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`IMMUNOGEN 2298, pg. 1
`Phigenix v. Immunogen
`|PR2014-00676
`
`IMMUNOGEN 2298, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`438a
`
`IMMUNOBIOLOGY AND BIOLOGIC THERAPY
`
`*1686
`PHASE I OPEN STUDY OF THE EFFECTS OF ASCENDINC DOSES OF THE
`CYTOTOXIC IMMUNOCONIUGATE CMB-4OI
`(HCTMOI-CALICHEAMICIN) IN PA-
`TIENTS WITH EPITHELIAL OVARIAN CANCER. AM. Gillespie, T.J. Broadhead,
`S.Y. Chan, J, Owen, A. Farnsworth, M. Sopwith and RE. Coleman. YCRC
`Dept, Clinical Oncology, Weston Park Hospital, Sheffield, U.K. Dept,
`Clinical Oncology, City Hospital, Nottingham, U.K. Ce/ltech Therapeutics
`Ltd, Slough, U.K.
`We have performed a Phase l study of the cytotoxic immunoconjugate
`CMBe401 (hCTMOl-calicheamicin)
`in women with epithelial ovarian
`cancer (EOC). hCTMO1 is a genetically engineered human antibody
`directed against polymorphic epithelial mucin which binds preferentially to
`EOC (tumour:blood ratio 8:1 — Cancer Res 1996;56:5179—518). The
`objectives of this two centre study were to identify end-organ toxicities and
`to establish maximum tolerated dose (MTD). Tumour response was also
`monitored. 34 patients were recruited with satisfactory WHO performance
`status, aged 20—75 years and with progressive EOC not amenable to
`platinum/standard therapy. Patients had received a mean of 3.2 previous
`chemotherapeutic regimens with a median interval smce last cnemother
`any of 182 days (range 344217). Patients received upto four cycles of a
`dual infusion of 35mg/m2 hCTMOl ‘pre-dose‘ followed by ascending doses
`of CMBe401 - a regimen which minimises drug uptake in normal tissues
`whilst enhancing delivery to the ovarian tumour. OMB-401 dosing com-
`menced at 2mglm2 and progressed via seven cohorts to 16 mg/m2.
`OMB-401 was generally well
`tolerated Transient malaise and emesrs
`occurred, necessitating routine prophylaXIs. WHO grade 3/4 toxicities,
`irrespective of causality, included: haematological (anaemia 21%, granuloe
`Cytopenia 9%, thrombocytopenia 9%); liver and renal (transaminases 3%,
`alkaline phosphatase 6%, urea 3%); sepsis 3%; haemorrhage 6%; nausea/
`vomiting 76%, pulmonary 6%; conscious state 6%. MTD was defined at
`16mglm” by malaise, haematological
`toxicities and the experience of
`gastrointestinal haemorrhage. During the study four patients had a greater
`than 50% reduction in CA125, and four patients had imaging evidence of
`reduction in tumour bulk. OMB-401 appears to have an acceptable toxicity
`profile with initial evidence of activity against EOC. Development will
`continue in a Phase ll study,
`
`*1688
`N7: COMBINATION CHEMOTHERAPY, RADIOIMMUNOTHERAPY AND ADIUVANT
`ANTIBODY THERAPY FOR HIGH-RISK NEUROBLASTOMA (NB). N. K. Cheung, B.
`Kushner, M. LaQuag/ia, K. Kramer, S. Gollarnudi, G. Heller, D. Wuest, M.
`Bymes, W Gerald, S. Yeh, R. Finn, S. Larson, l. Cheung, N. Rosenfield, S.
`Abramson, R. O’Reilly. Memorial Sloan—Kettering Cancer Center, New York.
`NY.
`
`N7 protocol builds on the N6 approach (JCO 12:2607, 1994, 40%
`progression-free (PF) survivors at 66 mo median followup) which utilizes
`dose-intensive cyciophosphamide (CPM), doxorubicin, Cisplatin and VP-16
`to achieve rapid cytoreduction, plus 400 mg/m2 anti-G02 monoclonal
`antibody 3F8 to eradicate microscopic disease. Distinct from N6,
`the
`addition of 20 mCi/kg of 131l-3F8 replaces conventional myeloablative
`chemotherapy/TEL Complete primary tumor resection is integrated With 7
`courses ofchemotherapy: #1, #2, #4, and #6 include CPM 7O mglkg/d ><2
`(With mesna) and 72hr continuous infusion of doxorubicm /5 mg/m2 plus
`vincristine 2 mglmz; #3, #5 and #7 contain Cisplatin 5O mg/ml/d ><4 and
`VP-16 200 mg/rnzld X3. Courses start when ANC reaches SOO/pL and
`platelet counts exceed 100klpL. GVCSF is given 24 hrs after chemotherapy
`until ANC recovers to >500/pL. 21 Gy is administered to the primary and
`metastatic sites to ensure local control. Among 24 consecutive patients
`(pts) newly diagnosed at >1 y of age (median age 3 y, 22 stage 4, 2 stage
`3U with MYCN amplification) most had metastases to marrow (17/24) and
`bones (18/24). Thirteen pts had elevated serum ferritin >142 ng/ml; 11
`MYCN amplification 210 copies, and 8 With serum LDH '> 1500 lUlmL.
