Combination Of Ibrutinib Research Articles

Updates from the 2017 American Society of Hematology Annual Meeting: Practice-Changing Studies in Untreated Chronic Lymphocytic Leukemia

The 2017 annual meeting of the American Society of Hematology took place 9–12 December in Atlanta, Georgia. At the meeting, the oral presentations included results from key studies on the first-line treatment of chronic lymphocytic leukemia. A series of phase ii studies focusing on the efficacy and safety of novel treatment strategies were especially notable. One concerned the health-related quality of life results from the gibb study, which had examined the combination of obinutuzumab and bendamustine. A second evaluated the venetoclax–ibrutinib regimen in patients with high-risk disease. The third assessed the combination of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab in patients with mutated immunoglobulin heavy-chain variable region genes. The fourth examined the combination of ibrutinib, fludarabine, cyclophosphamide, and rituximab in younger patients. And the final study evaluated obinutuzumab–ibrutinib followed by a minimal residual disease strategy in fit patients. Our meeting report describes the foregoing studies and presents interviews with investigators and commentaries by Canadian hematologists about the potential effects on Canadian practice.

Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON): a multicentre, open-label, single-arm, phase 2 trial

Regimens based on ibrutinib alone and lenalidomide and rituximab in combination show high activity in patients with relapsed or refractory mantle cell lymphoma. We hypothesised that the combination of all three drugs would improve efficacy compared with previously published data on either regimen alone. In this multicentre, open-label, single-arm, phase 2 trial, we enrolled patients aged 18 years or older with relapsed or refractory mantle cell lymphoma who had previously been treated with at least one rituximab-containing regimen, an Eastern Cooperative Oncology Group performance status score of 0-3, and at least one site of measurable disease, and who met criteria for several laboratory-assessed parameters. Treatment was divided into an induction phase of 12 cycles of 28 days with all three drugs and a maintenance phase with ibrutinib and rituximab only (cycle duration 56 days), given until disease progression or unacceptable toxicity. In the induction phase, patients received intravenous (375 mg/m2) or subcutaneous (1400 mg) rituximab once a week during cycle 1 and then once every 8 weeks. Oral ibrutinib (560 mg once a day) was given to patients every day in the cycle, whereas oral lenalidomide (15 mg once a day) was given on days 1-21. The primary endpoint was overall response assessed in the intention-to-treat population according to Lugano criteria. Safety analysis included all patients who received the treatment, irrespective of eligibility or duration of treatment. The trial is ongoing, but is no longer accruing patients, and is registered with ClinicalTrials.gov, number NCT02460276. Between April 30, 2015, and June 1, 2016, we enrolled 50 patients with relapsed or refractory mantle cell lymphoma at ten centres in Sweden, Finland, Norway, and Denmark. At a median follow-up of 17·8 months (IQR 14·7-20·9), 38 (76%, 95% CI 63-86) patients had an overall response, including 28 (56%, 42-69) patients who had a complete response and ten (20%, 11-33) who had a partial response. The most common grade 3-4 adverse events were neutropenia (in 19 [38%] of 50 patients), infections (in 11 [22%] patients), and cutaneous toxicity (in seven [14%] patients). There were three treatment-related deaths during the study, two due to sepsis and one due to embolic stroke. Our results provide preliminary evidence that the triplet combination of ibrutinib, lenalidomide, and rituximab is an active regimen in patients with relapsed or refractory mantle cell lymphoma, and should be evaluated in a prospective randomised controlled trial. Janssen and Celgene.

Safety and Efficacy of the Combination of Ibrutinib and Nivolumab in Patients with Relapsed Non-Hodgkin Lymphoma or Chronic Lymphocytic Leukemia

Safety and Efficacy of the Combination of Ibrutinib and Nivolumab in Patients with Relapsed Non-Hodgkin Lymphoma or Chronic Lymphocytic Leukemia

Phase II Study of Brentuximab Vedotin Plus Ibrutinib for Patients with Relapsed/Refractory Hodgkin Lymphoma

