Entry Detail
| General information | |
| Database: | DB00485 |
| Objective: | Thisphase Ib study determined the recommendedphase II dose (RP2D) and evaluated the safety and clinical activity of tivozanib plus temsirolimus, a mammalian target of rapamycin inhibitor. |
| Authors: | Fishman MN, et al |
| Title: | Phase Ib study of tivozanib (AV951) in combination with temsirolimus in patients with renal cell carcinoma. |
| Journal: | Eur J Cancer |
| Year: | 2013 |
| PMID: | 23726267 |
| Trial Design | |
| Clinical Trial Id: | NCT00563147 |
| Agent: | tivozanib |
| Target: | VEGF2 receptor Vascular endothelial growth factor receptor 3 Vascular endothelial growth factor receptor 1 |
| Cancer Type: | renal cell carcinoma |
| Cancer Subtype: | renal cell carcinoma with a clear cell component |
| Therapy Type: | com |
| Therapeutic Combination Type: | 2 |
| Therapeutic Combination Content: | tivozanib (AV951) + temsirolimus |
| Study Type: | a phase Ib, openlabel, multicenter, dose- escalation trial |
| Key Patients Feature: | Adults with a histologically confirmed diagnosis of RCC with a clear cell component wereeligible. Additional eligibility criteria included a history of progressive disease, less than and equal to 1 priorVEGFtargeted therapy; measureable disease by Response Evaluation Criteria In SolidTumours (RECIST); Karnofsky performance status >70%; adequate bone marrow, hepatic, and renal function; and no prior mTORtargeted therapy. Patients with prior chemotherapyor cytokine therapy were eligible. Key exclusion criteria included active/clinicallysymptomatic central nervous system metastases, haematologic malignancies and significantcardiovascular disease (including uncontrolled hypertension). Full inclusion/exclusioncriteria are provided in Supplementary Table S1 (online only) |
| Biomarker: | NA |
| Biomark Analysis: | NA |
| Control Group Info: | single arm |
| Treatment Info: | patients were administered openlabel tivozanib 0.5, 1.0 or 1.5mg/d orally (3 weeks on/1 week off) and temsirolimus 15 or 25 mg/week intravenously in a 3+3 doseescalation design and subsequent expansion cohort. |
| Primary End Point: | the recommendedphase II dose (RP2D) |
| Secondary End Point: | response |
| Patients Number: | 27 |
| Trial Results | |
| DLT_MTD: | Among 27 patients evaluable for safety, no DLTs were observed in cycle 1. Therefore, the RP2D was determined to be tivozanib 1.5 mg/d plus temsirolimus 25 mg/week, corresponding to the full recommended doses of each drug. An additional 12 patients were subsequently enrolled at the RP2D in an expansion cohort. Of note, treatmentemergent AEs (TEAEs; described below) were tabulated separately and differently from DLTs |
| Objective Response Rate: | The ORR was 23% (95% CI, 8-45%). Although no CRs were observed, PR was confirmed in five (23%) patients and SD was achieved in 15 (68%) patients (Fig. 2). Of these, all five patients with PR and 10 of 15 patients with SD had received prior VEGFRtargeted therapy. Among the 11 patients in the RP2D expansion cohort who were evaluable for response, two patients achieved PR and the remaining nine patients achieved SD. In this cohort, the median duration of SD was 9.2 months (95% CI, 9.2 months to not reached). The maximum changes in tumour size from baseline for all evaluable patients are shown in |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | The most common grade more than and equal to 3 adverse events were fatigue and thrombocytopenia (15% each). One patient each required dose reduction of tivozanib or temsirolimus due to an adverse event. |
| Conclusions: | In this smallphase Ib study, tivozanib and temsirolimus they were safely combined at the fully recommended dose and schedule of both agents. The observed clinical activity and manageable toxicity profile of this combination warrant further exploration in patients with RCC. |