Entry Detail
| General information | |
| Database: | DB00294 |
| Objective: | The mitogenactivated protein kinase (MAPK) pathway has been implicated in the molecular pathogenesis of human cancers, including metastatic colorectal cancer (mCRC). This provides a rationale for the development of MAPKtargeted agents such as pimasertib. |
| Authors: | Macarulla T, et al |
| Title: | Phase I study of FOLFIRI plus pimasertib as secondline treatment for KRASmutated metastatic colorectal cancer. |
| Journal: | Br J Cancer. |
| Year: | 2015 |
| PMID: | 25989270 |
| Trial Design | |
| Clinical Trial Id: | NA |
| Agent: | pimasertib |
| Target: | MEK2 protein kinase Dual specificity mitogenactivated protein kinase kinase 1 |
| Cancer Type: | colorectal cancer |
| Cancer Subtype: | KRASmutated metastatic colorectal cancer |
| Therapy Type: | com |
| Therapeutic Combination Type: | 2 |
| Therapeutic Combination Content: | FOLFIRI+ pimasertib |
| Study Type: | a twopart, openlabel, multicentre study (four European centres; two in Spain, one in Belgium and one in Italy) |
| Key Patients Feature: | patients were aged more than and equal to 18 years with histologically confirmed KRAS mt mCRC with disease progressing during or following firstline treatment for metastatic disease with oxaliplatin plus fluoropyrimidinebased chemotherapy (with or without bevacizumab). |
| Biomarker: | KRASmutated |
| Biomark Analysis: | NA |
| Control Group Info: | single arm |
| Treatment Info: | Treatment comprised 28day cycles of FOLFIRI and pimasertib. Patients received FOLFIRI on days 1 and 15 of each cycle. FOLFIRI comprised irinotecan (180 mg m 2) and FA (lleucovorin/FA 200 mg m 2 or DLleucovorin 400 mg m 2, 90min infusion), followed by 5FU (400 mg m 2 bolus then 2400 mg m 2 46h infusion). Pimasertib, at a starting dose of 45 mg per day, was administered orally on a 5day on/2day off schedule continuously during the cycle (days 1-5, 8-12, 15-19 and 22-26). |
| Primary End Point: | the maximumtolerated dose (MTD) and the recommendedphase II dose (RP2D). |
| Secondary End Point: | the pharmacokinetics (PK) and the antitumour activity. |
| Patients Number: | 16 |
| Trial Results | |
| DLT_MTD: | The MTD was considered to be 45 mg per day. Of the 15 patients included in the DLT analysis set, three experienced a DLT. |
| Objective Response Rate: | Of the 15 patients in the efficacy analysis group, two patients had partial response, nine patients had stable disease, three patients had progressive disease as their best overall response and one patient could not be evaluated. |
| 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 treatmentemergent adverse events were diarrhoea, nausea, vomiting, asthenia and skin/rash event. |
| Conclusions: | Dose escalation of pimasertib in combination with FOLFIRI was limited by toxicity. At the MTD of 45?mg per day, pimasertib was adequately tolerated in patients with mCRC and no unexpected or new safety signals or concerns they were identified. |