Digestion 2000;62(suppl 1):69–72
`
`OctreoTherTM: Ongoing Early Clinical
`Development of a Somatostatin-Receptor-
`Targeted Radionuclide Antineoplastic Therapy
`
`M. Charles Smitha Jingou Liua Tianling Chena Horst Schrana
`Ching-Ming Yeha François Jamarb Roelf Valkemac Willem Bakker c
`Larry Kvols d Eric Krenning c Stanislas Pauwels b
`
`aNovartis Pharmaceuticals Corporation, East Hanover, N.J., USA; bCatholic University of Louvain, Brussels,
`Belgium; cUniversity Hospital Rotterdam, The Netherlands; dMoffitt Cancer Center, University of South Florida,
`Tampa, Fla., USA
`
`Downloaded by:
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`Key Words
`Breast cancer W Clinical studies W DOTATOC W
`Neuroendocrine tumors W OctreoTherTM W Peptide
`radiotherapy W Small cell lung cancer W
`Somatostatin receptor W Yttrium-90
`
`lung cancer. A fixed-dose regimen of 120 mCi/cycle ! 3
`cycles administered with concomitant amino acid infu-
`sion has been chosen for the study. Phase I data and pub-
`lished literature support that this fixed dose regimen will
`be safely tolerated.
`
`Copyright © 2000 S. Karger AG, Basel
`
`Abstract
`OctreoTherTM (90Y-DOTA-D-Phe1-Tyr3-octreotide, a.k.a.
`90Y-SMT 487) consists of a somatostatin peptide ana-
`logue (Tyr3-octreotide), coupled with a complexing moi-
`ety (DOTA), and labeled with a tightly bound beta-emit-
`ter (yttrium-90). By targeting somatostatin receptor-posi-
`tive tumors (as imaged by OctreaScan®) it may deliver a
`tumoricidal dose of radiation. Phase I clinical trials, con-
`ducted in patients with neuroendocrine tumors, estab-
`lished the safety and tolerability of the dose selected for
`further study and demonstrated the capacity of Oc-
`treoTher to deliver radiation doses to tumors that re-
`sulted in significant neuroendocrine tumor shrinkage.
`Novartis-sponsored phase II studies will soon begin to
`test the efficacy of OctreoTher in breast and small cell
`
`Introduction
`
`OctreoTherTM is a Novartis development compound
`currently in phase I multicenter clinical trials to test its
`potential as a somatostatin-receptor-targeted radionu-
`clide antineoplastic therapy. These studies are sponsored
`in cooperation with Mallinckrodt Medical Incorporated.
`The overall goal of this development program is to dem-
`onstrate the disappearance or significant shrinkage of
`somatostatin receptor positive solid tumors (e.g. neu-
`roendocrine, breast or small cell lung tumors) in the
`absence of clinically apparent toxicity to major organ sys-
`tems in patients receiving OctreoTher. Data from the
`Novartis-sponsored ongoing phase I study in neuroendo-
`
`ABC
`Fax + 41 61 306 12 34
`E-Mail karger@karger.ch
`www.karger.com
`
`© 2000 S. Karger AG, Basel
`0012–2823/00/0625–0069$17.50/0
`
`Accessible online at:
`www.karger.com/journals/dig
`
`Chuck Smith, MD, PhD
`Novartis Pharma Corp., Bldg. 419, Room 2306, 59 Route 10
`East Hanover, NJ 07936-1080 (USA)
`Tel. +1 973 781 8960, Fax +1 973 781 5511
`E-Mail chuck.smith@pharma.novartis.com
`
`NOVARTIS EXHIBIT 2084
`Par v. Novartis, IPR 2016-01479
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`crine tumor patients along with recently published clini-
`cal studies not sponsored by Novartis have provided sup-
`port for the choice of regimen to be tested in a multicent-
`er phase II study. This phase II study, to begin this year
`at 12 centers in Australia, the United States and Europe,
`will examine the safety and efficacy of the chosen regi-
`men in approximately 60 patients with breast and small
`cell lung cancer.
