Phase 1 trial of ibrutinib and carfilzomib combination therapy for relapsed or relapsed and refractory multiple myeloma

Abstract

This phase 1, dose-finding study investigated ibrutinib and carfilzomib ± dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma (≥2 lines of therapy including bortezomib and an immunomodulatory agent). Of 43 patients enrolled, 74% were refractory to bortezomib and 23% had high-risk cytogenetics. No dose-limiting toxicities were observed. The recommended phase 2 dose was ibrutinib 840 mg and carfilzomib 36 mg/m² with dexamethasone. The most common ≥ grade 3 (>10%) treatment-emergent adverse events were hypertension, anemia, pneumonia, fatigue, diarrhea, and thrombocytopenia. Overall response rate was 67% (very good partial response, 21%; stringent complete response, 2%), with an additional 9% minimal response. Median progression-free survival was 7.2 months and was not inferior in refractory nor high-risk patients. Median overall survival was not reached. Ibrutinib plus carfilzomib demonstrated encouraging responses with a manageable safety profile in this advanced population.

Keywords:

• Ibrutinib
• carfilzomib
• Bruton’s tyrosine kinase
• multiple myeloma
• hematologic neoplasms

Introduction

Clonal proliferation of multiple myeloma (MM) cells in the bone marrow leads to end-organ damage including hypercalcemia, renal insufficiency, anemia, and lytic bone disease [1]. Despite novel drug combinations contributing to improved patient outcomes, relapse is inevitable in most MM patients, with a median overall survival of 9 months in patients refractory to proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs) [2,3]. The optimal treatment in the relapsed setting is uncertain because of older age, decreased performance status, comorbidities, and/or residual toxicities from prior treatments. Additionally, relapsed patients have biologically more aggressive disease, demonstrating a complex clinical need for this difficult-to-treat population.

Myeloma cells are highly dependent on signal transduction pathways within the bone marrow microenvironment for proliferation and survival; Bruton’s tyrosine kinase (BTK) is expressed in >85% of MM tumor cells and signaling may contribute to the development of drug-resistant MM cells [4]. BTK may also positively regulate myeloma cell stemness. Ibrutinib, a first-in-class, once-daily, potent, orally administered covalent inhibitor of BTK, is indicated for the treatment of various B cell malignancies [5]. In vitro, ibrutinib has shown cytotoxicity and synergy with bortezomib and lenalidomide in malignant plasma cells from patients with MM [6]. In a mouse model, ibrutinib reduced MM-induced bone lysis, decreased osteoclast number, and activity, and suppressed tumor growth [4]. Interestingly, when the Drug Response Prediction score based on correlation of growth inhibition to mRNA expression changes associated with various agents in human cancer cell lines was used to predict myeloma responses in high risk myeloma, sensitivity to ibrutinib was frequently predicted, including in 10 of 11 patients with predicted insensitivity to all agents used in the Total Therapy 3A protocol [7].

In patients with relapsed or relapsed and refractory MM (RRMM) who had a median of four prior therapies, ibrutinib plus dexamethasone demonstrated durable clinical activity, with a clinical benefit rate (CBR) of 28%, a median progression-free survival (PFS) of 4.6 months, and sustained stable disease (>4 cycles) in 23% of patients [8]. Carfilzomib, a next-generation, selective, and irreversible PI, is approved for patients with MM who have been previously treated with multiple lines of therapy [9]. Preclinical data suggest that carfilzomib-induced bone anabolic activity may be mediated through the induction of osteoblast differentiation [10]. Based on this evidence, we hypothesized a synergistic effect between ibrutinib and carfilzomib in patients with RRMM. This phase 1 part of a phase 1/2b, multicenter study evaluated the safety and efficacy of the ibrutinib and carfilzomib combination in RRMM patients who had multiple prior lines of therapy.

Methods

Patients

This study was approved by the Institutional Review Board at each site. All patients provided written informed consent. Patients had measurable, symptomatic RRMM according to International Myeloma Working Group (IMWG) criteria, [11] received ≥2 prior lines of therapy (including bortezomib and an IMiD), and had relapsed disease. Patients were categorized as refractory if there was no response or documented progressive disease (PD) within 60 days of completion of the most recent treatment regimen. Eligible patients had adequate hematologic (absolute neutrophil count ≥1000/µl, platelets ≥75,000/µl, hemoglobin level ≥8 g/dl), estimated creatinine clearance (Cockroft-Gault) ≥ 30 ml/min, adequate hepatic function, and an Eastern Cooperative Oncology Group (ECOG) performance status ≤2. Key exclusion criteria were prior treatment with carfilzomib if patients were refractory or nonresponsive, and requiring strong CYP3A inhibitors or vitamin K antagonists (other anticoagulant and antiplatelet agent use was allowed on study).

