Escalating Doses Of Carboplatin Research Articles

Randomized trial of intrapatient dose escalation of single agent carboplatin as first-line treatment for advanced ovarian cancer: An SGCTG study (SCOTROC 4)

5537 Background: In the absence of toxicity, carboplatin (the most widely used drug in ovarian cancer) is generally given at the same (flat) dose with each treatment cycle. However, retrospective data suggest a correlation between extent of myelosuppression and outcome, as has been observed in other diseases. Our hypothesis was therefore that intrapatient dose escalation, according to nadir blood counts, could lead to an improved outcome compared to conventional flat dosing. Methods: Patients with previously untreated stage IC to IV ovarian cancer were randomized to receive 6 cycles of carboplatin AUC 6 q3 w either with no dose modification except for toxicity (Arm A) or with dose escalations in cycles 2–6 based on nadir FBC (Arm B). The primary outcome measure was progression-free survival (PFS), and a target accrual of 1300 pts was envisaged, aimed at detecting a 20% increase in PFS with 80% power (5% 2-sided level of statistical significance). Results: From March 2004 to November 2008, 937 pts were recruited from 70 centres. Dose escalation occurred in 82% pts on Arm B. The median AUCs actually received were 6.0 (Arm A) and 6.84 (Arm B). As expected, more myelosuppression was seen in Arm B (p < 0.001 for all parameters). More grade 3/4 non-haematological toxicity was also seen in Arm B (31%, vs 22% in Arm A, p < 0.001) but there was no significant difference in global quality of life. To date, 477 PFS events have been observed out of a planned total of 950. The median PFS was 13.9m in Arm A, and 13.5m in Arm B, and the observed hazard ratio (Arm B/Arm A) is 1.04, with 95% C.I. of 0.87 to 1.24. This excludes the clinically relevant benefit of 0.83 used to design the study. A futility analysis also indicated that the probability of a statistically significant result in favour of Arm B at the planned study end was 0.12 at best. Conclusions: Following the Data Monitoring Committee recommendation, the trial has therefore been closed to recruitment, with no evidence of benefit for intra-patient dose escalation of carboplatin. A separate analysis of tissue samples, aimed at elucidating mechanisms of (single agent) carboplatin resistance is ongoing. No significant financial relationships to disclose.

A phase I study of a hypomethylating agent azacitidine in combination with carboplatin in patients with platinum resistant epithelial ovarian cancer

5087 Background: Hypermethylation is a common event associated with inactivation of a variety of genes and pathways involved in tumorigenesis and progression as well as drug resistance. Previous evidence displayed that hypomethylating agents could resensitize epithelial ovarian cancer cells to platinum treatment through reexpression of platinum sensitivity-related genes. Therefore, it is of great interest to use a hypomethylating agent to resensitize platinum resistant epithelial ovarian cancer cells to platinum treatment. Methods: This proof-of-concept study used a modified dose-escalation schema (3+3 design). All patients, who have progressed within the 6 months after a platinum-based regimen, are eligible if they have a pathologically confirmed epithelial ovarian cancer. All patients receive subcutaneous injection of azacitidine 75 mg/m2/day for 5 days on days 1–5 and intravenous infusion of carboplatin once on day 2 of each treatment cycle (28 days). Azacitidine is maintained at the same dosage during dose-escalation of carboplatin from AUC4 to AUC5. Results: Six patients have received a total of 16 cycles of treatment. There was no grade 2 or higher toxicity observed. Three patients were evaluable for response: 1 patient, who received 6 cycles of treatment, achieved complete response by CA125 criteria and stable disease by imaging criteria; 1 patient, who received 5 cycles of treatment, displayed stable disease; and the 3rd patient, who received 2 cycles of treatment, showed mixed response by imaging criteria. Conclusions: Preliminary data showed that a regimen of azacitidine 75 mg/m2/day for 5 days plus carboplatin AUC 5 on day 2 was well tolerated in patients with extensive prior treatment. No significant financial relationships to disclose.

