OOO8
`
`2525982330
`
`SUMMARY
`
`Title of Study: A Dose-Ranging Efficacy, Safely, and Pharmacokinetic Study of SingBe Intravenous
`Doses of RSo25259 for Prevention of Nausea and Vomiting in Chemotherapy-Naive Cancer Patients
`Receiving Highly Emetogenic Chemotherapy
`
`Stud~’ Nee and RS No.," 25259S2330 and RSo25259o197
`
`and Study Centers: Multiple
`
`Publications: None
`
`Study Period: April t994--Apfi11995
`
`Phase:
`
`Objectives= The objectives of this study were to (l) determine the dose=response relationsl~ip among
`single IV doses of RS-25259 over the dose range 1-90 pg/kg; 1he primary endpoint was the proportion of
`patients with a comple¢e antiemetic response (no vomiting or retching) for 24 hours after highly
`emetogenic chemotherapy in chemotherapy-naive cancer patients; the efficacy of each dose was
`compared w~th the efficacy of the lowest dose; (2) assess the safety of single ~V doses of RS-25259
`administered ~ver the range at doses tested in this patient popuJation; and (3) assess the
`pharrnacokinetics of single IV doses d RSo25259 over the range of doses tested in this patient
`population.
`
`~etho~o~egy: This was a randomized, double-blind, mu~ticenter, dose-ranging efficacy, safety, and
`pharmacokinetic study of W RS-2525g-197. Patients were randomized to ~eceive e~’~e of five doses of
`s{udy drug and ware observed as inpatienls and!or outpatients. Safety and efficacy eva~,~ations were
`recorded periodically during the first 24 hours and then dai~y far the next 6 days following administration
`of study medication. Additionally, each patient was contacted 14 days postdosing to obtain further safe:y
`information. Blood samples for pharmacokinelic analysis were taken from patients at selected
`investigationa! sites before dosing and at various times up io 168 hours after dosing with study drug; the
`plasma portion was assayed lot RSo25259 and RS-17825 (the N-oxide metabo~te) concentrations, from
`which pharmacoklnetic parameters were computed.
`
`Number of Subjects~ One hundred sixty-one patients (129 males, 32 females), 23-79 years o~ age
`were enrolled in this study. All patients are included in the safety evaluations. However, 13 patients
`were excluded from all efficacy analysis. Reasons lot exclusion included various prolocol violations
`(8 patients). Subsequently 1o establishing evaiuabiii~y, .5 additional patients, all of who~ received
`cyciophesphamide, were also excluded. Thus, efficacy analyses focused on only patients who received
`c~splatin-besed chemotherapy. The distribution of evaI,Jable patients by dose group is as foJiows: 0.3-
`1 #gtkg, 29 patients; 3 #g!kg, 24 patients; 10 ~gikg, 25 patients; 30 pg/kg, 24 patients; and 90
`46 patients.
`
`Diagnosis and Criteria fo;t ~nc~usior~: Patienfs were men and women who had histologically proven
`cancer, were chemotherapy naive, and were scheduled to receive ~heir first dose of emetogenic
`chemotherapy, either cispfetin (_>. 7~} mg/m2) or cyclophosphamide (> 1100 mg/rn~).
`
`Test P~oduet, Dose and ~’~ode of Administration, Formulation No., Batch/Lot No.: RS-25259 was
`supplied in 5-mL glass vials at a concentration of 500 #dime Patients were random!y assigned to one of
`five RS-28259 treatments. Prior to Amendments Ill and IV of the protocaL the treatments were 0.3, !, 3,
`
`s:\rs-25229’~259s2330, duc
`
`HIGHLY CONFIDENTIAL - OUTSIDE COUNSEL EYES ONLY
`
`HELSN0033954
`
`DTX-0227-0014
`
`Helsinn Healthcare Exhibit 2051
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00008
`
`Page 1 of 2
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`

`
`25259S23S0
`
`10, or 30 #g!kg; following those amendments, they were 1, 3, 10, 30, or 90 I~gtkg Normal sa~ine was
`used to dilute RS-25259 to a total injection volume of 25 mL Study drug was adminislered 30 minutes
`before start of chemotherapy and given as a single bolus IV dose over 30 seconds, The formulation
`number RS-25259 was No. F25259-006 (Lot Nos, 25259-!97-! 2479 and -1021 881 ).