Objectives

The phase 1 primary objective was to determine the maximum tolerated dose (MTD), toxicities associated with ibrutinib and carfilzomib in combination, with or without dexamethasone, and the recommended phase 2 dose (RP2D). Secondary objectives were to determine objective response rate (ORR) according to IMWG criteria and duration of response (DOR).

Study design

PCYC-1119 (NCT01962792) is a phase 1/2b, open-label, multicenter study. Protocol Amendment 2 was implemented to include additional cohorts with dexamethasone based on the clinical activity of ibrutinib plus weekly dexamethasone in PCYC-1111 [8]. Oral ibrutinib was administered daily at 560 or 840 mg on a 28-day cycle starting on day 8 of cycle 1. Intravenous carfilzomib was administered on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle through cycle 12, then on days 1, 2, 15, and 16. Carfilzomib starting dose was 20 mg/m² on days 1 and 2 of cycle 1, and if tolerated, increased to 27 or 36 mg/m² at day 8 and beyond. Oral dexamethasone 20 mg (10 mg for patients ≥75 years) was administered on days 1, 2, 8, 9, 15, 16, 22, and 23; cohorts 2b and 3b (Table 1). Phase 1 followed a 3 + 3 dose escalation design and 2 cohorts could be expanded up to 18 patients each in the absence of a dose-limiting toxicity (DLT) to better inform the RP2D. Three patients were enrolled in a dose level cohort. If the first three patients tolerated the first 28-day cycle without experiencing a DLT, the next dose level was allowed to enroll. The MTD was defined as the highest dose level at which <33% of patients in a cohort experienced a study treatment-related DLT. Patients were treated until PD, unacceptable toxicity, or other protocol-specified reason for discontinuation.

Table 1. Cohort descriptions (N = 43).

Treatment	Cohort 1(n = 3)	Cohort 2a(n = 5)	Cohort 2b(n = 17)	Cohort 3b(n = 18)
Ibrutinib	560 mg	560 mg	560 mg	840 mg
Carfilzomib	27 mg/m^2	36 mg/m^2	36 mg/m^2	36 mg/m^2
Dexamethasone	–	–	+	+

Cohort 3a not opened based on PCYC-1111 outcomes noted with the inclusion of dexamethasone to study treatment [8].

Assessments

Response was assessed by IMWG response criteria. Fluorescent in situ hybridization (FISH) was performed for t(4;14), t(11;14) and del17p on baseline bone marrow aspirate (locally at each study site) either at screening or within 90 days prior to study treatment. High-risk cytogenetics was defined as the presence of t(4;14) and/or del17p. DLTs were assessed by an independent data monitoring committee (DMC) per protocol. AEs were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03.

Data analysis

The point estimate of response rates and corresponding 95% exact binomial confidence interval were calculated. DOR was calculated using Kaplan–Meier estimates.

Results

Patients

Forty-three patients with RRMM were enrolled at 13 centers in the USA between January 15, 2014 and July 20, 2015. The first 13 patients were enrolled to the dose-escalation phase and all completed the DLT observation period. To further inform the RP2D, an additional 30 patients were enrolled during the dose expansion phase to cohorts 2b and 3b. The baseline patient characteristics were similar across all the dose cohorts, with a median age of 63 years (range, 44–83 years) and a median time from diagnosis of 4.2 years (range, 0.5–25.3 years; Table 2). FISH identified 19% of patients with t(4;14) translocation, 9% with t(11;14) translocation, and 7% with 17p deletion. Overall, patients received a median of three prior lines of therapy (range, 2–9), including 70% who received a prior autologous stem cell transplant. In addition, 74, 72, and 28% were refractory to bortezomib, lenalidomide, and pomalidomide, respectively; and 60% were refractory to both a PI and IMiD (Table 2). Moreover, 88% of patients were refractory to their last line of therapy, of which 53% included bortezomib, all of whom were actively progressing post-bortezomib.

