Combination Of Ibrutinib Research Articles

O-002 - Ibrutinib in combination with nab-paclitaxel and gemcitabine as first-line treatment for patients with metastatic pancreatic adenocarcinoma: results from the phase 3 RESOLVE study

O-002 - Ibrutinib in combination with nab-paclitaxel and gemcitabine as first-line treatment for patients with metastatic pancreatic adenocarcinoma: results from the phase 3 RESOLVE study

Abstract CT169: Pilot study testing the effects of BTK inhibitor ibrutinib and nivolumab on levels and function of myeloid-derived suppressor cells and other immune subsets in patients with metastatic solid tumors (NCT03525925)

Abstract Background: Myeloid-derived suppressor cells (MDSC) are a naturally occurring population of immature myeloid cells with immune suppressive function that curtail inflammatory processes. In cancer, these cells abnormally expand and migrate to tumor/lymphoid regions where they negatively impact antigen specific and innate immune effector cells. Circulating MDSC levels have also been associated with the higher tumor burden and decreased survival of patients with solid tumors. Preclinical studies performed by our group demonstrated that ibrutinib (PCI-32765), an irreversible inhibitor of Bruton’s tyrosine kinase, is capable of inhibiting MDSC generation and their immunosuppressive function (A. Stiff, CA Res, 2016). We also found that the combination of ibrutinib and a PD-L1 inhibitor worked synergistically in a mouse model of mammary carcinoma. Based on these results, targeting MDSC with ibrutinib has the potential to enhance the efficacy of immune checkpoint inhibitors such as nivolumab in patients with advanced solid tumors. Materials and Methods: This pilot study will assess the effect of single agent ibrutinib and ibrutinib in combination with nivolumab on levels and function of circulating myeloid-derived suppressor cells in 15 patients with advanced solid tumors. Eligible patients are required to have metastatic malignancy and be eligible for treatment with nivolumab as determined by the treating physician. Study subjects will be treated with ibrutinib at 420 mg given orally once daily. Nivolumab will be given at a standard dose of 240 mg IV over 30 minutes on days 1 and 15 on 28-day cycles. Ibrutinib dosing will be started 7 (+/-2) days prior to cycle 1 of nivolumab therapy and will be given until cycle 1, day 8 of nivolumab or total of 15 days (whichever comes first). Peripheral blood will be collected just prior to initiation of ibrutinib (at day -7), prior to day 1 of cycle 1, prior to day 8 of cycle 1, prior to day 1 of cycle 2 and at the time of disease progression. The primary objective is to evaluate the effect of the ibrutinib therapy on circulating levels of myeloid-derived suppressor cells (MDSC). The safety of the study combination, effect of ibrutinib/nivolumab on immune cell subsets and the length of progression-free survival will also be assessed. Conclusion: The study opened to accrual on August 10, 2018 and is currently enrolling the target 15 patients. To date 9 patients are on study. Citation Format: Brooke Benner, Megan Duggan, Andrew Stiff, Bhavana Konda, Robert D. Rupert, Paul Monk, Claire Verschraegen, Hiral Shah, Anne Noonan, William E. Carson, Robert Wesolowski. Pilot study testing the effects of BTK inhibitor ibrutinib and nivolumab on levels and function of myeloid-derived suppressor cells and other immune subsets in patients with metastatic solid tumors (NCT03525925) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT169.

Targeting CD38 Enhances the Antileukemic Activity of Ibrutinib in Chronic Lymphocytic Leukemia.

CD38 has emerged as a high-impact therapeutic target in multiple myeloma, with the approval of daratumumab (anti-CD38 mAb). The clinical importance of CD38 in patients with chronic lymphocytic leukemia (CLL) has been known for over 2 decades, although it's relevance as a therapeutic target in CLL remains understudied. We investigated the biological effects and antitumor mechanisms engaged by daratumumab in primary CLL cells. Besides its known immune-effector mechanisms (antibody-dependent cell-mediated cytotoxicity, complement-dependent death, and antibody-dependent cellular phagocytosis), we also measured direct apoptotic effects of daratumumab alone or in combination with ibrutinib. In vivo antileukemic activity was assessed in a partially humanized xenograft model. The influence of CD38 on B-cell receptor (BCR) signaling was measured via immunoblotting of Lyn, Syk, BTK, PLCγ2, ERK1/2, and AKT. In addition to immune-effector mechanisms; daratumumab also induced direct apoptosis of primary CLL cells, which was partially dependent on FcγR cross-linking. For the first time, we demonstrated the influence of CD38 on BCR signaling where interference of CD38 downregulated Syk, BTK, PLCγ2, ERK1/2, and AKT; effects that were further enhanced by addition of ibrutinib. In comparison to single-agent treatment, the combination of ibrutinib and daratumumab resulted in significantly enhanced anti-CLL activity in vitro and significantly decreased tumor growth and prolonged survival in the in vivo CLL xenograft model. Overall, our data demonstrate the antitumor mechanisms of daratumumab in CLL; furthermore, we show how cotargeting BTK and CD38 lead to a robust anti-CLL effect, which has clinical implications.

