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

Articles

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 Loretta J Nastoupil, Matthew A Lunning, Julie M Vose, Marshall T Schreeder, Tanya Siddiqi, Christopher R Flowers, Jonathon B Cohen, Jan A Burger, William G Wierda, Susan O’Brien, Peter Sportelli, Hari P Miskin, Michelle A Purdom, Michael S Weiss, Nathan H Fowler

Summary

Background 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. Methods 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. Findings 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 doseexpansion 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.

Lancet Haematol 2019; 6: e100–09 See Comment page e65 The University of Texas MD Anderson Cancer Center, Houston, TX, USA (L J Nastoupil MD, J A Burger MD, W G Wierda MD, N H Fowler MD); University of Nebraska Medical Center, Omaha, NE, USA (M A Lunning DO, J M Vose MD); Clearview Cancer Institute, Huntsville, AL, USA (M T Schreeder MD); City of Hope National Medical Center, Duarte, CA, USA (T Siddiqi MD); Emory University Winship Cancer Institute, Atlanta, GA, USA (C R Flowers MD, J B Cohen MD); University of California Irvine Cancer Center, Orange, CA, USA (S O’Brien MD); and TG Therapeutics, New York, NY, USA (P Sportelli, H P Miskin MS, M A Purdom PhD, M S Weiss) Correspondence to: Dr Loretta J Nastoupil, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA [email protected]

Interpretation 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. Funding TG Therapeutics. Copyright © 2019 Elsevier Ltd. All rights reserved.

www.thelancet.com/haematology Vol 6 February 2019

e100

Articles

Research in context Evidence before this study There is an unmet need for new therapies that aim to improve the efficacy, durability, and tolerability of treatments for patients with advanced chronic lymphocytic leukaemia and non-Hodgkin lymphoma. We searched PubMed for clinical trials published between Aug 1, 2013, and Aug 31, 2018, using the search terms “CLL”, “NHL”, and “ibrutnib”. We identified 43 trials including patients with relapsed high-risk chronic lymphocytic leukaemia and relapsed non-Hodgkin lymphoma. Durable and complete responses were rare, and development of ibrutinib resistance was common. Ublituximab in combination with umbralisib and ibrutinib represents a novel approach to the treatment of advanced chronic lymphocytic leukaemia and B-cell non-Hodgkin lymphoma, with the advantage of targeting malignant

Introduction Previous research on the pathogenesis of mature B-cell malignancies has led to the development of therapies that target aberrant intracellular activation of the B-cell receptor pathway. Malignant B cells often manipulate normal B-cell signalling to engage downstream pathways that are crucial for proliferation and survival. These pathways can be exploited in various ways—eg, via gainof-function mutations that activate signalling effectors, loss-of-function mu​ tations that inactivate negative regulators, or autocrine receptor activation.1–3 Activation of the B-cell receptor pathway can be triggered by exogenous antigens, such as microbial or autoantigens, or by recognition of epitopes within the B-cell receptor itself (ie, autonomous signalling),4,5 although the importance of these activation mechanisms has not been fully elucidated.3 Although little is known about pathway addiction in B-cell lymphomas, targeting B-cell receptor signalling is an attractive therapeutic approach. A number of B-cell receptor-associated tyrosine kinase inhibitors have shown efficacy across a variety of B-cell lymphomas.6 Combining targeted, non-chemotherapeutic therapies to improve the durability and depth of response in chronic lymphocytic leukaemia and non-Hodgkin lymphoma is an attractive goal. Ublituximab is a novel third-generation type I chimeric anti-CD20 monoclonal antibody bio-​ engineered for enhanced antibodydependent cytotoxicity. This compound has efficacy in patients with relapsed or refractory chronic lymphocytic leukaemia and non-Hodgkin lymphoma who have been previously treated with rituximab.7 Ublituximab depletes B cells via complement-dependent cytotoxicity, pro​ grammed cell death, and antibody-dependent cytotoxicity. A previous study8 has shown that combining ublituximab with ibrutinib is safe with promising activity in relapsed or refractory chronic lymphocytic leukaemia, whereby the overall response rate (ORR) was 80% for ublituximab plus ibrutinib compared with 47% for ibrutinib alone. e101

B-lymphocytes via separate, non-overlapping mechanisms of action. Added value of this study To our knowledge, this study is the first to show that the combination of ublituximab, umbralisib, and ibrutinib is safe with no new or unexpected adverse events. Implications of all the available evidence This novel combination of targeted therapy with non-overlapping mechanisms of action seems to be associated with a favourable safety profile. The responses observed across B-cell lymphoma subtypes indicates the need for further exploration of this therapeutic combination.

Umbralisib is a next-generation phosphoinositide 3-kinase δ (PI3Kδ) and casein kinase-1ε inhibitor.9 The drug has a unique structure and activity profile that is distinct from other PI3Kδ inhibitors in development, including greater selectivity for the PI3Kδ isoform and a prolonged half-life that enables once-daily dosing. Additionally, the safety profile of umbralisib differs from that of other PI3Kδ inhibitors, particularly with regard to hepatic toxicity and colitis.9 Umbralisib has been safely combined with ublituximab and showed efficacy in preliminary reports of patients with relapsed or refractory non-Hodgkin lymphoma and chronic lymphocytic leukaemia (ORR 57%).10 Ibrutinib is a first-in-class inhibitor of Bruton’s tyrosine kinase with single drug activity in chronic lymphocytic leukaemia and other B-cell malig­ nancies.2,11–15 However, new approaches are needed for patients who develop ibrutinib resistance since treatment outcomes can be poor in these individuals.16,17 Combined therapy with targeted drugs that have different mechanisms of action seems promising with regard to synergism and overcoming resistance; however, the safety of some combinations can present specific challenges.18,19 Umbralisib and ublituximab have shown synergistic activity in preclinical studies.20 Various combinations of umbralisib, ublituximab, and ibrutinib are being investigated in clinical studies. In preliminary analyses, umbralisib plus ublituximab (NCT02006485), umbralisib plus ibrutinib (NCT02268851), and ublituximab plus ibrutinib (NCT02301156) have all resulted in ORRs higher than 80% in patients with chronic lymphocytic leukaemia.8,21,22 Thus, we aimed to assess the safety, dose-limiting toxicities, and maximum tolerated dose of the triplet combination of ublituximab, umbralisib, and ibrutinib in patients with chronic lymphocytic leukaemia and small lymphocytic lymphoma and relapsed or refractory B-cell non-Hodgkin lymphoma. www.thelancet.com/haematology Vol 6 February 2019

Articles

Methods

Study design and participants

Procedures

In the dose-escalation cohort, umbralisib (TG In this multicentre, phase 1, open-label, dose-escalation Therapeutics, New York, NY, USA) was given orally once study, we recruited patients with histologically confirmed daily at 400 mg (dose level 1), 600 mg (dose level 2), or B-cell non-Hodgkin lymphoma, chronic lymphocytic 800 mg (dose level 3) in 28-day cycles. Commercially leukaemia or small lymphocytic lymphoma, or other available ibrutinib was given at 420 mg for chronic B-cell lymphoproliferative disorders at five centres in lymphocytic leukaemia or 560 mg for B-cell non-Hodgkin lymphoma orally once daily. Ublituximab (TG the USA. The study was divided into two parts. A dose-escalation Therapeutics) 900 mg was administered via intravenous phase assessed the safety, toxicity, and maximum- infusion on days 1, 8, and 15 of cycle 1, day 1 of cycles 2–6, tolerated dose of the combination of umbralisib with and on day 1 of cycles 9 and 12. Therapy was continued ublituximab and ibrutinib. A dose expansion phase until disease progression or intolerance. We applied dose assessed the safety, toxicity, and preliminary efficacy of reductions and interruptions as per protocol (appendix). the recommended phase 2 dose of umbralisib identified On the basis of reports of opportunistic infections in studies with other PI3Kδ inhibitors, the protocol was in the dose-escalation phase. We used a 3 × 3 design for the dose-escalation cohort, amended in June, 2015, to allow prophylactic treatment in which the chronic lymphocytic leukaemia and B-cell for pneumocystis pneumonia and antiviral therapy non-Hodgkin lymphoma cohorts were escalated before cycle 1 at the discretion of the treating investigator. We assessed toxicity during treatment and for 30 days independently. The protocol stated that patients included in the dose-escalation phase could progress to following discontinuation using Common Terminology higher doses of umbralisib if the maximum tolerated Criteria for Adverse Events version 4.03. Efficacy was dose was not reached at a lower dose. The decision of assessed at week 8 and approximately every 12 weeks whether to progress patients to a higher dose was made thereafter for 12 months. After 12 months, efficacy was on an individual basis and was at the investigator’s assessed at least every 6 months or at the treating discretion. If two of six patients within a dose cohort physician’s discretion. Response assessments were done had dose-limiting toxicities, that dose cohort was by the principal investigators, with central confirmation considered to exceed the maximum tolerated dose and of complete responses, according to the Revised no further dose escalation occurred. The previous dose Response Criteria for Malignant Lymphoma23 for patients cohort was then considered the maximum tolerated with the B-cell non-Hodgkin lymphoma and the dose. International Workshop on Chronic Lymphocytic Eligible patients were aged 18 years or older, had Leukaemia guidelines24 for patients with chronic measurable disease, adequate organ function (absolute lymphocytic leukaemia or small lymphocytic lymphoma. neutrophil count ≥0·75 × 10⁹/L, platelets ≥50 × 10⁹/L, total Scans used to identify measurable disease were done up bilirubin ≤1·5 times the upper limit of normal [ULN], to 30 days before day 1 of cycle 1. Assessment of dosealanine aminotransferase and aspartate amino-​limiting toxicities was done during the first 28-day cycle transferase ≤2·5 times the ULN if no liver involvement, of treatment. or ≤5 times the ULN if known liver involvement, and creatinine ≤2·0 mg/dL or clearance rate ≥50 mL/min, as Outcomes calculated by the Cockcroft-Gault method), and an The primary endpoints were safety, dose-limiting toxicities, Eastern Cooperative Oncology Group (ECOG) and the maximum tolerated dose of umbralisib, when performance status of 2 or less. Patients with B-cell given in combination with ublituximab and ibrutinib, in non-Hodgkin lymphoma were refractory to or had patients with B-cell lymphoma. The secondary endpoints relapsed after at least one previous treatment regimen. were the proportion of patients who achieved an overall Patients with chronic lymphocytic leukaemia or small response (defined as the sum of patients who achieved lymphocytic lymphoma initially had relapsed or complete responses and partial responses), progressionrefractory disease, and in March, 2016, after the 800 mg free survival (defined as the time from study entry to the umbralisib dose was demonstrated to be safe in these first documentation of tumour progression or death due to patients, the study was expanded to include patients who any cause), and duration of response (measured from time were previously untreated. Patients with known CNS of documentation of complete or partial response to lymphoma, active hepatitis B or C infection, or known tumour progression or death due to any cause). history of HIV were excluded. Full inclusion and Assessment of minimal residual disease in patients with exclusion criteria are listed in the appendix. chronic lymphocytic leukaemia was introduced after a The protocol was approved by local institutional review protocol amendment on Nov 28, 2016, and was defined by boards and complied with Good Clinical Practice peripheral blood samples collected and analysed in both guidelines and the Declaration of Helsinki (appendix). central and local laboratories using a minimum of fourAll patients or their legal representatives provided written colour flow cytometry with a lower limit of detection of less informed consent before enrolment. than 0·01%. www.thelancet.com/haematology Vol 6 February 2019

See Online for appendix

e102

Articles

50 patients assessed for eligibility 4 excluded due to screening failure 46 patients enrolled

24 patients in the dose-escalation phase

14 patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma

22 patients in the dose-expansion phase

10 patients with non-Hodgkin lymphoma

9 patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma 800 mg umbralisib +900 mg ublituximab + 420 mg ibrutinib

6 patients* 400 mg umbralisib + 900 mg ublituximab + 420 mg ibrutinib

3 patients 400 mg umbralisib + 900 mg ublituximab + 560 mg ibrutinib

5 patients† 600 mg umbralisib + 900 mg ublituximab + 420 mg ibrutinib

4 patients§ 600 mg umbralisib + 900 mg ublituximab + 560 mg ibrutinib

3 patients 800 mg umbralisib + 900 mg ublituximab + 420 mg ibrutinib

3 patients 800 mg umbralisib + 900 mg ublituximab + 560 mg ibrutinib

14 evaluable for safety 13 evaluable for efficacy‡

9 evaluable for safety and efficacy

13 patients with non-Hodgkin lymphoma 800 mg umbralisib + 900 mg ublituximab + 560 mg ibrutinib

13 evaluable for safety and 12 evaluable for safety¶

10 evaluable for efficacy 10 evaluable for safety

Figure 1: Trial profile *One dose-limiting toxicity was observed and thus prompted the inclusion of six patients in the 400 mg umbralisib cohort. †A total of five patients were included in the 600 mg umbralisib cohort because two patients (patients 3 and 4) were identified on the same day and were both enrolled since no previous dose-limiting toxicities were observed in the first two patients enrolled in this cohort. One patient consented to the study before the 800 mg cohort was open and was allowed to be enrolled in the 600 mg cohort as the fifth patient. ‡One patient with small lymphocytic lyphoma who received 600 mg umbralisib (dose level 2) died due to pneumonia unrelated to treatment after 6 weeks and thus had no post-treatment efficacy assessment. §Three patients with non-Hodgkin lymphoma were originally enrolled in the 600 mg cohort, but one patient progressed very rapidly and was replaced, bringing the total to four patients in this cohort. ¶One patient with follicular lymphoma who received 800 mg umbralisib in the dose-expansion phase stopped treatment after 6 weeks at the investigator’s discretion and thus had no post-treatment efficacy assessment.

Statistical analysis We did not do a formal sample size calculation for this trial. We planned to use a 3 × 3 dose escalation design and treat three to six patients at each dose level. The dose expansion phase allowed expansion of these cohorts using the recommended dose determined in the dose escalation phase. Descriptive statistics were used to summarise patient demographics and clinical characteristics. Overall response was reported for all evaluable patients and by disease subgroup. Duration of response was summarised using median (IQR) for the responders. Time-to-event endpoints were analysed using the Kaplan-Meier method. Unless otherwise stated, for all statistical analyses a two-sided p value of less than 0·05 was considered to indicate a statistically significant difference. e103

The efficacy analysis set included all patients who had at least one post-treatment efficacy measurement. The safety analysis set included all patients who received at least one dose of study drug. All safety analyses including assessment of toxicity were done on the safety analysis set. All statistical analyses were done using SAS 9.2 version 9.2 or higher. This trial is registered with ClinicalTrials.gov, number NCT02006485.

Role of the funding source The funder of the study designed the study and was involved in data analysis, data interpretation, and writing of the report. The funder of the study had no role in data collection. The corresponding author had full access to all study data and had final responsibility for the decision to submit for publication. www.thelancet.com/haematology Vol 6 February 2019

Articles

Results Between Sept 2, 2014, and Nov 6, 2017, 46 patients were enrolled (n=23 chronic lymphocytic leukaemia or small lymphocytic lymphoma; n=23 B-cell non-Hodgkin lymphoma; figure 1). 24 patients received treatment in the dose-escalation phase and 22 patients received treatment in the dose-expansion phase. In the dose-escalation phase, 14 patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma and 10 patients with non-Hodgkin lymphoma received umbralisib at either 400 mg, 600 mg, or 800 mg in combination with ibrutinib (420 mg for chronic

Age, years

lymphocytic leukaemia; 560 mg for B-cell non-Hodgkin lymphoma) and ublituximab 900 mg. One dose-limiting toxicity of reactivated varicella zoster virus was observed in the chronic lymphocytic leukaemia cohort at dose level 1 (400 mg umbralisib, 900 mg ublituximab, and 420 mg ibrutinib). This patient fully recovered with dose interruption and was successfully rechallenged. Any grade

Grade 3–4

Diarrhoea

27 (59%)

4 (9%)

Fatigue

23 (50%)

0

Infusion-related reaction

20 (43%)

0

Patients (n=46)

Dizziness

17 (37%)

1 (2%)

62 (56–67)

Nausea

17 (37%)

1 (2%)

Cough

16 (35%)

0

Sex Male

35 (76%)

Insomnia

15 (33%)

Female

11 (24%)

Neutropenia

15 (33%)

10 (22%)

Pyrexia

15 (33%)

2 (4%)

Thrombocytopenia

13 (28%)

3 (7%)

Peripheral oedema

12 (26%)

0

Stomatitis

11 (24%)

3 (7%)

Vomiting

11 (24%)

2 (4%)

Anaemia

10 (22%)

1 (2%)

Rash

10 (22%)

Histology Chronic lymphocytic leukaemia or small lymphocytic lymphoma*

23 (50%)

Treatment-naive chronic lymphocytic leukaemia

4/23 (17%)†

Previously treated chronic lymphocytic leukaemia

19/23 (83%)†

17p or 11q deletions B-cell non-Hodgkin lymphoma

9/23 (39%)† 23 (50%)

Diffuse large B-cell lymphoma

6/23 (26%)

Follicular lymphoma‡

8/23 (35%)

Mantle cell lymphoma

6/23 (26%)

Marginal zone lymphoma

3/23 (13%)

0

Headache

9 (20%)

2 (4%)

Pneumonia

9 (20%)

4 (9%)

8 (17%)

0

8 (17%)

0

Upper respiratory tract infection

8 (17%)

0

Abdominal pain

7 (15%)

1 (2%)

Contusion

7 (15%)

0

Dyspnoea

7 (15%)

1 (2)

Hyperglycaemia

7 (15%)

3 (7%)

Hypokalaemia

7 (15%)

0

Pleural effusion

7 (15%)

2 (4%)

6 (13%)

Sinusitis

7 (15%)

0

12 (26%)

1

33 (72%)

2

1 (2%) 3 (1–4) 27 (59%)

Previous treatment with PI3K inhibitor

9 (20%)

Constipation

0

Patients treated with three or more previous therapies

1 (2%)

Back pain

Blood creatinine increased

ECOG performance status

Previous treatment regimens

0

5 (11%)

Blurred vision

7 (15%)

0

6 (13%)

Vitamin D decreased

7 (15%)

0

3 (7%)

Anxiety

6 (13%)

0

42 (91%)

Cellulitis

6 (13%)

6 (13%)

14 (30%)

Ecchymosis

6 (13%)

0

Refractory to previous therapy

16 (35%)

Hypertension

6 (13%)

1 (2%)

Previous stem-cell transplant

8 (17%)

Hypophosphateamia

6 (13%)

2 (4%)

Bronchitis

5 (11%)

0

Dyspepsia

5 (11%)

0

Hypoalbuminaemia

5 (11%)

0

Hypocalcaemia

5 (11%)

0

Myalgia

5 (11%)

0

Neuropathy peripheral

5 (11%)

0

Oropharyngeal pain

5 (11%)

0

Refractory to previous therapy with PI3K inhibitor Previous treatment with BTK inhibitor Refractory to previous BTK inhibitor Previous treatment with CD20 therapy Refractory to previous CD20 therapy§

Data are median (IQR), n (%), or n/N (%). ECOG=Eastern Cooperative Oncology Group. PI3K=phosphoinositide 3-kinase. BTK=Bruton’s tyrosine kinase. *One patient with small lymphocytic lymphoma died due to non-related pneumonia after 6 weeks on study and was not included in the efficacy analysis. †Percentages do not sum to 100 because patients could be either treatment-naive or previously treated and have a 17p or 11q deletion. ‡One patient with follicular lymphoma discontinued treatment after 6 weeks at the investigator’s discretion and thus was not included in the efficacy analysis. §Patients progressing on or within 6 months of a rituximab-based regimen were considered refractory to previous CD20 therapy; this did not include patients treated with a lower dose of rituximab as maintenance therapy.

Table 1: Patient baseline characteristics

www.thelancet.com/haematology Vol 6 February 2019

Data are n (%).

Table 2: Adverse events occurring in more than 10% of all treated patients (n=46)

e104

Articles

Overall response (complete response + partial response)

Complete response

Partial response

Stable disease

Progressive disease

All patients

37/44 (84%)

13/44 (30%)

24/44 (55%)

1/44 (2%)

6/44 (14%)

Chronic lymphocytic leukaemia or small lymphocytic lymphoma

22/22 (100%)

8/22 (36%)

14/22 (64%)

··

··

··

Treatment naive

4/4 (100%)

4/4 (100%)

··

Previously treated

18/18 (100%)

8/18 (44%)

··

10/18 (56%)

··

··

17p or 11q deletion

8/8 (100%)

5/8 (63%)

3/8 (38%)

··

··

Follicular lymphoma

5/7 (71%)

1/7 (14%)

4/7 (57%)

Marginal zone lymphoma

3/3 (100%)

1/3 (33%)

2/3 (67%)

1/7 (14%) ··

1/7 (14%) ··

Mantle cell lymphoma

6/6 (100%)

3/6 (50%)

3/6 (50%)

··

··

Diffuse large B-cell lymphoma

1/6 (17%)

··

1/6 (17%)

··

5/6 (83%)

Data are n/N (%).

Table 3: Overall response by histology in the efficacy analysis set (n=44)

Change in tumour size from baseline (%)

25

Chronic lymphocytic leukaemia Mantle cell lymphoma Diffuse large B-cell lymphoma Follicular lymphoma Marginal zone lymphoma Small lymphocytic lymphoma

0

–25

–50

–75

–100 Patients

Figure 2: Best response per patient in the efficacy analysis set (n=44) The best percentage change in tumour size was determined by principal investigators. Each bar represents an individual patient.

One patient with small lymphocytic lymphoma who received 600 mg umbralisib (dose level 2) in the dose-escalation phase died due to pneumonia that was considered unrelated to study treatment after 6 weeks and one patient with follicular lymphoma who received 800 mg umbralisib in the dose-expansion phase discontinued therapy before the 8-week efficacy assessment for reasons unrelated to the therapy drugs; thus, 44 patients were included in the efficacy analysis set. Among all treated patients, the median age was 62 years (range 32–85), and most patients were men (table 1). 12 (26%) of 46 patients had an ECOG performance status of 0, 33 (72%) had a performance e105

status of 1, and one (2%) had a performance status of 2 (table 1). The median duration of treatment at data cutoff (June 1, 2018) was 16 months (IQR 6·8–24·5), and the longest duration of treatment was 44 months. 35 (76%) of 46 patients received treatment for 6 months or longer, and 18 (47%) remained on therapy at data cutoff. The maximum tolerated dose of umbralisib in combination with ublituximab and ibrutinib in chronic lymphocytic leukaemia and relapsed or refractory B-cell non-Hodgkin lymphoma was not reached within the tested dose range (≤800 mg daily). The recommended dose for the doseexpansion 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. Adverse events occurring in 10% or more of patients are shown in table 2. 15 (33%) of 46 patients received pneumocystis pneumonia and antiviral prophylaxis. In the safety population (n=46), the most common adverse events of any grade were diarrhoea (n=27 [59%]), fatigue (n=23 [50%]), infusion-related reaction (n=20 [43%]), dizziness (n=17 [37%]), nausea (n=17 [37%]), cough (n=16 [35%]), insomnia (n=15 [33%]), neutropenia (n=15 [33%]), pyrexia (n=15 [33%]), thrombocytopenia (n=13 [28%]), and peripheral oedema (n=12 [26%]). Grade 3–4 adverse events were infrequent, with the most common being neutropenia (n=10 [22%]) and cellulitis (n=6 [13%]). Of the ten patients who had grade 3–4 neutropenia, one patient (10%) had grade 3–4 febrile penia. Four (9%) of 46 patients had neutro­ grade 3 diarrhoea. No grade 4 diarrhoea was reported, and no cases of colitis of any grade were reported. One patient (2%) had grade 3 transaminitis. Grade 2 pneumonitis was observed in two (4%) of 46 patients, however, dose reduction was not required and both patients were rechallenged successfully without recurrence. Of the 27 patients with diarrhoea, two patients in the dose-expansion cohort required dose reduction (600 mg) of whom one patient discontinued treatment due to recurring diarrhoea. Overall, 20 patients given umbralisib (400 mg [n=4], 600 mg [n=3], 800 mg [n=13]) required dose reduction due to adverse events; however, all 20 patients were rechallenged successfully after initial umbralisib interruption. Serious adverse events occurred in 11 (24%) of 46 patients and included rash (n=2), pneumonia (n=2), atrial fibrillation (n=2), sepsis (n=2), abdominal pain (n=1), syncope (n=1), cellulitis (n=1), pneumonitis (n=1), headache (n=1), lung infection (n=1), skin infection (n=1), pleural effusion (n=1), pericardial infusion (n=1), upper gastrointestinal bleeding (n=1), diarrhoea (n=1), and weakness (n=1), which were associated with at least one of the three study drugs. No deaths due to treatment-related adverse events were observed, and at data cutoff only one death had occurred in a patient with small lymphocytic lymphoma who died after 6 weeks of treatment from www.thelancet.com/haematology Vol 6 February 2019

pneumonia, which was determined to be unrelated to study treatment. 24 (52%) of 46 patients given ublituximab, 20 (43%) patients given umbralisib, and 20 (43%) patients given ibrutinib had treatment interruptions, with infusionrelated reactions, neutropenia, and stomatitis being the most common reason for each, respectively (appendix). 15 (33%) of 46 patients had dose reductions of either umbralisib (n=6) or ibrutinib (n=9). Eight (17%) of 46 patients discontinued study treatment due to adverse events (n=4 in the dose-escalation phase; n=4 in the dose-expansion phase); two (4%) patients withdrew due to umbralisib (sepsis [n=1], pulmonary oedema [n=1]), five (11%) due to ibrutinib (atrial fibrillation or cardiac complications [n=1], sepsis [n=1], pneumonitis [n=1], pericardial effu­sion [n=1], and subdural hygroma [n=1]), and one (2%) withdrew due to ublituximab (sepsis). 37 (84%) of 44 patients achieved an overall response (table 3). Among 18 patients with previously treated chronic lymphocytic leukaemia, eight (44%) achieved a complete response and ten (56%) achieved a partial response. All eight evaluable patients with 17p deletion responded to treatment; five (63%) patients achieved a complete response and three (38%) patients achieved a partial response. Best response observed per patient is shown in figure 2. Among the nine patients with chronic lymphocytic leukaemia who were analysed for minimal residual disease, seven (78%) patients had no minimal residual disease, three (33%) achieved a complete response, and four (44%) achieved a partial response. Median follow-up in the safety population was 15 months (IQR 6·8–24·5) and median duration of response was 21·8 months (IQR 8·5–24·3). On-study treatment for all treated patients is shown in figure 3. The median duration of response was 22·7 months (IQR 8·6–25·9) in patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma, 14·6 months (5·5–22·2) in patients with mantle cell lymphoma, 20·0 months (7·3–23·8) in patients with marginal zone lymphoma, and 23·4 months (13·8–24·3) in patients with follicular lymphoma. Median time to first response in all patients was 1·8 months (IQR 1·7–1·9). Median progression-free survival in all patients was 38·2 months (95% CI 21·3–not estimable [NE]; figure 4). Considering progression-free survival by histological subtype, median progression-free survival was not reached (95% CI 24·5–NE) for patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma, not reached (10·2–NE) for patients with mantle cell lymphoma, not reached (21·3–NE) for patients with marginal zone lymphoma, 38·2 months (0·4–NE) for patients with follicular lymphoma, and 1·3 months (0·5–NE) for patients with diffuse large B-cell lymphoma.

Discussion Therapeutic targeting of the B-cell receptor signalling pathway has revolutionised the management of B-cell www.thelancet.com/haematology Vol 6 February 2019

Patients

Articles

Chronic lymphocytic leukaemia Mantle cell lymphoma Diffuse large B-cell lymphoma Follicular lymphoma Marginal zone lymphoma Small lymphocytic lymphoma 0

0·5

1·0

1·5

2·0

2·5

3·0

3·5

Years

Figure 3: Swimmer’s plot showing duration of response in all treated patients (n=46) Each bar represents an individual patient. Arrowheads indicate ongoing response.

lymphomas. Optimum combinations that result in longer periods of remission, possibly allowing for discontinuation of therapy, are needed. Ublituximab in combination with umbralisib and ibrutinib is a novel non-chemotherapeutic combination with separate, nonoverlapping mechanisms of action against B cells. This phase 1 study demonstrated that the combination of ublituximab, umbralisib, and ibrutinib is associated with a favourable safety profile, manageable adverse events, and no treatment-related deaths in heavily pretreated patients with B-cell non-Hodgkin lymphoma or patients with untreated chronic lymphocytic leukaemia or small lymphocytic lymphoma. The maximum tolerated dose for this triplet combination was not reached. Additionally, the proportion of patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma who achieved an overall response ranged from 71 to 100%. In this study, the umbralisib, ublituximab, and ibrutinib combination seems to be associated with a favourable toxicity profile and no new or unexpected adverse events were observed. 35 (76%) of 46 patients were treated for longer than 6 months. Although ten (22%) of 46 patients had grade 3–4 neutropenia, only one (2%) had febrile neutropenia. The proportion of e106

Articles

A 100

Progression-free survival (%)

80

60

40

Median PFS (95% CI) All patients CLL or SLL DLBCL FL MCL MZL

20

0

0 Number at risk All patients 46 CLL or SLL 23 6 DLBCL 8 FL 6 MCL 3 MZL

38·2 (21·3–NE) NR (24·5–NE) 1·3 (0·5–NE) 38·2 (0·4–NE) NR (10·2–NE) NR (21·3–NE)

10

20

30

40

50

31 20 0 4 4 3

20 14 0 1 3 2

5 3 0 1 1 0

2 1 0 0 1 0

0 0 0 0 0 0

B 100

Median PFS (95% CI) CLL or SLL Previously treated Treatment naive 17p or 11q deletion

Progression-free survival (%)

80

NR (24·5–NE) NR (21·0–NE) NR (NE–NE) NR (6·4–NE)

60

40

20

0 Number at risk CLL or SLL Previously treated Treatment naive 17p or 11q deletion

0

10

20

30

40

50

1 1 0 1

0 0 0 0

Time since treatment initiation (months) 23 19 4 9

20 16 4 7

14 12 2 6

3 3 0 2

Figure 4: Kaplan-Meier plots of progression-free survival (A) Progression-free survival by histological subtype for all treated patients (n=46). (B) Progression-free by key baseline patient characteristics for patients with CLL or SLL (n=23). CLL=chronic lymphocytic leukaemia. SLL=small lymphocytic lymphoma. DLBCL=diffuse large B-cell lymphoma. FL=follicular lymphoma. MCL=mantle cell lymphoma. MZL=marginal zone lymphoma. NR=not reached. NE=not estimable. PFS=progression-free survival.

patients with transaminitis and pneumonitis of any grade was low, and no cases of colitis were reported, which contrasts with the findings of previous studies with the PI3Kδ inhibitor idelalisib.18,19,25,26 A phase 2 study18 e107

of idelalisib in combination with rituximab in frontline chronic lymphocytic leukaemia reported an ORR of 97% (19% of patients achieved a complete response), but also reported a higher rate of grade 3 or worse diarrhoea or www.thelancet.com/haematology Vol 6 February 2019

Articles

colitis (42%) and transaminitis (23%). We hypothesise that impaired regulatory T-cell function via inhibition of PI3Kδ in a more immune competent host in the previous study contributed to the higher toxicity observed previously.18 Although our study included a smaller number of patients, we observed toxicity profiles similar to single-drug reports,9,11,25,27 suggesting that combination treatment might not increase toxicity concerns. Additionally, the use of prophylactic treatment for pneumocystis pneumonia and antiviral therapy at the investigator’s discretion was permitted in this study, which might account for the lower incidence of infections. Adherence to therapy is associated with improved patient outcomes. For example, a previous study28 reported that patients treated with ibrutinib who had treatment interruptions lasting less than 8 consecutive days had fewer progression-free survival events than patients for whom treatment was interrupted for 8 or more consecutive days. The favourable toxicity profile observed with ibrutinib in combination with ublituximab and umbralisib might explain the small number of patients who discontinued treatment due to adverse events and the high proportion of patients who remained on the study drug for more than 6 months. Manageable toxicity with drug interruption or dose modification might have contributed to the activity observed in this study. The optimum duration of therapy with targeted drugs remains unclear. In this study, umbralisib and ibrutinib were continued daily until disease progression or intolerance. A high proportion of patients achieved an overall response and meaningful progression-free survival with ongoing therapy. Although only a small number of patients have been studied so far, we observed complete responses across the indolent lymphoma subtypes and for mantle cell lymphoma. Although this study was not designed to investigate whether discontinuing therapy at minimal residual disease or complete response would affect efficacy, this concept is appropriate for future exploration. The patients with diffuse large B-cell lymphoma in this study did not achieve meaningful responses with this combination, suggesting the highly proliferative nature of such tumours might not be suitable for treatment with this approach. Only six patients with diffuse large B-cell lymphoma were included in this study, thus caution should be applied when making any conclusions regarding outcomes in this population. The combination of umbralisib, ublituximab, plus bendamustine in relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma is currently under investigation (NCT02793583); the cytotoxic activity of bendamustine might provide the necessary disease control when combined with targeted therapy in diffuse large B-cell lymphoma. One limitation of this study is the absence of pharmacodynamic comparisons to examine potential synergism or mechanisms of resistance. The emergence www.thelancet.com/haematology Vol 6 February 2019

of increasing numbers of therapeutic drugs with promising efficacy, such as immune modulators, BCL-2 inhibitors, and B-cell receptor-targeting drugs, is rapidly expanding the treatment landscape; however, few biomarkers are available to guide treatment decisions. Future studies are needed to identify appropriate biomarkers to improve prognostic abilities and guide treatment decisions. An additional limitation of this study is the inclusion of a heterogeneous patient population that resulted in small numbers of patients in each lymphoma subgroup. In conclusion, the findings of this study establish the tolerable safety profile of the ublituximab, umbralisib, and ibrutinib triplet regimen in chronic lymphocytic leukaemia or small lymphocytic lymphoma and relapsed or refractory B-cell non-Hodgkin lymphoma. This triplet combination is expected to be investigated further in future clinical trials in different patient populations. Additionally, various doublet combinations, such as ibrutinib plus umbralisib, are currently being examined in patients with relapsed or refractory chronic lymphocytic leukaemia and mantle cell lymphoma (NCT02268851). Additional follow-up from the expansion phase of this study will improve understanding of this novel, chemotherapy-free triplet combination with regard to the management of chronic lymphocytic leukaemia or small lymphocytic lymphoma, follicular lymphoma, marginal zone lymphoma, and mantle cell lymphoma. Contributors All authors conceptualised and designed the study. LJN, MAL, JMV, MTS, TS, CRF, JBC, JAB, WGW, SOB, PS, HPM, MAP, MSW, and NHF provided study materials or recruited patients. LJN, PS, HPM, and MAP collected, interpreted data, and did the statistical analysis. LJN drafted the first draft of the manuscript with input from coauthors. Subsequent drafts were prepared and reviewed by all authors. Declaration of interests LJN has received honoraria from TG Therapeutics, Genentech, and Janssen during the conduct of the study; and honoraria from Gilead, Novartis, and Spectrum outside the submitted work. MAL has received honoraria from TG Therapeutics and Janssen; grants from Celgene, Curis, Janssen, Juno Therapeutics, Pharmacyclics, and TG Therapeutics; and consultancy fees from AbbVie, ADC Therapeutics, AstraZeneca, Bayer, Celgene, Genentech, Gilead, Janssen, Pharmacyclics, Juno Therapeutics, Kite, Portola, Sanofi Genzyme, Seattle Genetics, Spectrum, TG Therapeutics, and Verastem. TS has received grants and reimbursement for meeting expenses from TG Therapeutics. CRF has received grants from AbbVie, Acerta, Celgene, Gilead, Genentech, Janssen Pharmaceutical, Takeda, Pharmacyclics, TG Therapeutics, Burroughs Wellcome Fund, Eastern Cooperative Oncology Group, National Cancer Institute, and the V Foundation; has served as a consultant for Genentech/Biogen-Idec/Roche (unpaid), Millennium/ Takeda (unpaid); received consultancy fees from Spectrum, Celgene, Denovo Biopharma, Seattle Genetics, GIlead, Bayer, Karyopharm, AstraZeneca, and Beigene; and received speaker fees from Clinical Care Options, Educational Concepts, PRIME Oncology, and Research to Practice. JBC reports grants and personal fees from Seattle Genetics; personal fees from Genentech; and grants from Takeda, Novartis, the American Society of Hematology, and the Lymphoma Research Foundation, outside the submitted work. JAB has served as a consultant for Janssen Oncology, Pharmacyclics, and Gilead, and has received research support from Gilead and Pharmacyclics. SOB has served as consultant for Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen

e108

Articles

Oncology, Aptose Biosciences, Vaniam Group, AbbVie, Alexion; has served as a consultant for and received grants from Gilead, Pharmacyclics, TG Therapeutics, Pfizer, and Sunesis; and has received grants from Kite, Regeneron, and Acerta. PS, HPM, MAP, and MSW are employees of TG Therapeutics and may have equity ownership. NHF has served on advisory boards for Celegene, Roche, and Janssen; and has received grants from AbbVie. JMV, MTS, and WGW declare no competing interests. Data sharing statement Data will be available upon request from the corresponding author. Acknowledgments The study was sponsored by TG Therapeutics. Medical writing support was provided by Devon Roll, funded by TG Therapeutics. We would like to thank all of the study participants and investigators. References 1 Shaffer AL 3rd, Young RM, Staudt LM. Pathogenesis of human B cell lymphomas. Annu Rev Immunol 2012; 30: 565–610. 2 Wilson WH, Young RM, Schmitz R, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med 2015; 21: 922–26. 3 Burger JA, Wiestner A. Targeting B cell receptor signalling in cancer: preclinical and clinical advances. Nat Rev Cancer 2018; 18: 148–67. 4 Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 2010; 463: 88–92. 5 Duhren-von Minden M, Ubelhart R, Schneider D, et al. Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling. Nature 2012; 489: 309–12. 6 Pal Singh S, Dammeijer F, Hendriks RW. Role of Bruton’s tyrosine kinase in B cells and malignancies. Mol Cancer 2018; 17: 57. 7 Sawas A, Farber CM, Schreeder MT, et al. A phase 1/2 trial of ublituximab, a novel anti-CD20 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma or chronic lymphocytic leukaemia previously exposed to rituximab. Br J Haematol 2017; 177: 243–53. 8 Sharman JP, Brander DM, Mato AR, et al. Ublituximab and ibrutinib for previously treated genetically high-risk chronic lymphocytic leukemia: results of the GENUINE phase 3 study. 2017 ASCO Annual Meeting; Chicago, IL; June 2–6. 7504. 9 Burris HA 3rd, Flinn IW, Patel MR, et al. Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol 2018; 19: 486–96. 10 Lunning MA, Vose J, Fowler N, et al. Ublituximab + TGR-1202 demonstrates activity and a favorable safety profile in relapsed/refractory B-cell NHL and high-risk CLL: phase I results. 57th American Society of Haematology Annual Meeting; Orlando, FL: Dec 5–8, 2015. 1538. 11 Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013; 369: 32–42. 12 Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014; 371: 213–23. 13 O’Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol 2014; 15: 48–58.

e109

14 Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2013; 369: 507–16. 15 Noy A, de Vos S, Thieblemont C, et al. Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma. Blood 2017; 129: 2224–32. 16 Jain P, Keating M, Wierda W, et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood 2015; 125: 2062–67. 17 Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol 2015; 1: 80–87. 18 O’Brien SM, Lamanna N, Kipps TJ, et al. A phase 2 study of idelalisib plus rituximab in treatment-naive older patients with chronic lymphocytic leukemia. Blood 2015; 126: 2686–94. 19 Jones JA, Robak T, Brown JR, et al. Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial. Lancet Haematol 2017; 4: e114–26. 20 Deng C, Sportelli P, Rodriguez R, et al. Novel PI3K inhibitors demonstrated marked cytotoxicity in T cell lymphoma models, caused apoptosis and were synergistic with a novel anti-CD20 monoclonal antibody ublituximab in B cell lymphoma models. Blood 2012; 120: 3725. 21 Davids MS, Kim HT, Nicotra A, et al. Updated results of a multicenter phase I/Ib study of TGR-1202 in combination with ibrutinib in patients with relapsed or refractory MCL or CLL. Hematol Oncol 2017; 35: 54–55. 22 Lunning MA, Vose J, Fowler N, et al. Ublituximab + TGR-1202 demonstrates activity and a favorable safety profile in relapsed/refractory B-cell NHL and high-risk CLL: phase I results. Blood 2015; 126: 1538. 23 Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007; 25: 579–86. 24 Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008; 111: 5446–56. 25 Gopal AK, Kahl BS, de Vos S, et al. PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 2014; 370: 1008–18. 26 Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. Blood 2014; 123: 3390–97. 27 Sharman JP, Farber CM, Mahadevan D, et al. Ublituximab (TG-1101), a novel glycoengineered anti-CD20 antibody, in combination with ibrutinib is safe and highly active in patients with relapsed and/or refractory chronic lymphocytic leukaemia: results of a phase 2 trial. Br J Haematol 2017; 176: 412–20. 28 Barr PM, Brown JR, Hillmen P, et al. Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL. Blood 2017; 129: 2612–15.

www.thelancet.com/haematology Vol 6 February 2019