Many longitudinal studies and clinical trials are designed to compare rates of change over time in one or more outcome variables in several groups. Most such studies have incomplete data because some ...patients drop out before completing the study. The missing data may induce bias and inefficiency in naive estimates of important parameters. This paper uses Monte Carlo methods to compare the bias and efficiency of several two-stage estimators of the effect of treatment on the mean rate of change when the missing data arise from one of four processes. We also study the validity of confidence intervals and the power of hypothesis tests based on these estimates and their standard errors. In general, the weighted least squares estimator does relatively well, as does an analysis of covariance type estimator proposed by Wu et al. The best estimates of variance components are based on complete cases or maximum likelihood.
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Introduction: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) primarily affects older patients (pts) who often have medical comorbidities along with disease-related ...immunosuppression and myelosuppression. Although alkylating agents such as chlorambucil (clb) have been commonly used in these pts, novel therapies are needed. Ibrutinib (ibr) is a first-in-class, oral, covalent inhibitor of Bruton's tyrosine kinase FDA-approved for pts with CLL who received ≥1 prior therapy and for del17p CLL (including first-line). Ibr showed high activity in treatment-naïve pts age ≥65 years, with an overall response rate (ORR) of 84% (complete response CR in 23%) and 30-month progression-free survival (PFS) of 96% (Byrd et al. Blood 2015). We conducted a randomized, open-label phase 3 trial to evaluate efficacy and safety of single-agent ibr vs clb in treatment-naïve older pts with CLL/SLL.
Methods: Pts aged ≥65 years with treatment-naïve CLL/SLL were randomized 1:1 to receive 420 mg ibr daily until progression or clb 0.5 mg/kg (up to maximum of 0.8 mg/kg) on days 1 and 15 of a 28-day cycle for up to 12 cycles. Pts with del17p were excluded. Primary endpoint was independent review committee (IRC)-assessed PFS per iwCLL 2008 criteria, with 2012 clarification for treatment-related lymphocytosis. Secondary endpoints included overall survival (OS), ORR, event-free survival (EFS), rate of hematologic improvement, and safety. Pts with IRC-confirmed progression could transfer to an extension study where next-line therapy (including ibr) could be initiated if they had an iwCLL indication for treatment.
Results: Among 269 pts enrolled, median age was 73 years (70% ≥70 years). Baseline characteristics were balanced between arms; 45% had advanced Rai stage, 20% had del11q, and 69% had comorbidities at baseline including CIRS score >6, reduced creatinine clearance, or ECOG status of 2. For pts treated with clb, 40% completed 12 cycles of therapy (mean dose 0.6 mg/kg). At a median follow-up of 18.4 months (mos), ibr significantly prolonged IRC-assessed PFS vs clb (median not reached NR vs 18.9 mos; HR 0.16, 95% CI 0.09-0.28, P<0.0001); this was consistent within subgroups including age ≥70 years, del11q, and unmutated IGHV. As assessed by investigator, ibr reduced the risk of progression or death by 91% (HR 0.09; 95% CI, 0.04-0.17; P<0.0001; Figure 1A), with an 18-mo PFS of 93.9% vs 44.8%. Ibr significantly prolonged OS vs clb (median NR for either arm; HR 0.16, 95% CI 0.05-0.56, P=0.0010; Figure 1B); 24-mo OS was 97.8% vs 85.3%, respectively. Three deaths occurred on the ibr arm vs 17 deaths on clb arm. The IRC-assessed ORR was 86.0% with ibr (4.4% CR/CRi) vs 35.3% with clb (1.5% CR/CRi). ORR with ibr was higher than clb at all evaluated time points; at 8 mos, ORR was 84% and 31%, respectively. Investigator-assessed ORR was 90.4% (9.6% CR/CRi) vs 35.3% (4.5% CR/CRi), respectively. Median EFS was also prolonged with ibr (NR vs 12 mos; HR 0.17, 95% CI 0.10-0.26; P<0.0001). A ≥50% reduction in lymph node burden was observed in 91.2% vs 36.8% (P<0.0001), and reduction in spleen enlargement in 75.7% vs 39.1% (P<0.0001), for ibr and clb, respectively. Rates of sustained hematologic improvements were significantly higher with ibr vs clb, including in pts with baseline anemia (84% vs 45%; P<0.0001) or thrombocytopenia (77% vs 43%; P=0.0054). Median duration of treatment was 17.4 mos with ibr and 7.1 mos with clb. Most frequent (≥20% of pts) adverse events (AEs) with ibr included diarrhea, fatigue, cough and nausea. Most frequent AEs with clb included nausea, fatigue, neutropenia, anemia and vomiting. AEs leading to treatment discontinuation were less frequent with ibr (9% vs 23%). Atrial fibrillation occurred in 6% (6 pts grade 2 and 2 pts grade 3) with ibr and 1% with clb. Hypertension was noted more frequently on ibr, but was limited to grade 1-3 and managed without ibr dose modification or discontinuation. Major hemorrhage occurred in 4% (1 pt grade 2, 4 pts grade 3, 1 pt grade 4) with ibr over median follow-up of approximately 1.5 years, and in 2% with clb. At the time of study closure, 87% of pts randomized to ibr continue to receive ibr.