Table 2. Baseline characteristics.

Characteristic	Cohort 1 (n = 3)	Cohort 2a (n = 5)	Cohort 2b (n = 17)	Cohort 3b (n = 18)	Total (N = 43)
Median age, years (range)	69 (68–71)	72 (60–82)	60 (47–83)	59 (44–76)	63 (44–83)
Median time from diagnosis, years (range)	8.2 (1.7–18.6)	4.2 (2.0–12.5)	5.0 (2.1–25.3)	4.0 (0.5–9.7)	4.2 (0.5–25.3)
Male, %	67	80	35	50	49
ECOG performance status, %
0	33	20	24	33	28
1	67	80	71	50	63
2	0	0	6	17	9
Chromosomal abnormalities by FISH, %
t(11;14)	33	20	6	6	9
t(4;14)	0	20	12	28	19
del17p	0	0	6	11	7
High-risk cytogenetics^a	0	20	18	33	23
ISS stage at baseline, n
I	3	1	10	8	22
II	0	2	3	6	11
III	0	2	3^b	3^b	8
Median prior lines of therapy, n (range)	3 (2–9)	3 (2–7)	3 (2–5)	2.5 (2–7)	3 (2–9)
Disease status to last treatment, %
Relapsed	0	40	12	6	12
Refractory	100	60	88	94	88
Autologous stem cell transplant, %	100	60	76	61	70
Alkylator, %	100	100	76	94	88
IMiD,^c %
Thalidomide	0	40	29	22	26
Thalidomide refractory	0	20	0	11	7
Lenalidomide	100	100	94	100	98
Lenalidomide refractory	100	60	71	72	72
Pomalidomide	33	20	41	22	30
Pomalidomide refractory	33	20	35	22	28
PI,^c %
Bortezomib	100	100	100	100	100
Bortezomib refractory	67	60	76	78	74
Carfilzomib	0	0	6	17	9
Carfilzomib refractory	0	0	0	0	0

ECOG: Eastern Cooperative Oncology Group; FISH: fluorescence in situ hybridization; IMiD: immunomodulatory drug; PI: proteasome inhibitor.

^at(4;14) and/or del17p.

^bData not available for two patients at baseline.

^cReceived in last line of therapy: no PI or IMiD (n = 3); PI and IMiD (n = 12); PI or IMiD (n = 28).

Toxicity

Of the 43 enrolled patients, all experienced at least 1 treatment-emergent AE (any grade), with grade ≥3 treatment-emergent AEs observed in 37 patients (86%; Table 3). No DLTs were observed during dose escalation. Hematologic AEs included anemia (35%), thrombocytopenia (28%), and neutropenia (9%; 7% grade ≥3); all events of grade 3 thrombocytopenia (n = 5) occurred early and resolved, whereas both grade 4 events occurred in the setting of PD. The most frequent nonhematologic grade ≥3 AEs were hypertension (23%), pneumonia (19%), fatigue (16%), and diarrhea (14%; Table 3). Of the 10 patients (23%) with grade 3 hypertension, all reported a prior history at the time of study entry, and the time to onset varied (range, 36–491 days). Eight patients were managed with antihypertensive medication, two required no intervention, and one had the carfilzomib dose reduced. Resolution to baseline was reported in all but two of the cases, and no patients required treatment discontinuation. Two patients developed grade 3 peripheral neuropathy (PN), both of which resolved, one with carfilzomib dose reduction and one with topical analgesic. Three cases of grade 3 renal events occurred in the setting of either PD (n = 1) or sepsis (n = 2). Three cases of grade 3 rash were reported, none of which required dose modification of study drugs or intervention for resolution.

Table 3. Adverse events (> 15% and/or grade ≥ 3 in ≥ 3 patients).