`
`Reference Therapy, Dose and Mode o~ Administration~ Formulation No., BatehfLot No.: None
`
`Duration of Treatment: Patients received a single IV dose at RS-25259-197 over 30 seconds and were
`subsequently foI~owed for a total of 14 days.
`
`Criteria for Evaluation: CtinicalDa~a--The prima~y efficacy variable was ~he proportion of patients with
`a complete antiemetic response (no vomiting or retching, no rescue medication) far 24 hours after the
`start of chemotherapy. The efficacy of each dose was compared wi~h the efficacy of the lowest dose.
`Seconda~ effi~cy vadaMes ~ncluded the time Io the first emetic episode, time 1o administration d
`rescue therapy, area under the nauseaqntens~y-by-time (NIT) cu~e based on calegorJcal scale, ~ime to
`treatmenl failure (eithe~ emesis or need for rescue medication, whichever occurred firs0, practice d
`patients w~h complete control of emes~s (no vamping and only mild nausea or no naus~), and global
`rating of satisfaction with the control ol nausea and vomRinfl based on a visual analog scale. These
`variables were supplemenled by physical examination and v~a~ s~gns data, Iaborato~ findings, and
`adverse event da~a. Pharmacokinetic Data-....-Plasma concentrations and computed phal~aco~netic
`par~mete~ for RS-25259 and RS-17825 were assessed.
`
`Statistical Methods." Demographic and safety de.to were summarized; plasma concentrations and
`computed pharmacokinetic parameters were Iisted and statistically summarized by dose group;
`individual and mean plasma concentrations were plotted ve~’sus time; and com~suled pararnetem were
`analyzed for a dose relationship (e.g., dose proportionality, dose linearily).
`
`Su~-~r~a~ and Cor~c~usions= RS-25259, administered as a single bolus intravenous injection of 3, 10,
`3,1 or 90 p~kg 30 minutes prior to high-dose cisplatin chemotherapy, was effective in suppressing
`chemotherapy-induced emesis for 24 hours. AI~ four doses were approximately equally effective as
`compared w~h the combined results from a cohort of 0.3 and 1 I~g/kg. The following table summarizes
`key efficacy parameters.
`
`Parameters
`II % O~e Control (24 hours)
`24
`~ C "ompl~te Response {24 hours)
`24
`II Median Time (hourS) ~ ~ailure (first 5.6
`~ emetic episode or rescue
`
`0.::~1
`
`]
`
`RSo25259 Dose ~q[kg[
`
`4~ 40
`39
`4O
`22.7~
`19.0
`
`50~
`48
`
`i > 24~
`
`90
`
`46
`46
`21.8*
`
`*statisfical!y significant differences (p < 0,05) vs. ~owest dose group
`
`Safety evaluations and comparisons made between treatment groups all suggest that RS-25259 is a
`refative~y safe therapeutic agent. No dose response-related adverse events were observed. One
`hundred twenty-nine of the 161 patients in the safety analyses (80.1%) experienced at least one adverse
`event during the study. A maiority of events were rated as rnild or moderate (469/559, 83.9%) and were
`considered probably no~ related to test medication (481/559, 86.0%}. Incidence, frequency, severity, and
`relationships of adverse events appeared to be essentially equally distributed among the RS-25259
`treatment groups. The most frequent adverse event reported was headache, fol~owed by constipation,
`pain, asthenia, anorexia, arid diarrhea. Serious adverse events that occurred were el! iudged by the
`treating physicians to be probably not relaled to chemotherapy. No dose-related ~oxicity was observed in
`electrocarc~iograms o~ laboratory parameters eva~uations.
`
`s:Ws-25229~259s2330.doc
`
`HIGHLY CONFIDENTIAL - OUTSIDE COUNSEL EYES ONLY
`
`HELSN0033955
`
`DTX-0227-0015
`
`Page 2 of 2