November 1995
`Vol. 31A Supplement 5
`
`ISSN 0959-8049
`
`Afiéfig‘
`2Novl995
`L
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`
`Wednesday 1 November 1995
`
`S193
`
`ORAL
`
`927
`A PHASE I AND BIOAVAILABILITY STUDY OF ORAL
`TOPOTECAN
`]. Eckardt, H. Harris, _7. Rizzo, S. Fields, G. Rodriguez, 1? DelaCruz,
`S. Hodges, D. Van Huff, ]. Kuhn
`The’ Cancer Therapy and Research Center and The University of Texas
`Health Science Center, 78229 San Antonio, Texas, U.S./1.
`Topotecan (T) is an inhibitor of topoisomerase I undergoing clinical de-
`velopment. The oral bioavailability (F) of T in dogs is 36%, however,
`bioequivalent toxicity is closer to lO0°/o. The objectives of this study
`were to determine the MTD (part 1) and absolute F (part 2) of T All
`patients (pts) fasted 4 hours prior to and 2 hours after treatment with
`oral T. Pharmacokinetic analysis was performed by HPLC. In part 1, 12
`pts (median age 63, median PS 1, 6 M/6 F) received a total of 51 courses
`of therapy The initial starting dose of 17.5 mg/mi was well tolerated
`IV but was accompanied by grade 4 neutropenia and thrombocytope-
`nia when given orally The oral dose was reduced to 14.0 mg/m2 where
`l /6 patients developed grade 4 neutropenia. Non-hematologic toxicities
`were mild (<grade 2). In part 2, 18 pts were randomized to either 14.0
`mg/m2 oral T on cycle 1 and 17.5 mg/m2 IV on cycle 2 or visa versa. T
`demonstrated 44% F with rapid oral absorption (peak 0.74 hr) and peak
`lactone conc. (50 :: 22) l0>< less than IV (493 :: 221 ng/ml). There was
`no difference in clearance or Vdss. The AUC achieved PO (275 3: 113)
`is Z.8>< lower than IV (776 :1: 167 rlgxhr/ml). APR in a pt with H&N
`cancer and a MR in a pt with melanoma were observed. Even with lower
`peak conc and AUC’s, oral T maintains its biologic activity
`
`ORAL
`
`928
`PHASE I TRIAL OF THE TOPOISOMERASE I INHIBITOR
`GG211 AS A 72-HOUR INFUSION
`I2‘ 0’Dwyer', L. Pa.i—/lrezz, R. Kunkai, D. DeMaria', I Cassidyz,
`S. Kaye}, S. DePee3, D. Littlefie1d3, K. Selingerj, I? Beranek’, _?. Graham’,
`1? Wisseli
`‘Fax Chase Cancer Center, Phila. PA, USA.
`ZWestern Infirmary, Glasgow, U.K.
`3Glaxa, Inc. RTE NC 27709, USA.
`In a Phase I trial of the water soluble camptothecin analog GG2l1,
`44 patients received a 72-hour infusion at doses ranging from 0.25 to
`2.5 mg/m2/day. Myelosuppression is close limiting. At doses 22.0
`mg/I112 /day, 6 of 14 patients experienced grade 4 granulocytopenia and
`2 of 14 grade 4 thrombocytopenia. Additional side effects (zgrade 2)
`included nausea, vomiting, anorexia, diarrhea, fatigue, and phlebitis.
`One patient at the highest dose had grade 3 mucositis in association
`with myelosuppression. Partial responses have been observed in ovarian,
`colon, and breast cancers and hepatoma. Additional minor responses
`have been observed in colon cancer. Whole blood GGZ1l lactone C5,
`concentrations increased linearly with dose. The mean terminal half life
`was 7.5 :: 3.5 hrs, and mean clearance 922 i 292 ml/min/m2. Pharma-
`codynamic analyses demonstrated that steady—state concentrations were
`predictive of toxicity. Phase II studies with this novel compound are in
`progress.
`
`ORAL
`
`929
`CLINICAL PHASE I TRIAL OF PKI (HPMA C0-POLYMER
`DOXORUBICIN)
`I?/I. Vasey‘, R. Dunctmz, SB. Kaye’, _7. Cassidy’
`‘CRC Department ofMea'ical Oncology, Western Infirmary, Glasgow, U.K.
`ZLnndun School ofPharmacy, 29/39 Brunswick Square, London, UK.
`]Deparlmenz of Oncology, University of/lberdeen, U.K.
