Am .rl (‘l't'n ()rtml [CU-“l ZUI'r’JJ: 573—576. {99.7.
`
`'9 l9“)? Lippineoll- Raven Publishers. Philadelphia
`
`Phase II Trial of Intravenous CI—980
`
`(NSC 370147) in Patients with Metastatic
`
`Colorectal Carcinoma
`
`Model for Prospective Evaluation of Neurotoxicity
`
`Two phase I protocols with Cl—980 have been con-
`
`R. Pazdur, M.D., C. Meyers, Ph.D., E. Diaz-Canton, M.D.,
`J. L. Abbruzzese, M.D.. Y. Part, M.o.. W. Grove, M.S.,
`and J. Ajani, M.D.
`
`Cl—980 (NSC 37014?)—a synthetic mitotic inhibitor that
`binds to luhulin at the colehicine binding siteéhas signifi-
`cant activity against a broad spectrum of tumor models and
`greater in vitro eytotoxicity when given over >24 hours than
`4 hours or less. Phase I studies demonstrated central nervous
`system (CNS) toxicity to he dose-limiting when CI-980 was
`administered as a 24-hour infusion. When a 72-hour infusion
`was given. CNS toxicity was reduced and granulocytopenia
`became the dose-limiting toxicity. In this phase II study, CI-
`980. 4.5 iogfniz, was administered as a 24-hour continuous
`intravenous infusion for 3 consecutive days and repeated
`every 2| days. Fourteen patients who had measurable mela—
`static coloreclal cancer were entered in the trial. Eight pa-
`tients had received one prior chemotherapy regimen for met—
`astatic disease. Patients were prospectively monitored by
`neurologic examinations and neuropsychologic assessment
`ol' cognitive Functioning. No complete or partial responses
`were observed. Grade 4 granulocytopenia was the dose-lini-
`itittg toxicity. Reversible declines in recent memory function
`were noted in all patients. After each course of (21-980,
`there were also transient non—significant declines in motor-
`coordination, compared with the preinl‘usion assessment. At
`the stated dose and schedule. Cl-980 lacks activity in meta-
`static eolorcctal carcinoma. The agent's toxicity prolile
`(granulocytopenia and CNS effects) was comparable with
`previously described el'lects of this agent.
`Key Words: Cl—‘JSO—Colorectal carcinoma—Colon carci—
`noma—Rectal can:inoma—Neurotoxicity—-CNS toxicity.
`
`
`From the Department ol' Gastrointestinal Medical Oncology and
`Digestive Diseases tR.I’., F..D.—C.. .I.L.A.. Y.P.. LA.) and the Depart—
`ment of Noam-Oncology (CMJ. The University of Texas M. D.
`Anderson (lancer Center. Houston. Tean . lJ.S.A.; and Parke-Davis
`Pharmaceutical Research tW.G.}. Division of Warner Lambert 0)..
`Ann Arbor. Michigan, USA.
`Supported in part by a contract from Parke-Davis l’l‘iarniaceulical
`Research. Division of Wm'ner—Lamhen Co. (Ann Arbor. Michigan.
`U.S.A.).
`Address correspondence and reprint requests to Dr. Richard Pazdur.
`Division of Medicine. The University of Texas M. D. Anderson Cali-
`Cer Center. l5l5 Holcombe Boulevard. Houston. TX 77030. U.S.A.
`
`Fluorouracil (S—I’U} is the most active agent in the
`treatment of metastatic colon carcinoma. with response
`rates of approximately 10% for bolus schedules and
`30% for protracted continuous—infusion schedules.'
`Modulation of SwFU's activity with leucovorin has
`been extensively investigated. Compared with 5—FU
`bolus therapy.
`the combination produces higher re—
`sponse rates, although its effect on survival has not
`been clearly established.'
`lrinotecan tPharmaeia—Up—
`john. Kalamazoo, MI) has recently been approved for
`the treatment of metastatic adenocarcinoma. having
`demonstrated response rates of 33% in previously ult—
`treated patients and 17% to 27% in previously treated
`patients but no impact on survival.” Thus, new agents
`or treatment strategies for advanced colerectal cancer
`should be actively investigated.
`CI-980. a synthetic mitotic inhibitor that binds to
`tubttlin at the colehicine binding site. inhibits tubuliu‘s
`polymerization and blocks cell-cycle progression in
`mitosis.4 (31-980 is similar to colehicine in structure
`and function but unlike the latter, also crosses the
`blood—brain barrier (Fig.
`l). (ll—980 has signilicant
`activity against a broad spectrum oftumor models and
`retains activity against a panel ol‘ tumor models that
`are cross-resistant
`to vincristine. vinblastine,
`na—
`vclbinc, and doxorubicin.