Conclusions: Treatment with single-agent ibr was superior to clb in terms of PFS, OS, ORR, EFS and hematologic improvement in treatment-naïve older CLL/SLL patients, with an 84% reduction in risk of death, and an acceptable safety profile.
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Off Label Use: ibrutinib in first-line CLL (including non-del17p CLL). Barr:Gilead: Consultancy; Abbvie: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Robak:Janssen: Consultancy, Research Funding; MorphoSys AG: Consultancy, Honoraria, Research Funding. Owen:Janssen: Honoraria; Lundbeck: Honoraria; Gilead: Honoraria; Roche: Honoraria. Ghia:Adaptive: Consultancy; Pharmacyclics: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; GSK: Research Funding; AbbVie: Consultancy; Janssen: Consultancy; Roche: Consultancy, Research Funding; Acerta Pharma BV: Research Funding. Hillmen:Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Roche Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Bartlett:Novartis: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Gilead: Consultancy, Research Funding; Genentech: Research Funding; MERC: Research Funding; Insight: Research Funding; Colgene: Research Funding; Medimmune: Research Funding; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Kite: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding. Coutre:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding. Quach:Celgene Corp, ONYX, Janssen, Takeda, Novartis, BMS: Honoraria, Research Funding. Janssens:Mundipharma: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy. O'Dwyer:Celgene: Honoraria, Research Funding. Hellmann:BMS: Consultancy, Other: funding of travel, accomodations or expenses, Speakers Bureau; Novartis: Consultancy, Other: funding of travel, accomodations or expenses, Research Funding, Speakers Bureau. Schuh:Acerta Pharma BV: Research Funding. Siddiqi:Seattle Genetics: Speakers Bureau; Pharmacyclics/Jannsen: Speakers Bureau; Kite pharma: Other: attended advisory board meeting. Tam:AbbVie: Honoraria; Roche: Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Keating:Glaxo-Smith-Kline Inc.: Other: Advisory board; Celgene Corp.: Consultancy. Suri:Pharmacyclics LLC, an AbbVie Company: Employment. Zhou:Pharmacyclics LLC, an AbbVie Company: Employment. Clow:Pharmacyclics LLC, an AbbVie Company: Employment. Styles:Pharmacyclics LLC, an AbbVie Company: Employment. James:Pharmacyclics LLC, an AbbVie Company: Employment. Kipps:Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor; Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor. Burger:Pharmacyclics LLC, an AbbVie Company: Research Funding.
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Background: Patients with chronic lymphocytic leukemia (CLL) with deletion of the short arm of chromosome 17 (del 17p) follow an aggressive clinical course and demonstrate a median survival of less ...than 2 years in the relapsed/refractory (R/R) setting. Ibrutinib (ImbruvicaTM), a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor, has been approved for previously treated patients with CLL and for patients with del 17p CLL. We report results from the primary analysis of the Phase II RESONATETM-17 (PCYC-1117-CA) study, designed to evaluate the efficacy and safety of single-agent ibrutinib for treatment of patients with R/R del 17p CLL or small lymphocytic leukemia (SLL).
Methods: Patients with del 17p CLL or SLL who failed at least one therapy were enrolled to receive 420 mg oral ibrutinib once daily until progression. All patients receiving at least one dose of ibrutinib were included in the analysis. The primary endpoint was overall response rate (ORR) per an independent review committee (IRC). Other endpoints included duration of response (DOR), progression-free survival (PFS), and safety of ibrutinib.
