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A phase I trial of the combination taxotere® (docetaxel) and cisplatin in patients with advanced non-small cell lung cancer (NSCLC)
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MVC REGIMEN IN NON SMALL CELL LUNG CANCER (NSCLC): A PHASE-II TRIAL OF CARBOPLATIN (CP), VINBLASTIN (VBL) AND MITOMYCIN-C (MMC). A.Paccagnella, A.Favaretto, F.Oniga, A.Morabito, R.Ruffatto, F.Sartore, MV.Fiorentino. Division of Medical Oncology General Hospital, Padova I3.5128 ITALY. Supported in part by CNR Grant 92.0234O.PF39 and AIRC Study objective: to evaluate the effectiveness and toxicity of a combination similar to Cisplatin(DDP), Vbl and Mmc (MVP,Gralla 1989), but with Cp instead of DDP to make it more feasible in an outpatient setting. Inclusion criteria: inoperable patients(pts) with NSCLC; PS > 50 %; no previous chemotherapy; refusal to participate to randomized trials. Results: From Aug. 91 to Aug. 93.47 pts entered the trial and 46 were evaluable for response and toxicity. Median age was 62(4O-73) years. The M/F ratio was 36111 (77103%); LD/ED: 18/29 (38%/62%). Median PS was 80%(60-90). A total of 188 cycles (median: 4(1-6) per pt) were delivered, 174088 (92%) in an outpatient setting with only 3 pts requiring hospitalisation for treatment delivery. Overall response rate(RR) was 35% (1 CR, 2%; 15 PR, 33%). Median duration of response was 31( 16-77+) weeks. In LD pts the RR was 44% and in ED pts was 28%. Four pts(9%) had a minor response, 18(39%) a NC, 7(1.5%) a PD. 1(2%) an Early Death. Treatment delays 2 lweek were required in 32% of cycles. Hematologic toxicity was the major side effect and it was responsible for 80% of treatment delays and dose reductions. Grade 3 and 4 leukopenia, however, were seen only in 16% and 2% and thrombocytopenia in 14% and 1.5% of cycles, respectively. Grade 1 infection occurred in 21% of cycles with only 1 case of sepsis; mild constipation in 13%. It is noteworthy that no cases of Gr.>l alopecia, renal or neuro-toxicity were observed. Compliance with treatment was good with no refusals after the first cycle. Conclusion: chemotherapy for advanced NSCLC is still controversial since effectiveness in terms of RR and symptom control has to be weighed with treatment toxicity and costs. From our study it seems that MVC is easy to deliver in an outpatient setting with a good pt compliance and promising RR and response duration. A phase III study comparing MVC and MVP should be considered.
SCBEDULE MODIFICATION OF VINORELBINE IN TBE COMBINATION WITB CISPLATIN AS A CONSEQUENCE OF SEVERE TOXICITY IN ADVANCED NON SMALL CELL LUNG CANCER G.V. Scagliotti, F. De
Marinis’. R. Rimoldi2,G. Piacenza3, M. Micela, A. ~osedal F. Salvatil. F. Gozzeline. E. Pozzi. University of Twine, Department of Clinical & Biological Sciences, ‘Forlanini Hospital. Rome, 2Mu1tizonale Hospital, Varese and 3Borsalino Hospital. Alessandria, ITALY. Cisplatin (CDDP) 100 mg/sqm on days l-29 and then every 6 weeks combined wth Vinorelbine (VNR) 30 m&m weekly for the first month then every 2 weeks were tested in 22 patients (M/F ratio 17/5. median age 58 years, range 35-70 yrs.) with advanced Non Small Cell Lung Cancer (NSCLC) [ stage IIIB 3, stage IV 19; squamo”s 8, adenccarcinoma 11, large cell 2 undifferentiated I] Ten out of 22 patients were not w&able for response because of WHO grade IV toxicity (4 baematological. 3 septic shocks. 