C28001

17 evidence topics · 3 sources

Objective

First-in-human study in adults with advanced solid tumors

“Primary objectives were to evaluate the safety of tovorafenib administered once every other day (Q2D) or once weekly (QW), and to determine the maximum-tolerated and recommended phase 2 dose (RP2D) on these schedules. Secondary objectives included evaluation of antitumor activity and tovorafenib pharmacokinetics.” (opens the source at this quote in a new tab)

Location and study date

Enrollment period and data cutoff

“Between September 13, 2011 and September 5, 2016, 149 patients were enrolled and received at least 1 dose of tovorafenib (safety population).” (opens the source at this quote in a new tab)
“The data cutoff date for the current analysis was April 11, 2017, at which time, a small number of patients remained on treatment.” (opens the source at this quote in a new tab)

Registry record: sponsor, actual study dates, and number of study locations

Field	Registry record
Sponsor	“Millennium Pharmaceuticals, Inc.”
Responsible party	“Takeda (Millennium Pharmaceuticals, Inc.)”
Study status	“Completed”
Study start (actual)	“2011-09-15”
Primary completion (actual)	“2017-04-11”
Study completion (actual)	“2018-10-16”
Study locations	“This study has 16 locations”
Last update posted	“2020-08-10”

Study design

Dose escalation and melanoma dose expansion

“We conducted a first-in-human, phase 1, multicenter, open-label study of tovorafenib in patients with relapsed or refractory advanced solid tumors. The study included a dose escalation phase and a dose expansion phase, with the latter including molecularly defined cohorts of patients with locally advanced, metastatic, and/or unresectable melanoma.” (opens the source at this quote in a new tab)
“The study was initially designed to investigate a Q2D schedule. Subsequently, a protocol amendment introduced planned QW dose escalation cohorts.” (opens the source at this quote in a new tab)

Eligibility criteria

Adult participants

“Eligible patients were aged ≥ 18 years, with relapsed or refractory advanced solid tumors (excluding lymphoma but including melanoma), who had progressed on/after, or were not candidates for standard therapies or for whom no approved therapy was available” (opens the source at this quote in a new tab)

Treatment

Fasting oral administration and dose levels

“Tovorafenib was administered orally (tablet formulation), with patients fasting (except for water) for at least 2 h before and at least 2 h after taking their dose.” (opens the source at this quote in a new tab)
“Planned QW doses to be administered on days 1, 8, 15, and 22 of a 28-day cycle were a starting dose of 400 mg, followed by dose level increases of 200 mg (i.e., doses of 600 mg, 800 mg, and 1000 mg) in each subsequent cohort until the MTD/RP2D was reached.” (opens the source at this quote in a new tab)

Study outcomes

Rationale for using dose-limiting toxicity as the primary endpoint

Safety, dose-limiting toxicity, response, and pharmacokinetic assessments

“Following baseline evaluation, response was assessed by investigators every two cycles by computed tomography or magnetic resonance imaging according to Response Evaluation Criteria in Solid Tumors (version 1.1)” (opens the source at this quote in a new tab)

Statistical analysis description

Number of participants (Planned and analyzed)

No formal power calculation

“No formal power calculations were carried out. In the dose escalation phase, enrollment of approximately 54 patients was envisaged, with the actual number dependent on the number of dose escalation steps and the number of patients per cohort.” (opens the source at this quote in a new tab)

Participants by schedule

“Tovorafenib was administered Q2D to 30 patients in the dose escalation phase and 80 patients in the dose expansion phase (including 20 patients in a PK expansion cohort) and QW to 20 patients in the dose escalation phase and 19 patients in the dose expansion phase.” (opens the source at this quote in a new tab)

Description of analysis sets

Safety, DLT-evaluable, response-evaluable, and PK-evaluable populations

“The safety population was defined as all patients who received any amount of tovorafenib.” (opens the source at this quote in a new tab)
“The response-evaluable population included all patients with measurable disease who received any amount of tovorafenib and who had at least 1 postbaseline response assessment.” (opens the source at this quote in a new tab)