`PKI is a novel compound consisting ofN~(2—Hydroxypropyl) methacry-
`lamide (HPMA) hompolymer bound to doxorubicin (DOX) via a pep-
`tidyl spacer which is cleaved intracellularly by lysosomal proteinases,
`(once the compound has entered the cell via endocytosis), releasing free
`DOX intratumourally.
`Improved antitumour activity compared to free
`drug has been demonstrated preclinically, especially in solid tumour
`models. The stability of the linkage in the bloodstream also reduces
`general toxicities such as cardiotoxicity and myelosuppression in animal
`studies, and we have therefore initiated a phase I clinical trial. The start-
`ing dose in humans was 20 mg/m2 given as an iv infusion every 3 weeks.
`Concurrent pharmacokinetic studies and tumour imaging using radiola—
`belled drug are also being performed. To date 19 patients have been
`treated (ages 34-72, mean 57 years). Tumour types are: colorectal 3,
`ACUP 3, biliary tract 3, head and neck 2, NSCLC 2, breast 2, others 4.
`Dose levels 20 mg/m2, 40 mg/m2 and 80 mg/m2 demonstrated CTC
`grade I nausea, vomiting and anorexia——toxicities also seen at higher
`
`dose levels. 3 patients were entered at 120 mg/m2; grade I neurotoxic—
`ity (paraesthesia) (2/3), grade I hepatotoxicity (reversible transatninase
`elevations) (2/3) and grade I lethargy (1/3) was observed. Six patients
`have been entered at I80 mg/m2. The first developed reversible grade
`IH neurocerebellar toxicity.'Other toxicities seen; grade II neutropenia
`(1/6), grade I mucositis (1/6) and grade II nausea (1/6) requiring pro-
`phylactic antiemetics. No alopecia or cardiotoxicity has been observed.
`One patient has been entered at 240 mg/m2 (3-4>< the MTD of free
`DOX) and has experienced grade II anaemia, and grade I emesis to date.
`There is evidence of antitumour activity, and the study continues to ac-
`crue patients.
`
`ORAL
`
`930
`A CLINICAL PHASEI STUDY OF AN
`ANTI-CD25-DEGLYCOSYLATED RICIN A-CHAIN
`IMMUNOTOXIN (RFT5 -SMPT-DGA) IN PATIENTS WITH
`REFRACTORY HODGI(IN’S DISEASE
`R. Schnell‘, M.-TI Hatwig’, A. Radszulm’, E Cebe’, S. Drillich’,
`G. Schan’, H. Balilen’, M.—L. Hansmann‘, ji Schindlers, V Gherz'e3,
`7. Uhr’, VDiehl', E.S. Vitetta3,A. linger!’
`‘Med. Universitdtsklinik I
`Zlnstitutflir Pathalagie, Cologne, Germany
`3Deparzment of Microbiology and Cancer Immunobiolagy Center, UTSC,
`Dallas, Texas, U.S.A.
`Twelve patients with resistent Hodgkin’s lymphoma were treated in
`an ongoing Phase-I trial with the immunotoxin (IT) RFT5—SMPT-
`dgA consisting of a moab directed against the oz-chain of the IL-2 re-
`ceptor (CD25) chemically linked to deglycosylated ricin A-chain. Se-
`lective toxicity of RFT5-SMPT-dgA has been demonstrated against
`Hodgkin/Reed-Stemberg cells in vitro and against solid and dissemi-
`nated human Hodgkin’s lymphoma in nude and SCID mice. All patients
`were heavily pretreated with a mean of4 (range 2-7) different prior ther-
`apies including ABMT in 8 of 12. The mean age was 29 years (19 to
`34). 11/12 patients had advanced disease (stage IV) with massive tumor
`burdens and 7/12 had B-symptoms. The IT was administered intra-
`venously over 4 hours every other day for 7 days. Patients received one
`to four courses of 5, 10 or 15 mg/m2. Peak serum concentration of intact
`IT as measured by ELISA was dose-related ranged from 7-780 pg/ml
`and Tl/2s ranging from l.5-9.7 hours (mean 4.8). Side effects were
`related to the vascular leak syndrome, i. e. decrease in serum albumin,
`edema, weight gain, hypotension, tachycardia, rnyalgia and weakness. In
`2 patients an allergic reaction WHO grade 2 with generalized urticaria
`and mild bronchospasm occurred. At 15 mg/m2 dosage 1 patient ex-
`perienced grade 3 myalgia and 1 patient grade 2 thrombocytopenia. 7
`patients made human anti ricin antibodies (>1 pg/ml) and none made
`human anti mouse antibodies (>1 /cg/ml). 6 of 12 evaluable patients had
`progressive disease and 5 patients had stable disease and 1 patient a par-
`tial rernjssionl The maximal tolerated dose has not been reached yet and
`enrollment continues.