`Cl—980 exhibited marked schedule dependency in
`vitro. Willi extended exposure (>24 hours}. the inhibi-
`tory concentrations were thousands of times lower than
`inhibitory concentrations at
`short exposures
`[44
`hours). In contrast, the cumulative maximum tolerated
`dose in vivo was relatively constant, regardless of the
`regimen used. Preclinical animal toxicology studies in
`Wister rats demonstrated dose—related reversible my-
`elosuppression and testicular
`tubular degeneration.
`These studies did not reveal neurotoxicity. even at ap—
`proximately lethal doses."a
`
`NOVARTIS EXHIBIT 2067
`Par v. Novartis, IPR 2016-01479
`Page 1 of 4
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`

`

`R. PA ZI) UR ET AL.
`
`-H0CH2CH2503 H
`FIG. 1.
`(31—980 structure.
`
`ducted. In the first, CI-980 was admintstered to 25
`patients as a continuous infusion for 24 hours t‘cpgalfid
`every 2] days at doses ranging from 1-2 “1921”de
`to 19.2 mgr‘lnzlday.‘l The dose-limiting toxicity was
`reversible CNS toxicity consisting of ataxia or 011le
`signs of cerebellar dysfunction, confusion, or dlE-Efll'li'j‘n'
`tation. In the second study. CI-980 was admtmstmed
`intravenously for 3 consecutive days and repeated 3""
`cry 2| days at infusion durations ranging from 1 1101-"
`to 24 hourst’day.7“’ On this 3-day schedule. CI-980w2l5
`substantially more myclosuppressant when adnnnts—
`tered as a continuous infusion than when gtven-bi’
`shorter infusions. Granulocytopenia was the dose-hm—
`iting toxicity for the 72—hour infusion schedule, but
`CNS toxicity developed in only 1 of 13 patients treated
`on this schedule.
`
`In phase I evaluations, 3 patients on the 24—hour
`infusion schedule demonstrated evidence of antitumor
`activity: a partial response in 1 patient who had ad—
`vanced colon cancer and metastatic liver disease and
`a reduction in CA-lZS levels in 2 patients who had
`advanced ovarian canoer. Pharmacokinetic studies
`showed CI-980 to have an extensive distribution into
`tissues and high systemic clearance?3
`Based on the lower incidence of CNS toxicity asso-
`ciated with prolonged infusions, the 72—hour schedule
`of Cl-980 at 4.5 mgfmzr'day (13.5 tngl’mzt'course) was
`selected for phase [1 testing. We report here the results
`Ofa phase II trial of (31—980 in patients who had meta—
`static colorectal carcinoma.
`
`count nadir (40,000/tfil4 clinically signilieant treatment-rc-
`
`aticnt‘s eligibility. provided that the radiation field had not
`included the site of measurable disease.
`informed consent
`was required of all patients. PttllCllls‘ could not-have known
`01. Hus-peered brain metastases, overt psychosis or mental
`disability. active congestive heart
`lailnrc. uncontrolled an—
`gimL myocardial
`infarction in the (i months before study
`or hypertension uncontrolled by medication. Standard
`entry.
`I m
`response and toxicity criteria were uset
`Pretreatment evaluation included a complete medical his-
`ml-y‘ physical examination, complete blood count. a multi—
`channel chemistry pt'olilc (glucose. BUN. serutn creatnnnc.
`total protein. albumin. bilirubin. calcium. serum alanine ami—
`nmmnst‘crase, alkaline phosphatase, sodium. chloride. and
`potassium); urinalysis; clcctrocardtogram; chest radiograph:
`and computed tomography scans to deltne extent 0| discus;
`Complete blood, platelet. and differential counts were ob-
`tained weekly. and serum chemistrics were repeated at least
`once every course. If the AGC decreased to <1500ipL. a
`complete blood count was repeated twice weekly until the
`count recovered to normal. Computed tomography scans
`were repeated every two courses. and the electrocardiogram
`was repeated when the patient discontinued therapy.
`Patients were also prospectively monitored by neurologie
`examinations and neuropsychologic assessment of cognitive
`functioning. The neuropsychologic battery contained live
`tests: the Mini-Mental State Examination for a brief global
`screening of cognitive function to detect serious neurotoxic
`side ell‘ects,‘J the Mattis Dementia Rating Scale as a compre-
`hensive assessment of cognitive functioning.'2 the Hopkins
`Verbal Learning test for a detailed assessment of learning
`and memory,” the Grooved Pegboard test as art assessment
`of tine-motor speed and cotn'dination.” and the Functional
`Assessment of Cancer Therapy to assess quality of life.'5
`These were performed during screening and repeated on day
`4 of each course as close to the end of the infusion as
`possible. If the procedure done on day 4 detected a clinically
`significant change. the procedure was repeated daily until
`functions recovered to normal.
