8322
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`Thursday 16 September I999
`
`Proffercd Papers
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`1291
`
`PUBLICATION
`
`Phase II study results on safety and efficacy of CAELYX®
`(DOXIL®) in combination with paclitaxei in the treatment of
`metastatic breast cancer
`
`BJ. Woll‘, J. Carmichael‘, 3. Chan‘, A. Howellz, M. Ransonz, D. Miles3,
`H. Calvert“. H. Welbank5. ’Nottingham City Hosptial, CHO Academic Unit
`of Clinical Oncology, Nottingham; 2Christie Hospital, CFiC Department of
`Medical Oncology, Manchester; 3Guy’s Hosplial, lCRF Clinical Oncology
`Unit, London; 4Newcastle General Hosptial, Northern Centre for Cancer
`Treatment, Newcastle; 5SEOUUS Pharmaceuticals. Inc, Brentford,
`Middlesex, United Kingdom
`The combination of doxorubicin and paclitaxel has produced encourag-
`ing response rates in the treatment of metastatic breast cancer. However,
`this regimen has conSiderable toxicities. in particular cardiac toxicny with
`high cumulative doses. CAELYX® is a doxorubicin formulation in which
`the drug is encapsulated within pegylated (STEALTH®) liposomes. The
`altered characteristics imparted by the encapsulation may reduce the risks
`of myelosuppresslon and cardiotoxicity in combination with paclitaxel. Forty
`three patients with confirmed metastatic cancer have been treated with
`paclitaxel and Caelyx to investigate the efficacy and toxicities of this combi-
`nation. Patients were permitted up to 2 prior chemotherapy regimens which
`could have included prior anthracyline (16 pts) and/or taxane (3 pts). Median
`age 54.5 (range 73-31). The starting dose of CAELYX was 50 mg/m2 every
`6 weeks (n = 6), but was changed to 30 mglm2 every 3 weeks mglm2 (n
`= 37). Twenty five patients are currently evaluable for efficacy: 1 complete
`response, 14 partial responses, 3 stable disease, 7 progressive disease,
`(Five patients are not assessable for efficacy and 13 are too early for
`assessment) Twenty four patients have completed treatment with a median
`of 5 doses (range 1-10) of paclitaxel and 4 doses (range 1—8) of CAELYX
`was administered The most commonly observed toxicities were mucositis
`when Caelyx was given every 6 week, palmar-plantar erythrodysaesthesia
`(PPE) when Caelyx was given every 3 weeks and neutropenia. Accordingly
`dose reductions and delays were scheduled for >grade 2 PPE, myeiosup-
`pression or muoositis.. CAELYX doses were reduced in 13 patients and
`paclitaxei doses in 2 patients. Dose delays were required in 18 patients.
`Eighteen patients are still being treated of whom 11 have had close delays
`and 2 reductions in the dose of Caelyx.
`
`1292
`
`PUBLICATION
`
`A Phase II study of lncelTM (biricodar, VX—710) in
`combination with paclitaxel in women with advanced breast
`cancer refractory to paclitaxel
`D. Toppmeyer‘, A. Seidman‘, B, Overmoyer‘, M. Pollak‘. S. Verma‘,
`C. Russell‘, K. Tkaczuk', S. Del Prete‘. G. Schwartz', M.W. Hardingz.
`’lncel Breast Cancer Study Group; 2 Vertex Pharmaceuticals Incorporated,
`Cambridge, MA, United States
`IncelTMNX-71U is a potent inhibitor of MDFi mediated by P-glycoprotein
`and MFiP expression. We conducted a Phase II study evaluating safety,
`tolerabiiity and efficacy of lncel/paclitaxel (P) in breast cancer patients
`(pts) refractory to prior P therapy. inclusion criteria: ' 2 prior chemotherapy
`regimens for advanced disease, progressive disease on P. or relapse within
`a months of prior P therapy, ECOG performance status " 2; normal bilirubin,
`AST and ALT ’ 1.5 x ULN; baseline ANC and platelets " 1500 and 100,000,
`respectively. Pts received Incel (120 mg/mzlhr) as a 24-hr infusion with 3-hr
`P at 80 mg/rn2 (P AUC and time > 0.05 mM comparable to 175 mg/m2
`P). The study enrolled 38 pts. Demographics, treatment, and safety data
`are available from 30 pts who received 76 treatment cycles. Demographics:
`median age 49 yr. (range 29 to 65 yr), 27/30 with ECOG performance
`status 0 or 1. prior treatment included adjuvant chemotherapy (18 pts),
`2 prior regimens for advanced disease (17 pts), and P as initial therapy
`for advanced disease (13 pts). The majority of pts were resistant to initial
`P therapy. Incel/P has been well tolerated with myelosuppression as the
`principal treatment toxicity. Hematology data available for 34 cycles shows
`that median WBC and ANC nadirs for the first 2 cycles ranged from 2.1
`to 2.6 x 103lmm3 and 0.5 to 0.70 x 103lmm3, respectively, Gr 3 or
`Gr 4 neutropenia was observed in 32% and 53% of cycles, respectively.