Background:Brentuximab vedotin (BV), an antibody drug conjugate (ADC), selectively delivers anti-tubulin agent monomethyl auristatin E (MMAE) to CD 30+ cells. In a a multi-center phase II trial in patients with relapsed/refractory Hodgkin lymphoma (HL), BV showed an overall response rate (ORR) of 75%, a complete response (CR) rate of 34%, and a median duration of response (DOR) of 6.7 months (Younes A et al, JCO 2012). Although this drug has high ORR in HL, the CR rate and the DOR can be improved.Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, has demonstrated antitumor activity in B-cell lymphomas. Ibrutinib is also an irreversible inhibitor of interleukin-2-inducible kinase (ITK), which has a critical role in T cell signaling. Inhibition of ITK leads to increased Th1 based immune response (Dubovsky JA, Blood 2013). As a single agent at standard dose, ibrutinib does not have antitumor activity in HL cell line (Figure 1). However, we have shown that standard dose ibrutinib is synergistic with BV in L428, a HL cell line (Figure 1). Based on our preclinical model, we hypothesize that ibrutinib may enhance the antitumor activity of BV in HL patients. It is also possible Ibrutinib may enchance the activity of BV through ITK inhibition of T cells in the HL microenvironment. Thus we designed and conducted a phase II trial using the combination of ibrutinib plus BV in patients with R/R HL. We report the planned interim analysis of efficacy and safety.Patients and Methods:This is a prospective, multicenter phase II trial with a 3-patient lead-in cohort in patients with relapsed/refractory HL. All patients must be > 15 years old and have biopsy proven relapsed/refractory HL. Patients are treated with 1.8 mg/kg of BV intravenously every 3 weeks and ibrutinib 560 mg PO daily (420 mg PO daily in the lead-in cohort). Patients could have received prior BV. The primary endpoint was the CR rate according to Lugano 2014. Secondary endpoints were toxicities, ORR, duration of response, and, BTK/ITK receptor occupancy, and changes in T/B/NK cell subsets in peripheral blood.Results:Sixteen out of 39 patients were accrued thus far, all 16 pts were evaluable for toxicity, and 13 patients were evaluable for efficacy (3 lead-in pts excluded). The baseline characteristics (Figure 1) are: male (56%), Caucasian (75%), median age of 33 (17-69), stage III/IV at diagnosis (50%), primary refractory to induction (50%), refractory to last therapy (37%), and 4 patients had prior BV (25%). The overall best response (CR+PR) rate was 69%, CR rate was 46%, stable disease rate was 31%, and no progressive disease (PD) was seen. The disease control rate (CR+PR+SD) was 100%. One patient who was refractory to prior BV achieved a PR, and an additional patient who had a previous best response of PR to BV now achieved a CR.Treatment was well tolerated. There were no Grade 4 events. Grade 3 possibly-related toxicities included neutropenia (n=2) and hypokalemia (n=1). Grade I/II possibly related toxicities >20% included diarrhea (n=8, 7 grade 1), nausea (n=6, all grade 1), fatigue (n=5, all grade 1), rash (n=5, 4 grade 1), and thrombocytopenia (n=4, all grade 1).Conclusion:The combination of BV + ibrutinib is well tolerated. Although the ORR of 69% maybe similar to BV alone, the CR of 46% and disease control rate of 100% appears promising. Especially encouraging is the 1 PR and 1 CR seen in patients previously exposed to BV. The study has met the interim analysis endpoint and warrants further accrual to investigate the final CR rate. [Display omitted] DisclosuresChen:Pfizer: Consultancy; Merck: Consultancy, Speakers Bureau; Genentech: Speakers Bureau; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Affimed: Research Funding; Pharmacyclics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Herrera:Seattle Genetics: Research Funding; Merck: Consultancy; Genentech: Consultancy; BMS: Consultancy; Pharmacyclics: Consultancy. Kwak:Pepromene Bio: Consultancy, Equity Ownership; Celltrion, Inc: Consultancy; InnoLifes: Consultancy, Equity Ownership.

Abstract A34: The identification of combinatorial therapeutic approaches with BCR inhibitors in B cell malignancies

Abstract Introduction: It was shown that BCR inhibitors such as ibrutinib interrupt microenvironmental interactions and mobilize malignant B cells of chronic lymphocytic leukemia (CLL) from immune niches into the blood stream. It has been suggested that this mobilization will sensitize malignant B cells to other drugs, providing a possibility to introduce synthetically lethal combinations of drugs with an acceptable toxicity profile. This might be limited to a subgroup of CLL patients with specific underlying molecular mechanisms of disease biology or reaction to BCR inhibitors. The aim of this study was to test for the effect of ibrutinib on the expression of genes and activity of pathways that could be potentially targeted by clinically available drugs to achieve highly potent combinations. Results: We performed gene expression profiling in samples obtained from CLL patients treated with ibrutinib as a single agent (pre-ibrutinib vs. day 15 and/or week 5/12/15; N=12 pairs) to identify potential therapeutic targets. We have primarily focused on analyzes of cell-surface proteins and anti-apoptotic Bcl2 family members, since therapeutic antibodies and small molecular inhibitors for these molecules are available. We have analyzed changes in >30 cell-surface molecules, 8 members of the Bcl2 family, and members of other potentially relevant pathways (chemokines, adhesion, Akt, Erk, Ras, NFkB). Notably, we have observed that the mRNA and B cell-surface levels of CD20 are strongly down-modulated with ibrutinib, which indicates that the previously suggested combination of ibrutinib and anti-CD20 antibodies (such as rituximab or ofatumumab) is likely not ideal. Indeed, we showed that CLL cells with lower levels of CD20 are more resistant to rituximab in vitro, but also in vivo (P<0.01). We also showed that the effect of ibrutinib on CD20 levels is mediated by inhibition of CXCR4/SDF-1 axis, which impairs the SDF-1α (ligand for CXCR4) mediated regulation of CD20 expression (P<0.01). Notably, it has been shown that addition of rituximab to ibrutinib in vivo is able to partially eliminate CLL cells despite lower levels of CD20 suggesting that there must be other mechanism of ibrutinib action that allows for the effect of rituximab. The screening of anti-apoptotic molecules revealed that Mcl1 levels were significantly down-modulated after ibrutinib treatment in vivo (P=0.002), and ibrutinib also inhibited Mcl1 induction in CLL cells co-cultured with stromal cells (HS-5). As Mcl1 was described to directly protect CLL cells from rituximab, we suggest that ibrutinib-mediated Mcl1 reduction is a mechanism that facilitates rituximab efficacy. On the other hand we have shown that several members of Bcl2 family are up-regulated in CLL samples obtained after >3 weeks on ibrutinib therapy. We have also shown that interactions of stromal cells (HS-5) with CLL cells lead to up-regulation of these molecules while ibrutinib inhibits this in vitro (P<0.01). This suggest that the observed in vivo up-regulation of specific Bcl2 family members is due to an adaptation of B cells or selection of malignant B cells with high-level expression of anti-apoptotic molecules sufficient to survive the BCR signalling inhibition. We observed that the survival of CLL cells treated with ibrutinib is dependent on Bcl2, and subsequent Bcl2 inhibition can act synergistically with ibrutinib in B cell lines and CLL samples. These anti-apoptotic molecules therefore represent primary candidates with synthetically lethal potential in combination with ibrutinib. Additionally, we have identified dependence of a subtype of CLL cases on integrin signalling. The inhibition of integrin VLA-4 with anti-VLA4 antibody or integrin-associated kinase overcame the resistance of CLL cells to chemotherapy drugs and also to anti-CD20 antibodies, and synergized with the effects of ibrutinib. Conclusion: We have performed gene expression analysis of primary samples obtained from patients on ibrutinib, and identified gene expression changes that are associated with adaptation of B cells and/or selection of B cell resistant to BCR inhibition. We have shown that malignant B cells are dependent on integrin-signalling and the up-regulation of Bcl2 protein, which makes them synergistically lethal targets. Supported by: The results of this research have been acquired within CEITEC 2020 (LQ1601) project with financial contribution made by the Ministry of Education, Youths and Sports of the Czech Republic within special support paid from the National Programme for Sustainability II funds. Citation Format: Gabriela Pavlasova, Katerina Musilova, Vaclav Seda, Katerina Cerna, Eva Vojackova, Veronika Svobodova, Marek Mraz. The identification of combinatorial therapeutic approaches with BCR inhibitors in B cell malignancies [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A34.

