Phase 2 randomized, flexible crossover, double-blinded, placebo-controlled trial of the farnesyltransferase inhibitor tipifarnib in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas

Abstract

Background: RAS is dysregulated in neurofibromatosis type 1 (NF1) related plexiform neurofibromas (PNs). The activity of tipifarnib, which blocks RAS signaling by inhibiting its farnesylation, was tested in children and young adults with NF1 and progressive PNs.

Methods: Patients aged 3-25 years with NF1-related PNs and imaging evidence of tumor progression were randomized in a double-blinded fashion to receive tipifarnib (200 mg/m(2) orally every 12 h) or placebo (phase A) and crossed over to the opposite treatment arm at the time of tumor progression (phase B). PN volumes were measured with MRI, and progression was defined as ≥20% volume increase. Time to progression (TTP) in phase A was the primary endpoint, and the trial was powered to detect whether tipifarnib doubled TTP compared with placebo. Toxicity, response, and quality of life were also monitored.

Results: Sixty-two patients were enrolled. Tipifarnib and placebo were well tolerated. On phase A, the median TTP was 10.6 months on the placebo arm and 19.2 months on the tipifarnib arm (P = .12; 1-sided). Quality of life improved significantly compared with baseline on the tipifarnib arm but not on the placebo arm. Volumetric tumor measurement detected tumor progression earlier than conventional 2-dimensional (WHO) and 1-dimensional (RECIST) methods.

Conclusions: Tipifarnib was well tolerated but did not significantly prolong TTP of PNs compared with placebo. The randomized, flexible crossover design and volumetric PN assessment provided a feasible and efficient means of assessing the efficacy of tipifarnib. The placebo arm serves as an historical control group for phase 2 single-arm trials directed at progressive PNs.

Keywords: RAS signaling; neurofibromatosis type 1; phase 2 trial; plexiform neurofibroma; trial design.

Figures

Fig. 1.

(A) Trial status of eligible participants at the time of trial unblinding. (B) Progression-free survival on phase A. The median time to progression for tipifarnib (n = 31) was 19.2 months and for placebo (n = 29) 10.6 months (1-tailed P = .12). Participants who were removed from study for reasons other than progression had their follow-up censored at the times shown with tick marks. (C) Progression-free survival on phase B. The median time to progression for tipifarnib (n = 22) was 13.3 months and for placebo (n = 18) 14.5 months (1-tailed P = .14). Participants who were removed from the study for reasons other than progression had their follow-up censored at the times shown with tick marks. (D) Progression-free survival for all participants who received placebo or tipifarnib irrespective of the treatment phase. The median time to progression for placebo (n = 47) was 13.0 months and for tipifarnib (n = 53) 18.2 months. Forty participants are represented on both curves. Participants who were removed from the study for reasons other than progression had their follow-up censored at the times shown with tick marks.

Fig. 2.

(A) Examples of plexiform neurofibroma growth rate on phase A and phase B in 4 participants. The plexiform neurofibroma growth rate appears constant within patients but variable among patients, and more rapid growth occurs in younger patients. (B) Percent change in target plexiform neurofibromas (circles) or target nodular lesions (squares) volumes per year on phase A for participants treated with tipifarnib or placebo. (C) Comparison of time to progression for 60 participants enrolled on phase A using 1D (RECIST, progression = ≥20% increase in sum of longest diameters), 2D (WHO, progression = ≥25% increase in sum of products of longest perpendicular diameters), and 3D criteria (progression = ≥20% increase in plexiform neurofibroma volume) used in this trial. Median time to progression was 14.3 months for 3D, 52.5 months for 2D, and was not reached for 1D analysis.