`Incel/P had no effect on platelet counts. Myelosuppression observed with
`inceliP is similar to 24—hr P infusion. Non—hematological toxicities included:
`mild to moderate asihenia, fever, anemia, paresthesia, headache, nausea
`and myalgia. Analysis of P pharmacokinetics for 19 pts indicates a mean
`weight normalized CLs of 0.120 Llhrlkg and Vss of 1.65 L/hr/kg indicating
`P exposure is comparable to a 3-hr 175 mg/m2 infusion. Thirty five pts are
`evaluable for response: 3 pts achieved PFis, 2 pts had minor responses
`(430% shrinkage) and 5 pts are continuing therapy. These results suggest
`
`that Incel/P therapy can benefit some breast cancer pts with strictly defined
`P refractory disease, and provides a rationale for studies in pts with less
`advanced disease.
`
`1293
`
`PUBLICATION
`
`Phase II trial of docetaxel and Herceptin (R) as first- or
`second-line chemotherapy for women with metastatic breast
`cancer whose tumours overexpress HER2
`H.A. Burris‘, J.D. Hainesworth‘, K, Albain‘, M. Huntington‘, F.A. Greco‘.
`J. Erlandz, A. HussainB, C.L. Vogel‘. ’Sarah Cannon Cancer Center, Drug
`Development, Nashville, TN; 2Loyola University, Chicago, lL, 3Tel‘on
`Medical Center, ldaho Falls, lD; 4Columbia Cancer Research Network of
`Florida, Avenlura, FL. United States
`Purpose: Women with metastatic breast cancer whose tumours overex-
`press HER2 have more aggressive disease and shortened survival. Her-
`ceptin (trastuzumab) as a single agent has shown activity in such patients
`and the addition of Herceptin to chemotherapy has improved the response
`rate and time to disease progression. Docetaxel
`is an active agent in
`the treatment of metastatic breast cancer and has shown response rates
`superior to that of doxorubicin.
`Methods: This trial was the first to assess the safety and efficacy of
`combining Herceptin and docetaxel. The treatment regimen was docetaxel
`75 mg/m2 every 3 weeks for 6 cycles, with Herceptin initiated on day 1 as a
`4 mg/kg loading dose followed by 2 mglkg weekly until disease progression.
`Patients were premedicated with a standard 3-day dexamethasone regimen
`of 8 mg po bid. Herceptin was administered first, followed by a 1-hour
`docetaxel infusion. Eligibility criteria included: measurable metastatic breast
`cancer; 2+ or 3+ HER2 overexpreSSIon (DAKO kit); no prior faxoid therapy;
`less than or equal
`to one prior regimen for metastatic breast cancer;
`cumulative doxorubicin dose < 250 mg/mz; and normal LVEF. Primary
`endpoints included: response rate; response duration; time to treatment
`failure; and safety/tolerabilityl
`Results: To date, a total of 14 patients have received more than 50
`cycles (range 1+ to 7+) of therapy. There have been 2 confirmed PR5. 3
`minor responses and no reports of serious toxicities. One patient who was
`ineligible secondary to laboratory parameters was inadvertently enrolled
`and experienced an early death attributable to progressive disease.
`Conclusions: These preliminary data indicate that the combination of
`docetaxel and Herceptin is well tolerated and accrual continues to a total of
`30 patients. Further response data will be presented at the meeting.
`
`1294
`
`PUBLICATION
`
`Phase I/II trial of oral UFT/Leucovorin (LV) and paclltaxel (P)
`in the second line treatment of patients (PTS) with
`metastatic breast cancer (MBC)
`U. Klaassen, S. Lang, D. Borquez, C. Oberhoit, S. Benner, A. Harstrick,
`S. Seeber. Department 0] Int Medicine (Cancer Research). West German
`Cancer Center, University of Essen, Germany
`Introduction: Phase II studies demonstrate efficacy and low toxicity for
`the continuous infusion of low dose 5-FU (Ann. Oncol. 7: 807—13, 1996)
`in pretreated pts with M86.
`in our hands P in combination with weekly
`5-FU/LV constitutes an active salvage regimen for pts with MBC (Ann. One.
`9: 45—50, 1998). UFT/LV allows delivery of prolonged exposure to 5-FU
`without the need for central venous catheters or infusion pumps.
`of
`Patients
`and Methods:
`UFT,
`which
`is
`composed
`1-(2-tetrahydro-fury|)-5-FU (ftorafur) and UfaClI
`in a molar
`ratio of
`1:4, was administered orally plus LV and in combination with P. Pts
`were treated as a part of an ongomg phase I/II protocol
`in order to
`determine the safety, activity and pharmacokinetics of this combination.
`After premedication, pts received a fixed dose of P 175 mglm2 3 h i.v. on
`day (d) 1 at all dose levels (dl). UFT was administered in combination with
`90 mgld of LV in three divided doses for 14 d’s. The UFT dl's were on 300,
`die 400, dl3 500, dl4 600 and dis 700 mg/d. The cycles were repeated
`every 21 do. So far 26 pts entered the trial: 6 pts dl1, 5 pts dl2, 3 pts die, 6
`pts did and 8 pts dl5. All pts have had prlOl' CTX either as an adjuvant, for
`M80 or in both settings.
`Toxicity and Results: The main hematological toxicity (CTC grade ililiV)
`was neutropenia in 32%. CTC grade II” toxicity including PNP, arthraigia
`and myalgia were common but not dose limiting Dose limiting toxicities
`(DLT) were: dl1ia: 14 pts (74 cycles) no DLT‘s; dIA: 6 pts (28 cycles) febrile
`neutropenia: dis: 6 pts (20 cycles) diarrhea, nausea/vomiting, thrombopenia
`> 35 d. MTD was reached with dis and dl4 is used within the ongoing phase
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`Hospira v. Genentech
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`IPR2017-00805
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`Genentech Exhibit 2068
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