`
`Preclinical Rationale
`
`OctreoTher (90Y-DOTA-D-Phe1-Tyr3-octreotide, a.k.a.
`90Y-SMT 487) consists of a somatostatin peptide ana-
`logue (Tyr3-octreotide), coupled with a complexing moi-
`ety (DOTA), and labeled with a tightly bound beta-emit-
`ter (yttrium-90). By targeting somatostatin receptor-posi-
`tive tumors (as imaged by OctreoScan®) it may deliver a
`tumoricidal dose of radiation. Yttrium-90 (90Y) is a high-
`energy beta-emitter with a mean path length of 5 mm in
`tissue and a physical half-life of 64.1 h. SMT 487 binds
`with high affinity to somatostatin receptors (subtypes 2
`and 3) and retains both its binding properties and its
`physiological function when labeled with 90Y.
`The preclinical rationale for the use of OctreoTher is
`based on evidence that:
`(1) OctreoTher accumulates in somatostatin receptor-
`containing tissue or tumors.
`(2) Receptors remain present and able to bind Oc-
`treoTher during treatment.
`(3) Tumor regression was demonstrated in vivo [1].
`In tumor-bearing nude mice, OctreoTher was effective
`in somatostatin receptor-positive tumors, a single dose
`both shrinking the tumor and prolonging survival. A sin-
`gle dose in rats caused pancreatic tumors to disappear
`without regrowth. No difference in tumor regression was
`seen between perilesional, intraperitoneal or intravenous
`administration of OctreoTher, so the more convenient
`intravenous application was selected for clinical develop-
`ment.
`
`dose, plasma radioactivity is !1% of the injected dose/l).
`The rapid clearance of OctreoTher from the circulation
`gives this radiopharmaceutical a major advantage over
`radiolabeled antibodies, whose long plasma half-lives
`(several days) cause higher levels of whole-body irradia-
`tion. OctreoTher is not significantly taken into erythro-
`cytes. A correlation between creatinine clearance and
`total body radioactivity clearance was observed reflecting
`that the kidney is the principal drug eliminating organ
`and suggesting that OctreoTher is not recommended in
`subjects whose creatinine clearance is less than 40 ml/
`min. Radioactivity exposure was mainly to kidney,
`spleen, urinary bladder wall, and tumors. Gamma scin-
`tigraphy with 111In-pentetreotide (OctreoScan) may be
`used to identify OctreoTher-binding tumors. The relative
`biodistribution and pharmacokinetic profile of Octreo-
`Ther was not altered by changes in the absolute peptide
`dose over the range of 50–500 Ìg. Notably, concomitant
`administration of amino acids reduced renal radioactivity
`uptake without altering tumor uptake in a phase I study.
`Cationic amino acids appear to be responsible for the
`‘blocking’ of renal tubular uptake of proteins or peptides
`[2, 3]. A variety of other maneuvers have been attempted,
`so far, without success in further lowering the relative
`renal uptake of OctreoTher.
`Phase I clinical trial results support the safety and
`tolerability of the dose selected for further study. The
`organ of dose-limiting toxicity was confirmed to be pri-
`marily the kidney and secondarily the hematopoietic
`system. Acute radiation nephritis may appear as a syn-
`drome of hypertension, proteinuria and anemia present-
`ing up to a year after the causal radiation exposure [4].
`Furthermore, these studies demonstrated the capacity
`of OctreoTher to deliver radiation doses to tumors
`that resulted
`in significant neuroendocrine tumor
`shrinkage. The planned phase II study will assess the
`safety and anti-tumor activity of OctreoTher in refracto-
`ry small cell lung cancer and advanced metastatic breast
`cancer.
