 601, and 721
`weeks. Reasons for therapy discontinuation were progres-
`sive disease in 20 patients, drug toxicity in five, and
`intercurrent event (for which relatedness to drug therapy
`could not be definitively determined) in five. These latter
`events included a gastrointestinal hemorrhage on day 3 of
`therapy, depression and suicidal ideation on day 3, hypercal-
`cemia and increasing back pain during week 4, a line
`infection during week 19, and a pulmonary embolism during
`week 47. At a median follow-up of 14 months, the median
`survival is 56 weeks (Fig 1).
`Table 2 depicts observed toxicities that were interpreted to
`have some possible relation to the study drug by each
`investigator. Therapy, was, in general, well tolerated, al-
`though neurocortical toxicities were common. These symp-
`toms were not usually associated with objective neurologic
`findings. Because no formal neuropsychiatric tests were
`performed, they were conveniently categorized as cerebellar
`symptoms, confusion, and other psychiatric symptoms. In
`total, 67% of patients experienced at least one of these
`toxicities. Although these toxicities were usually mild, in
`five patients they were considered severe and led to drug
`discontinuation. Fatigue and asthenia were also common
`
`A 1.0
`
`0.8
`
`0.6
`
`ro >
`·:,;;
`:::,
`(f)
`Q)
`[I'
`LL
`c 0.4
`Q) > w
`
`0.2
`
`0.0
`
`B 1.0
`
`0.8
`
`ro > 0.6
`2' :::,
`
`(f)
`~
`Q) 0.4
`>
`0
`
`0.2
`
`0.0
`
`0
`
`2543
`
`20
`
`40
`
`60
`
`80
`
`Time (weeks)
`
`20
`
`40
`
`60
`
`80
`
`Time (weeks)
`
`(A) Event-free and (B) overall survival for all enrolled patients. Tick
`Fig 1.
`marks represent censured patients. Events included progressive disease and
`toxicity necessitating discontinuation of therapy.
`
`and occurred in 60% of patients. Because therapy was
`administered three times per week, and because there was
`poor documentation in the clinical notes, it was difficult to
`discern whether the fatigue was worse on the treatment days.
`However, patients did not seem to become tolerant to these
`effects, nor did there seem to be a cumulative effect, as is
`seen with prolonged IFN-a or IL-2 therapy. All fatigue and
`neurocortical symptoms resolved rapidly after TNP-470 was
`discontinued.
`Other severe toxicities included pain, pulmonary embo-
`lism and gastrointestinal hemorrhage (as noted previously),
`and hypotension. The treating physician interpreted the first
`three events to be most likely disease-related, but contribu-
`tion from TNP-470 could not be ruled out. The hypotension
`event was correlated with drug infusion and persisted during
`treatment and was thus considered probably drug-related.
`Five patients underwent a protocol-defined dose reduction
`from 60 to 45 mg/m2 due to neurologic toxicities.
`
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`Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
`
`NOVARTIS EXHIBIT 2073
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`

`2544
`
`Table 2. Total Number of Patients Who Experienced an Adverse Event
`Interpreted by Investigator to Have Some Relation to the Study Drug
`
`Toxicity
`
`Grade 1
`
`Grade 2
`
`Grade 3
`
`Grade 4
`
`Cerebellar symptoms*
`Confusion
`Other psychiatric†
`Fatigue/asthenia
`Pain‡
`Fever/chills
`Anorexia
`Nausea/vomiting
`Other§
`
`21
`8
`15
`9
`16
`7
`8
`11
`0
`
`8
`2
`5
`7
`4
`0
`4
`1
`0
`
`4
`0
`1
`2
`1
`0
`0
`0
`2
`
`0
`0
`0
`0
`0
`0
`0
`0
`1
`
`NOTE. A large number of unusual toxicities were described in various ways
`by individual investigators. Several have been grouped as symptom complexes.
`Some patients had more than one toxic event recorded. See Results for
`percentage of patients experiencing selected toxicities.
`*Abnormal gait, ataxia, dizziness, incoordination, tremor, and vertigo.
`†Abnormal dreams, anxiety, depression, emotional lability, insomnia, ner-
`vousness, and somnolence.
`‡Abdominal pain, back pain, chest pain, flank pain, headache, pelvic pain,
`and pain not otherwise specified.
`§Gastrointestinal hemorrhage (grade 4), pulmonary embolism, hypotension.
`
`DISCUSSION
`We have demonstrated that TNP-470, when administered
`to a group of heavily pretreated patients with metastatic
`renal cell carcinoma, is well tolerated, even when adminis-
`tered for prolonged time periods. TNP-470 administration,
`however, does not lead to significant objective responses;
`thus this trial did not meet
`its primary objective, and
`TNP-470 must be considered ineffective per the original trial
`design. Based on animal data, it has been hypothesized that
`TNP-470 may only prevent further tumor growth and not
`necessarily lead to tumor shrinkage.12-14 Whether the pro-
`longed median survival and prolonged progression-free
`survival in several patients was due to TNP-470 or simply a
`reflection of these patients’ natural disease history cannot be
`determined by this study.
`
`STADLER ET AL
`
`TNP-470 has now been evaluated in several clinical
`trials.16-18 Our study supports observations in previous
`studies of low response rate and good general tolerability,
`but asthenia and neurocortical toxicity are dose-limiting.
`Nevertheless, our observations suggest that further studies
`with TNP-470 may be indicated. Such studies should seek to
`specifically answer the question of whether TNP-470 truly
`delays progression and may be best performed in the
`minimal disease or adjuvant setting.9,12 Future trials should
`also include more formal neuropsychiatric evaluations to
`better delineate the neurocortical
`toxicities and perhaps
`identify patients who are particularly vulnerable to such
`difficulties. Combination studies of TNP-470 and other
`known or putative angiogenesis inhibitors may also be
`indicated. A potentially attractive candidate for metastatic
`renal cell carcinoma is IFNa, which has both antiangiogen-
`esis and direct antitumor properties.19
`Before such studies commence, it is likely that a more
`convenient formulation for TNP-470 will need to be devel-
`oped. Animal studies suggest that prolonged exposure to
`TNP-470 may be necessary to fully realize all of its
`antiangiogenic properties. Pharmacokinetic studies, how-
`ever, have shown that the half-life of TNP-470 and its active
`metabolite are only 2 and 6 minutes, respectively (M.
`Dordal, personal communication, September 1998).16,18,20,21
`Ongoing studies should determine the feasibility and toxic-
`ity of more prolonged exposure to TNP-470.
`In conclusion, TNP-470 is one of the first specific
`antiangiogenesis drugs to undergo wide clinical evaluation.
`Our study shows that prolonged therapy with TNP-470 is
`feasible and tolerable in patients with metastatic renal cell
`cancer but does not lead to an appreciable objective response
`rate. Additional studies with formulations or schedules that
`give more prolonged TNP-470 exposure to determine its
`effect on tumor progression in renal cell carcinoma may be
`indicated.
`
`REFERENCES
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`Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
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`TNP-470 IN METASTATIC RENAL CARCINOMA
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`Downloaded from ascopubs.org by Reprints Desk on February 23, 2018 from 072.037.250.188
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`Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
`
`NOVARTIS EXHIBIT 2073
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