TGR-1202 in Combination with Ibrutinib in Patients with Relapsed or Refractory CLL or MCL: Preliminary Results of a Multicenter Phase I/Ib Study
Authors: Davids Matthew S. , Kim Haesook T. , Nicotra Alyssa , Savell Alexandra , Francoeur Karen , Hellman Jeffrey , Miskin Hari P. , Sportelli Peter , Bashey Asad , Stampleman Laura , Rueter Jens , Boruchov Adam , Arnason Jon , Jacobson Caron A. , Fisher David C. , Brown Jennifer R. 
Published: October 2019

Abstract
Introduction
The oral BTK inhibitor ibrutinib is highly effective at inducing partial responses (PR) in relapsed or refractory (R/R) CLL and MCL; however, complete responses (CR) are rare, and the durability of response for CLL patients (pts) with complex cytogenetics or del(17p) and for pts with MCL is limited. TGR-1202 is a novel oral PI3K-delta specific inhibitor designed to have less toxicity than other PI3K inhibitors, making it a logical drug to explore in combination regimens. We hypothesized that PI3K/BTK blockade would be tolerable and efficacious in R/R CLL and MCL.
Methods
This is a phase I/Ib investigator-initiated multicenter trial with primary objectives of determining the RP2D (recommended phase 2 dose) and the safety/tolerability of TGR-1202 plus ibrutinib in pts with R/R CLL or MCL. Secondary objectives are to assess overall response rates (ORR), CR rates, PFS, and OS. Pts receive continuous daily oral dosing of ibrutinib (420 mg CLL, 560 mg MCL) and TGR-1202. In phase I, TGR-1202 dose levels started at 400 mg daily and escalated in a standard 3 + 3 design to 600, then 800 mg daily. CLL and MCL pts were evaluated in separate arms, with a 28 day DLT observation period. Pts continue both drugs until progression or unacceptable toxicity. Eligibility criteria: ≥1 prior therapy, requiring treatment by IW-CLL criteria (CLL arm), ECOG PS ≤2, and adequate hematologic and organ function. Prior BTK or PI3K inhibitors were allowed. CTCAE v4 and IW-CLL or Cheson criteria (MCL) were used to evaluate toxicity and efficacy, with response evaluations after 2 mo., every 3 mo. up to 1 year, and every 6 mo. thereafter.
Results
As of July 26, 2016, 28 pts were evaluable, including 17 CLL and 11 MCL pts. The median age at enrollment was 67 yrs. (range 48-83). The median number of prior therapies was 2 for CLL (range 1-6, including 2 who started ibrutinib prior to enrollment and 3 with prior PI3Ki who came off prior PI3Ki for reasons other than progressive disease) and 3 for MCL (range 2-5, including 4 with prior autoSCT and 2 with prior ibrutinib). In CLL pts, del(17p) was present in 4/17 (24%), del (11q) in 7/17 (41%), unmutated IGHV in 11/17 (65%), and NOTCH1 or TP53 (without del(17p)) mutation in 2 pts each.
In phase I, there were no DLTs in either arm, and the RP2D of TGR-1202 for both CLL and MCL was identified as 800 mg. Hematologic toxicities in CLL include: neutropenia (18%: 6% gr3, 12% gr4), thrombocytopenia (12%, all gr1), and anemia (12%, all gr1/2). All grade non-hematologic toxicities in >20% of CLL pts include: diarrhea (24%: 18% gr1, 6% gr2) and nausea (24%, all gr1). SAEs include gr 3 atrial fibrillation, lipase elevation, and adrenal insufficiency in 1 pt each, 1 pt with CNS aspergillus infection that likely preceded enrollment, and 1 case of sudden death of uncertain cause. Three CLL pts had dose-reduction of ibrutinib (atrial fibrillation, palpitations, vitreous hemorrhage). Hematologic toxicities in MCL include: neutropenia (18%, 6% gr4), thrombocytopenia (18%, 6% gr3), and anemia (18%, 6% gr3). All grade non-hematologic toxicities in >20% of MCL pts include: diarrhea (29%, all gr1), fatigue (29%, all gr1/2), and 24% each for nausea (all gr1/2) and dizziness (all gr1). SAEs included gr3 hypophosphatemia in 2 pts and gr4 lipase elevation in 1 pt. One MCL pt had dose reduction of TGR-1202 (dizziness). Study-wide, 5/28 (18%) pts had transaminitis, all gr1, and bleeding events included gr1 epistaxis, hematuria, and vitreous hemorrhage in 1 CLL pt each.
For CLL, the ORR is 82% (14/17), with 35% PR-L (6/17), 41% PR (7/17), and 6% CR (1/17) with bone marrow MRD positivity. 6/8 CLL pts in PR on treatment for ≥6 mo. have residual LN's <2 cm in long axis. All 3 pts with prior PI3Ki exposure responded, and as did 1 of the 2 pts with prior ibrutinib exposure. The median time on study for CLL pts is 9.3 mo. (range 2.5-19.7 mo.). For MCL, the ORR is 67%, with 6/9 pts achieving PR including 1 of the 2 pts with prior ibrutinb. The median time on study for MCL pts is 10.9 mo. (range 1.1-19.8 mo.).
Conclusions
We report preliminary results of the first dedicated study to look at a PI3Ki plus BTKi doublet in B cell malignancies. TGR-1202 plus ibrutinib is well-tolerated in pts with R/R CLL and MCL, with no DLTs observed. The RP2D of TGR-1202 for both CLL and MCL is 800 mg daily. Preliminary efficacy data suggest a high response rate in both diseases, with several CLL pts close to radiographic CR. Phase Ib expansion cohorts at 800 mg continue to accrue in this ongoing study (NCT 02268851).

Disclosures
Davids: Infinity: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Gilead: Honoraria; Abbvie: Consultancy, Honoraria; TG Therapeutics: Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding. Miskin:TG Therapeutics, Inc: Employment, Equity Ownership. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Arnason:Gilead: Consultancy. Jacobson:Kite: Membership on an entity's Board of Directors or advisory committees. Fisher:Pharmacyclics: Consultancy. Brown:Janssen: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Infinity: Consultancy; Sun BioPharma: Consultancy; Roche/Genentech: Consultancy; Gilead Sciences: Consultancy; Pfizer: Consultancy.