The γ-secretase inhibitors enhance the anti-leukemic activity of ibrutinib in B-CLL cells.

Ibrutinib blocks B-cell receptor signaling and interferes with leukemic cell-to-microenvironment interactions. Ibrutinib plays a key role in the management of B-CLL and is recommended for first line treatment of high-risk CLL patients with 17p deletion. Therefore, elucidating the factors governing sensitivity/resistance to Ibrutinib represents a relevant issue. For this purpose, in 3 B-CLL patient samples harboring functional TP53 mutations, the frequency of the mutated clones was monitored during in vivo Ibrutinib therapy, revealing a progressive decline of the frequency of TP53mut clones during 12 months of treatment. In parallel, the anti-leukemic activity of Ibrutinib was assessed in vitro on B-CLL patient cell cultures in combination with γ-secretase inhibitors (GSI). In the in vitro assays, the combination of Ibrutinib+GSI exhibited enhanced cytotoxicity on B-CLL cells also in the presence of stroma and it was coupled to the down-regulation of the stroma-activated NOTCH1 and c-MYC pathways. Moreover, the combined treatment was effective in reducing CXCR4 expression and functions. Therefore, the ability of GSI to enhance the Ibrutinib anti-leukemic activity in B-CLL cells, by down-regulating the NOTCH1 and c-MYC pathways, warrants further experimentation for its potential therapeutic applications.

Abstract 4408: Metabolic alterations induced by ibrutinib in CLL cells as a basis for drug combinations to enhance ibrutinib therapeutic activity

Abstract The use of ibrutinib, which targets the Bruton tyrosine kinase, has significantly improved the therapeutic outcome for patients with chronic lymphocytic leukemia (CLL), especially in cases with chromosome 17p deletion, which usually respond poorly to conventional chemotherapy. However, ibrutinib is not completely curative, and a small portion of CLL patients exhibit resistance. The main objectives of this study were to investigate the effect of ibrutinib on CLL mitochondrial metabolism and to develop novel strategies to enhance the therapeutic activity of ibrutinib. Ibrutinib-induced changes in mitochondrial functions were analyzed by measuring oxygen consumption rate (OCR) as an indicator of mitochondrial respiration and extracellular acidification rate (ECAR) as a parameter of lactate production from glycolysis using an extracellular flux analyzer. In a primary CLL cell-stromal cell co-culture system (which maintains long-term CLL cell viability), ibrutinib induced little change in OCR and ECAR during the first 48-72 h. However, prolonged drug exposure (up to 7 days) in vitro caused a consistent and significant decrease in OCR compared to that in untreated co-cultured CLL cells. Importantly, CLL cells isolated from patients treated with ibrutinib for 7 days also had significantly decreased OCR compared to pre-treatment samples from the same patients, suggesting that the impact of ibrutinib on mitochondrial functions occurred in vivo and was clinically relevant. On western blot analysis, ibrutinib induced decreases in expression of certain respiratory chain components associated with AMPK activation. On electron microscopy, CLL cells treated with ibrutinib in vitro for 6 days exhibited lower numbers of mitochondria than untreated cells, which was confirmed by flow cytometry analysis of cells stained with Mitotracker Green. Functional analysis showed that ibrutinib caused CLL cells to take up less glutamine but did not affect glucose uptake, suggesting that ibrutinib has a preferential impact on glutamine metabolism. On testing the possibility that the metabolic alterations and mitochondrial dysfunction induced by ibrutinib render CLL cells vulnerable to compounds that affect mitochondria or inhibit glutamine metabolism, we found that combinations of ibrutinib with metformin (inhibitor of mitochondrial OXPHOS) or with C968 (glutaminase inhibitor) resulted in synergistic activity against CLL cells and induced massive leukemia cell death compared to either drug alone. Notably, the combination of ibrutinib and C968 was synergistic in killing CLL cells with 17p deletion. Overall, our results suggest that ibrutinib induces metabolic alterations characterized by decreased mitochondrial respiration and attenuated glutamine metabolism. Such metabolic alterations provide a biochemical basis for mechanism-based drug combination to enhance the therapeutic activity of ibrutinib. Citation Format: Helene Pelicano, Li Feng, William G. Wierda, Michael J. Keating, Peng Huang. Metabolic alterations induced by ibrutinib in CLL cells as a basis for drug combinations to enhance ibrutinib therapeutic activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4408. doi:10.1158/1538-7445.AM2017-4408

