MKC-1 is a novel, orally active cell cycle inhibitor. Previous phase I studies have been conducted with MKC-1 using a variety of intermittent dosing schedules for patients with solid tumors. Myelosuppression and mucositis are the dose limiting toxicities with the intermittent schedules. Partial responses and disease stabilization were reported from these and other studies with MKC-1.2,3
Because the efficacy of MKC-1 was postulated to improve with sustained exposure, the University of Wisconsin conducted a Phase I study with the primary objective of defining the MTD of continuous MKC-1 using the modified TITE-CRM algorithm. This statistical design was chosen as an optimal method for incorporating toxicity and tolerability, both being important for a continuously administered oral regimen. Dose escalation was stopped at 320 mg/d when the cumulative dose of MKC-1 per 28-day cycle exceeded that reached with the intermittent dosing schedules.
Given that human BSA generally ranges from 1.5 to 2.2 m2, the MTDs defined on the intermittent dosing schedules (540 mg/m2/day for 4 days of 21-days cycle; 400 and 250 mg/m2/day fro 7- and 14-days of a 28 day cycle) translate into roughly 150 - 275 mg/day. The majority of patients on this study received cumulative doses in excess of 150 mg/day. Despite this, treatment of continuous MKC-1 was very well tolerated with few side effects. The only DLT was grade 3 fatigue. Myelosuppression or mucositis did not occur, unlike with the intermittent dosing schedules. Day 28 pharmacokinetics indicated absorption and active metabolites at levels consistent with known efficacious doses of MKC-1.
The prolonged exposure with continuous oral administration avoided high peak drug concentrations, and likely explains the lack of myelosuppression.12
Two other potential explanations exist for the general lack of toxicity. First, analysis of prior studies suggested that low albumin levels predicted greater toxicity with MKC-1; therefore, unlike prior studies, we required an albumin ≥3.0 g/dL. This might have improved the toxicity profile compared with other Phase I trials. Another explanation is that previous studies used BSA, while this study used a flat dose. Using a flat dose can lead to under-dosing of larger patients and hence, less toxicity. However, the BSAs on this study fall in the expected range 1.6 to 2.2 m2
Despite evidence that continuous MKC-1 dosing achieved levels of active metabolites consistent with known efficacious doses of MKC-1, the efficacy was very modest. Three patients (1 renal cell carcinoma, 1 parotid adenocarcinoma and 1 breast cancer) achieved stable disease for 28, 16 and 16 weeks respectively. Given the nature of these disease types, the stable disease seen on continuous MKC-1 may have simply indicated slowly progressive disease. The study did include patients with disease types that had previously demonstrated signs of clinical activity with MKC-1 (3 ovarian, 2 breast, 1 lung, 1 pancreatic cancer); however, these patients were relatively heavily pretreated, as is typical for a Phase I trial.
Our study employed a novel dose-escalation design which modeled DLTs during the first three cycles along with discontinuation due to intolerability rather than the traditional 3+3 dose-escalation of most Phase I trials. A traditional 3+3 design emphasizes toxicity during cycle 1 – a paradigm that works fairly well for intermittently administered intravenous drugs. A traditional 3+3 design cannot easily account for chronic intolerable symptoms (such as persistent grade 2 nausea) or late toxicities (such as hand-foot symptoms in cycle 3). Both chronic and late toxicities are of significant concern with a continuous oral medication. Moreover, simulations have shown that CRM-based methods more accurately find the true MTD and treat more patients at optimal dose levels – both of which are highly desirable outcomes.
However, the 3+3 design remains the most common design for Phase I studies, because it is well understood by oncologists.6,8,9,13
Few examples exist in the literature of a CRM being used for an oral anticancer agent in a Phase I study. Although a modified CRM was employed safely on our study and functioned well overall, a few difficulties were encountered and are notable. We report these here for the benefit of those wishing to employ a CRM in place of a 3+3 design.
First, a CRM requires significant statistical support, far more than a traditional 3+3 design. Simulation studies should be conducted before initiating a study to evaluate the operating characteristics for various dose-toxicity relationships. Based on the results of these simulation studies, an appropriate prior distribution for the dose-toxicity relationship should be identified. Moreover, the implementation of such a CRM dose-escalation design is a logistically challenging endeavor requiring continuous communication with the study statistician. Second, despite occurring at a single, academic institution, with extensive briefing on the study design, the referring clinicians remained uncomfortable with CRM dose escalation.
In summary, continuous MKC-1 is well tolerated at 320 mg/d, and this is the MTD as defined by the CRM dose escalation algorithm. A modest efficacy signal was observed. A CRM algorithm was used safely to assign doses for the Phase I study of an anti-cancer agent and study late or chronic toxicities.
Statement of Clinical Relevance
This manuscript describes the results of a phase I study of MKC-1 in patients with advanced solid malignancies. Preclinical and clinical studies of MKC-1 have demonstrated activity in a variety of tumors including breast and lung cancer. Here, we evaluate the safety and tolerability of continuously dosed MKC-1, which may provide additional mechanisms of antitumor activity over intermittent dosing strategies. We also describe the application of an unusual dose-escalation design and important considerations for applying reassessment models to continuous oral chemotherapy in which extended drug tolerability (in addition to toxicity) is important.