Results: Among 144 treated patients (137 with CLL, 7 with SLL), the median age was 64 (48% 65 years or older) and all had del 17p. Baseline characteristics included 63% of patients with Rai Stage III or IV disease, 49% with bulky lymphadenopathy of at least 5 cm, and 10% with lymphadenopathy of least 10 cm. The median baseline absolute lymphocyte count (ALC) was 32.9 x 109/L with 57% of patients with a baseline ALC at least 25.0 x 109/L. Baseline beta-2 microglobulin levels were at least 3.5 mg/L in 78% of patients (range 1.8-19.8 mg/L), and lactate dehydrogenase levels were at least 350 U/L in 24% of patients (range 127-1979 U/L). A median of 2 prior therapies (range 1-7) was reported. Investigator-assessed ORR was 82.6% including 17.4% partial response with lymphocytosis (PR-L). Complete response (CR)/complete response with incomplete bone marrow recovery (CRi) were reported in 3 patients. IRC-assessed ORR is pending. At a median follow up of 13.0 months (range 0.5-16.7 months), the median PFS (Figure 1) and DOR by investigator determination had not been reached. At 12 months, 79.3% were alive and progression-free, and 88.3% of responders were progression-free. Progressive disease was reported in 20 patients (13.9%). Richter transformation was reported in 11 of these patients (7.6%), 7 of the cases occurring within the first 24 weeks of treatment. Prolymphocytic leukemia was reported in 1 patient. The most frequently reported adverse events (AE) of any grade were diarrhea (36%; 2% Grade 3-4), fatigue (30%; 1% Grade 3-4), cough (24%; 1% Grade 3-4), and arthralgia (22%; 1% Grade 3-4). Atrial fibrillation of any grade was reported in 11 patients (7.6%; 3.5% Grade 3-4). Seven patients reported basal or squamous cell skin cancer and 1 patient had plasma cell myeloma. Most frequently reported Grade 3-4 AEs were neutropenia (14%), anemia (8%), pneumonia (8%), and hypertension (8%). Major hemorrhage was reported in 7 patients (4.9%, all Grade 2 or 3). Study treatment was discontinued in 16 patients (11.1%) due to AEs with 8 eventually having fatal events (pneumonia, sepsis, myocardial or renal infarction, health deterioration). At the time of data cut, the median treatment duration was 11.1 months, and 101 of 144 patients (70%) continued treatment with ibrutinib.
Conclusions: In the largest prospective trial dedicated to the study of del 17p CLL/SLL, ibrutinib demonstrated marked efficacy in terms of ORR, DOR, and PFS, with a favorable risk-benefit profile. At a median follow up of 13 months, the median DOR had not yet been reached; 79.3% of patients remained progression-free at 12 months, consistent with efficacy observed in earlier studies (Byrd, NEJM 2013;369:32-42). The PFS in this previously treated population compares favorably to that of treatment-naïve del 17p CLL patients receiving fludarabine, cyclophosphamide, and rituximab (FCR) (Hallek, Lancet 2010;376:1164-74) or alemtuzumab (Hillmen, J Clin Oncol 2007;10:5616-23) with median PFS of 11 months. The AEs are consistent with those previously reported for ibrutinib (Byrd, NEJM 2014;371:213-23). These results support ibrutinib as an effective therapy for patients with del 17p CLL/SLL.
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O’Brien:Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity’s Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Jones:Pharmacyclics: Consultancy, Research Funding. Coutre:Janssen, Pharmacyclics: Honoraria, Research Funding. Mato:Pharamcyclics, Genentech, Celegene, Millennium : Speakers Bureau. Hillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding. Tam:Pharmacyclics and Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Siddiqi:Janssen: Speakers Bureau. Furman:Pharmacyclics: Consultancy, Speakers Bureau. Brown:Sanofi, Onyx, Vertex, Novartis, Boehringer, GSK, Roche/Genentech, Emergent, Morphosys, Celgene, Janssen, Pharmacyclics, Gilead: Consultancy. Stevens-Brogan:Pharmacyclics: Employment. Li:Pharmacyclics: Employment. Fardis:Pharmacyclics: Employment. Clow:Pharmacyclics: Employment. James:Pharmacyclics: Employment. Chu:Pharmacyclics: Employment, Equity Ownership. Hallek:Janssen, Pharmacyclics: Consultancy, Research Funding. Stilgenbauer:Pharmacyclics, Janssen Cilag: Consultancy, Honoraria, Research Funding.