The safety of Bruton’s tyrosine kinase inhibitors for the treatment of chronic lymphocytic leukemia

ABSTRACTIntroduction: The approval of ibrutinib has revolutionized the therapeutic landscape of chronic lymphocytic leukemia (CLL). Currently ibrutinib is indicated for patients that are both treatment naïve as well as those with relapsed CLL. Ibrutinib is generally well-tolerated with durable responses that improve over time in most patients. Important toxicities include atrial fibrillation and bleeding.Areas cover: This review covers the pharmacokinetics, pharmacodynamics, safety and efficacy of ibrutinib in the treatment of CLL. We also compare ibrutinib with other kinase inhibitors and chemoimmunotherapy regimens using data from clinical trials. A literature search utilized the PubMed database.Expert opinion: Despite the efficacy and tolerability of ibrutinib, important questions remain, which include selection of patients receiving ibrutinib in the first and subsequent lines of treatment, optimal dosing, sequential use of ibrutinib versus other kinase inhibitors and combination therapy. Prospective studies should incorporate minimal residual disease (MRD) status as a clinical endpoint to determine whether patients can be taken off kinase inhibitors.

Microenvironmental agonists generate de novo phenotypic resistance to combined ibrutinib plus venetoclax in CLL and MCL.

De novo resistance and rapid recurrence often characterize responses of B-cell malignancies to ibrutinib (IBR), indicating a need to develop drug combinations that block compensatory survival signaling and give deeper, more durable responses. To identify such combinations, we previously performed a combinatorial drug screen and identified the Bcl-2 inhibitor venetoclax (VEN) as a promising partner for combination with IBR in Mantle Cell Lymphoma (MCL). We have opened a multi-institutional clinical trial to test this combination. However, analysis of primary samples from patients with MCL as well as chronic lymphocytic leukemia (CLL) revealed unexpected heterogeneous de novo resistance even to the IBR+VEN combination. In the current study, we demonstrate that resistance to the combination can be generated by microenvironmental agonists: IL-10, CD40L and, most potently, CpG-oligodeoxynucleotides (CpG-ODN), which is a surrogate for unmethylated DNA and a specific agonist for TLR9 signaling. Incubation with these agonists caused robust activation of NF-κB signaling, especially alternative NF-κB, which led to enhanced expression of the anti-apoptotic proteins Mcl-1, Bcl-xL, and survivin, thus decreasing dependence on Bcl-2. Inhibitors of NF-κB signaling blocked overexpression of these anti-apoptotic proteins and overcame resistance. Inhibitors of Mcl-1, Bcl-xL, or survivin also overcame this resistance, and showed synergistic benefit with the IBR+VEN combination. We conclude that microenvironmental factors, particularly the TLR9 agonist, can generate de novo resistance to the IBR+VEN combination in CLL and MCL cells. This signaling pathway presents targets for overcoming drug resistance induced by extrinsic microenvironmental factors in diverse B-cell malignancies.

The BTK Inhibitor Ibrutinib (PCI-32765) Overcomes Paclitaxel Resistance in ABCB1- and ABCC10-Overexpressing Cells and Tumors

Paclitaxel is one of the most widely used antineoplastic drugs in the clinic. Unfortunately, the occurrence of cellular resistance has limited its efficacy and application. The ATP-binding cassette subfamily B member 1 (ABCB1/P-glycoprotein) and subfamily C member 10 (ABCC10/MRP7) are the major membrane protein transporters responsible for the efflux of paclitaxel, constituting one of the most important mechanisms of paclitaxel resistance. Here, we demonstrated that the Bruton tyrosine kinase inhibitor, ibrutinib, significantly enhanced the antitumor activity of paclitaxel by antagonizing the efflux function of ABCB1 and ABCC10 in cells overexpressing these transporters. Furthermore, we demonstrated that the ABCB1 or ABCC10 protein expression was not altered after treatment with ibrutinib for up to 72 hours using Western blot analysis. However, the ATPase activity of ABCB1 was significantly stimulated by treatment with ibrutinib. Molecular docking analysis suggested the binding conformation of ibrutinib within the large cavity of the transmembrane region of ABCB1. Importantly, ibrutinib could effectively enhance paclitaxel-induced inhibition on the growth of ABCB1- and ABCC10-overexpressing tumors in nude athymic mice. These results demonstrate that the combination of ibrutinib and paclitaxel can effectively antagonize ABCB1- or ABCC10-mediated paclitaxel resistance that could be of great clinical interest. Mol Cancer Ther; 16(6); 1021-30. ©2017 AACR.

