A Phase I Study of BKM120 (Buparlisib) and Rituximab in Patients with Relapsed or Refractory B-Cell Non-Hodgkins Lymphoma (NHL)
Authors: Maddocks Kami J. , Cohen Jonathon B. , Christian Beth A , Benson Don M , Blum Kristie A. 
Published: October 2019

Introduction:
BKM120 is a potent and highly specific oral pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor. Several PI3K inhibitors have single agent activity in relapsed or refractory B-cell NHL. We are conducting a phase I trial of the combination of BKM120 and rituximab to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLT), tolerability and preliminary efficacy in patients with relapsed or refractory NHL.
Methods:
Patients ≥ 18 years with relapsed or refractory B-cell NHL including follicular lymphoma (FL), marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma/waldenstrom's macroglobulinemia (LPL/WM), mantle cell lymphoma (MCL), and activated B cell subtype diffuse large B cell lymphoma (ABC DLBCL) who have received at least one prior therapy were eligible. Additional eligibility included ECOG Performance Status 0-2, adequate renal and liver function, absolute neutrophil count (ANC) ≥ 750/mm3, platelets ≥ 50,000/mm3, INR ≤ 2.0, and fasting glucose < 120 mg/dL. Prior autologous or allogeneic transplant was allowed if patient did not require immunosuppressive therapy for GVHD. Prior treatment with a pan-selective PI3K inhibitor was not allowed but prior therapy with a selective PI3K inhibitor, Bruton's tyrosine kinase inhibitor or other B-cell receptor targeting agent was allowed. Patients with active moderate or severe major mood or psychiatric disorders were excluded given mood-associated toxicities. Treatment consisted of escalating doses of BKM120 (mg/day) days 1-28 and standard rituximab dosing at 375 mg/m2 days 2, 8, 15, and 22 of cycle 1 and then day 1 of cycles 3, 5, 7, 9, 11 for 28-day cycles. A standard 3+3 dose escalation schema was followed. DLT was defined during cycle 1 and included: treatment delays > 28 days for toxicity; grade 5 toxicity: grade 3 febrile neutropenia > 7 days; grade 4 febrile neutropenia or infection; grade 3 or 4 somnolence, cognitive changes, altered mood, anxiety, or confusion; grade 2 somnolence, cognitive changes, altered mood, anxiety, or confusion that does not resolve to ≤ grade 1 within 14 days; other grade 3 or 4 non-hematologic toxicity with the exception of grade 3 nausea, vomiting, diarrhea, or electrolyte abnormalities that are reversible within 72 hours of holding treatment. Patients without toxicity were allowed to continue treatment until disease progression. To further evaluate safety, preliminary efficacy and correlatives, an expansion cohort of an additional 12 patients to be treated at the MTD was planned, 6 patients with indolent NHL or MCL and 6 patients with ABC DLBCL. 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 July 2015, seven patients were enrolled in this trial. The median age was 67 (range 52-71). Histologies included FL (n=5) and MZL (n=2). Three patients were treated at dose level (DL) 1 (BKM120 80 mg/day). No DLT's occurred. Four patients have been treated at DL2 (BKM120 100 mg/day). One patient experienced a DLT consisting of grade 3 maculopapular rash. The rash occurred cycle 1 day 15 and resolved with interruption of therapy which was continued on day 22 at a reduced dose of BKM120 at 80 mg without any recurrence. The rash was confounded by the simultaneous initiation of allopurinol. Grade 3 toxicities occurred in 2/7 (29%) patients, including grade 3 maculopapular rash in one patient (DLT) and grade 3 hyperglycemia in one patient. Patients have received a median 3 cycles of therapy to date (range 1-9) and six remain on therapy. At DL1, two patients with FL achieved a partial response (PR). At DL2, one patient with FL achieved a PR. Overall response rate for the 5 evaluable patients is 60%. The other two evaluable patients had best response of stable disease. One patient discontinued study to pursue alternative therapy.
Conclusions:
Combined therapy with the pan-PI3 kinase inhibitor BKM and rituximab in patients with relapsed or refractory B-NHL has been well tolerated, with only one DLT of maculopapular rash that resolved with therapy interruption and did not recur at a lower dose. Patients continue to enroll at the current and final dose level of BKM120 mg administered at 100 mg daily with standard rituximab dosing, with a planned expansion cohort at the MTD. While the number of patients treated has been small, preliminary efficacy has been observed including all enrolled FL patients assessable for response achieving a PR.

Disclosures
Maddocks: Pharmacyclics: Consultancy, Research Funding; Novartis: Research Funding; Janssen: Research Funding. Cohen:BMS, Janssen: Research Funding; Celgene, Pharmacyclics, Millennium, Seattle Genetics: Consultancy. Christian:Seattle Genetics: Consultancy, Research Funding; Novartis: Other: IDSM; Celgene: Consultancy; Pharmacyclics: Research Funding; Acerta: Research Funding; Janssen: Research Funding; Immunomedics: Research Funding. Blum:Janssen: Research Funding; Pharmacyclics: Research Funding; cephalon: Research Funding; Celgene: Research Funding.