Abstract CT133: Interim results of a Phase I/II trial of intratumoral CpG, local low-dose radiation, and oral ibrutinib in patients with low-grade B-cell lymphoma

Abstract In situ vaccination for the treatment of cancer aims to trigger an immune response locally that propagates systemically. We recently showed that local treatment with intratumoral CpG and low-dose radiation can elicit antitumor immune responses and global tumor shrinkage in patients with low-grade lymphoma (Frank, Cancer Discov, 2018). Ibrutinib is a small molecule that compromises B cell survival by inhibiting Bruton’s tyrosine kinase (BTK) but also modulates T cell phenotypes by inhibiting interleukin-2-inducible T-cell kinase (ITK). In a mouse model of lymphoma, systemic ibrutinib plus intratumoral CpG was curative of systemic disease in all treated mice, an effect that was fully T-cell dependent (Sagiv-Barfi, Blood, 2015). Thus, we initiated a Phase I/II clinical trial combining oral ibrutinib (560mg), intratumoral CpG (SD-101) and local low-dose radiation in patients with recurrent low-grade lymphoma (NCT02927964). As of January 2nd, 2019, we have completed a pre-specified initial safety assessment phase and met criteria (no DLTs) to proceed to the Phase II portion. In total, 13 patients (12 FL, 1 MZL) have been enrolled thus far. All are evaluated for safety, and 12 are currently evaluable for efficacy. CT scans are performed at 3, 6, 12, 18, and 24 months. Common Terminology Criteria for Adverse Events (CTCAE) are used to track treatment-emergent safety events, and Lugano criteria (Cheson, J Clin Oncol, 2014) are used to assess response to therapy. Fine needle aspirates are obtained from CpG-injected and non-injected sites pre- and post-treatment, and analyzed by flow cytometry. When available, viably preserved tumor and peripheral blood cells are used for in vitro immune response assays. Among 13 patients treated thus far, adverse event (AE) profiles have been similar to those seen with each therapy. No novel or synergistic AEs have been observed, and no grade 4 or 5 events have occurred. AEs have led to ibrutinib dose reduction or discontinuation in 3 patients. With a median follow-up of 7.7 months, 6 of 12 patients have obtained a partial response overall (50% ORR), and 8 of 12 have seen at least a 30% reduction in distal tumor burden, with 3 patients experiencing greater than 50% reduction in distal tumor burden. Injection of CpG decreased T follicular helper cells and increased CD4 and/or CD8 effector T cells and CD137+ activated T cells in the injected lymph node. Abscopal immune effects in distant non-injected lesions were also observed, most notably an increase in Granzyme B+ cytotoxic T cells. Treatment also induced tumor-specific immune responses in peripheral blood T cells of all 6 evaluable patients in an in vitro immune response assay. Thus, early data suggest that the combination of oral ibrutinib, intratumoral CpG, and local low-dose radiation is likely safe and effective in generating systemic antitumor immune responses and systemic tumor shrinkage. Citation Format: Tanaya Shree, Michael S. Khodadoust, Debra Czerwinski, Matthew J. Frank, Wan X. Hong, Rachel Greenstein, Summer Guo, Steven Long, Brock A. Martin, Ronald Levy. Interim results of a Phase I/II trial of intratumoral CpG, local low-dose radiation, and oral ibrutinib in patients with low-grade B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT133.

A Phase 1b/2 Study of the Bruton Tyrosine Kinase Inhibitor Ibrutinib and the PD-L1 Inhibitor Durvalumab in Patients with Pretreated Solid Tumors

Background: Ibrutinib, a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase, is approved in the United States for the treatment of various B-cell malignancies. Preclinical data suggest synergistic antitumor activity of ibrutinib with programmed death-ligand 1 (PD-L1) inhibitors in solid tumors. This study evaluated ibrutinib plus durvalumab, a PD-L1-targeting antibody, in patients with relapsed/refractory solid tumors. Methods: This open-label, multicenter, phase 1b/2 study enrolled previously treated patients with stage III/IV pancreatic adenocarcinoma, breast cancer, or non-small cell lung cancer (NSCLC). Phase 1b determined the recommended phase 2 dose (RP2D). In phase 2, patients were treated at the RP2D to evaluate the safety and antitumor activity of ibrutinib plus durvalumab. Results: The RP2D was identified as ibrutinib 560 mg p.o. daily and durvalumab 10 mg/kg i.v. every 2 weeks, with 122 patients treated at the RP2D. Median age was 61 years, and the majority of patients (94%) had stage IV disease. Overall response rates (complete or partial responses) were 2% for pancreatic cancer, 3% for breast cancer, and 0% for NSCLC. Median progression-free survival was 1.7, 1.7, and 2.0 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. Median overall survival was 4.2, 4.2, and 7.9 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. The safety profiles observed across tumor types were consistent with the known safety profiles for ibrutinib and durvalumab. Grade ≥3 adverse events in ≥5% of all patients were hyponatremia (10%), dyspnea (7%), maculopapular rash (7%), pneumonia (7%), anemia (6%), and diarrhea (6%). Conclusions: The combination of ibrutinib 560 mg daily and durvalumab 10 mg/kg every 2 weeks had an acceptable safety profile. The antitumor activity of the ibrutinib-durvalumab combination was limited in our study population.

Rituximab and ibrutinib in the treatment of Waldenström's macroglobulinemia.

The Bruton's tyrosine kinase inhibitor ibrutinib represents a highly effective single substance in the treatment of Waldenström's macroglobulinemia. Ibrutinib monotherapy is a valid therapeutic option either in the relapsed or refractory setting or in patients first line, particulary when they are ineligible for chemotherapy. However, the treatment success depends on the genotype. Recent data suggest that ibrutinib in combination with rituximab may partially overcome this genotype dependency.

How to approach CLL in clinical practice.

How to approach CLL in clinical practice.