`Cl—‘JSU was provided in IO-mg vials by Parke-Davis l’har—
`maceutical Research. Division of Warner-Lambert Co. (Amt
`Arbor. MI. USA). The drug was reconstituted with 5 mL
`water for injection (USP). resulting in a concentration of 2
`Ingt'mL. The calculated dose was further diluted in [000 ml.
`5% dextrose in water (USP) and administered as a constant
`rate infusion over 24 hours for 3 consecutive days. Courses
`were repeated every 21 days.
`The starting dose for all patients was 4.5 lllgfl'l‘lgfdily (total
`dose, 13.5 mgr'ma over 72 hours}. The lirst course ofthcrapy
`and the first escalated dose were administered in the hospital
`to allow careful monitoring ofCNS toxicity. lfwcll tolerated.
`subsequent courses were given on an outpatient basis.
`Dose escalations by 0.5 mgfmzr'day above the previous
`course‘s dose (Cl—980 maximum dose allowed was 5.5 Inga"
`ineiday or 16.5 mgr’mzlcourse) were permitted if in the previ-
`ous course the AGC nadir was >1000r’nL, the platelet nadir
`was > |00.0001,u.[., the maximum grade of nonhcimttologic
`toxicity experienced was grade | (excluding alopecia, local
`vein reaction. or grade 2 nausea or vomiting), and no treat—
`ment—related CNS adverse events had occurred. The Cl—980
`
`PATIENTS AND METHODS
`
`Patient eligibility criteria included metastatic histologi-
`cally confirmed and bidimensionally measurable adenocarei—
`norna of the colon or rectum. Patients could have received
`one prior regimen for metastatic disease in addition to adju-
`vant chemotherapy. Patients were required to ltave a World
`l-Iealth Organization performance status of 0 to 2 and an
`expected Survival duration of longer than 9 weeks. Other
`study inclusion requirements were adequate hematologic
`function (absolute granulocytc count
`[AGC] 2:!5001uL,
`platelet count 2; 100.0001;th renal function (serum creati—
`nine value a 2.0 tngi’dL); and hepatic function (total biliru-
`bin 5 2.0 mgr'dL). Prior radiotherapy did not preclude a
`
`Am J Clin ()ncof (CCU. Vol. 20. No. 6. E997
`
`dose in the subsequent cotlrse was reduced by 10 night]?!
`day if any of the following occurred: AGC nadir (SUOJ'uL
`for 5 days or longer. or AGC nadir €500pr
`associated with
`fever .2 1004"]: or with a documented infection; platelet
`
`NOVARTIS EXHIBIT 2067
`Par v. Novartis, IPR 2016-01479
`Page 2 of 4
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`

`

`(II—980 FOR MI‘TIASTATIC COLORECTAL CARCINOMA
`
`575
`
`TABLE 1. Toxic effects of Cl—980 by grade
`{n = 14 patients)
`Grade
`
`
`
`Toxic effect 2
`
`31 1 54 4
`
`Granulocytopenia
`Thrombocytopenia
`Anemia
`Infection
`Neutmpenic (ever
`Fever of unknown origin
`Fatigue
`Lethargy
`Stomatitis
`Diarrhea
`Chills
`Dizziness
`Myalgia
`Proetitis
`Skin reactions
`Alopeeia
`Central nervous system effects
`Cortical
`
`Am .l' Clio ()m‘pl' {C(‘TJ. Vol. 2f}, No. 6. we?
`
`_L_I.b0345-
`
`Sensory
`Cerebellar
`
`lalcd grade 3 or 4 nonhematologic adverse event; grade 2
`CNS toxic effect of cerebellar dysfunction. confusion, or
`disorientation; or a decrease in tlte total score of the Mini-
`Mental State Examination of 2:3 points. The Cl—980 dose
`had to be reduced by 2.0 mgimzlday il‘ CNS toxic effects =3
`grade 3 occurred.
`
`R ES UL'I‘S
`
`Fourteen patients (7" men. it Women) with a median
`age of 54 years (range, 40—75 years) were entered on
`this trial. Tttmor response and drug toxicity could be
`evaluated in all 14. Eight patients had received one
`prior chemotherapy regimen for metastatic disease.
`Sites of measurable disease included liver ( [2 patients}
`and lung (3 patients}. The median number of courses
`given was two (range. 2—6). A total of 36 courses of
`Cit—980 were given: 23 courses (I4 patients} at 4.5 mg/
`milday; 10 courses (7" patients) at 5.0 Ingr’mzi’day; and
`3 courses (3 patients) at 3.5 mgi‘mzi’day.
`Neither partial nor complete responses were ob-
`served. The median titne to progression was 7 weeks
`(range, 6— l 8 weeks}. Three patients experienced stable
`disease lasting 9.
`l l. and [5 weeks.