1 neurotosicity) or refmals (two patients). Four e”t of 12 evaluable patients had objective response (I complete response and 3 partial responses). -I stable disease and 4 progressive disease. Subsequently a modified schedule for VNR (30 mg/sqm every 2 weeks from the start of therapy) was tested m further 28 patients (M/F ratio 23/j. median age 59 years. range 32-68:stage RIB 9. stage IV 19: squamws 12. adenocarcinoma 10. large cell 4. adenosquamous 2) obtaimng a 40% o@clive response (1 complete response and 7 partial responses) in 20 evaluable patlents Nine patients had stable disease and 3 progressive disease: in 4 cases is too early. Swymne and I20 c~“rses of VNR were admmistered accoxhng m the first or the modified schedule. respectively. Wdh both VNR schedules the “ccurrence of objective response was not related to the histotype or the extent of disease. With the modified schedule toxicitv consisted mainlv in leucooen~a made III-IV in I2 courses. thrombocytopenia in’ 1. anemia in 3. mild gas&“&inal toxicity in 5. elevation of sewn w&nine > 2 mgidl in 2. neurotosicity in I). Reduced or delayed administration of VNR was necessary in 61% of the courses with the first schedule and in 40% of the modified one. Phlebitis at the site of VNR Injection was mild in 30% of the courses and seldom severe to require the “se of analgesics. In conclusion: in advanced NSCLC the combination of CDDP 100 mgisqm and VNR 30 mgisqm evev 2 weeks seem te be a” effective and feasible regrmen worth of being tested in further randomized trials.
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ICE CHEMOTHERaPY WlTH DOSE ESCALATION OF THE DRUG RESISTANCE MODULATOR ETANIDAZOLE FOR A.D. Elias, A.T. Skarin, G. ADVANCED LUNG CANCER. Strauss, L. Shuhnan, B.A. Teicher, N. Coleman, E. Frei III. DanaFarber Cancer Institute, Brigham & Womens Hospital, The Joint Center for Radiation Therapy, Boston, MA, USA. New agents and strategies are needed to counter systemic drug resistant lung cancer. Extensive preclinical work has demonstrated potent radiation sensitization by the nitroimidazole compound etanidazole, particularly affecting hypoxic tumor cells. Extension of this work demonstrates marked enhancement of chemotherapeutic efficacy in similar systems. In the clinic, dose limiting sensory nemupathy has been reported with cumulative doses of 22 g/m2 as a 96 hour infusion, or 30 g/m2 when given over 6 weeks with This trial was designed to assess the toxicity & radiation. pharmacokinetics of etanidazole when given with combination chemotherapy & to observe whether the addition of etanidazole would force compromise of the chemotherapy drug doses. Between 7/92 & 1 l/93,43 patients (pts) with advanced lung cancer were treated with ifosfamide, carboplatin, & etoposide (ICE) at 6OGO,300,225 mg/m2 respectively q 3 weeks for 3 cycles. Bolus etanidazole was escalated from 2.5 to 6.0 g/n-?/day day l-3 in cohorts of 3-5 pts. Dose limiting subacute grade 2-3 sensory neuropathy was encountered after cumulative doses of 54 g/m2 over 9 weeks. The maximal tolerated dose is 5.5 g/m2/day. Full dose ICE could be delivered since no other toxicities appeared to be enhanced. First cycle etanidazole phmetics are currently being analyzed. Phase II or III studies will be pursued if the clinically achievable etanidazole serum level approaches that required to modulate alkylating agent activity in preclinical modelling.