`16 pts have completed chemotherapy achieving CR/VGPR in 15/16. 12 pts
`have completed 131eriF8, and 8 pts all treatment. 20 pts (83%) are PF
`(median followup 12.3 mon, 2 CNS relapse, 2 PD on therapy). Compared to
`N6, peripheral neuropathy was decreased. Acute toxicities of 3F8 were
`pain, fever and urticaria; thyroid was protected during 131l-3F8 treatment
`by SSKI, Cytomel and perchloracap. All pts required intensive antibiotic,
`nutritional and blood transfusion support. Optimally—timed 3F8 treatment
`for in vivo and in vitro purging will allow earlier harvest of CD34+ stem cells
`and accelerate the eradication of microscopic disease.
`
`Proceedings of ASCO Volume I 7 l 998
`
`*1687
`PHASE I DOSE ESCALATION TRIAL OF PRETARGETED RADIOIMMUNOTHERAPY
`(PRIT) WITH YTTRIUM 90. A. Martha, R Weiden, S. Knox, H, Breitz, M.
`Gar/s, D. Axworthy, C. Seller, P, Beaumier, K. Bryan, J. Reno. Stanford
`University, Stanford, CA,- Virginia Mason Medical Center and NeoRx Corp,
`Seattle, WA.
`radioimmunotherapy in the treatment of
`The efficacy of conventional
`‘iuman cancer is limited by inadequate localization of antibody in tumor
`and toxicity to marrow from circulating radioactivity. PRIT offers the
`advantages of (1) rapid, efficient, specific, and stable binding of tumor
`ocalized antibody receptor, and (2) rapid elimination of radioactivity from
`he whole body. We pretargeted epithelial tumors with a conjugate of a
`pancarcinomaereactive monoclonal antibody (NR-LUJO) and streptavidin
`0 act as a prelocalized, tumor-specific high affinity receptor. Forty-eight
`tours later the remaining circulating Conjugate was cleared with biotiriyl~
`ated human serum albumin. Finally 24 hours later radioactIVity was
`delivered using a small molecule 90Y—DOTA—biotin ligand. After preliminary
`Phase I studies to optimize the doses and timing of the components of this
`PRIT regimen, 40 patients with refractory epithelial neoplasms (11 ovary,
`10 colon, 9 prostate, 6 breast, 4 misc) were injected With increasing doses
`of 9°Y, Dosimetry estimates for normal tissues and tumor were obtained. Of
`33 patients currently evaluable for response, there were 2 partial responses
`(prostate and ovary), 4 minor responses (2 ovary, 1 colon, 1 prostate) and 9
`Datients with stable disease. Toxicity has consisted of nausea and vomiting
`(Grade ll”, 20 pts; Grade Ill/IV, 3 pts); elevated liver function tests (Grade
`in, 16 pts; Grade Ill/IV, 2 pts); thrombocytopenia (Grade llll, 9 pts; Grade
`“AV, 7 pts); neutropenia (Grade llll, 8 pts, Grade Ill/IV, 4 pts); and
`diarrhea (Grade ll”, 6 pts, Grade ill/IV, 4 pts). The dose iimitingtoxicity of
`this PRIT was diarrhea at a dose level of 140 mCi/m2 WY. Phase II trials of
`9W PRIT at 120 mCi/m2 are planned in patients with prostate, colon or
`small cell lung cancer,
`
`
`
`*1689
`
`RANDOMIZED PHASE II STUDY OF ALL-TRANS RETINOIC ACID (ATRA) 1 or
`INTERFERON (IFN) IN SOUAMOUS CELL CARCINOMA (SCC). C. Domenge, A.Le
`Cesne, P. Pautier, A. Kramar, TLe Chevalier, N. Bouvet, L, Thill, B.
`Escudler. l.G. Roussy, l/illejuif and Roche Company, France.
`Based on previous in vitro and in vivo data demonstrating synergy between
`IFN and retinoids in SCC, we designed a randomized phase ll study
`comparing ATRA alone or associated with lFN in metastatic patients (pts)
`with SCC of head and neck (HNC), lung (NSCLC) and cervix cancers (CC).
`Methods: pts were randomly treated with either ATRA, 45 mg/mz/d [3.0. for
`7 d every other week, or ATRA (same regimen) plus subcutaneous IFN
`(Roferon, Roche) 9.10a lU 3 times a week, every week, until progression of
`the disease or unacceptable toxicity. Tumor evaluation was repeated every 6
`weeks, Results: 48 pts have been enrolled in this study. All the pts with
`NSCLC and CC had been previously treated, while all but 2 pts with HNC
`were untreated. As initially designed, an interim analysis after enrollment
`of 18 pts in each arm demonstrated the lack of response in the ATRA alone
`arm; we thus stopped this arm and are continuing the study as a phase II
`study of ATRA + lFN association. Tolerance was satisfactory, and toxicity
`was mainly attributable to lFN. ATRA induced around 50% of skin toxicity 5
`grade 2 and few cases of mild hypertriglyceridemia. Among 30 pts treated
`in the combined arm (HNC 2 15, NSCLC = 8, CC = 7), we observed 2
`responses in HNC (1 CR and 1 PR) but none in NSCLC and CC. The 2
`responders were previously untreated and had lung metastases. Conclu-
`sion.- ATRA alone is not active in SCC. Moreover, despite some minor
`activity in non pretreated HNC, ATRA combined with IFN is poorly efficient
`in SCC.
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`
`
`IMMUNOGEN 2298, pg. 2
`Phigenix v. Immunogen
`IPR2014-00676
`
`