PS1158 IBRUTINIB PLUS RITUXIMUB IN STEROID REFRACTORY AUTOIMMUNE HEMOLYTIC ANEMIA: ELABORATION OF TREATMENT APPROACH (ISRAEL): AN INTERIM ANALYSIS OF THE ROHS TRIAL

Background:Autoimmune hemolytic anemia (AIHA) and pure red cell aplasia (PRCA) are well recognized autoimmune complications (AIC) of chronic lymphocytic leukemia (CLL). Both AIHA and PRCA complicate patient management, have significant impact on quality of life and can be fatal. Ibrutinib is an irreversible inhibitor of BTK and ITK (interleukin‐2 inducible tyrosine kinase), mediating antibody dependent cellular cytotoxicity, which makes it attractive in treatment of AIC in the context of CLL. We present a pre‐planned interim analysis of a multicentre trial evaluating efficacy of ibrutinib in AIC.Aims:The primary objective of this study is to evaluate efficacy (response rate and its duration) of ibrutinib in combination with rituximab for steroid refractory AIHA and PRCA in patients with CLL.Methods:ISRAEL is an open‐label, multicentre, single arm, two staged study of combination of ibrutinib and rituximab in patients with AIHA/PRCA and underlying CLL. In stage I (induction) patients received ibrutinib 420 mg/day and rituximab (9 weekly with subsequent 3 monthly infusions); in stage II (maintenance) – ibrutinib was only given until relapse, progression or unacceptable toxicity. Inclusion criteria included proven diagnosis of CLL per iwCLL guidelines, the presence of clinically significant hemolysis with positive direct antiglobulin test (DAT) in case of AIHA, the presence of erythroblastopenia, confirmed by immunohistochemical staining with Glycophorin A and platelet level >100.000/mkl in case of PRCA, relapse of AIHA/PRCA after steroids, splenectomy or rituximab or refractoriness to glucocorticosteroid hormones.Results:Thirty three patients with CLL and AIC have been enrolled since February, 2017. The median age was 66 years (range 50 ‐ 82), 14 (42%) were female. 30 patients had AIHA and 3 PRCA. The median hemoglobin level at day of 1st infusion was 8,2 g/dL (range 6,5 – 11,3). Twenty two patients (66%) were transfusion‐dependent. Five patients (15%) had deletion 17p and 8 (24%) deletion 11q. Patients had received a median of 2 (range 1 – 6) lines of prior treatment for AIC, including steroids (n = 31), rituximab (n = 6), splenectomy (n = 3), RCD/R‐CVP (n = 13), alemtuzumab (n = 1), BR (n = 7) and other (n = 8). At time of reporting, 22 patients have completed induction. The median duration of ibrutinib treatment was 281 days (range 22 – 673). Adverse events were reported from 31 participants (94%). Of the 351 AEs, 321 (91,5%) were graded as CTCAE grade 1 – 2 and 30 (8,5%) as grade >3. The latter were represented by infections (n = 7), neutropenia (n = 7), arrhythmias (n = 4), arterial hypertension (n = 7), myalgias (n = 3). Two cases of sudden death were reported. Response of AIHA was evident in all patients. By day 141 4 (21%) patients achieved a DAT‐ve CR, 10 (53%) DAT+ve CR, 1 – DAT‐ve PR and 4 (21%) DAT+ve PR. All PR patients achieved transfusion independence. Two patients with PRCA achieved a CR by days 84 and 150, and 1 patient did not respond. Response of CLL, assessed at day 225 by IWCLL 2008 criteria was available in 19 patients. Seven patients (37%) achieved a CR, including one MRD‐negative case. Twelve patients (63%) were classified as PRs because of residual bone marrow infiltration (n = 12) along with persistent splenomegaly (n = 3) or persistent neutropenia (n = 2). No patients have relapsed so far.Summary/Conclusion:The combination of ibrutinib and rituximab demonstrated high activity in the treatment of patients with relapsed and steroid refractory AIHA with underlying CLL. The safety profile of IR combination corresponded to published data.

PS1162 COMBINATION THERAPY TO PREVENT IBRUTINIB WITHDRAWAL: CONTINUED IBRUTINIB WITH THE ADDITION OF VENETOCLAX AT TIME OF PROGRESSION IN IBRUTINIB‐TREATED PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