A PHASE I TRIAL OF THE COMBINATION TAXGTERE@ (docetaxel) AND CISPLATIN IN PATIENTS WITH ADVANCED NON-SMALL CELL LUNG CANCER SCLC). J.F BishopI, J. Zalcberg!?, L.K. Webster], M.J. Millwardl, A. Zimet2, D. ~ischh~l, M. Urchl, J. Laird2, G.C. ~onerl, W C0solo2, K White2, C Blanc3, lDepar”ne”t of Haematology and Medical Oncolo Peter MacCallum Cancer Institute, Melbourne 3000, Australia, POncology Department, Heidelberg Repatriation Hospital, 3081, Australia, 3Rh6nePoulenc Row, Antony Cedex, France. Taxetere@ (RF’56976, docetaxel - Rh6ne-Poulenc Row) (T), is a semisynthetic drug, belonging to a new anti-cancer group, the taxoids, and has “romisine activitv in NSCLC with a reswnse rate of 33o/dCemv ef al. Proc. ASCO, 12; 331, 1993). Cisplatin(P) l’s considered the most active’single agent in advanced NSCLC. In this Phase I trial 16 patients (pts) received T as a 1 hr infusion immediately followed by P as a I hr infusion. Hydration was given beginning 2 hn prior to T, and ending 22 hrs post P. Ondametmn and dexunethasone were given as anti-emetics. Cycles repeated every 21 days. Eligibility included - locally advanced/metastatic NSCLC, no prior chemotherapy, age 18.75, WHO perfm’“u”cz stahls O-2, creatinine clearance 5 60mVmin, bilirubin < 1.25 x normal, SGOT < 2 x normal and no baseline neurapathy. Dose levels: Level 1: T 50 mg!m2 P 75 mg/m2 (3pts), Level 2: T 75mg/m2, P 75m m2, (5pts), Level 3: T lOOmg/“? P 5mg/m2 (Zpts), Level 4: T 75mg/mq , P 100mg/m2 (6pts). At level 3, lpt died of sepsis with diarrhcea and renal failure and the other pt had neutropenic enterowlitis with grade IV neutmpe”ia, thrombocytopenia and diarrhoea but recovered with intensive support. At level 4, 516 had grade IV neutropenia with 316 febrile neutmpenia, 216 grade II delayed emesis, 3/6 grade IL/III diarrhaea. At level 2, 4/5 had short duration grade IV neutropenia with 2/4 febrile neutrapenia but no > grade III “onhaematological toxicity. A” alternative schedule of cisplatin over 3 hr commencing 3 hr aflex T is being examined for levels 2 and 4. Responses have occurred. Phannacokinetics of T and P were performed. I” conclusion, the combination T and P appear promising in NSCLC with dose-limit& toxicities reached at levels 3 and 4. I
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414
MVC REGIMEN IN NON SMALL CELL LUNG CANCER (NSCLC): A PHASE-II TRIAL OF CARBOPLATIN (CP), VINBLASTIN (VBL) AND MITOMYCIN-C (MMC). A.Paccagnella, A.Favaretto, F.Oniga, A.Morabito, R.Ruffatto, F.Sartore, MV.Fiorentino. Division of Medical Oncology General Hospital, Padova I3.5128 ITALY. Supported in part by CNR Grant 92.0234O.PF39 and AIRC Study objective: to evaluate the effectiveness and toxicity of a combination similar to Cisplatin(DDP), Vbl and Mmc (MVP,Gralla 1989), but with Cp instead of DDP to make it more feasible in an outpatient setting. Inclusion criteria: inoperable patients(pts) with NSCLC; PS > 50 %; no previous chemotherapy; refusal to participate to randomized trials. Results: From Aug. 91 to Aug. 93.47 pts entered the trial and 46 were evaluable for response and toxicity. Median age was 62(4O-73) years. The M/F ratio was 36111 (77103%); LD/ED: 18/29 (38%/62%). Median PS was 80%(60-90). A total of 188 cycles (median: 4(1-6) per pt) were delivered, 174088 (92%) in an outpatient setting with only 3 pts requiring hospitalisation for treatment delivery. Overall response rate(RR) was 35% (1 CR, 2%; 15 PR, 33%). Median duration of response was 31( 16-77+) weeks. In LD pts the RR was 44% and in ED pts was 28%. Four pts(9%) had a minor response, 18(39%) a NC, 7(1.5%) a PD. 1(2%) an Early Death. Treatment delays 2 lweek were required in 32% of cycles. Hematologic toxicity was the major side effect and it was responsible for 80% of treatment delays and dose reductions. Grade 3 and 4 leukopenia, however, were seen only in 16% and 2% and thrombocytopenia in 14% and 1.5% of cycles, respectively. Grade 1 infection occurred in 21% of cycles with only 1 case of sepsis; mild constipation in 13%. It is noteworthy that no cases of Gr.>l alopecia, renal or neuro-toxicity were observed. Compliance with treatment was good with no refusals after the first cycle. Conclusion: chemotherapy for advanced NSCLC is still controversial since effectiveness in terms of RR and symptom control has to be weighed with treatment toxicity and costs. From our study it seems that MVC is easy to deliver in an outpatient setting with a good pt compliance and promising RR and response duration. A phase III study comparing MVC and MVP should be considered.