Results

Participant disposition

Treatment exposure and discontinuation

“Patients received a median of 2 cycles of treatment in both the dose escalation and dose expansion phases. The primary reasons for treatment discontinuation were disease progression and adverse events (Supplementary Tables S2 and S3).” (opens the source at this quote in a new tab)

Baseline characteristics

Primary diagnoses

“The most common primary diagnoses in the dose escalation phase were colon cancer and melanoma. In line with the eligibility requirements, most patients in the dose expansion phase had a primary diagnosis of melanoma.” (opens the source at this quote in a new tab)

Efficacy results

Adult melanoma and solid tumors: responses by cohort

“Responses were seen in 10 (15%) of 68 evaluable patients in the Q2D expansion phase, including in 8 of 16 (50%) patients with BRAF mutation-positive melanoma naïve to RAF and MEK inhibitors. In the QW dose expansion phase, there were no responses in 17 evaluable patients with NRAS mutation-positive melanoma naïve to RAF and MEK inhibitors; 9 patients (53%) had a best response of stable disease.” (opens the source at this quote in a new tab)

Pharmacokinetics of once-weekly dosing

“The mean plasma terminal half-life ( t 1/2 ) of tovorafenib was approximately 70 h (range 31–119 h) as defined in 20 evaluable patients receiving 600 mg QW.” (opens the source at this quote in a new tab)
“While no apparent accumulation was observed with the QW dose regimens, Q2D administration resulted in approximately 2.5-fold accumulation in AUC 48 at steady state.” (opens the source at this quote in a new tab)

Health-related quality of life and patient-reported outcomes

No evidence found.

Safety results

Recommended phase 2 dose and dose-limiting toxicities

“In the QW dose escalation phase, cohorts of patients received tovorafenib doses of 400 mg, 600 mg, and 800 mg, in 28-day cycles. DLTs occurred in cycle 1 in 2 patients in the 800 mg cohort; 1 patient had grade 3 hyperbilirubinemia and 1 had grade 3 rash. The MTD selected for the QW expansion cohort was therefore 600 mg to be administered over 28-day cycles.” (opens the source at this quote in a new tab)

Grade 3 or higher adverse events, discontinuations, and deaths

“In the dose expansion phase, 68% of patients experienced a grade 3 or higher TEAE, including 73% of patients in the Q2D cohorts and 47% in the QW cohort.” (opens the source at this quote in a new tab)
“In the QW cohort of the dose expansion phase, 4 of 19 patients (21%) had TEAEs resulting in permanent discontinuation, including atrial flutter, dyspnea, erythema multiforme, and fatigue (1 patient each).” (opens the source at this quote in a new tab)
“There were 13 on-study deaths. The fatal SAEs associated with these deaths predominantly related to the underlying disease or complications thereof and are listed in Supplementary Table S8. Only one death, associated with respiratory failure in a patient in the 280 mg Q2D dose escalation cohort, was deemed by the study investigators to be treatment related.” (opens the source at this quote in a new tab)

Study limitations

Summary: limited relevance of C28001 to pLGG

C28001 enrolled 149 adults (median age 62.5 to 66.0 years across phases) with relapsed or refractory advanced solid tumors, mostly melanoma and colon cancer; it included no participants with pLGG and no children. Dosing was flat (600 mg once weekly recommended) and fasting was required, whereas pediatric trials used body surface area-based dosing without food restrictions. No formal power calculations were performed, response was investigator assessed by RECIST 1.1 without independent review, and median treatment exposure was 2 cycles, so the study provides no information on long-term toxicities relevant to children such as growth velocity. Its relevance to this report is limited to the safety profile in adults, the once-weekly schedule, and pharmacokinetics (mean terminal half-life of approximately 70 hours at 600 mg once weekly).