`
`POSTER
`931
`ORAL FOLIC ACID IMPROVES IDMETREXOL TOXICITY
`PROFILE: A PHASE I STUDY
`N. Bailey, A. Hurnphreys, S. Laahavinij, M. Lind, L. Robson, A. Calvert
`Cancer Research Unit, University ofNewcastle upon Tyne, Newcastle, UK.
`Lometrexol, the antipurine antifolate, has an MTD of 12 mg/m2 when
`given as a single agent every 4 weeks. The dose limiting toxicities,
`myelosuppression and diarrhea, were substantially reduced in mice given
`a high folic acid diet.
`In an ongoing phase I dose escalation study of
`lometrexol coadministered with folic acid (5 mg/day for 14 days), 32 pa-
`tients received lometrexol at doses of 12 mg/m3 (3 pts), 16 mg/m2 (4
`pts), 30 mg/m2 (5 pts), 45 mg/m2 (11 pts), 60 mg/m2 (6 pts) and 78
`mg/m2 (3 pts). Tumour types were: 6 breast, 5 ovary, 5 melanoma, 1
`renal, 7 colorectal, 2 NSCLC, Z pancreas, and 4 primary unknown. Ini-
`tial doses were given at 28 day intervals with subsequent reduction to a
`21 day cycle after 8 patients had been treated at 45 mg/m2. A median
`of 2 courses was given (range 1-5). Haematological toxicity was mild.
`One patient experienced a grade 3 neutropenia and 2 patients grade 3/4
`thrombocytopenia (toxicities at 45 mg/m2 ). No grade 3/4 haematolog-
`ical toxicity was seen at 60 mg/m2 or 78 mg/m2. Grade 3 diarrhea (45
`mg/m2), nausea (45 mg/m2) and mucositis (60 mg/m2) were seen in 3
`separate patients. We previously reported a 21-50% {all in GFR with re-
`peated dosing. At 60 mg/m2 the change in pretreatment GFR measured
`by “Cr-EDTA was between -lll9% and 4-23.8%. No alteration ir1
`serum creatinine was seen at any dose level. [flnEMQer9o@22ggl2,
`
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`
`SJ94
`
`Wednesday 1 November 1995
`
`breast cancer) had a partial response of 6 weeks duration. The MTD has
`not been reached and the next dose escalation will be 100 mg/m2 • It is
`clear that coadministration of folic acid ameliorates the clinical toxicities
`seen with lometrexol.
`
`POSTER
`932
`IDGH DOSE CONTINUOUS INFUSION (CI) IFOSFAMIDE
`WITHOUT HEMATOPOIETIC SUPPORT IN HEAVILY
`PRETREATED BREAST CANCER (BC) AND SARCOMA (S)
`PATIENTS
`J Bellmunt, A. Ribas, S. Casado, J Albanell, J Carulla, L.A. SoU
`Hospital General Universitari Vall d'HebronJ BarcelonaJ Spain
`Ifosfamide (IFO) is an oxazophosphorine with a different activity and
`toxicity profile than cyclophosphamide. Its use together with uropro(cid:173)
`tective agents has allowed safe administration and dose-escalation. We
`report the results of a phase II trial of IFO at high doses in heavily
`pretreated BC and S patients. IFO was administered in a 168 hour(cid:173)
`CI through a central venous access, for a total dose of 14 gjm2 q3w.
`MESNA was administered together at equimolar doses. Ondansetron, 8
`mg/8 h po was used as antiemetic treatment. No hematopoietic support
`was used. We included 10 BC and 14 S patients with disease progres(cid:173)
`sion during salvage chemotherapy at conventional doses. Mean previous
`lines of therapy 3 (range 1-5), 20 had received previous treatment with
`conventional-dose cyclophosphamide or IFO. All had received previous
`adriamycin. Median age 44 (range 18-62), 12 males and 12 females.