`
`Phase I Clinical Studies of Neuroendocrine
`Tumors
`
`Phase I clinical trials, conducted in patients with neu-
`roendocrine tumors, established that following an intra-
`venous infusion, plasma radioactivity disposition of
`OctreoTher was multiphasic (terminal t½ F8.6 h). Un-
`bound radioactivity was excreted in urine. By 24 h post-
`
`Planned Phase II Clinical Study of Small Cell
`Lung and Breast Cancers
`
`Small cell lung cancer (SCLC) comprises approximate-
`ly 18% of all primary lung cancer, virtually all of the
`tumors bearing somatostatin receptors [5–8]. Although
`SCLC is highly sensitive to radiation, coexistent lung tis-
`sue damage and the early occurrence of distant metastases
`limit the utility of external beam irradiation. Resistance
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`Valkema/Bakker/Kvols/Krenning/Pauwels
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`to chemotherapy often develops early during treatment.
`Prognosis is correspondingly poor; approximately 95% of
`those afflicted succumbing to their disease, regardless of
`therapy or earliness of diagnosis. Hence, OctreoTher, by
`providing systemic, yet targeted irradiation to metastatic
`SCLC, should provide a much-needed, additional thera-
`peutic modality.
`Breast cancer is the commonest malignancy among
`women. The prognosis is variable and first- and second-
`line therapies are well established. Approximately 70% of
`primary breast cancers express somatostatin receptors [5,
`9–11]. Patients with advanced metastatic breast cancer,
`who are shown by OctreoScan to have high somatostatin
`receptor levels, may benefit from therapy.
`
`(1.84 m2) would correspond to a cumulative dose of ca.
`368 mCi per patient which was safe and tolerated. Some,
`but not all, of the administered cycles were in the presence
`of concomitant amino acid infusion. There was no adjust-
`ment for renal dosimetry, which was also not performed/
`reported. Four patients, who all received 17,400 MBq/
`m2, developed renal toxicity: 2 patients who received
`cumulative doses of 360 and 385 mCi, respectively,
`showed stable renal insufficiency; 2 other patients who
`received 380 and 410 mCi, respectively, showed complete
`renal failure (dialysis dependent). None of the 4 patients
`who developed renal toxicity received any concomitant
`amino acid infusion. Thus, all doses at or below 360 mCi
`administered with concomitant amino acids appear to
`have been tolerated safely.
`
`Primary Study Objectives
`
`Conclusion
`
`1 To evaluate the efficacy of OctreoTher in advanced
`metastatic breast cancer and refractory small cell lung
`cancer as measured by tumor response rate (PR + CR
`SWOG criteria).
`2 To evaluate the safety of OctreoTher as measured by
`the rate of (mild/moderate/severe/life-threatening) ad-
`verse events, and serious adverse events and the moni-
`toring of selected laboratory evaluations.
`
`Novartis-sponsored phase II studies will soon begin to
`test the efficacy of OctreoTher in breast and small cell
`lung cancer. A fixed-dose regimen of 120 mCi/cycle ! 3
`cycles administered with concomitant amino acid infu-
`sion has been chosen for the study. Phase I data and pub-
`lished literature support that this fixed dose regimen will
`be safely tolerated.
`
`Secondary Study Objectives
`
`1 To measure the overall survival of patients treated
`with OctreoTher.
`2 To evaluate the effect of OctreoTher on quality of life
`as measured by the EURO-QOL EQ-5D.
`3 To assess the frequency of tumors which are positive
`(tumor uptake 1 liver uptake) for OctreoScan within
`the screened population.
`
`Data from Non-Novartis-Sponsored Studies in
`the Literature
`
`Investigators not affiliated with Novartis have pro-
`duced and conducted clinical trials with a compound,
`which appears to be identical to OctreoTher, called
`Yttrium-90 DOTATOC [12–14]. To summarize the renal
`toxicity reported by these investigators, for purpose of
`comparison, 24 patients received ^7,400 MBq/m2. This
`limit (7,400 MBq/m2) corresponds to 200 mCi/m2, and,
`using the average reported BSA of these 24 patients
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`OctreoTherTM: Early Clinical Development
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`Smith/Liu/Chen/Schran/Yeh/Jamar/
`Valkema/Bakker/Kvols/Krenning/Pauwels
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