Background:We have previously reported that ∼50% of CLL patients (pts) experience rapid flare of disease when they discontinue ibrutinib therapy due to progression of disease (CLL or Richter's transformation [RT]) (Hampel et al, JCO suppl, 2018). This lead to the clinical practice of overlapping venetoclax with ibrutinib for combination therapy in this setting to prevent ibrutinib withdrawal.Aims:To evaluate the role of continuing ibrutinib beyond the start of salvage venetoclax in pts who have progression of disease on ibrutinib monotherapy, both in preventing ibrutinib withdrawal associated with ibrutinib discontinuation and in disease response.Methods:We identified all CLL pts at Mayo Clinic (3/2017–11/2018) who had disease progression on ibrutinib therapy, where venetoclax was added as subsequent treatment while ibrutinib was continued. CLL‐specific characteristics, treatment timeline and toxicities, and disease course following combination therapy were ascertained. All pts started venetoclax according to the weekly ramp‐up per the package instructions.Results:Eighteen pts treated with the addition of venetoclax to ibrutinib therapy were identified; indications were CLL progression (n = 13) and RT (n = 5). BTK or PLCG2 mutations were present in 8/13 pts. Median duration of follow‐up was 9.6 months after the start of combination therapy.The target venetoclax dose was reached by 5 weeks in 13 pts; reasons for delaying or stopping dose escalation included diarrhea (n = 2), sepsis (n = 2), and neutropenia (n = 1). No patient experienced a disease flare during venetoclax ramp‐up.The median duration of combination ibrutinib and venetoclax therapy was 3 months (range, 0–14 months). Of 18 pts who started combination therapy with ibrutinib and venetoclax, ibrutinib was discontinued in 10 pts. Reasons included hematopoietic stem cell transplant (n = 2), planned stop after adequate disease control (n = 4), financial reasons (n = 1), toxicity (neutropenia n = 1, immune thrombocytopenia/bleeding risk n = 1), and death (n = 1). Only 1 patient experienced ibrutinib withdrawal, which occurred following planned discontinuation after clinical complete response (CR) with a 41 day overlap and toleration of venetoclax 400 mg daily; management with re‐initiation of ibrutinib was effective in regaining disease control. Of 9 pts who stopped ibrutinib, 4 pts had a slow taper over 2–8 weeks, and 2 pts also received corticosteroids at the time of ibrutinib discontinuation.Among the other 8 pts who did not discontinue ibrutinib, 6 pts remain on the combination with venetoclax (median duration 6.5 months, range 3–14 months), and 2 pts continued on ibrutinib following venetoclax discontinuation due to disease progression (both pts received further combination of ibrutinib with multi‐agent chemotherapy).The overall response rate (ORR) to combination therapy with ibrutinib and venetoclax was 81% (CR/clinical CR n = 9, partial response n = 4, stable disease n = 1, and primary refractory disease n = 2). The duration of combination therapy was <4 weeks in 2 pts, precluding response assessment. The estimated 12‐month event‐free survival was 54% (95% CI 33–87%), and the estimated 12‐month overall survival from start of combination therapy was 79% (95% CI 60–100%); see Figure 1.Summary/Conclusion:Among CLL pts who develop progression of disease on ibrutinib monotherapy, continued ibrutinib therapy with addition of venetoclax was feasible, ameliorated ibrutinib withdrawal, and was associated with high ORR.image

PF374 IBRUTINIB PLUS FLUDARABINE, CYCLOPHOSPHAMIDE, AND RITUXIMAB (IFCR) AS INITIAL THERAPY FOR YOUNGER PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA: A SINGLE‐ARM, MULTICENTER, PHASE 2 TRIAL

Background:Fludarabine, cyclophosphamide, rituximab (FCR) can provide prolonged disease free survival for young, fit chronic lymphocytic leukemia (CLL) patients with mutated IGHV; however, patients with unmutated IGHV rarely have durable response. The oral Bruton Tyrosine Kinase inhibitor, ibrutinib, is highly effective for patients irrespective of IGHV mutation status, but requires continuous therapy. We hypothesized that a time‐limited regimen of ibrutinib plus FCR (iFCR) would have curative potential for a broad population of young, fit CLL patients.Aims:The primary objective was to determine the rate of complete remission (CR) with undetectable bone marrow minimal residual disease (BM‐uMRD) two months after completing iFCR combination therapy. Secondary objectives were to assess clinical response rates, progression‐free and overall survival, rates of best response and BM‐uMRD, safety/tolerability, ibrutinib pharmacokinetics (PK), and association of established CLL prognostic factors with clinical response.Methods:We performed a multicenter, open‐label, non‐randomized, phase 2 investigator sponsored trial of iFCR, and enrolled CLL patients age ≤65 years without restriction by IGHV mutation status, all of whom met iwCLL criteria for initial treatment. Ibrutinib 420 mg daily was given for 7 days, followed by combination ibrutinib with FCR for up to 6 cycles. Responders continued on ibrutinib maintenance, and patients with BM‐uMRD after 2 years of maintenance discontinued therapy. Response was assessed by 2008 iwCLL criteria, and toxicity was assessed by CTCAE v4.03 and iwCLL criteria. This trial is registered with ClinicalTrials.gov (NCT02251548).Results:Between October, 2014, and April, 2018, 85 patients were enrolled at 9 US sites. The median age was 55 years (range 38–65). IGHV was unmutated in 46/79 patients (58.2%). Deletion of 17p and TP53 mutation were present in 4/83 (4.8%) and 3/81 (3.7%) patients, respectively; 2 of these patients had both. The median number of FCR cycles completed was 6 (range 1–6). The median AUC of ibrutinib in combination with FCR was 337.2 (IQR 198.6–553.9), and the median Cmax was 97.3 (IQR 65.1–168.8). These PK parameters are similar to ibrutinib monotherapy in prior studies, and did not appear to be altered by FCR. The rate of CR‐BM‐uMRD 2 months post‐FCR was 33% (28/85 patients, 95% CI: 0.25–1.0)), with a best rate at any point on trial that increased to 41% (35/85), and a best rate of CR/CRi irrespective of MRD status of 66%. The best rate of BM‐uMRD irrespective of IW‐CLL response status was 84% (71/85), and did not differ by IGHV mutation status (Figure 1). With a median follow‐up of 16.5 months (range 3.1–48.9), one patient progressed and one died due to a presumed cardiac event. The most common treatment‐emergent grade 3/4 adverse events were hematologic, including neutropenia 35%, thrombocytopenia 32%, and anemia 11%. Eight patients (9%) experienced grade ≥3 febrile neutropenia. No cases of Richter's Syndrome have been observed.Summary/Conclusion:The rate of BM‐uMRD induced by iFCR is, to our knowledge, the highest ever reported for a regimen treating a population of CLL patients unrestricted by prognostic marker status. The safety profile of iFCR was generally favorable, with typical toxicities of ibrutinib and FCR observed, and no additional toxicities discernable with the combination. These data establish iFCR as a highly effective novel‐agent‐containing time‐limited combination for initial therapy for young, fit CLL patients.image