Selective inhibition of Bruton's Tyrosine Kinase (BTK) is a novel approach to target diseases driven by BCR activation, such as B-cell lymphoma and chronic lymphocytic leukemia. Ibrutinib (PCI-32765) ...is a potent small molecule that binds covalently to a cysteine residue (Cys-481) in the BTK active site, resulting in inhibition of proliferation, migration and adhesion in CLL cells. Single agent ibrutinib orally-administered to relapsed/refractory (R/R) CLL patients was highly active as evidenced by an IWCLL overall response rate (ORR) of 71% and estimated 26 month PFS of 75% (Byrd et al, NEJM 2013). The chemoimmunotherapy regimen of bendamustine (B) and rituximab (R) (BR) is an active and well-established treatment regimen in R/R CLL patients and we report here the final data on the combination of ibrutinib with BR.
The primary objective of the study was to evaluate the safety and tolerability of ibrutinib in combination with BR administered to R/R CLL patients. The secondary objective was to estimate the efficacy of this novel combination.
30 patients with R/R CLL/SLL and a median of 2 prior therapies (range 1-3) received up to 6 cycles of BR with a continuous fixed ibrutinib dose of 420 mg/day; ibrutinib dosing continued past 6 cycles until disease progression or other reason for discontinuation. (B was administered at 70 mg/m2 on D1 and D2 combined with R 375 mg/m2 on D1 for C1 and 500 mg/m2 on D1 for subsequent courses). Response was evaluated according to IWCLL criteria.
The median age of the enrolled patients was 62 yrs (range 41-82) and the majority were male (83%). 53% of patients were Rai stage III/IV and 23% and 43% tested positive for del17p and del11q by FISH, respectively. Bulky disease (lymph nodes > 5 cm) was present in 53%. The observed safety profile for this combination therapy was generally consistent with the safety profile of BR and monotherapy ibrutinib. The most frequently reported treatment-emergent AEs were diarrhea (70%), nausea (66.7%), fatigue (46.7%), neutropenia (40%) and upper respiratory tract infection (36.7%). The most frequently reported treatment emergent AEs Grade 3 or higher in severity were neutropenia (40.0%), maculopapular rash and fatigue (10.0% each), and thrombocytopenia, febrile neutropenia, and cellulitis (6.7% each). Patients completed a median 6 cycles of BR (range 2-6); there have been no treatment discontinuations due to AEs and no deaths within 30 days after last dose. Of interest, the initial transient treatment-related lymphocytosis, seen in 78% of patients with ibrutinib monotherapy (Byrd et al, NEJM 2013), occurred less frequently (27%) in this combination approach. The study was completed on 12 November 2012. At the time of study completion 21 patients (70%) who were still receiving ibrutinib monotherapy after completion of BR rolled over to a long term extension study to continue treatment with ibrutinib. Nine patients (30%) discontinued the study treatment, 5 (17%) of whom proceeded to SCT and 4 (13%) of whom discontinued due to PD. With a median treatment duration of 16 months, the ORR was 93% (28/30 patients, including 5 CRs and 3 nPRs), and one additional patient achieved a PR with lymphocytosis. The estimated 12 month PFS was 90%. Moreover, responses appeared independent of high-risk features.
Ibrutinib orally-administered in combination with BR was tolerable and highly active in patients with R/R CLL/SLL. The high ORR and good tolerability compares very favorably with historical controls and is currently under further global investigation in a Ph3 trial (NCT01611090).
Brown:Novartis: Consultancy; Genentech: Consultancy; Vertex: Consultancy; Pharmacyclics: Consultancy; Onyx: Consultancy; Emergent: Consultancy; Celgene: Consultancy; Sanofi: Consultancy, Research Funding. Off Label Use: The combination of bendamustine + rituximab and ibrutinib (a small molecule inhibitor of BTK) and the combinations of FCR+I to treat relapsed CLL patients is under investigation. Barrientos:AbbVie: Research Funding; Pharmacyclics: Research Funding; Gilead: Consultancy, Research Funding. Barr:Pharmacyclics: Research Funding. Flinn:Pharmacyclics: Research Funding. Burger:Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Salman:Pharmacyclics: Employment, Equity Ownership. Clow:Pharmacyclics: Employment, Equity Ownership. James:Pharmacyclics: Employment, Equity Ownership. Graef:Pharmacyclics: Employment, Equity Ownership. Rai:Teva: Consultancy; Sanofi: Consultancy; GSK: Consultancy; Genentech: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees. O'Brien:Pharmacyclics: Research Funding.
Introduction: Multiple myeloma (MM) remains an incurable disease in need of new therapies with unique targets. Ibrutinib is a first-in-class, once-daily, oral, covalent inhibitor of Bruton’s tyrosine ...kinase (BTK), an essential enzyme in the B-cell receptor signaling pathway. While BTK is essential for the development and function of B cells and is down-regulated in plasma cells, the expression of BTK in malignant plasma cells is increased 4-fold and comparable to BTK expression levels in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). In addition, pre-clinical models show that BTK inhibition with ibrutinib led to direct inhibition of both osteoclast bone resorption and the release of osteoclast-derived tumor growth factors (Tai et al, Blood 2012). Taken together these data suggest that ibrutinib may have a role in the treatment of MM.
Methods: This open label phase 2 dose escalation study was designed to enroll patients in 4 cohorts (Figure) to evaluate efficacy (≥MR) and secondary endpoints of safety, PK, ORR and DOR. Patients must have had documented non-responsive/progressive disease at the time of study entry following at least 2 prior lines of therapy including at least one immunomodulatory agent. Efficacy and safety were assessed at 4 weeks intervals using the IMWG response criteria for efficacy assessments (Rajkumar et al, Blood 2011), while safety was assessed according to CTCAE v4.0 criteria.
Results: As of 15 May 2014 and a median follow up of 15.2 months, 69 patients with a median age of 64 years (range 43-81) were dosed, of which 20% had either a del 17p or p53 deletion. The number of median prior therapies was 4 (range, 2-14), 41% had ≥ 5 prior therapies and 80% had undergone autologous stem cell transplant. Sixty-two percent of patients were refractory to their last line of therapy and of the 65 patients that had received prior therapy with both an immunomodulatory agent and a proteasome inhibitor, 44% were refractory to both.
Anti-tumor activity was noted across all cohorts. The highest activity with a clinical benefit rate (CBR) of 25% including 1 PR, 4 MR and 5 sustained (>4 cycles) SD was observed in Cohort 4. (Table) This led to expansion of Cohort 4 per protocol design. In Cohorts 1 and 3, 14 patients had dex added following PD, resulting in 1 PR and 9 SD.
Overall, 57% experienced a Grade 3 or higher adverse event. The most commonly reported non-hematologic toxicities (any grade) were diarrhea (51%), fatigue (41%), nausea (35%), dizziness (25%), and muscle spasms (23%). The majority were Grade 1 and 2. Myelosuppression had a reported overall incidence of any grade anemia (29%), thrombocytopenia (23%), and neutropenia (7%) with 16%, 9% and 4% being Grade 3, respectively. There were no clinically meaningful differences among dose levels. Twenty-three patients experienced a SAE for a total of 47 reported events with 16 assessed as possibly/definitely related to ibrutinib per investigator. At least one dose modification occurred in 22% of patients, with 6 discontinuing due to an adverse event.
At the time of the data cut-off 7 patients remain on study treatment. The most common reason for treatment discontinuation was PD in 47% of patients, with additional patients discontinuing due to investigator discretion (18%), patient decision (7%) and non-compliance (3%).
Conclusions: In this heavily pre-treated patient population ibrutinib, as a single agent and in combination with dex, demonstrated evidence of anti-tumor activity. There was a trend toward improved efficacy (≥MR) in Cohort 4 and treatment was well tolerated with manageable toxicities. Ongoing correlative studies are being conducted to determine changes in cytokines, chemokines and indices of bone metabolism and to determine the effect of dex, a known CYP3A4/5 inducer, on the pharmacokinetic profile of ibrutinib. In addition, ibrutinib is currently being evaluated in combination with carfilzomib in an ongoing Phase1/2b study. (NCT01962792)
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TableConfirmed Response by Assigned TreatmentCohortResponse, n (%)1 (n=13)2 (n=18)3 (n=18)4 (n=20)PR11-1MR1--4SD ≥ 4 cycles2465SD < 4 cycles5641PD4575Not evaluable-214Not evaluable – no post-baseline assessments
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Off Label Use: Discussion of efficacy and safety data with ibrutinib as single-agent and in combination with dexamethasone in patients with relapsed and relapsed/refractory multiple myeloma treated in a phase 2 clinical trial. Huff:Celgene, Millenium: Consultancy. Bensinger:Pharmacyclics, Novartis, Celgene, Millenium, Sanofi, Acetylon: Consultancy, Research Funding. Siegel:Celgene, Millennium, Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Jagannath:Celgene, BMS, Jansen, Sanofi-Aventis: Honoraria. Lebovic:Onyx, Celgene: Speakers Bureau. Anderson:Celgene, Millenium, