a Phase I Study of BKM120 (Buparlisib) and Rituximab in Patients with Relapsed or Refractory (R/R) B-Cell Non-Hodgkin's Lymphoma (NHL)
Authors: Maddocks Kami J. , Cohen Jonathon B. , Huang Ying , Christian Beth A , Benson Don M , Jones Jeffrey , Flowers Christopher , Heffner Leonard T. , Jenkins Cynthia , Sexton Jennfer , Neal Alison , Kives Melissa , Blum Kristie A. 
Published: October 2019

Abstract
Background:
Buparlisib is a potent and highly specific oral pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor. Several PI3K inhibitors have single agent activity in r/r B-cell NHL, most notably, idelalisib, a PI3K delta inhibitor, idelalisib, is FDA approved for relapsed NHL. We are conducting a phase I trial of the combination of buparlisib and rituximab (R) to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLT), tolerability and preliminary efficacy in patients (pts) with r/r NHL.
Methods:
Pts ≥ 18 years with r/r B-cell NHL including follicular lymphoma (FL), marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia (LPL/WM), and mantle cell lymphoma (MCL), after ≥ 1 prior therapy were eligible. Additional eligibility included ECOG Performance Status 0-2, normal renal and liver function, absolute neutrophil count ≥ 750/mm3, platelets ≥ 50,000/mm3, INR ≤ 2.0, and fasting glucose < 120 mg/dL. Exclusion criteria included previous allogeneic transplant requiring immunosuppressive therapy for GVHD and active major mood or psychiatric disorders. Treatment consisted of escalating dose levels (DL) of buparlisib (DL1: 80mg/day, DL2: 100mg/day) days 1-28 continuously with R 375 mg/m2 days 2, 8, 15, and 22 of Cycle 1 and day 1 of cycles 3, 5, 7, 9, 11. A standard 3+3 dose escalation schema was followed. DLT was defined during cycle 1 and included: treatment delays > 28 days; grade (Gr) 5 adverse event (AE); Gr 3 febrile neutropenia > 7 days; Gr 4 febrile neutropenia or infection; Gr 3 or 4 somnolence, cognitive changes, altered mood, anxiety, or confusion; Gr 2 somnolence, cognitive changes, altered mood, anxiety, or confusion that did not resolve to ≤ Gr 1 within 14 days; other Gr 3 or 4 non-hematologic toxicity with the exception of Gr 3 nausea, vomiting, diarrhea, or electrolyte abnormalities that are reversible within 72 hours of holding treatment. Pts without treatment limiting AE continued treatment until disease progression. To further evaluate safety, preliminary efficacy and correlatives, an expansion cohort of 12 additional pts at the MTD was planned. Response was assessed by CT or PET/CT after cycles 2, 4, 6, and then every 3 months while on therapy.
Results:
From August 2014 until April 2016, 14 pts were enrolled in this trial. Median age was 63 (range 42-77) and median number of prior therapies was 3 (range 1-9). Histologies included FL (n=8), MZL (n=3), MCL (n=2) and WM (n=1). Three pts were treated at DL1 and six pts were treated at DL2. One pt experienced a DLT at DL2 consisting of Gr 3 maculopapular rash, occurring cycle 1 day 15 and resolving with interruption of therapy followed by dose reduction to buparlisib 80 mg without recurrence. The rash was confounded by simultaneous initiation of allopurinol. DL2 was defined as the MTD with 5 additional pts enrolled in the 12 pt expansion. Gr 3-4 hematologic AE included neutropenia (7%), febrile neutropenia (7%) and lymphopenia (14%). Gr 3-4 non-hematologic AE regardless of attribution included 3 pts (21%) with hyperglycemia and 1 pt with each of the following: hypertension, anxiety, sinusitis, peripheral neuropathy, wrist fracture. Gr 1-2 AE related to treatment included hyperglycemia, rash, diarrhea, depression, infusion related reaction, photosensitivity, and dry skin (7% each). Pts received a median 8 cycles of therapy (range 1-20) and 5 pts remain on therapy. Reasons for discontinuation include progression (n=3), AE (n=4), patient choice (n=1), and allogeneic stem cell transplantation (n=1). Overall response rate is 64%, all partial responses (PR) with an additional pt (7%) continuing on study with stable disease (SD). With a median follow up of 7.8 months, median progression-free survival (PFS) has not been reached with estimated 1-year PFS at 74%. Of the 8 pts with FL, 7 achieved a PR (87.5%), 1 went off prior to first response assessment due to toxicity.
Conclusions:
Combined therapy with buparlisib and R in pts with r/r B-NHL is well tolerated, with one DLT of maculopapular rash. Enrollment in the expansion cohort at MTD (buparlisib 100 mg/day) in combination with R 375 mg/m2 weekly x 4 and then q2 months x 5 continues. While the number of pts treated thus far is small, encouraging preliminary efficacy is encouraging, including an 87.5% ORR in the FL pts without significant infectious toxicity.

Disclosures
Cohen: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Christian:Janssen: Research Funding; Pharmacyclics: Research Funding. Jones:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Flowers:Roche: Consultancy, Research Funding; ECOG: Research Funding; Acerta: Research Funding; Infinity: Research Funding; NIH: Research Funding; Mayo Clinic: Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Millenium/Takeda: Research Funding; AbbVie: Research Funding; Gilead: Consultancy, Research Funding. Heffner:Pharmacyclics: Research Funding; AbbVie: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Blum:Pharmacyclics: Research Funding.