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Purpose:Dual blockade of Bruton's tyrosine kinase with ibrutinib and selinexor has potential to deepen responses for patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL).Patients and Methods:In this phase I study (clinicaltrials.gov: NCT02303392), adult patients with CLL/NHL, relapsed/refractory to ≥1 prior therapy were enrolled. Patients received weekly oral selinexor and daily oral ibrutinib in 28-day cycles until progression or intolerance. Primary objective was to determine MTD.Results:Included patients had CLL (n = 16) or NHL (n = 18; 9 Richter transformation, 6 diffuse large B-cell lymphoma, and 3 mantle cell lymphoma). Median prior therapies were 4 (range = 1–14) and 59% previously received ibrutinib. The established MTD was 40 mg of selinexor (days 1, 8, 15) and 420 mg daily ibrutinib. Common nonhematologic adverse events were fatigue (56%), nausea (53%), anorexia (41%), and diarrhea (41%) and were mostly low grade. Overall response rate was 32%. An additional 47% achieved stable disease (SD), some prolonged (up to 36 months). Median progression-free survival for patients with CLL and NHL was 8.9 [95% confidence interval (CI), 3.9–16.1] and 2.7 (95% CI, 0.7–5.4) months, respectively. For patients with CLL who did not receive prior ibrutinib, only 20% (1/5) progressed. Estimated 2-year overall survival was 73.7% (95% CI, 44.1–89.2) and 27.8% (95% CI, 10.1–48.9) for patients with CLL and NHL, respectively.Conclusions:The selinexor and ibrutinib combination has demonstrated tolerability in patients with relapsed/refractory CLL/NHL. Responses were durable. Notable responses were seen in patients with CLL with minimal prior therapy. Future study of this combination will focus on efforts to deepen remissions in patients with CLL receiving ibrutinib therapy.

Supplementary Data from Selinexor Combined with Ibrutinib Demonstrates Tolerability and Safety in Advanced B-Cell Malignancies: A Phase I Study

Purpose: Dual blockade of Bruton's tyrosine kinase with ibrutinib and selinexor has potential to deepen responses for patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Patients and Methods: In this phase I study (clinicaltrials.gov: NCT02303392), adult patients with CLL/NHL, relapsed/refractory to ≥1 prior therapy were enrolled. Patients received weekly oral selinexor and daily oral ibrutinib in 28-day cycles until progression or intolerance. Primary objective was to determine MTD. Results: Included patients had CLL (n = 16) or NHL (n = 18; 9 Richter transformation, 6 diffuse large B-cell lymphoma, and 3 mantle cell lymphoma). Median prior therapies were 4 (range = 1–14) and 59% previously received ibrutinib. The established MTD was 40 mg of selinexor (days 1, 8, 15) and 420 mg daily ibrutinib. Common nonhematologic adverse events were fatigue (56%), nausea (53%), anorexia (41%), and diarrhea (41%) and were mostly low grade. Overall response rate was 32%. An additional 47% achieved stable disease (SD), some prolonged (up to 36 months). Median progression-free survival for patients with CLL and NHL was 8.9 [95% confidence interval (CI), 3.9–16.1] and 2.7 (95% CI, 0.7–5.4) months, respectively. For patients with CLL who did not receive prior ibrutinib, only 20% (1/5) progressed. Estimated 2-year overall survival was 73.7% (95% CI, 44.1–89.2) and 27.8% (95% CI, 10.1–48.9) for patients with CLL and NHL, respectively. Conclusions: The selinexor and ibrutinib combination has demonstrated tolerability in patients with relapsed/refractory CLL/NHL. Responses were durable. Notable responses were seen in patients with CLL with minimal prior therapy. Future study of this combination will focus on efforts to deepen remissions in patients with CLL receiving ibrutinib therapy.