`Median number of cycle 3 (range 1-8) for a total of 81 cycles of ther(cid:173)
`apy. Worst WHO grade toxic reaction for each patient: grade III-IV
`leukopenia in 65%, grade III nausea and vomiting in 40%, grade III
`neurotoxicity in 5%, grade II nephrotoxicity in 5%. Neurologic and
`renal toxicity were reversible. 9 patients were admitted for neutropenic
`fever, with two documented septic episodes. Treatment had to be dis(cid:173)
`continued in 2 patients after 2 cycles ( 1 renal toxicity, 1 gastro-intestinal(cid:173)
`GI-toxicity). 20 patients are evaluable for response (4 did not finish the
`first cycle of therapy, 3 for early disease progression, 1 for unacceptable
`GI toxicity). Partial responses in 2/8 (25%) BC, and in 3/12 (25%) S.
`No complete responses were recorded. 65% had disease stabilization,
`and 10% had disease progression. 3 with Sand 1 BC underwent fur(cid:173)
`ther high dose chemotherapy with transplantation after assessment of
`chemotherapy sensitivity with high-dose IFO. Median duration of re(cid:173)
`sponse was 5 months. Median overall survival was 6 months (range 2-
`11 + ). In conclusion, CI of IFO for 168 hours is an active regimen in
`highly pretreated BC and S. The addition of hematopoietic growth fac(cid:173)
`tors and further antiemetic agents could improve the toxicity of this regi(cid:173)
`men. Additionally, this regimen could be combined with non-myelotoxic
`drugs.
`
`POSTER
`933
`OXALIPLATIN (L-OHP®): GLOBAL SAFETY IN 682 PATIENTS
`(PTS)
`, J Vignoud1
`S. Brienza1
`, M. ltzhaki2 , A. Krikorian
`1 DebiopharmJ Villejui}; France
`2 Hop. P. BrousseJ Villejui}; France
`L-OHP® is a Dach platinum with significant activity in pretreated ad(cid:173)
`vanced colorectal cancer. In order to describe its safety profile, we gath(cid:173)
`ered the individual data of 682 patients (pts) who received 4303 cycles
`(cy) from 9 studies (seven phase II and two phase III).
`Treatment: L-OHP® was given as a single agent (SA, in 4 studies
`(40% of pts) and combined with 5-FU folinic acid (FFL) in 5 studies
`(60% of pts). L-OHP® was administered in 5 different schedules: 130
`mgfsqmfdl iv over 2 hrs q3 wks in 37% ofpts, 130 mgfsqm/d1 iv over
`6 hrs q3 wks in 5% of pts, 100-200 mg/sqm continuous infusion (CI)
`over 5 days q3 wks in 20% of pts and 100-200 mg/sqm chronomodu(cid:173)
`lated (CM) on 5 days q3 wks in 38% of pts. PT Characteristics: Sex
`MjF: 63/37% PS (WHO) 0-1/2-3: 81/19%. Median age: 60 yrs. Tu(cid:173)
`mor diagnosis: colorectal80%, H&N 6%, melanoma 5%, other 9%.
`Pretreatment by chemotherapy (CT): 47%. Baseline abnormality grade
`(gr) 1-2: anemia 13%, WBC 3%, renal 2%, hepatic 88%, diarrhea
`6%. Methodology: Separate univariate and multivariate analyses were
`performed for single agent and combination studies, influence of the fol(cid:173)
`lowing prognostic factors was sought: age, sex, PS, previous CT, modal(cid:173)
`ity, renal baseline status. Each toxicity was evaluated according to the
`overall incidence (gr 1-4), severity (gr 3-4) and baseline status. Results
`(WHO and WHO modified scale): No drug related toxic death occurred.
`Global results are shown in the following table.
`
`Toxic effects
`
`Incidence
`
`SA
`Hematology 22%
`N-V*
`65%
`30%
`Diarrhea
`Neurologic** 80%
`
`(gr 1-4)
`FFL
`35%
`90%
`85%
`83%
`
`Severity Prognostic
`(gr 3-4) factors
`SA FFL
`2% 6%
`11% 22%
`4% 25%
`3% 19%
`
`Sex:F-PS:2-3***
`None
`None
`Cumulative dose
`
`*With prophylactic antiemetic treatment. **WHO modified scale.
`***Anemia.
