Phase I pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies

Abstract

Background: SF1126 is a peptidic pro-drug inhibitor of pan-PI3K/mTORC. A first-in-human study evaluated safety, dose limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of SF1126, in patients with advanced solid and B-cell malignancies.

Patients and methods: SF1126 was administered IV days 1 and 4, weekly in 28day-cycles. Dose escalation utilised modified Fibonacci 3+3. Samples to monitor PK and PD were obtained.

Results: Forty four patients were treated at 9 dose levels (90-1110 mg/m(2)/day). Most toxicity was grade 1 and 2 with a single DLT at180 mg/m(2) (diarrhoea). Exposure measured by peak concentration (C(max)) and area under the time-concentration curve (AUC(0-)(t)) was dose proportional. Stable disease (SD) was the best response in 19 of 33 (58%) evaluable patients. MTD was not reached but the maximum administered dose (MAD) was 1110 mg/m(2). The protocol was amended to enrol patients with CD20+ B-cell malignancies at 1110 mg/m(2). A CLL patient who progressed on rituximab [R] achieved SD after 2 months on SF1126 alone but in combination with R achieved a 55% decrease in absolute lymphocyte count and a lymph node response. PD studies of CLL cells demonstrated SF1126 reduced p-AKT and increased apoptosis indicating inhibition of activated PI3K signalling.

Conclusion: SF1126 is well tolerated with SD as the best response in patients with advanced malignancies.

Conflict of interest statement

Conflict of interest statement: The authors declare no conflict of interest.

Copyright © 2012 Elsevier Ltd. All rights reserved.

Figures

Fig. 1

(A) SF1101 PK AUC0–t versus Dose: SF1101 Concentrations for dose cohorts ≥140 mg/m2 achieve higher than targeted exposure levels; (B) SF1101 PK Cmax versus Dose: mean and standard deviation for Cmax versus dose, SF1101 concentrations reach 20–30 μM.

Fig. 2

18FDG-PET response in a patient with (A) Metastatic ovarian cancer treated at 180 mg/m2 (SUV >30% decrease from baseline) and (B) Metastatic colon cancer treated at 840 mg/m2 (SUV >25% decreased from baseline).

Fig. 3

(A and B). A pancreas cancer patient treated at 240 mg/m2 indicated that a liver lesion had a complete pS6 inhibition at 22.5-h after the 8th dose of SF1126 and (C and D). A skin punch of the same patient showed pS6 continued to be elevated pre- and post-SF1126 treatment (261 min).

Fig. 4

Western blotting analysis of a representative CLL patient showed pAkt and PARP cleavage matched % apoptosis. Phospho-Akt decreased at 4–6-h, increased at 24-h but decreased at 72-h and 1 week post-SF1126; PARP cleavage was opposite to the pAkt profile.

Fig. 5

SF1126 plus rituximab is effective in a therapy resistant CLL patient. The patient was treated with SF1126 for 2 cycles with stable disease. Rituximab when added to SF1126 at cycle 3 d 1 and 8 showed significant decrease in the absolute lymphocyte count.