22 year phase 1/2 study of single agent carboplatin in metastatic seminoma: Potential for acceleration by a new surrogate end point, 72 hr PET scan response?

14565 Background: That metastatic seminoma may be more chemo-curable than non-seminoma was first suggested by Samuels (1980 Proc ASCO 21 abst 415) 4 of 5 patients durable CR to single agent cisplatin and by Oliver (1984 Proc ASCO 3. Abst 636) 9 of 10 durable responses. Carboplatin proved less effective and in randomised trials involving 361 patients relapse free survival was 72% with Carbo and 92% with cisplatin-based combination. Prompted by successful dose escalation of carboplatin in ovarian cancer, the initial phase 1 study that preceded the UK randomised trial was reopened and dosage escalated to AUC 8 and then 10. This abstract updates this study and provides more prolonged follow up of the previous reported cases. Methods: Initially patients received Carboplatin 450 mg/m2 (1983–7) and then AUC 7 (88–94), 8 (95–6) and 10 (97–06). The treatment was repeated q21 when possible and if delayed because of toxicity blood counts were repeated every 24 hours. Results: 60 metastatic seminoma patients have been treated between 1983 and 2006. 79%/95% of 19 receiving 450 mg/m2, 88%/94% of 17 receiving AUC 7 or 8 and 92%/100% of 24 receiving AUC 10 are progression free/alive. Overall 58 (97%) are alive and with 28 patients followed more than 10 years there have been no relapses after 26 months. Mild and rapidly recovering (med 14 d) transaminitis in 64% of AUC × 10 (med 93 range 51–541) suggests this may be the upper limit for safe use. As a pilot study 5 seminomas receiving AUC × 10 and 6 non-seminomas receiving BEP had PET scan before and at 72 hours after treatment. The only patient failing to respond substantially was a seminoma who showed increased PET activity on AUC × 10 but achieved complete remission of PET activity after one course of BEP. Conclusion: This data confirms the need for more studies of single agent platinum analogues in seminomas and reinforces the view that it may be preferable to radiotherapy for patients electing adjuvant treatment. With increasing attention being paid to late events, minimizing treatment toxicity and finding a fast track approach to proving safety is an increasing need. The data presented demonstrates the potential of early PET scan as a surrogate for response and could have accelerated the phase 1/2 study reported. No significant financial relationships to disclose.

Phase I Dose Escalation Study of Carboplatin to a Fixed Dose of Irinotecan as First-Line Treatment of Small Cell Lung Cancer

Background: Superiority of irinotecan (CPT-11) plus cisplatin over etoposide plus cisplatin in small cell lung cancer (SCLC) has recently been demonstrated. This study determines dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of escalating doses of carboplatin to a fixed dose of irinotecan in Caucasians with small cell lung cancer. Patients and Methods: Patients with extensive small cell lung cancer received 50 mg/m² irinotecan on day 1, 8, and 15. Dose escalation of carboplatin on day 1 started in dose level 1 at an AUC of 5 mg × min/ml and was escalated to AUC 6 in level 2. Cycles were repeated on day 29. Dose escalation was evaluated after 3 consecutive patients. If no grade IV neutropenia lasting for ≧7 days or thrombopenia or non-hematologic toxicity ≧ grade III occurred, treatment was continued in the next dose level. Results: 16 patients were treated. DLT was reached in dose level 2 with 2 grade IV neutropenias and 1 grade IV thrombopenia and diarrhea. Toxicity was further investigated at dose level 1 in a total of 10 patients, which revealed 2 grade III neutropenias and 1 grade III diarrhea. Of 15 evaluable patients, 10 had a partial response, 3 had disease stabilization and 2 progressed. Conclusion: Dose level 1 was found to be MTD, this dose is currently compared to the combination of etoposide plus carboplatin within a randomised phase II/III trial.