Phase I study of RO4929097, a gamma secretase inhibitor of Notch signaling, in patients with refractory metastatic or locally advanced solid tumors

Abstract

Purpose: To determine the maximum-tolerated dose (MTD) and assess safety, pharmacokinetics, pharmacodynamics, and evidence of antitumor activity of RO4929097, a gamma secretase inhibitor of Notch signaling in patients with advanced solid malignancies.

Patients and methods: Patients received escalating doses of RO4929097 orally on two schedules: (A) 3 consecutive days per week for 2 weeks every 3 weeks; (B) 7 consecutive days every 3 weeks. To assess reversible CYP3A4 autoinduction, the expanded part of the study tested three dosing schedules: (B) as above; modified A, 3 consecutive d/wk for 3 weeks; and (C) continuous daily dosing. Positron emission tomography scans with [(18)F]fluorodeoxyglucose (FDG-PET) were used to assess tumor metabolic effects.

Results: Patients on schedule A (n = 58), B (n = 47), and C (n = 5; expanded cohort) received 302 cycles of RO4929097. Common grade 1 to 2 toxicities were fatigue, thrombocytopenia, fever, rash, chills, and anorexia. Transient grade 3 hypophosphatemia (dose-limiting toxicity, one patient) and grade 3 pruritus (two patients) were observed at 27 mg and 60 mg, respectively; transient grade 3 asthenia was observed on schedule A at 80 mg (one patient). Tumor responses included one partial response in a patient with colorectal adenocarcinoma with neuroendocrine features, one mixed response (stable disease) in a patient with sarcoma, and one nearly complete FDG-PET response in a patient with melanoma. Effect on CYP3A4 induction was observed.

Conclusion: RO4929097 was well tolerated at 270 mg on schedule A and at 135 mg on schedule B; the safety of schedule C has not been fully evaluated. Further studies are warranted on the basis of a favorable safety profile and preliminary evidence of clinical antitumor activity.

Fig 1.

Original study design with changes to show end of study treatments at END CYCLE 2 (ie, day 42), indicated by the addition of arrows for continuous dosing from day 1 to 42 in schedule C.

Fig 2.

Pharmacokinetics shown as area under the concentration versus time curve from time 0 to 24 hours (AUC_0-24), with annotated preclinical efficacious levels of exposure. The mean ± standard deviation RO4929097 AUC_0-24 (ng·h/mL) is shown for each dosing cohort in (A) schedule A and (B) schedule B on day 1 of cycle 1 (C1D1), on day 10 of cycle 1 (C1D10) or day 7 of cycle 1 (C1D7), and on day 1 of cycle 2 (C2D1) in the dose-escalation part of the study. Efficacy exposure levels observed in nude mouse models with (solid line) 10 mg/kg (1,758 ng·h/mL) and (dotted line) 30 mg/kg (5,280 ng·h/mL) daily dosing. Schedule A: RO4929097 for 3 days on/4 days off during weeks 1 and 2 every 3 weeks for the first two cycles, followed by a third week off treatment, then 3 days on/4 days off during subsequent cycles; schedule B: RO4929097 on 7 consecutive days every 3 weeks.

Fig 3.

Relationship between RO4929097 plasma concentration and amyloid beta-40 (Aβ-40; a product of the proteolytic cleavage of amyloid precursor protein by gamma secretase) percent change from baseline. Solid blue circles indicate individual patient data; red line indicates linear regression. Blood plasma samples were collected at baseline and then serially for assessments of Aß-40 by using an enzyme-linked immunosorbent assay (Amyloid β40 ELISA high sensitive; The Genetics Company, Basel, Switerland).

Fig 4.

Percent change for interleukin-6 from baseline in patients with and without clinical benefit. Solid blue circles indicate individual patient data. Blood plasma samples were collected at baseline and then serially (schedule A: cycle 1 day 2, cycle 1 day 10, and cycle 2 day 2; schedule B: cycle 1 day 2, cycle 1 day 7, and cycle 2 day 2). Analysis was performed by using multianalyte profiling technology at Rules-Based Medicine (Austin, TX). 0C represents patients without stable disease, 2C represents patients with two cycles of confirmed stable disease, and 4C represents patients with at least four cycles of confirmed stable disease. Schedule A: RO4929097 for 3 days on/4 days off during weeks 1 and 2 every 3 weeks for the first two cycles, followed by a third week off treatment, then 3 days on/4 days off during subsequent cycles; schedule B: RO4929097 on 7 consecutive days every 3 weeks. H, hours.

Fig A1.

Mean ± standard deviation exposure at area under the concentration versus time curve to infinity (AUC_∞) of midazolam with error bars at baseline and after RO4929097 treatment for the original schedule A (RO4929097 for 3 days on/4 days off during weeks 1 and 2 every 3 weeks for the first two cycles, followed by a third week off treatment, then 3 days on/4 days off during subsequent cycles), modified schedule A (same as schedule A except for dosing on 3 consecutive d/wk for 3 weeks), and schedule C (continuous dosing once a day for 3 weeks).

Fig A2.

Mean ± standard deviation exposure at area under the plasma concentration versus time curve to infinity ratios of 1-hydroxymidazolam:midazolam at baseline and after RO4929097 treatment for patients with data for original schedule A (RO4929097 for 3 days on/4 days off during weeks 1 and 2 every 3 weeks for the first two cycles, followed by a third week off treatment, then 3 days on/4 days off during subsequent cycles), modified schedule A (same as schedule A except for dosing on 3 consecutive d/wk for 3 weeks), and schedule C (continuous dosing once a day for 3 weeks).

Fig A3.

Relationship between RO4929097 at area under the plasma concentration versus time curve for time zero to 24 hours (AUC_0-24) and vascular endothelial growth factor receptor 2 (VEGFR-2) percent change from baseline. Solid circles indicate individual patient data; red line indicates linear regression. Blood plasma samples were collected at baseline and then serially and analyzed for VEGFR-2 at Rules-Based Medicine (Austin, TX) by using an enzyme-linked immunosorbent assay from R&D Systems (Minneapolis, MN).

Fig A4.

Relationship between RO4929097 plasma concentration and Hes-1 expression changes in hair follicles. Solid circles indicate individual patient data for changes in hair follicles; red line indicates linear regression. Hair follicles in the anagen phase were collected at baseline and at 4 and 8 hours after dosing on day 1 of cycle 1. Hes-1 mRNA expression was assessed by reverse transcriptase polymerase chain reaction and normalized against a housekeeping gene (Alas-1) by using the ΔΔCt method. Increasing values demonstrate a downregulation of Hes-1 treatment with RO4929097.

Fig A5.

Partial response in a patient with colorectal adenocarcinoma with neuroendocrine features: computed tomography scans at baseline and post-treatment; (A) scans at baseline and (B) post-treatment four courses Schedule B; (C) magnified baseline and (D) post-treatment four courses; (C, D) arrows depict nodal regression after four treatment cycles.

Fig A6.

Case study, metastatic melanoma: baseline and post-treatment positron emission tomography scan.