`Sensitive peripheral neuropathy is the most frequent limiting toxic(cid:173)
`ity. Grade III neurotoxicity (functional impairment) appears in 12% of
`the pts at a median dose of 900 mgfsqm (range: 200-2525). According
`to Kaplan-Meier model, the risk of developing a severe neurotoxicity is:
`10% after 6 cy (780 mgjsqm) and 50% after 9 cy (1170 mgfsqm). Its re(cid:173)
`versibility was evaluated after discontinuation in 78% of pts with ~gr 2
`neuropathy. Regression of symptoms was observed in 82% of these pts
`(median follow-up: 3-4 months) and disappearance for 41% of them
`(median follow-up: 6-8 months). Hematological and digestive toxicities
`were acceptable and caused discontinuation of the treatment in only 3
`pts. Other severe toxicities were immediate intolerance (hypotension,
`faintness) in 1% of pts. There was no renal or auditive toxicity episode.
`Conclusion: Oxaliplatin can be administered safely by CI, CM or 2-6 hrs
`infusion at 130 mgfsqm q3 wks. Its association with 5-FUjfolinic acid
`does not enhance its toxicity as it is very well tolerated.
`
`POSTER
`934
`PACLITAXEL (P) AND EPIRUBICIN (E) IN ADVANCED BREAST
`(ABC) AND OVARIAN CANCER (AOC): A PHASE I STUDY
`P.R Conte, A. Michelotti, A. Romanini, E. Baldini, P.G. Giannessi,
`M. DaPrato, C. Tibaldi, M. Conti, A. Tognoni, B. Salvadori, A. Gentile1,
`0. Biadz"Z, M. Mariani2
`U. 0. Oncologia Medica Ospedale S. ChiaraJ Pis a
`1 Bristol Myers Squibb
`2 lstituto di CardiologiaJ Universita di Pisa
`We have started a phase I study in ABC and AOC pts to determine the
`maximum tolerated dose (MTD) ofP to be given with E. Up to now, 21
`pts (1 0 MBC and 11 AOC) have been accrued. Patient characteristics:
`median age 59 y (36-71); median PS (ECOG) 0 (0-1); all MBC pts had
`received adjuvant chemotherapy and all AOC pts were pretreated with
`cisplatin regimens; 18 pts were pretreated with a cumulative E dose of
`360 mgfsqm. P was given i. v. by a 3 hrs c.i. at 135 mgfsqm (9 pts); 155
`mgjsqm (6 pts); 175 mgfsqm (5 pts) and 200 mgjsqm (1 pt). E was given
`at a fixed dose of 90 mg/sqm i. v. bolus. Courses were repeated every
`21 days. All the pts have been submitted to a clinical and instrumental
`cardiological monitoring including: physical examination, EKG, EKG
`Holter, late potentials, transoesofageal electrophysiologic study, cardiac
`echo-doppler. 81 courses have been administered: 46 at level 1, 26 at
`level 2, 12 at level 3 and 1 at level 4. The main side effeCts was: G4
`neutropenia in 57% of the courses lasting a median of 4 days (1-6). No
`cardiac toxicity has been observed; the median left ejection fraction was
`59% at study entry and 54% after 7 courses (total cumulative dose of E
`= 990 mgfmq). Response rate was 62.5% in ABC and 44.4% in AOC.
`PE is an active regimen; the main toxicity is short-lasting neutropenia
`and the M TD has not yet been reached. The study is ongoing.
`
`, N. AzlP,
`
`POSTER
`935
`A PHASE I STUDY OF THE COMBINATION OF DOCETAXEL
`(D) AND ADRIAMICIN (AD) IN FIRST LINE CT TREATMENT
`OF METASTATIC BREAST CANCER (MBC)
`V. Dieral, G. Gruia2
`, P. Pouillart1
`, E. Cvitkovicl, M. Gentin3
`, JL. Misset2
`A. Riva3
`1 Institut Curie
`2 Hopital Paul-Brousse
`3 RhOne-Poulenc Rorer, Antony, France
`The combination of D and AD is a logical attempt to optimize MBC
`therapy. The ongoing phase I trial has the objective to determine the
`DLT, MTD and RD in previously untreated pts with CT for MBC with
`measurable and/or eval disease receiving AD IV bolus followed by D 1
`h IV infusion q3w. Prior Adjuvant CT with anthracycline (less than 300
`mg/m2 ) was allowed provided at least a ~ 12 month interval before study
`entry. Pts were required to have normal baseline LVEF monitored every
`2 cycles. Prophylactic premedication is given with 3d. steroids (starting
`from d-1 8 mg every 6 hours) and Tanakan® from the day of 1st infu(cid:173)
`sion. At least 3 pts are entered by dose level. The main toxicities are as
`follows:
`
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