Ibrutinib and Venetoclax for First-Line Treatment of CLL

BackgroundIbrutinib, an inhibitor of Bruton’s tyrosine kinase, and venetoclax, an inhibitor of B-cell lymphoma 2 protein, have been approved for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations have indicated potential synergistic interaction of their combination.MethodsWe conducted an investigator-initiated phase 2 study of combined ibrutinib and venetoclax involving previously untreated high-risk and older patients with CLL. All patients had at least one of the following features: chromosome 17p deletion, mutated TP53, chromosome 11q deletion, unmutated IGHV, or an age of 65 years or older. Patients received ibrutinib monotherapy (420 mg once daily) for 3 cycles, followed by the addition of venetoclax (weekly dose escalation to 400 mg once daily). Combined therapy was administered for 24 cycles. Response assessments were performed according to International Workshop on Chronic Lymphocytic Leukemia 2008 criteria. Minimal residual disease was assessed by means of multicolor flow cytometry in bone marrow (sensitivity, 10−4).ResultsA total of 80 patients were treated. The median age was 65 years (range, 26 to 83). A total of 30% of the patients were 70 years of age or older. Overall, 92% of the patients had unmutated IGHV, TP53 aberration, or chromosome 11q deletion. With combined treatment, the proportions of patients who had complete remission (with or without normal blood count recovery) and remission with undetectable minimal residual disease increased over time. After 12 cycles of combined treatment, 88% of the patients had complete remission or complete remission with incomplete count recovery, and 61% had remission with undetectable minimal residual disease. Responses were noted in older adults and across all high-risk subgroups. Three patients had laboratory evidence of tumor lysis syndrome. The adverse-event profile was similar to what has been reported with ibrutinib and venetoclax.ConclusionsIn this study, combined venetoclax and ibrutinib was an effective oral regimen for high-risk and older patients with CLL. (Funded by AbbVie and others; ClinicalTrials.gov number, NCT02756897.)

The efficacy of ibrutinib-based combination therapy for mantle cell lymphoma: A systematic review.

e19043 Background: Mantle Cell Lymphoma (MCL) is generally treated with rituximab (R) in combination with other drugs. However, treatment for relapsed or refractory (RR) MCL is challenging. For Ibrutinib (Ibr), we aim to determine the efficacy in combination therapy for newly diagnosed (ND) and RR MCL. Methods: Per PRISMA guidelines, a systematic review was performed using four databases. Results: Eleven studies with 363 patients were identified, most commonly studied regimens were ibrutinib in combination with R in 2 phase II studies and 2 studies on Ibr in combination with venetoclax. Ibr was also studied as part of the three-drug regimens in combination with bendamustine & R, lenalidomide & R, and obinutuzumab & venetoclax. Ibr was studied in combination with other drugs such as palbociclib, ublituximab, and bortezomib as part of the two-drug regimens. Results summarized in Table. Adverse events included cytopenia, atrial fibrillation, septic shock, tumor lysis syndrome, and GI toxicities. Conclusions: Ibr in combination with R demonstrated the highest overall ORR and CR in treatment of ND MCL, whereas combination with venetoclax and obinutuzumab demonstrated highest overall ORR and CR in treatment of RR MCL. Additional studies are needed to further assess and confirm its role in treatment. [Table: see text]

Clinical Experience With Ibrutinib Alone or in Combination With Either Cytarabine or Azacitidine in Patients With Acute Myeloid Leukemia

BackgroundPreclinical studies have suggested a role for Bruton tyrosine kinase (BTK) as a potential therapeutic target in acute myeloid leukemia (AML), and anti-AML activity in vivo has been demonstrated with BTK inhibitors. Patients and MethodsIn this open-label phase 2a study, patients with AML were treated with ibrutinib 560 mg per day alone (cohort 1; n = 7), or ibrutinib in combination with either cytarabine 20 mg administered subcutaneously twice daily for 10 days of a 28-day cycle (cohort 2; n = 21) or azacitidine 75 mg/m2 administered intravenously once daily on days 1 to 7 of a 28-day cycle (cohort 3; n = 8). Best overall response (primary end point), overall survival, and safety were summarized. ResultsA total of 36 patients were enrolled and received treatment; median duration of ibrutinib treatment was 5.4 weeks, and median time on study was 16 months. Of 24 patients evaluable for response, 1 partial remission (cohort 3) and 1 complete remission (cohort 2) were observed; the remaining responses were treatment failures. Median overall survival was 4.0 months in cohort 1, 2.2 months in cohort 2, 2.8 months in cohort 3, and 2.4 months for the overall population. No unexpected safety signals were identified. Grade 3 or higher adverse events that occurred in ≥ 10% of patients included AML progression, febrile neutropenia, pneumonia, anemia, thrombocytopenia, fatigue, asthenia, and respiratory failure. ConclusionIbrutinib alone or in combination with cytarabine or azacitidine demonstrated an acceptable safety profile. However, limited efficacy with ibrutinib was observed in patients with AML.