Highlights of This Issue

Pancreatic adenocarcinoma (PDAC), with dismal survival rates, is the fourth-leading cause of cancer death in the United States. Very few therapeutic options exist for PDAC patients. Langdon and colleagues describe a combinatorial drug screen to identify therapeutic regimens that can inhibit the growth of PDAC cells. One of several effective combinations, consisting of bromodomain inhibitor, JQ1, and neddylation inhibitor MLN-4924, super-additively inhibited the growth of PDAC cells and xenografts. Dysregulation of reactive oxygen species-induced DNA damage responses contributed to the impact of this combination. These, and other high-ranking combinations including US FDA-approved agents, offer some promise for control of PDAC.Fibroblast growth factor receptors (FGFRs) are frequently activated by gene amplification, point mutation or chromosomal rearrangement in a variety of human cancers. FGFRs are recognized as an important oncogenic driver pathway for therapeutic intervention. In this study, Perera and colleagues report the discovery and pharmacologic characterization of erdafitinib (JNJ-42756493), a highly selective and potent pan-FGFR inhibitor. Erdafitinib demonstrated selective inhibition of FGFR-mediated signal transduction, proliferation and in vivo anti-tumor efficacy. These results support the ongoing clinical development of erdafitinib in malignancies and other disorders associated with constitutive FGFR activation.Paclitaxel is a commonly used chemotherapeutic drug. However, resistance to paclitaxel has limited its clinical application. ABCB1 and ABCC10 are the major transporters causing efflux of paclitaxel, leading to paclitaxel resistance. Here, Zhang, Patel and colleagues report that ibrutinib antagonized the efflux function of the transporters. Ibrutinib effectively enhanced the anti-tumor efficacy of ABCB1 and ABCC10-overexpressing resistant tumors in mice. Molecular docking analysis revealed that ibrutinib interacts with ABCB1 within its large cavity in the transmembrane region. This study demonstrated that combination of ibrutinib with paclitaxel can reverse ABCB1- or ABCC10-mediated paclitaxel resistance that could be of great clinical interest.Acute myeloid leukemia (AML) is the most common leukemia diagnosed in adults and a disease of high unmet need with few therapies delivering durable benefit to patients. Floc'h and colleagues report activity of a highly potent and selective Aurora kinase B inhibitor AZD2811 formulated in a nanoparticle. The AZD2811 nanoparticle delivered durable responses in pre-clinical models of AML, as monotherapy and combined with chemotherapy, including targeting tumor cells resident in the bone marrow. Targeting Aurora B with the AZD2811 nanoparticle formulation has the potential to build on the promising clinical activity seen with cell cycle agents in AML.

IBRUTINIB INCREASES THE SYSTEMIC EXPOSURE OF RITUXIMAB: PHARMACOKINETIC RESULTS FROM THE HELIOS TRIAL

Introduction: In the phase 3 HELIOS trial, coadministration of ibrutinib with bendamustine + rituximab (I + BR) improved patient outcomes compared with placebo + BR (Pbo + BR) in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma. We used a modeling approach to explore the pharmacokinetic (PK) interactions between ibrutinib, B, and R from the HELIOS trial. Methods: In total, 578 patients were randomized to 420 mg ibrutinib (n = 289) or pbo (n = 289) in combination with 6 cycles of BR until disease progression or unacceptable toxicity. B was dosed at 70 mg/m2 on days 2–3 of cycle 1 and days 1–2 of cycles 2–6; R was dosed at 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 in cycles 2-6. Ibrutinib PK samples were obtained from all patients at predose, 1, 2, and 4 hr on day 1 of cycles 1 and 2. In a subset of patients, B PK samples were obtained on day 2 of cycles 1 and 2 at predose, end of infusion, and at 1, 2, and 4 hr; R samples were obtained on days 1 and 15 of cycle 1, predose on day 1 of cycles 2–6, and day 1 of cycles 7–9, in the washout phase. Dose-normalized B and R concentration-time data were stratified by treatment. R PK was assessed using a nonlinear mixed-effects compartmental approach (NONMEM v7.1.0). R v3.2.4 (www.R-project.org) was used for model diagnostics and plots. Results: Ibrutinib PK data were assessed in 280 patients. BR PK data were assessed in 178 patients (84 [Pbo + BR] and 94 [I + BR]). Dose-normalized plasma concentration-time data of B from both arms were comparable, indicating that ibrutinib did not alter B PK. Systemic exposure of R was higher with I + BR than with Pbo + BR; mean predose serum concentrations were 2- to 3-fold higher in the first three cycles and 1.2- to 1.7-fold higher in subsequent cycles (Figure). Systemic exposure of ibrutinib (mean AUCss ± SD = 447.5 ± 298.2 ng·h/mL) was comparable to those observed with single agent ibrutinib in other trials, indicating that BR did not impact ibrutinib PK. A previously reported population PK model, which includes a clearance term decreasing exponentially with time, was used to model R exposure (n = 147). Inclusion of both treatment arm as a categorical covariate and tumor burden as a continuous time-varying covariate on overall R clearance significantly improved the fitting of the data. No relevant differences in safety profile were observed between the I + BR and Pbo + BR arms with the increase in R exposure. All-grade infusion-related reactions were reported in 22% of the Pbo + BR arm and 16.7% of the I + BR arm; the incidence of chills was comparable (~11%). Dose interruptions, dose reductions, and discontinuations due to infusion-related reaction were more frequent with Pbo + BR (34.8% vs. 27.9%). Keywords: chronic lymphocytic leukemia (CLL); ibrutinib; rituximab.

Phase 1B of ibrutinib and high-dose methotrexate for recurrent/refractory CNS lymphoma.

