Wilder,
<< It is obvious I will never have any information for you. Since I do not just take, and I do not like the account to get too long, here is my word: If you are not the 2001 Contest winner, Wilder doubles his pledge and will send Mama Margareta the other 1/2. I may not even wait until 12/31.>>
Mama Margareta foundation will be grateful. You can image what $100-200 means for this poor families.
It was not my intention to pick on you or to brush IMCL. Only that for constructive dialog and discussion one need to go deep and look at every aspect possible.
For instance, IMCL today got good burst from ML and LB based on ASCO abstracts (I do guess that ML guy do have more data in front of him, talking about being equal <g>):
<<Biopharmaceutical company released data related to its 121-patient Phase II study of C225 in chemotherapy-refractory colorectal cancer; results demonstrated that 17% of patients in the trial had a major response to therapy while 31% had minor responses or disease stabilization.>>
Without knowing entry level status of this pts (they suppose to be refractory), regime for combination therapy (CPT-11, irinotecan, doses?) and type of the objective (I guess major means objective or clinical relevant) response it is hard to tell what will be FDA reaction. 17% seams close to my projection of the ~20%, but without time to disease progression or duration of response , overall survival data and median survival time I would not even guess how will oncologists react in real word? However, based on PR machine from IMCL my guess is that other data are also good and will support NDA.
Two relevant Irino stand alone result, and combination, for future comparison:
AUTHOR: Rothenberg ML, Eckardt JR, Kuhn JG, Burris HA, Nelson J, Hilsenbeck SG, Rodriguez GI, Thurman AM, Smith LS, Eckhardt SG, Weiss GR, Elfring GL, Rinaldi DA, Schaaf LJ, Von Hoff DD
TITLE: Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer.
OURCE: J Clin Oncol; 14(4):1128-35 1996 UI: 96243075
LINKS: PDQ® - summaries that cite this article ABSTRACT: PURPOSE: To evaluate irinotecan (CPT-11; Yakult Honsha, Tokyo, Japan) in patients with metastatic colorectal carcinoma that had recurred or progressed following fluorouracil (5-FU)-based therapy. PATIENTS AND METHODS: Patients were treated with irinotecan 125 to 150 mg/m2 intravenously (IV) every week for 4 weeks, followed by a 2-week rest. Forty-eight patients were entered onto the study and all were assessable for toxicity. Forty-three patients completed one full course of therapy and were assessable for response. RESULTS: One complete and nine partial responses were observed (response rate, 23%; 95% confidence interval [CI], 10% to 36%). The median response duration was 6 months (range, 2 to 13). The median survival time was 10.4 months and the 1-year survival rate was 46% (95% CI, 39% to 53%). Grade 4 diarrhea occurred in four of the first nine patients (44%) treated on this study at the 150-mg/m2 dose level. The study was amended to reduce the starting dose of irinotecan to 125 mg/m2. At this dose, nine of 39 patients (23%) developed grade 4 diarrhea. Aggressive administration of loperamide also reduced the incidence of grade 4 diarrhea. Grade 4 neutropenia occurred in eight of 48 patients (17%), but was associated with bacteremia and sepsis in only case. CONCLUSION: Irinotecan has significant single-agent activity against colorectal cancer that has progressed during or shortly after treatment with 5-FU-based chemotherapy. The incidence of severe diarrhea is reduced by using a starting dose of irinotecan 125 mg/m2 and by initiating loperamide at the earliest signs of diarrhea. These results warrant further clinical evaluation to define the role of irinotecan in the treatment of individuals with colorectal cancer.
AUTHOR: Cunningham D, Pyrhonen S, James RD, Punt CJ, Hickish TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Awad L, Jacques C, Herait P
TITLE: Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer.