`Toxic reactions observed in the 14 study patients
`are listed in Table I. Granulocytopenia was common:
`8 patients experienced grade 4 granulocytnpenia. The
`median granulocyte nadir, occurring on day 14, was
`l?()()r'uL (range, 0—47tltli’piL), with a median duration
`of granulocyte suppression of 8.5 days (range. ch23).
`Only 1 patient developed neutropenic fever that re-
`quired admission to tlte hospital, however. Thrombo—
`cytopenia was rare, with only I patient developing a
`grade 2 platelet count during the first course of treat—
`
`ment; this did not recur in the next course at the same
`
`dose. Dose reductions were mandatory for grade 4 neu-
`tropenia, as previously described. TWo patients ne-
`ecived granulocyle colony-stimulating factor as treat—
`ment for neutropenia. Other non—CNS toxic effects
`included fatigue, lethargy, infection, fever, skin reac-
`tionS, alopeeia, dizziness, anemia. stomatitis. diarrhea,
`chills, and myalgia. Cardiotoxicity was not noted in
`this trial.
`
`Neurologic evaluation and neuropsychologic assess-
`ment of cognitive function revealed a significant but
`reversible decline in recent memory functioning in all
`patients after each course of (31-980 but with no effect
`on overall mental status or neurologic function. Neuro-
`logic examinations revealed no clinically significant
`changes other titan subjective complaints of memory
`decline and unsteady gait. typically occurring at
`the
`conclusion of the infusion and lasting 2 to 3 days.
`There were no clinically detected motor or sensory
`changes on neut‘ologic examination.
`Significant effects of Cl-980 were detected on the
`neuropsyehologic assessment. Although there was no
`change in overall cognitive functioning. there was a
`significant decline in memory performance (both learn—
`ing and recognition of items presented): 67% of pa-
`tients performed 2 LS standard deviations below the
`nonnative mean after the first course of treatment.
`
`Theue were also transient, non—significant declines in
`motor coordination after each course of CI—98t), com—
`pared with the preinfusion assessment. No changes in
`quality of life were noted. The details of this neuropsy~
`chologic evaluation have been described iii a separate
`report.”
`
`DISCUSSION
`
`Cl-980 at the dose and schedule studied failed to
`
`demonstrate any clinical activity in patients with meta-
`static colorcctal carcinoma. Granulocytopenia was
`common, yet 50% of the patients were able to receive
`one dose escalation. The toxic effects observed were
`
`consistent with those reported in the phase I trial of
`the 72—hour schedule, except that all patients in our
`trial experienced some evidence of mild CNS toxicity.
`CI-980 caused a specific, reversible dysfunction of
`memory, presumably related to its action on eholincr-
`gic neurons in the hippocampus.” Motor speed and
`dexterity also declined slightly after each treatment.
`Cl-980 had no effect on overall cognitive functioning
`or subjective quality of life and did not cause clinically
`detectable neurologic deficits nor changes in quantita-
`tive sensory testing.
`At the dose and schedule studied, Cl—98t} probably
`did not affect enough cholinergie neurons in the hippo—
`campal region to result in persistent memory loss. Be—
`cause disease progressed after two courses in most
`patients and they did not receive 0—980 for multiple
`courses, the agent’s long-term and cumulative neuro—
`toxic side—effects cannot be assessed. The neurotoxic-
`
`NOVARTIS EXHIBIT 2067
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`5 76
`
`R.
`
`[’AZDUR ET AL.
`
`ity noted with Cl-980 is consistent with colchicine‘s
`recognized effects on the brain. '3‘")
`In another phase II trial of Cl-980 administered at
`the same dose and schedule for advanced epithelial
`platinum-refractory ovarian carcinoma, only one re—
`sponse was observed in 16 patients.3”‘2' Grade 4 neutro-
`penia occurred in 50% of the patients, and CNS toxic-
`ity was similar to that reported in our trial.
`Preclinical studies of (31-980 did not predict CNS
`toxicity, and the phase I study of the extended-infusion
`schedule observed a lower frequency of CNS toxicity.
`These phase 1 trials, however, did not use the prospec-
`tive neuropsychologic testing performed iit our trial.
`Prospective neurologic examinations and neuropsy—
`chologic assessment of cognitive functioning in ottr
`clinical trial more accurately described Cl—98tl’s CNS
`toxicity profile.
`The effects of Cl-980 on memory function were
`reversible and did not appear Cumulative. Because of
`rapid disease progresrsion. however, the study patients
`did not receive prolonged treatment with Cl—980. Thus,
`its CNS toxicity profile may be more completely de-
`fined in patient populations treated for longer dura-
`tions, and sequential prospective CNS evaluations
`should be performed. Clinical trials of CI—980 in pre-
`viously treated soft-tissue sarcoma and recurrent gli-
`oma are ongoing.
`(E
`
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