SCBEDULE MODIFICATION OF VINORELBINE IN TBE COMBINATION WITB CISPLATIN AS A CONSEQUENCE OF SEVERE TOXICITY IN ADVANCED NON SMALL CELL LUNG CANCER G.V. Scagliotti, F. De
Marinis’. R. Rimoldi2,G. Piacenza3, M. Micela, A. ~osedal F. Salvatil. F. Gozzeline. E. Pozzi. University of Twine, Department of Clinical & Biological Sciences, ‘Forlanini Hospital. Rome, 2Mu1tizonale Hospital, Varese and 3Borsalino Hospital. Alessandria, ITALY. Cisplatin (CDDP) 100 mg/sqm on days l-29 and then every 6 weeks combined wth Vinorelbine (VNR) 30 m&m weekly for the first month then every 2 weeks were tested in 22 patients (M/F ratio 17/5. median age 58 years, range 35-70 yrs.) with advanced Non Small Cell Lung Cancer (NSCLC) [ stage IIIB 3, stage IV 19; squamo”s 8, adenccarcinoma 11, large cell 2 undifferentiated I] Ten out of 22 patients were not w&able for response because of WHO grade IV toxicity (4 baematological. 3 septic shocks. 1 neurotosicity) or refmals (two patients). Four e”t of 12 evaluable patients had objective response (I complete response and 3 partial responses). -I stable disease and 4 progressive disease. Subsequently a modified schedule for VNR (30 mg/sqm every 2 weeks from the start of therapy) was tested m further 28 patients (M/F ratio 23/j. median age 59 years. range 32-68:stage RIB 9. stage IV 19: squamws 12. adenocarcinoma 10. large cell 4. adenosquamous 2) obtaimng a 40% o@clive response (1 complete response and 7 partial responses) in 20 evaluable patlents Nine patients had stable disease and 3 progressive disease: in 4 cases is too early. Swymne and I20 c~“rses of VNR were admmistered accoxhng m the first or the modified schedule. respectively. Wdh both VNR schedules the “ccurrence of objective response was not related to the histotype or the extent of disease. With the modified schedule toxicitv consisted mainlv in leucooen~a made III-IV in I2 courses. thrombocytopenia in’ 1. anemia in 3. mild gas&“&inal toxicity in 5. elevation of sewn w&nine > 2 mgidl in 2. neurotosicity in I). Reduced or delayed administration of VNR was necessary in 61% of the courses with the first schedule and in 40% of the modified one. Phlebitis at the site of VNR Injection was mild in 30% of the courses and seldom severe to require the “se of analgesics. In conclusion: in advanced NSCLC the combination of CDDP 100 mgisqm and VNR 30 mgisqm evev 2 weeks seem te be a” effective and feasible regrmen worth of being tested in further randomized trials.