Combination of Enzastaurin and Ibrutinib synergistically induces anti-tumor effects in diffuse large B cell lymphoma

BackgroundDiffuse large B cell lymphoma (DLBCL) is the most common form of lymphoma. Although durable remissions can be achieved in more than half of these patients, DLBCL remains a significant clinical challenge, with approximately 30% of patients not being cured. BCR-associated kinases (SYK, BTK, and PI3K) inhibitors have exhibited encouraging pre-clinical and clinical effects, as reported by many researchers. Early studies demonstrated that protein kinase C-β (PKCβ) inhibitors alter phosphorylation level the Bruton’s tyrosine kinase (BTK), which leads to enhanced BTK signaling. Here, for the first time, we investigate whether the combination of PKCβ inhibitor enzastaurin and BTK inhibitor ibrutinib has synergistic anti-tumor effects in DLBCL.MethodsIn vitro cell proliferation was analyzed using Cell Titer-Glo Luminescent Cell Viability Assay. Induction of apoptosis and cell cycle arrest were measured by flow cytometry. Western Blotting analysis was used to detect the essential regulatory enzymes in related signaling pathways. RNA-seq was conducted to evaluate the whole transcriptome changes brought by co-treatment with low doses of enzastaurin and ibrutinib. The synergistic anti-tumor effects of enzastaurin and ibrutinib were also evaluated in vivo.ResultsCombination of enzastaurin and ibrutinib produced a lasting synergistic effect on the survival and proliferation of DLBCL cells, including reduction of proliferation, promoting apoptosis, inducting G1 phase arrest, preventing cell invasion and migration, and down-regulating activation of downstream signaling. More importantly, whole-transcriptome changes results showed that combination therapy worked synergistically to regulate whole-transcriptome expression compared with enzastaurin and ibrutinib alone. Co-treatment with low doses of enzastaurin and ibrutinib could effectively downregulate BCR, NF-κB, JAK and MAPK related signaling pathway. Furthermore, the mRNA expression analysis further indicated that co-treatment significantly decreased the mRNA levels of NOTCH1. The combination effect in inhibiting proliferation of DLBCL cells probably was realized through suppression of NOTCH1 expression. Finally, the anti-tumor activity of co-treatment also was demonstrated in vivo.ConclusionsCombination of enzastaurin and ibrutinib had synergistic anti-tumor effects in DLBCL, independent of molecular subtype. These results provided a sound foundation for an attractive therapeutic treatment, and the simultaneous suppression of BTK and PKCβ might be a new treatment strategy for DLBCL.

Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma

AbstractIbrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK) and has shown single-agent activity in recurrent/refractory central nervous system (CNS) lymphoma. Clinical responses are often transient or incomplete, suggesting a need for a combination therapy approach. We conducted a phase 1b clinical trial to explore the sequential combination of ibrutinib (560 or 840 mg daily dosing) with high-dose methotrexate (HD-MTX) and rituximab in patients with CNS lymphoma (CNSL). HD-MTX was given at 3.5 g/m2 every 2 weeks for a total of 8 doses (4 cycles; 1 cycle = 28 days). Ibrutinib was held on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after HD-MTX clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. We also explored next-generation sequencing of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) before and during treatment. The combination of ibrutinib, HD-MTX, and rituximab was tolerated with an acceptable safety profile (no grade 5 events, 3 grade 4 events). No dose-limiting toxicity was observed. Eleven of 15 patients proceeded to maintenance ibrutinib after completing 4 cycles of the ibrutinib/HD-MTX/rituximab combination. Clinical responses occurred in 12 of 15 patients (80%). Sustained tumor responses were associated with clearance of ctDNA from the CSF. This trial was registered at www.clinicaltrials.gov as #NCT02315326.

Efficacy and Toxicity of CD19-Specific Chimeric Antigen Receptor T Cells Alone or in Combination with Ibrutinib for Relapsed and/or Refractory CLL

Background In relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) patients (pts) who had previously failed ibrutinib, we observed durable responses after CD19 chimeric antigen receptor-modified T-cell immunotherapy (Turtle CJ et al, JCO, 2017; NCT01865617). The combination of CD19 CAR-T cells with ibrutinib might improve response and decrease toxicity. Objectives To evaluate the efficacy and toxicity of CD19 CAR-T cell immunotherapy alone or in combination with ibrutinib for R/R CLL. Methods Our phase 1/2 study of CD19 CAR-T cell immunotherapy established a preferred regimen for R/R CLL pts of cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion followed by 2 × 106 CD19 CAR-T cells/kg (Turtle, JCO, 2017). We then compared outcomes of these pts (No-ibr cohort) with a subsequent cohort receiving Cy/Flu with 2 × 106/kg JCAR014 CAR-T cells with concurrent ibrutinib (420 mg/d) from at least 2 weeks prior to leukapheresis until at least 3 months after JCAR014 infusion (Ibr cohort). Results We treated 19 and 17 pts in the No-Ibr and Ibr cohorts, respectively. Pt characteristics were comparable (Table 1). Median follow-up in responders was 764 and 98 days in the No-ibr and Ibr cohorts, respectively. Administration of ibrutinib with Cy/Flu and CD19 CAR-T cells was well tolerated in most pts; ibrutinib was reduced or discontinued in 6 pts (35%) at a median of 21 days after JCAR014 infusion. In the Ibr cohort 1 pt with grade 2 CRS (Lee, Blood, 2014) developed fatal presumed cardiac arrhythmia and 1 pt developed a subdural hematoma in the setting of trauma and thrombocytopenia. Although the proportions of pts with grade ≥1 CRS were similar between cohorts (76% vs 89%, P = 0.39), the severity of CRS (grade ≥3 CRS: Ibr, 0%; No-Ibr, 26%; P = 0.05) and serum peak IL-8 (P = 0.04), IL-15 (P = 0.003) and MCP-1 (P = 0.004) concentrations were lower in the Ibr cohort. However, we found higher peak CD4+ CAR-T cell counts (P = 0.06) and comparable peak CD8+ CAR-T cell counts (P = 0.29) in blood in the Ibr compared to the No-Ibr cohort. Sixteen pts (94%) and 18 pts (95%) in the Ibr and No-ibr cohorts, respectively, were evaluable for response. We observed a higher proportion of responders (complete response and partial response) by 2008 IWCLL criteria in the Ibr compared to the No-ibr cohort (88% vs 56%, respectively, P = 0.06). In pts with no disease by BM flow cytometry after treatment (N = 23), a higher proportion of pts in the Ibr cohort had no malignant IgH sequences at 4 weeks (83% vs 60%, P = 0.35). Using multivariable logistic regression (Table 2), treatment in the Ibr cohort and a lower pre-treatment SUVmax were associated with a higher probability of response (Ibr cohort, OR = 14.02, P = 0.05; SUVmax, OR = 1.31 per SUV unit decrease, P Conclusion The combination of ibrutinib with CD19 CAR-T cell immunotherapy was well tolerated in most pts, and might decrease the incidence of severe CRS and improve responses in pts with R/R CLL.

