Background

PI3K-δ is highly expressed in cells of hematopoietic origin and is often upregulated in lymphoid malignancies. TGR-1202 is a novel, next generation PI3K-δ inhibitor shown to inhibit Akt phosphorylation and induce apoptosis in lymphoma and leukemia cell lines, displaying activity in numerous pre-clinical models with potentially superior pharmacokinetic (PK) properties to other PI3K-δ inhibitors in development, including an extended half-life observed in pre-clinical animal studies. In addition, the chemical structure of TGR-1202 was designed specifically to avoid heterocylic nitrogen moieties in the backbone of the molecule, known to interact with hepatic enzymes, in an effort to mitigate a class effect of hepatotoxicity. Herein we present preliminary results of a Phase I, first in human, open label study of the oral PI3K-δ inhibitor, TGR-1202.

Methods

The dose escalation portion of the study will determine the maximum tolerated dose (MTD) of TGR-1202 using a standard 3+3 dose escalation design. Patients (pts) with a confirmed diagnosis of B-cell non-Hodgkin lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), peripheral T-cell lymphoma, or other lymphoproliferative disorders previously treated with at least one prior therapy are eligible. Additional eligibility criteria include ECOG PS ≤ 2 and measurable/evaluable disease. Primary endpoints are safety and PK measurement; secondary endpoints include pharmacodynamic (PD) analysis and efficacy (overall response rate). TGR-1202 will be administered orally QD until unacceptable toxicity, disease progression, or withdrawal from treatment. Treatment cycles are 28 days. Efficacy evaluations are planned every 8 weeks. AEs are assessed using the CTCAE v4.0. For pts with CLL/SLL, hematologic toxicity is graded according to IWCLL guidelines.

Results

Thirteen patients have been enrolled to date across 4 dose levels: QD 50mg, 100mg, 200mg, and 400mg. Pts are 83% male, ECOG 0/1: 54%/46%, with a median age of 69 yrs (range: 49-82). Patients had a median of 2 (range: 1-5) prior treatment regimens, and 38% were refractory to prior treatment. Lymphoma histologies include follicular lymphoma (5 pts), CLL/SLL (4 pts), and lymphoplasmacytic lymphoma, mantle cell lymphoma, DLBCL, and atypical hairy cell leukemia (1 pt each). Twelve of the thirteen patients are evaluable for DLT assessment (one patient in Cohort 1 was replaced within first week of treatment due to rapid disease progression). Of the 12 evaluable patients, 8 are currently on study; 4 patients discontinued treatment due to disease progression. To date, there have been no DLTs. One patient experienced G3 neutropenia and thrombocytopenia which resulted in a dose reduction. No other G3/4 related hematologic or non-hematologic toxicities have been observed. Notably, aside from unrelated G1 elevation of GGT in one patient, there has been no hepatotoxicity. Of the 7 patients who completed 2 cycles of treatment (8 wks) at 200mg daily dosing or less, 3 (43%) showed SD and 4 (57%) had PD. Five additional patients have not reached their first response assessment.

TGR-1202’s preliminary mean pharmacokinetic parameters determined on Day 1 of Cycle 1 (table) are: median Tmax of 2 hrs (range 1-8hrs), harmonic mean t1/2 of 13 (± 8.06) hr, and CL/F of 48.97 (± 15.6) L/hr. CL values over the 4 dose levels are independent of dose (r = 0.07, p > 0.20). A linear relationship (Spearman’s) exists between dose and both AUC (r = 0.95) and Cmax (r = 0.80). Steady-state levels are reached by Day 15. The ave. accumulation Cmin ratio between Cycle 1 t24hr & Cycle 2 t0hr is 8 (± 2.65).

Preliminary PK data from the first 4 cohorts is summarized below.

Dose50 mg
(n=4)
100 mg
(n=3)
200 mg
(n=3)
400 mg
(n=3)
Cmax (ng/mL) 107 (± 47) 179 (± 41) 157 (± 12.5) 585 (± 243) 
AUC (ug x hr/mL) 1.3 (± 0.61) 2.1 (± 0.14) 4.2 (± 1.01) 6.2 (± 3.56) 
Dose50 mg
(n=4)
100 mg
(n=3)
200 mg
(n=3)
400 mg
(n=3)
Cmax (ng/mL) 107 (± 47) 179 (± 41) 157 (± 12.5) 585 (± 243) 
AUC (ug x hr/mL) 1.3 (± 0.61) 2.1 (± 0.14) 4.2 (± 1.01) 6.2 (± 3.56) 
Conclusions

To date, TGR-1202 has been well tolerated in patients with relapsed/refractory hematologic malignancies. There have been no DLTs observed and toxicities have been minimal to date. Enrollment continues at higher dose cohorts. Updated safety, efficacy, PK, and PD data will be presented.

Disclosures:

Lanasa:Rhizen Pharmaceuticals S A: Research Funding. Kuhn:TG Therapeutics, Inc.: Consultancy. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Sportelli:TG Therapeutics, Inc. : Employment, Equity Ownership. Vakkalanka:Rhizen Pharmaceuticals S A: Employment, Equity Ownership.

Author notes

*

Asterisk with author names denotes non-ASH members.

Sign in via your Institution