475
416
ICE CHEMOTHERaPY WlTH DOSE ESCALATION OF THE DRUG RESISTANCE MODULATOR ETANIDAZOLE FOR A.D. Elias, A.T. Skarin, G. ADVANCED LUNG CANCER. Strauss, L. Shuhnan, B.A. Teicher, N. Coleman, E. Frei III. DanaFarber Cancer Institute, Brigham & Womens Hospital, The Joint Center for Radiation Therapy, Boston, MA, USA. New agents and strategies are needed to counter systemic drug resistant lung cancer. Extensive preclinical work has demonstrated potent radiation sensitization by the nitroimidazole compound etanidazole, particularly affecting hypoxic tumor cells. Extension of this work demonstrates marked enhancement of chemotherapeutic efficacy in similar systems. In the clinic, dose limiting sensory nemupathy has been reported with cumulative doses of 22 g/m2 as a 96 hour infusion, or 30 g/m2 when given over 6 weeks with This trial was designed to assess the toxicity & radiation. pharmacokinetics of etanidazole when given with combination chemotherapy & to observe whether the addition of etanidazole would force compromise of the chemotherapy drug doses. Between 7/92 & 1 l/93,43 patients (pts) with advanced lung cancer were treated with ifosfamide, carboplatin, & etoposide (ICE) at 6OGO,300,225 mg/m2 respectively q 3 weeks for 3 cycles. Bolus etanidazole was escalated from 2.5 to 6.0 g/n-?/day day l-3 in cohorts of 3-5 pts. Dose limiting subacute grade 2-3 sensory neuropathy was encountered after cumulative doses of 54 g/m2 over 9 weeks. The maximal tolerated dose is 5.5 g/m2/day. Full dose ICE could be delivered since no other toxicities appeared to be enhanced. First cycle etanidazole phmetics are currently being analyzed. Phase II or III studies will be pursued if the clinically achievable etanidazole serum level approaches that required to modulate alkylating agent activity in preclinical modelling.
A PHASE I TRIAL OF THE COMBINATION TAXGTERE@ (docetaxel) AND CISPLATIN IN PATIENTS WITH ADVANCED NON-SMALL CELL LUNG CANCER SCLC). J.F BishopI, J. Zalcberg!?, L.K. Webster], M.J. Millwardl, A. Zimet2, D. ~ischh~l, M. Urchl, J. Laird2, G.C. ~onerl, W C0solo2, K White2, C Blanc3, lDepar”ne”t of Haematology and Medical Oncolo Peter MacCallum Cancer Institute, Melbourne 3000, Australia, POncology Department, Heidelberg Repatriation Hospital, 3081, Australia, 3Rh6nePoulenc Row, Antony Cedex, France. Taxetere@ (RF’56976, docetaxel - Rh6ne-Poulenc Row) (T), is a semisynthetic drug, belonging to a new anti-cancer group, the taxoids, and has “romisine activitv in NSCLC with a reswnse rate of 33o/dCemv ef al. Proc. ASCO, 12; 331, 1993). Cisplatin(P) l’s considered the most active’single agent in advanced NSCLC. In this Phase I trial 16 patients (pts) received T as a 1 hr infusion immediately followed by P as a I hr infusion. Hydration was given beginning 2 hn prior to T, and ending 22 hrs post P. Ondametmn and dexunethasone were given as anti-emetics. Cycles repeated every 21 days. Eligibility included - locally advanced/metastatic NSCLC, no prior chemotherapy, age 18.75, WHO perfm’“u”cz stahls O-2, creatinine clearance 5 60mVmin, bilirubin < 1.25 x normal, SGOT < 2 x normal and no baseline neurapathy. Dose levels: Level 1: T 50 mg!m2 P 75 mg/m2 (3pts), Level 2: T 75mg/m2, P 75m m2, (5pts), Level 3: T lOOmg/“? P 5mg/m2 (Zpts), Level 4: T 75mg/mq , P 100mg/m2 (6pts). At level 3, lpt died of sepsis with diarrhcea and renal failure and the other pt had neutropenic enterowlitis with grade IV neutmpe”ia, thrombocytopenia and diarrhoea but recovered with intensive support. At level 4, 516 had grade IV neutropenia with 316 febrile neutmpenia, 216 grade II delayed emesis, 3/6 grade IL/III diarrhaea. At level 2, 4/5 had short duration grade IV neutropenia with 2/4 febrile neutrapenia but no > grade III “onhaematological toxicity. A” alternative schedule of cisplatin over 3 hr commencing 3 hr aflex T is being examined for levels 2 and 4. Responses have occurred. Phannacokinetics of T and P were performed. I” conclusion, the combination T and P appear promising in NSCLC with dose-limit& toxicities reached at levels 3 and 4. I
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