Tolerability and activity of ublituximab, umbralisib, and ibrutinib in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: a phase 1 dose escalation and expansion trial

Therapeutic approaches for B-cell malignancies continue to evolve, especially with regard to combination approaches. We assessed the safety and efficacy of the triplet ublituximab, umbralisib, and ibrutinib in patients with advanced B-cell malignancies. We did an open-label, phase 1 study with dose-escalation and dose-expansion phases, at five centres in the USA. Eligible patients were aged 18 years or older with histologically confirmed lymphocytic leukaemia or relapsed or refractory B-cell non-Hodgkin lymphoma, had measurable disease, adequate organ function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. Patients with known CNS lymphoma, active hepatitis B or C infection, or HIV were excluded. In the dose-escalation cohort, patients were treated in cycles of 28 days with escalating doses of oral umbralisib (400, 600, or 800 mg) and fixed doses of intravenous ublituximab (900 mg) and oral ibrutinib (420 mg for patients with chronic lymphocytic leukaemia; 560 mg for patients with B-cell non-Hodgkin lymphoma) in a standard 3 × 3 design until disease progression or intolerance. In the dose-expansion phase, patients were given the recommended dose of the drug combination as determined from the dose-escalation phase. The primary endpoints were safety, dose-limiting toxicities, and the maximum tolerated dose of umbralisib, when given in combination with ublituximab and ibrutinib. Safety was assessed in patients who received at least one dose of study drug; activity was assessed in all patients who had at least one post-treatment efficacy measurement. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT02006485. Between Sept 2, 2014, and Nov 6, 2017, we enrolled 46 patients: 24 in the dose-escalation cohort (n=14 chronic lymphocytic leukaemia or small lymphocytic lymphoma; n=10 B-cell non-Hodgkin lymphoma) and 22 in the dose-expansion cohort (n=9 chronic lymphocytic leukaemia or small lymphocytic lymphoma; n=13 B-cell non-Hodgkin lymphoma). 46 patients received at least one dose of study drug. The maximum tolerated dose of umbralisib was not reached. The recommended dose for the dose-expansion phase was umbralisib 800 mg orally once daily plus ibrutinib orally once daily and intravenous ublituximab 900 mg administered on days 1, 8, and 15 of cycle 1, day 1 of cycles 2-6, and on day 1 of cycles 9 and 12. 37 (84%) of 44 patients achieved an overall response (complete or partial response). The most common any-grade adverse events were diarrhoea (n=27 [59%]), fatigue (n=23 [50%]), infusion-related reaction (n=20 [43%]), dizziness (n=17 [37%]), nausea (n=17 [37%]), and cough (n=16 [35%]). Grade 3-4 adverse events were manageable with the most common being neutropenia (n=10 [22%]) and cellulitis (n=6 [13%]). Serious adverse events occurred in 11 (24%) of 46 patients and included rash (n=2 [4%]), pneumonia (n=2 [4%]), atrial fibrillation (n=2 [4%]), sepsis (n=2 [4%]), abdominal pain (n=1 [2%]), syncope (n=1 [2%]), cellulitis (n=1 [2%]), pneumonitis (n=1 [2%]), headache (n=1 [2%]), lung infection (n=1 [2%]), skin infection (n=1 [2%]), pleural effusion (n=1 [2%]), pericardial infusion (n=1 [2%]), upper gastrointestinal bleeding (n=1 [2%]), diarrhoea (n=1 [2%]), and weakness (n=1 [2%]). No deaths related to adverse events occurred. The combination of ublituximab, umbralisib, and ibrutinib seems to be tolerable and is associated with encouraging activity in advanced chronic lymphocytic leukaemia and B-cell non-Hodgkin lymphoma. This triplet combination will require further investigation in future studies to improve understanding of this novel, chemotherapy-free triplet combination in the management of these cancers. TG Therapeutics.

Combined chemosensitivity and chromatin profiling prioritizes drug combinations in CLL.