7533 Background: Primary CNS Lymphoma (PCNSL) is an aggressive primary brain tumor. Outcome and treatment options for patients with recurrent/refractory (r/r) disease are poor. We have observed promising efficacy of single agent ibrutinib in r/r PCNSL and secondary CNS lymphoma (SCNSL). In this phase 1B trial, we investigate the toxicity of ibrutinib in combination with high-dose methotrexate (HD-MTX) in r/r PCNSL/SCNSL. Methods: Eligible patients had r/r PCNSL/SCNSL or newly diagnosed SCNSL, age≥18, ECOG≤2, normal end-organ function, and with any number and type of prior therapies. In patients with SCNSL disease, systemic disease needed to be absent. HD-MTX was given at 3.5g/m2 every 2 weeks for a total of 8 doses. To minimize adverse events, ibrutinib was stopped on days of HD-MTX infusion and was restarted 5 days after MTX infusion or after completion of MTX-clearance, if clearance of MTX required more than 5 days. Ibrutinib was continued daily after completion of 8 doses of MTX. Results: Six patients have been enrolled; 3 received 560mg and 3 received 840mg ibrutinib in combination with HD-MTX. Median age was 62 (range 43-74); median ECOG 1 (0:2; 1:3; 2:1). Two had r/r PCNSL and 4 SCNSL. Three had brain disease, one isolated cerebrospinal fluid (CSF) involvement and two parenchymal and CSF involvement. Three patients had recurrent (2 PCNSL; 1 SCNSL), two refractory (both SCNSL), and one newly diagnosed disease (SCNSL). There were no grade 4 adverse events. Grade 3 events were observed in 5 patients (lymphopenia in 3, ALT elevation in 2, diarrhea in 1, electrolyte changes in 1, hypertension in 1). The most common adverse events were hypokalemia, low WBC, hyperglycemia, ALT and AST elevation. There was no dose reduction of methotrexate or ibrutinib in any patient. After a median follow-up of 130 days, all patients were evaluated for response after 4 doses of HD-MTX, with 4/6 (67%) showing a response: 2 CR, 2 PR, and 1 SD, 1 PD; both non-responders were refractory SCNSL. Ibrutinib concentrations were measured in plasma and CSF. Conclusions: Patients with CNS lymphoma tolerate the combination of HD-MTX and Ibrutinib (at 560 and 840mg) well. Continued enrollment into a combination arm that includes rituximab, methotrexate and ibrutinib is ongoing. Clinical trial information: NCT02315326.

A multicenter, randomized, double-blind, placebo-controlled phase III study of the Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, in combination with rituximab versus placebo in combination with rituximab in patients with treatment-naive follicular lymphoma (PERSPECTIVE).

TPS7576 Background: Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma. A limited number of chemotherapy-free options exist for patients with treatment-naïve (TN) FL who are older or who have comorbidities. Single-agent rituximab is considered a treatment option for elderly or infirm patients. In a phase 2 study, frontline treatment with ibrutinib in combination with rituximab for 4 weekly doses without maintenance resulted in an ORR of 85% (CR, 35%) with a median follow-up of 22 months and an 18-month PFS rate of 87% (Fowler Blood 2016). The phase 2 study serves as the basis for the randomized, double-blind, placebo-controlled phase 3 PERSPECTIVE (PCYC-1141-CA) trial. PERSPECTIVE will be conducted in two parts and will uniquely test (1) whether frontline treatment with ibrutinib in combination with rituximab results in prolongation of PFS compared to rituximab alone, and (2) whether continuous versus finite treatment with ibrutinib affects PFS outcomes. Methods: In the ongoing PERSPECTIVE trial, approximately 440 patients with TN FL meeting at least one Groupe d'Etude des Lymphomes Folliculaires (GELF) criterion will be randomized if they also meet one of the following criteria: age ≥70 years or age 60 to 69 with one or more comorbidities (creatinine clearance 30-59 mL/min or ECOG performance status of 2). Patients will be randomized to receive either ibrutinib or oral placebo once daily. All patients will be given rituximab for 4 weekly doses followed by maintenance. After at least 2 years of treatment in Part 1, patients randomized to ibrutinib who still remain on ibrutinib will be re-randomized in Part 2 to continue ibrutinib or switch to placebo. Key exclusion criteria include any prior treatment for FL, evidence of CNS involvement, or transformation. Analyses will be conducted in two distinct parts, both with a primary endpoint of PFS. The study is open for enrollment with sites planned in the US, EU, and Asia Pacific. Clinical trial information: NCT02947347.

A randomized, double-blind phase III study of ibrutinib versus placebo in combination with corticosteroids in patients with new onset chronic graft versus host disease.

TPS7072 Background: Chronic graft versus host disease (cGVHD) is a common complication of allogeneic stem cell transplantation, with pathophysiology involving alloreactive and dysregulated T and B cells and innate immune populations. Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is indicated by the US FDA for the treatment of patients (pts) with CLL/SLL. Ibrutinib recently received breakthrough therapy and orphan drug designation for the treatment of pts with cGVHD who did not respond to one or more lines of systemic therapy. Ibrutinib reduces severity of cGVHD in murine models and recently was shown to achieve an NIH-defined overall response rate of 67% in pts with steroid relapsed/refractory cGVHD (Miklos Blood 2016). Methods: The primary objective of this Phase 3, multicenter, international, randomized, controlled, double-blind study is to evaluate the 24-week response rate of ibrutinib versus placebo in combination with prednisone. Pts with newly diagnosed moderate or severe cGVHD, as per NIH Consensus Development Project Criteria (2014), will be randomized in a 1:1 ratio to receive either oral ibrutinib (arm A) or placebo (arm B) in combination with oral prednisone. Ibrutinib or placebo will be given until unacceptable toxicity, relapse of underlying disease, death, or the need for a new systemic treatment for progressive cGVHD. Eligible study pts (age ≥12 yrs) must require systemic treatment with corticosteroids and have no prior systemic treatment for cGVHD. The primary endpoint is response rate (complete or partial response) at 24 weeks, as per NIH Consensus Development Project Criteria, and must occur in the absence of both new therapy for cGVHD and relapse/return of the underlying disease that was the indication for transplant. Secondary endpoints will assess for additional clinical benefit including corticosteroid dose reduction, improvement of Lee cGVHD Symptom Scale scores, withdrawal of all immunosuppressants, and overall survival. This study is currently enrolling pts. Funding source: Pharmacyclics LLC, an AbbVie Company. Clinical trial information: NCT02959944.

Tolerability and activity of chemo-free triplet combination of TGR-1202, ublituximab, and ibrutinib in patients with advanced CLL and NHL.

7511 Background: Novel targeted agents are emerging for B-cell malignancies, but few studies have safely combined these agents. Ublituximab (UTX) is a novel glycoengineered mAb targeting a unique epitope on the CD20 antigen. TGR-1202 is a next generation, once daily PI3Kδ inhibitor, demonstrating a favorable safety profile compared to prior inhibitors, including in long-term follow up (Burris, 2016). This Ph 1 trial evaluates the safety/efficacy of the triplet combination of a novel anti-CD20 mAb + PI3Kδ + BTK inhibitor (ibrutinib) in pts with B-cell malignancies. Methods: Eligible pts had CLL or rel/ref NHL w/o limit to prior therapies, including those ref to prior PI3Kδ or BTK inhibitors. UTX dosed on D1, 8, 15 of C1; D1 of C2-6, and C9 & 12. TGR-1202 dose escalated (400/600/800mg QD), ibrutinib dosed at 420mg (CLL) or 560mg (NHL), both on C1D1. Results: 38 pts were enrolled: 20 CLL/SLL and 18 NHL, including 6 follicular (FL), 6 DLBCL, 4 mantle cell (MCL) and 2 marginal zone (MZL). Med age 65 yrs (range 32-85); 29 M/9 F; med prior tx = 3 (range 0-6). 2 pts were ref to prior PI3Kδ and 2 were prev treated with ibrutinib (1 ref/1 rel). MTD was not reached. Most common ( > 20%) all causality AE’s were fatigue (42%), diarrhea (39%), dizziness (34%), nausea (32%), neutropenia, pyrexia, rash, infusion reaction, insomnia (each at 29%), thrombocytopenia, cough (each at 26%), anemia (24%) and sinusitis (21%). GR 3/4 AE’s were minimal, the only event > 10% was neutropenia (16%). ORR amongst 36 evaluable pts is shown in the table below. 53% of evaluable CLL pts had high-risk cytogenetics and 4/6 DLBCL pts were non-GCB. One CLL pt (17p/11q del) ref to both PI3Kδ and ibrutinib achieved a CR. Med time on study is 10 mos (range 1 – 27+ mos). Med DOR not reached (range 3 – 24+ mos). Conclusions: This is the first known triple combination of an anti-CD20 mAb + PI3Kδ + BTK inhibitor. The combination of UTX, TGR-1202, and ibrutinib has been well tolerated with activity observed across heavily pre-treated and high-risk B-cell malignancies. Expansion cohorts at the highest dose (800mg TGR-1202 + full dose ibrutinib) are underway. Future trials for the triplet are warranted. Clinical trial information: NCT02006485. [Table: see text]

Phase I dose escalation of ibrutinib and buparlisib in relapsed/refractory diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL).

7544 Background: In vitro studies of BTK and PI3K inhibitors demonstrate synergy in non-Hodgkin lymphoma (NHL). We embarked on a phase I/Ib investigator-initiated clinical trial evaluating the combination of ibrutinib (BTK inhibitor) and buparlisib (pan-PI3K inhibitor) in relapsed/refractory (R/R) NHL. The completed dose escalation is reported. Methods: Patients (pts) were eligible if they had R/R DLBCL, MCL, or FL with ECOG≤2 and adequate organ function. Ibrutinib and buparlisib were given daily by mouth on a 28-day cycle. Dose reductions were permitted after cycle 1. Tumor response was based on Lugano Classification however CR required both PET resolution and ≥ PR by CT. Results: As of Dec 16, 2016, 13 pts were enrolled and evaluated for toxicity (DLBCL 5, FL 2, MCL 6). Dose levels and DLT per table. Six pts discontinued treatment for disease progression (DLBCL 4, FL 2). Hematologic AE ≥ grade 3 are anemia (2), leukocytosis (2), and leukopenia (4). Relevant non-hematologic AEs of any grade ≥ 20% across all pts were fatigue (77%), diarrhea (62%), anorexia (54%), rash (46%), hyperbilirubinemia (46%), gastric reflux (46%), CMV reactivation (31%), mood change (31%), and hypertension (23%). Most common related grade 3/4 toxicity is rash (N = 3). No grade 5 toxicities noted. Serious adverse events (SAE) include: grade 2 pleural effusion and grade 2 nausea (N = 1), grade 1 fever with hospitalization (N = 1), grade 2 confusion and grade 4 hyponatremia (N = 1) were unrelated to therapy. Responses noted in 13 pts: MCL (N = 6: CR 4, PR 2), FL (N = 2: SD 2), DLBCL (N = 5: SD 1). One CR was a MCL pt with CR after 2 cycles on combination therapy and continues in remission on ibrutinib alone because of buparlisib toxicity. Conclusions: Combination of ibrutinib and buparlisib while generally well tolerated has predicted toxicities of both BTK and PI3K inhibitors. The recommended phase 2 dose is ibrutinib 560 mg and buparlisib 100 mg though dose reductions for tolerability may be needed for long term oral therapies. Promising efficacy is observed in MCL. Clinical trial information: NCT02756247. [Table: see text]

Combination ibrutinib (Ibr) and venetoclax (Ven) for the treatment of mantle cell lymphoma (MCL): Primary endpoint assessment of the phase 2 AIM study.

7520 Background: Both ibr and ven have activity in relapsed/refractory (R/R) MCL, but complete remissions (CR) are attained in <25% with either. We sought to determine the activity of the combination in an investigator-initiated, phase 2 study. Methods: Enrolment of 24 patients (pts) with R/R (n=23) or frontline (n=1) MCL completed in 09/16. Pts received 4 weeks of ibr (560mg/d), followed by introduction of ven (weekly ramp-up to target 400mg/d). The primary endpoint was CR rate at week 16, as assessed by PET/CT, BMAT, flow & molecular MRD, and endoscopy (if baseline gut involvement). Response was calculated separately with and without knowledge of the PET result by IWG criteria (Cheson JCO 2007), in order to compare with published studies (ibr, 9% CR at wk16; ven, best CR rate 21%). Results: Median age of pts was 68 (range, 47-81) years. For the R/R pts (n=23), median lines of prior therapy was 2 (1-6), 48% were refractory to last treatment, and 30% had failed previous autologous SCT. As of data cutoff on Jan 11 2017, 18 pts remain on therapy, and 6 stopped treatment due to progressive disease (4), adverse event (1) or unrelated death (1). At week 16, ORR was 71% (63% CR) and 80% of complete responders were flow-cytometry negative in the marrow (sensitivity 10-3 to 10-4). Using CT without PET, the comparison responses were CR 42%, CRu 17%, PR 17% (ORR 78%). After a median follow-up of 8.3 (range 1.4-17.7) months, the 8-month estimates of PFS and OS months are 74% and 81%. Adverse events ≥20%, irrespective of attribution, were fatigue (71%), diarrhea (67%), nausea (50%), URTI (38%), gastro-esophageal reflux (33%), neutropenia (33%), cough (25%) and bruising (21%); with the exception of neutropenia (25% grade 3-4), these were predominantly grade 1-2 in severity. Tumour lysis syndrome occurred in 2 pts with high tumour burden, leading to revision of the protocol ven starting dose from 50mg, to 20mg/d. Conclusions: The combination of ibr and ven was tolerable and achieved CR rate of 63% at week 16 in pts with MCL. The efficacy results compare favorably with historical results, and warrant further phase III investigation. Clinical trial information: NCT02471391.

CD19 CAR-T cells combined with ibrutinib to induce complete remission in CLL.

7509 Background: Immunotherapy with anti-CD19 CART cells induces complete remission (CR) in the minority of patients with CLL, but where CRs occur they tend to be durable. Based on preclinical evidence of synergy, we combined anti-CD19 CAR T cells with ibrutinib to test the hypothesis that pre- and concurrent treatment would enhance the CR rate. Methods: This is a pilot trial of anti-CD19 CAR T cells in adults with CLL/SLL who were not in CR despite at least 6 months of ibrutinib. Pts must have failed at least 1 regimen before ibrutinib, unless they had del(17)(p13.1) or a TP53 mutation. T cells were lentivirally transduced to express a CAR comprising CD3z, 4-1BB, and humanized anti-CD19 scFv (CTL119). Pts were lymphodepleted 1 week before infusion. Ibrutinib was continued throughout the trial. Results: Manufacturing was successful in all pts. Ten pts (9M, 1F; ages 47-77; 0-12 regimens prior to ibrutinib) have been infused. All had abnormalities of TP53 or ATM and two pts had increasing BTK C481S clones. Median marrow CLL burden was 10% (range 10-50%). The median follow-up is 6 months (range 0.5-9). Cytokine release syndrome (CRS) developed in 9 pts; gr1 in 2, gr2 in 6 and gr3 in 1 pt. One pt developed gr4 tumor lysis syndrome. Treatment of CRS with the IL-6 receptor antagonist tocilizumab was not required. At 3 months, 8 evaluable pts had achieved an MRD-ve marrow CR (89%) by 9-color flow, and all remain in marrow CR at last F/U. There was modest residual splenomegaly in 3/5 patients, and adenopathy resolved in 4/6 subjects with progression in 1/6. MRD assessment by deep sequencing will be presented. Conclusions: We observed 89% MRD-ve marrow CR in pts with high-risk CLL using a well-tolerated combination of CART cells and ibrutinib. Longer follow-up will reveal the durability of these results and could support evaluation of a first-line combination approach in an attempt to obviate the need for chronic therapy. Clinical trial information: NCT02640209.

Response of renal cell carcinoma to ibrutinib, a bruton tyrosine kinase inhibitor, in a patient treated for chronic lymphocytic leukemia.

Ibrutinib is a bruton tyrosine kinase (BTK) inhibitor approved for B cell malignancies. Although there are currently two clinical trials evaluating ibrutinib in combination with nivolumab (programmed cell death protein 1, PD-1, inhibitor) or everolimus (mammalian target of rapamycin, mTOR, inhibitor) for metastatic renal cell carcinoma (RCC), there are no reports of RCC (metastatic or non-metastatic) showing response to a BTK inhibitor in humans. Here we report a 22-month clinical response of biopsy-proven RCC to ibrutinib. This is unexpected, given that BTK is not wellimplicated in RCC pathophysiology. We explore a possible mechanism for the response of RCC to ibrutinib through inhibition of interleukin-2-inducible T-cell kinase (ITK) leading to enhanced antitumour immune responses.