SOURCE: Lancet; 352(9138):1413-8 1998 UI: 99023140
ABSTRACT: BACKGROUND: In phase II studies, irinotecan is active in metastatic colorectal cancer, but the overall benefit has not been assessed in a randomised clinical trial. METHODS: Patients with proven metastatic colorectal cancer, which had progressed within 6 months of treatment with fluorouracil, were randomly assigned either 300-350 mg/m2 irinotecan every 3 weeks with supportive care or supportive care alone, in a 2:1 ratio. FINDINGS: 189 patients were allocated irinotecan and supportive care and 90 supportive care alone. The mean age of the participants was 58.8 years; 181 (65%) were men and 98 (35%) were women. WHO performance status was 0 in 79 (42%) patients, 1 in 77 (41%) patients, and 2 in 32 (17%) patients. Tumour-related symptoms were present in 134 (71%) patients and weight loss of more than 5% was seen in 15 (8%) patients. With a median follow-up of 13 months, the overall survival was significantly better in the irinotecan group (p=0.0001), with 36.2% 1-year survival in the irinotecan group versus 13.8% in the supportive-care group. The survival benefit, adjusted for prognostic factors in a multivariate analysis, remained significant (p=0.001). Survival without performance-status deterioration (p=0.0001), without weight loss of more than 5% (p=0.018), and pain-free survival (p=0.003) were significantly better in the patients given irinotecan. In a quality-of-life analysis, all significant differences, except on diarrhoea score, were in favour of the irinotecan group. INTERPRETATION: Our study shows that despite the side-effects of treatment, patients who have metastatic colorectal cancer, and for whom fluorouracil has failed, have a longer survival, fewer tumour-related symptoms, and a better quality of life when treated with irinotecan than with supportive care alone
CPT-11 has been compared to either retreatment with 5-FU or best supportive care in a pair of randomized European trials of patients with colorectal cancer refractory to 5-FU. In both trials, there was a survival and quality-of-life advantage for patients treated with CPT-11 over 5-FU or supportive care.49[Levels of evidence: 1iiA,1iiC];50[Levels of evidence: 1iiA,1iiC]
Two phase III prospective randomized, controlled trials were designed to evaluate the combination of 5-FU, leucovorin, and CPT-11 to 5-FU and leucovorin alone. The first of these trials compared the bolus 5-FU, leucovorin, and CPT- 11 to bolus 5-FU and leucovorin alone and to CPT-11; the primary endpoint was progression-free survival.51 The trial demonstrated significant benefit in terms of confirmed response rates, time-to-tumor progression, and overall survival.51[Level of evidence: 1iiA] The combination treatment showed confirmed responses in 39% of patients, compared with 21% in patients treated with 5-FU and leucovorin alone and 18% in patients treated with CPT-11. This benefit was highly significant in favor of the combination. In addition, time- to-tumor progression was significantly prolonged with the combination (7.0 versus 4.3 months, P=.004). Median survival was also improved with the combination; median survival was 14.8 months for patients on the combination arm and 12.6 months for patients on the 5-FU and leucovorin arm (P=.042).
The second pivotal trial of combination chemotherapy with CPT-11 compared 2 different regimens of infusional 5-FU and folinic acid (either the AIO [Arbeitsgemeinschaft Internische Onkologie] or the deGramont regimen).52 Either weekly or biweekly CPT-11 was administered according to the schedule of the infusional 5-FU. This trial also demonstrated improvements in response rate, time-to-tumor progression, and median survival. For the most important endpoint, median survival, the combination arm was associated with a median survival of 17.4 months, compared with 14.1 months for the 5-FU and folinic acid arm (P=.032).52[Level of evidence: 1iiA] A combined analysis of the survival advantages seen in these 2 trials was presented at the 2000 American Society of Clinical Oncology meeting.53 The combined survival for the combination of CPT-11, 5-FU, and leucovorin was 15.9 months, compared to 13.3 months for the non-CPT-11 regimen (P=.003). This represents a survival hazard ratio of 0.79.
Miljenko
PS: Watch for SU5416 + Irino result in advance colorectal cancer (both are PNU compounds).
PSS: Still without info on new IMCL patent. |