Introduction Blocking Bruton tyrosine kinase (BTK) with ibrutinib has demonstrated efficacy in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) patients (pts). However, resistance to therapy is common. Preclinical data suggest selinexor (oral selective inhibitor of nuclear export) downregulates BTK (Hing 2015). We hypothesized that dual BTK blockade by combining ibrutinib and selinexor would be tolerable and efficacious in CLL/NHL pts. Herein, we report the phase I combination study with expansion cohorts. Methods Pts with histologically confirmed CLL/NHL were enrolled (n=33). Eligible pts were age ≥18 years (yrs), had ≥1 prior therapy and ECOG performance status of 0-1. CLL pts met iwCLL 2008 criteria for therapy. Pts received selinexor orally 1-2 times weekly (3 weeks of 4-week cycle) and daily oral ibrutinib (420mg) starting Cycle 1 Day 8. Treatment cycles were repeated until disease progression, intolerance, death or discontinuation of trial participation. Primary endpoint was determination of maximum tolerated dose (MTD). Dose-finding proceeded using a modified continual reassessment method targeting a probability of dose limiting toxicity (DLT) Results Median age was 66 yrs (50-80). Included pts had CLL (n=16), Richter's transformation (RT=8), diffuse large B-cell lymphoma (DLBCL, n=6), and mantle cell lymphoma (MCL=3). Median number of prior therapies was 4 (1-14) and 58% had received ibrutinib. Baseline characteristics are detailed in Table 1. The combination was tolerated. MTD was 40mg of selinexor (D1, 8, 15) and 420mg daily ibrutinib [dose level 1 (DL1)]. Two pts were treated with selinexor 30mg twice weekly and 420mg of daily ibrutinib (DL2) and both experienced significant fatigue and discontinued therapy. These adverse events (AE) were considered DLTs. The remainder of pts received DL1. Grade ≥3 hematologic AEs were rare with 3 (9%) and 1 (3%) pt experiencing neutropenia and anemia, respectively. Most common non-hematologic AEs of any grade were nausea (39%) diarrhea (33%), fatigue (33%), and anorexia (27%). Grade ≥3 non-hematologic AEs were uncommon with 2 pts (6%) experiencing hypertension and 1 pt each (3%) experiencing diarrhea, nausea, elevated alkaline phosphatase, cataract, weight gain, upper respiratory tract infection, pancreatitis, pneumonitis, and multi-system organ failure. Other AEs of interest were weight loss, bleeding, and tachycardia, experienced by 5 (15%), 4 (12%), and 3 (9%) pts, respectively. There were 5 pt deaths while on study; 3 related to disease progression and 2 related to infection. In total, 81% achieved disease control with 33% achieving CR or PR (partial response) and 48% achieving stable disease (SD; Table 2). All CLL pts who received prior ibrutinib or had complex karyotype achieved at least SD, and all who did not receive prior ibrutinib had CR or PR. Two CLL pts with known BTK mutation had response to therapy and 7 had SD. One CLL pt who received 1 prior therapy achieved CR with no detectable residual disease. One of the 8 RT pts achieved CR and 5 achieved SD. In the 11 pts who achieved at least PR, the median duration of response was not reached (NR). In the 15 pts with SD and >2 mos of follow-up, 20% (3/15) maintained SD for >6 mos. Median PFS for pts with CLL and NHL was 8.9 (95%CI:4.6-NR) and 2.7 (95%CI:0.7-NR) mos, respectively (Figure 1). For CLL pts who received and did not receive prior ibrutinib, 64% (7/11) and 20% (1/5) progressed, respectively. For CLL pts who received 1-2 and ≥3 prior therapies 20% (1/5) and 64% (7/11) progressed, respectively. With median follow-up of 5.3 (range:1.2-22.5) and 5.5 (range:0.7-33.1) mos, median OS for CLL and NHL pts was NR (95%CI:15.4-NR) and 5.4 (95%CI:2.6-NR) mos, respectively (Figure 2). Conclusions Ibrutinib (420mg daily) and selinexor (40mg weekly) was tolerable and demonstrated efficacy in this heavily pretreated, high-risk population of CLL/NHL pts. Efficacy may be greater in earlier lines of therapy. Further investigation is needed to optimize response rates and durability. Disclosures Stephens: Karyopharm: Research Funding; Gilead: Research Funding; Acerta: Research Funding. Rogers:Janssen: Research Funding; Acerta: Consultancy; Abbvie: Research Funding; Genentech: Research Funding. Bhat:Janssen: Consultancy; Pharmacyclics: Consultancy. William:Guidepoint Global: Consultancy; Defined Health: Consultancy; Techspert: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy. Jaglowski:Kite: Consultancy, Other: advisory board, Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding; Juno: Consultancy, Other: advisory board; Unum Therapeutics Inc.: Research Funding. Glenn:BMS: Research Funding; Merck: Research Funding; Genentech: Research Funding. Byrd:Genentech: Research Funding; Acerta: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Genentech: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Acerta: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; BeiGene: Research Funding; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau. Woyach:Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. OffLabel Disclosure: Selinexor is an oral inhibitor of nuclear export. This presentation will describe the combination of ibrutinib and selinexor, which is an off-label use for the drug.