	Cohort 1 (n = 3)		Cohort 2a (n = 5)		Cohort 2b (n = 17)		Cohort 3b (n = 18)		Total (N = 43)
Adverse event, %	All	Grade ≥3	All	Grade ≥3	All	Grade ≥3	All	Grade ≥3	All	Grade ≥3
Fatigue	0	0	80	40	65	18	44	11	53	16
Diarrhea	0	0	60	20	65	24	39	6	49	14
Cough	33	0	40	0	41	0	56	0	47	0
Constipation	33	0	60	0	35	0	44	0	42	0
Nausea	0	0	0	0	41	6	50	0	37	2
Anemia	33	33	60	40	35	24	28	6	35	19
Pyrexia	33	0	60	0	41	24	17	0	33	9
Upper respiratory tract infection	33	0	0	0	41	12	33	0	33	5
Dyspnea	0	0	60	20	35	6	22	6	30	7
Headache	33	0	40	0	47	6	11	0	30	2
Hypertension	33	33	40	40	35	29	22	11	30	23
Insomnia	0	0	0	0	41	0	33	0	30	0
Epistaxis	0	0	60	0	29	0	22	0	28	0
Hypokalemia	0	0	40	0	41	12	17	6	28	7
Thrombocytopenia	33	33	20	0	18	6	39	17	28	12
Urinary tract infection	0	0	20	0	29	12	28	6	26	7
Arthralgia	0	0	60	0	24	0	11	0	21	0
Peripheral edema	0	0	20	0	18	0	28	0	21	0
Abdominal pain	0	0	20	0	24	0	17	0	19	0
Acute kidney injury	33	0	20	0	24	12	56	6	19	7
Muscle spasms	0	0	20	0	18	0	22	0	19	0
Pneumonia	33	33	40	40	12	12	17	17	19	19
Rash maculo-papular	0	0	0	0	24	18	17	0	16	7
Vomiting	0	0	20	0	24	12	11	0	16	5
Back pain	0	0	0	0	24	12	11	6	14	7
Hyperglycemia	0	0	0	0	18	12	17	11	14	9
Neutropenia	0	0	20	20	12	6	6	6	9	7
Sepsis	0	0	0	0	18	18	0	0	7	7

Overall, 13 (30%) patients discontinued study treatment due to AEs, and this was consistent across dose cohorts. Of these, four patients discontinued because of grade ≥3 pneumonia, which was considered possibly related to both ibrutinib and carfilzomib. Two events of grade ≥3 pneumonia resolved and the other two patients with grade ≥3 pneumonia died with the AE ongoing in the setting of worsening MM. Four cardiac events led to treatment discontinuation, one grade 3 heart failure that resolved after treatment discontinuation and three cases of arrhythmia (grade 2 atrial fibrillation [n = 2] and grade 3 atrial flutter [n = 1]) with possible relationship to both ibrutinib and carfilzomib, although two cases of arrhythmia occurred in the setting of infection. No major bleeding events were reported despite the use of non-vitamin K antagonist anticoagulants and/or antiplatelet therapy in 58% of patients. In addition, 10 (23%) patients discontinued carfilzomib due to AEs. Overall, 5 (12%) patients had a dose reduction of ibrutinib and 8 (19%) had a dose reduction of carfilzomib due to AEs.

At time of analysis, one patient remains on study treatment. Median time on the study was 20.5 months. The most common reason for treatment discontinuation was PD (n = 18 [42%]), followed by AEs as noted above (n = 13 [30%]), investigator decision (n = 5 [12%]), and withdrawal by patient (n = 6 [14%]). Thirteen patients had died at the time of analysis. Deaths were due to PD (n = 8), infections (n = 4) and metastatic non-small cell lung cancer (n = 1). Of note, two of the deaths due to infection occurred after subsequent anticancer therapy administration.

Efficacy

Forty-two patients were evaluable for response. The ORR was 67%, and the CBR was 76%, with one patient (2%) achieving a stringent complete response, 9 (21%) achieving a very good partial response (VGPR), 18 (43%) patients achieving a PR, and four patients (10%) achieving a minimal response (MR; Table 4). The median duration of response (DOR) for patients who achieved ≥ PR (n = 28) was 12.9 months (range, 0.3–16.6 months), with a median DOR for cohort 2b of 9.1 months (n = 12; range, 0.3–15.3 months) and for cohort 3b of 7.2 months (n = 12; range, 0.5–16.6).

Table 4. Best response by IMWG response criteria.

Treatment, %	Cohort 1 (n = 3)	Cohort 2a (n = 5)	Cohort 2b (n = 17)	Cohort 3b^a (n = 17)	Total (N = 42)
sCR/CR	0	0	0	6	2
VGPR	0	0	29	24	21
PR	67	40	41	41	43
MR	0	0	12	12	10
ORR (≥PR)	67	40	71	71	67
CBR (≥MR)	67	40	82	82	76

CBR defined as ≥ MR by International Myeloma Working Group criteria.

CBR: clinical benefit rate; CR: complete response; MR: minimal response; ORR: overall response rate; PR: partial response; sCR: stringent complete response; VGPR: very good partial response.

^aOne patient not evaluable for response because of early discontinuation.

In patients refractory to bortezomib in cohorts 2b and 3b, the ORR was 73%. A median DOR of 9.1 months (range, 0.3–16.6 months) was observed in these patients overall. In those refractory to both an IMiD and bortezomib, the ORR was 70% with a median DOR of 6.4 months (range, 0.5–16.6 months). In high-risk patients (del17p and/or t[4;14]), the ORR was 78%, with a median DOR of 9.1 months (range, 2.7–14.5 months).

With a median follow-up of 20.5 months, the median PFS was 7.2 months (range, 0.2–20.3 months; Figure 1(A)). In the expansion cohorts 2b and 3b, the median PFS was 8.1 months (range, 1.4–16.3 months) and 6.4 months (range, 0.2–20.3 months), respectively. The estimated 1-year PFS rate was 35% for the overall population and 33% for both cohorts 2b and 3b. In high-risk patients defined as those with either del17p and/or t(4;14) (n = 10) the median PFS was 8.1 months (range, 1.1–15.6 months), with an estimated 1-year PFS rate of 30% (Figure 1(B)). Importantly, the PFS of these high-risk patients was comparable to that of non-high-risk patients. Additionally, the median PFS in patients refractory to prior IMiD and PI was 6.4 months (range, 0.2–20.3 months), with an estimated 1-year PFS rate of 33% (Figure 1(A)) and was comparable with those who were not double refractory. As of this analysis, 29% of patients with ≥ PR (8 of 28) were alive without PD and median overall survival for all patients was not reached.

Figure 1. PFS in specific subgroups. PFS by refractory status and overall (A). PFS in patients with high-risk cytogenetics [t(4;14); del17p] (B). PFS: progression-free survival; PI: proteasome inhibitor; IMiD: immunomodulatory drug.

Pharmacokinetics/pharmacodynamics

After administration, ibrutinib demonstrated rapid absorption and elimination, as previously observed [8]. Systemic exposure to ibrutinib, when coadministered with carfilzomib and dexamethasone, in patients with MM trended higher than that observed in MM patients receiving dexamethasone only (Figure 2). Whether coadministration of carfilzomib with or without dexamethasone resulted in higher systemic ibrutinib exposure remains unknown, given the large interpatient variability and limited pharmacokinetic data. Pharmacodynamic studies are ongoing in the phase 2b portion of the study.

Figure 2. Pharmacokinetics of ibrutinib in patients with multiple myeloma. Mean steady-state ibrutinib plasma concentration–time profiles in the current study (PCYC-1119) and PCYC-1111 (A). Steady-state ibrutinib area under the curve (AUC; with background carfilzomib), with and without dexamethasone in the current study cohorts and PCYC-1111 (B). ^aPCYC-1111 was a phase 1/2, open-label, nonrandomized, multicenter study of ibrutinib with or without dexamethasone in relapsed or relapsed and refractory multiple myeloma; dexamethasone dose was 4 mg weekly [8].

Discussion

This study is the first to evaluate the combination of ibrutinib with a standard backbone treatment of MM, carfilzomib, and dexamethasone, with the aim, in phase 1, to determine the MTD and RP2D of this combination. Ibrutinib with a PI and dexamethasone had a manageable safety profile with no DLTs observed in this advanced patient population. The MTD was established as ibrutinib 840 mg with carfilzomib 36 mg/m² and dexamethasone adjusted for age. No new safety signals were identified, and the observed toxicity profile of the combination was similar to that of these agents used individually.

Although 30% of patients discontinued treatment due to toxicity, four of these were due to pneumonia. Grade ≥3 pneumonia was reported in eight patients, all resolved with the exception of two patients who died with this AE in the setting of PD. Infections are not uncommon in RRMM, particularly in a population with a median of three lines of prior lines of therapy and 60% of patients who were dual refractory to both a PI and an IMiD. Indeed, in PX-171-003-A1 study of carfilzomib, grade 3/4 upper respiratory infection as well as pneumonia and febrile neutropenia occurred in 4.5, 9.4, and 0.8%, respectively [12]. In addition, the low incidence of grade 3 neutropenia and thrombocytopenia is encouraging as myelosuppression is common with other agents used in this population.

Despite known cardiac toxicities associated with carfilzomib and ibrutinib as individual agents, the cardiac AEs with the combination did not meet DLT criteria and were manageable with rechallenge or dose reduction. While 4 cardiac events led to discontinuations, two of these were in the setting of infections. Also no increase in toxicity appeared to be associated with ibrutinib dose escalation. Ultimately, toxicities and/or treatment discontinuations could be attributed to comorbidities, underlying disease factors, or toxicities due to prior therapies. It is difficult to determine the proper attribution of toxicity in a phase 1 study and while the outcomes of the ongoing phase 2b study may help better define the safety profile of this treatment regimen, a more definitive attribution would require a randomized study.

This combination resulted in promising and durable responses. Most patients enrolled were refractory to their last therapy (88%) and had advanced MM, with a median of three prior lines of therapy, including 28% with four or more prior therapies. Sixty percent were refractory to both bortezomib and an IMiD. The median PFS of 7.2 months is encouraging considering the poor outcomes often observed in this group. Similar responses were observed in both expansion cohorts, despite the difference in ibrutinib dose. This could be attributed to the small sample size, but may also be related to differences in baseline characteristics (e.g. t[4;14] abnormality and refractoriness to the most recent therapy both may predict a worse prognosis and were more prevalent in cohort 3b). In addition, the ORR of 70% and median PFS of 8.1 months observed in patients (n = 10) with unfavorable cytogenetics (del17p and/or t[4;14]) and short expected survival shows promise and is consistent with the approval of ibrutinib in high-risk CLL with del17p [13]. A notable finding was that responses in patients who were refractory to prior bortezomib were both deep and durable, with an ORR of 71% and a median DOR of 9.1 months. In patients previously exposed to bortezomib (including 20–73% refractory to bortezomib) studies have reported ORRs of approximately 17–19% [12,14] with the PX-171-004 study reporting a of CBR 31% and a median PFS of 4.6 months [14]. While in ENDEAVOR, carfilzomib with dexamethasone demonstrated a 77% ORR, patients received a higher dose of carfilzomib (56 mg/m²), had fewer prior lines of therapy (median, 2), and could not be refractory to PIs [15]. Given this, our observations support preclinical findings that inhibition of BTK may lead to resensitization to PIs [7].

Ibrutinib is approved in four related B-cell malignancies and has potential as a combination partner in patients with RRMM. Considering the potential effects of the combination under study on bone metabolism, further evaluation of the synergistic effect between ibrutinib and PIs in the RRMM population is warranted. In addition, preclinical data warrant further evaluation in other stages of disease (i.e. high-risk smoldering myeloma [NCT02943473] and/or maintenance) and with other combination partners (i.e. IMiDs), such as that currently underway in a phase 1/2b study of the combination of ibrutinib, pomalidomide and dexamethasone (NCT02548962). Enrollment in the phase 2b of the present study is ongoing, while another phase 2 study of ibrutinib with bortezomib and dexamethasone in patients with RRMM after 1–3 prior lines of therapy is also ongoing (NCT02902965).

Author contributions

All authors: writing—reviewing and editing, resources. Ajai Chari: conceptualization, methodology, investigation. Sarah Larson, Beata Holkova, Robert F. Cornell, Cristina Gasparetto, Chatchada Karanes, Jeffrey V. Matous, Ruben Niesvizky, Jason Valent, Matthew Lunning, Saad Z. Usmani, Larry D. Anderson, Saurabh Chhabra: investigation. Lipo Chang: project administration. Yihua Lee: formal analysis, data curation, project administration. Yvonne Pak: formal analysis, data curation. Zeena Salman, Thorsten Graef, Elizabeth Bilotti: conceptualization, methodology, project administration.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at https://doi.org/10.1080/10428194.2018.1443337.

Acknowledgments

We thank Juthamas Sukbuntherng, PhD, for support and oversight in the pharmacokinetic/pharmacodynamic analysis and Brian Haas, PhD, for medical writing support funded by Pharmacyclics LLC, an AbbVie Company.