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib has substantially improved therapeutic options for chronic lymphocytic leukemia (CLL). Although ibrutinib is not curative, it has a profound effect on CLL cells and may create new pharmacologically exploitable vulnerabilities. To identify such vulnerabilities, we developed a systematic approach that combines epigenome profiling (charting the gene-regulatory basis of cell state) with single-cell chemosensitivity profiling (quantifying cell-type-specific drug response) and bioinformatic data integration. By applying our method to a cohort of matched patient samples collected before and during ibrutinib therapy, we identified characteristic ibrutinib-induced changes that provide a starting point for the rational design of ibrutinib combination therapies. Specifically, we observed and validated preferential sensitivity to proteasome, PLK1, and mTOR inhibitors during ibrutinib treatment. More generally, our study establishes a broadly applicable method for investigating treatment-specific vulnerabilities by integrating the complementary perspectives of epigenetic cell states and phenotypic drug responses in primary patient samples.

TLR Signaling Is Activated in Lymph Node-Resident CLL Cells and Is Only Partially Inhibited by Ibrutinib.

Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells driven by B-cell receptor (BCR) signaling and activated primarily in the lymph node. The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib effectively inhibits BCR-dependent proliferation and survival signals and has emerged as a breakthrough therapy for CLL. However, complete remissions are uncommon and are achieved only after years of continuous therapy. We hypothesized that other signaling pathways that sustain CLL cell survival are only partially inhibited by ibrutinib. In normal B cells, Toll-like receptor (TLR) signaling cooperates with BCR signaling to activate prosurvival NF-κB. Here, we show that an experimentally validated gene signature of TLR activation is overexpressed in lymph node-resident CLL cells compared with cells in the blood. Consistent with TLR activation, we detected phosphorylation of NF-κB, STAT1, and STAT3 in lymph node-resident CLL cells and in cells stimulated with CpG oligonucleotides in vitro. CpG promoted IRAK1 degradation, secretion of IL10, and extended survival of CLL cells in culture. CpG-induced TLR signaling was significantly inhibited by both an IRAK1/4 inhibitor and ibrutinib. Although inhibition of TLR signaling was incomplete with either drug, the combination achieved superior results, including more effective inhibition of TLR-mediated survival signaling. Our data suggest an important role for TLR signaling in CLL pathogenesis and in sustaining the viability of CLL cells during ibrutinib therapy. The combination of ibrutinib with a TLR pathway inhibitor could provide superior antitumor activity and should be investigated in clinical studies. SIGNIFICANCE: CLL relies on the concomitant cooperation of B-cell receptor and Toll-like receptor signaling; inhibition of both pathways is superior to inhibition of either pathway alone. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/2/360/F1.large.jpg.

Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: a phase 1/2a study

Preclinical studies have shown synergistic antitumour effects between ibrutinib and immune-checkpoint blockade. The aim of this study was to assess the safety and activity of ibrutinib in combination with nivolumab in patients with relapsed or refractory B-cell malignant diseases. We did a two-part, open-label, phase 1/2a study at 21 hospitals in Australia, Israel, Poland, Spain, Turkey, and the USA. The primary objective of part A (dose escalation) was to assess the safety of daily oral ibrutinib (420 mg or 560 mg) in combination with intravenous nivolumab (3 mg/kg every 2 weeks) to ascertain a recommended phase 2 dose in patients with relapsed or refractory high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, or diffuse large B-cell lymphoma. Dose optimisation was investigated using a modified toxicity probability interval design. The primary objective of the part B expansion phase was to establish the preliminary activity (the proportion of patients who achieved an overall response) of the combination of ibrutinib and nivolumab in four cohorts: relapsed or refractory high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, diffuse large B-cell lymphoma, and Richter's transformation. All participants who received at least one dose of treatment were included in the primary analysis and analyses were done by disease cohort. This trial is registered with ClinicalTrials.gov, number NCT02329847. The trial is ongoing. Between March 12, 2015, and April 11, 2017, 144 patients were enrolled in the study. Three patients died before receiving study treatment; thus, 141 patients were included in the analysis, 14 in part A and 127 in part B. One dose-limiting toxicity (grade 3 hyperbilirubinaemia) was reported at the 420 mg dose in the diffuse large B-cell lymphoma cohort, which resolved after 5 days. The combination of ibrutinib and nivolumab led to overall responses in 22 (61%) of 36 patients with high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma, 13 (33%) of 40 patients with follicular lymphoma, 16 (36%) of 45 patients with diffuse large B-cell lymphoma, and 13 (65%) of 20 patients with Richter's transformation. The most common all-grade adverse events were diarrhoea (47 [33%] of 141 patients), neutropenia (44 [31%]), and fatigue (37 [26%]). 11 (8%) of 141 patients had adverse events leading to death; none were reported as drug-related. The most common grade 3-4 adverse events were neutropenia (40 [28%] of 141 patients) and anaemia (32 [23%]). The incidence of grade 3-4 neutropenia ranged from eight (18%) of 45 patients with diffuse large B-cell lymphoma to 19 (53%) of 36 patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma; incidence of grade 3-4 anaemia ranged from five (13%) of 40 patients with follicular lymphoma to seven (35%) of 20 patients with Richter's transformation. The most common serious adverse events included anaemia (six [4%] of 141 patients) and pneumonia (five [4%]). The most common grade 3-4 immune-related adverse events were rash (11 [8%] of 141 patients) and increased alanine aminotransferase (three [2%]). The combination of ibrutinib and nivolumab had an acceptable safety profile and preliminary activity was similar to that reported with single-agent ibrutinib in chronic lymphocytic leukaemia or small lymphocytic lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. The clinical response in patients with Richter's transformation was promising and supports further clinical assessment. Janssen R&D.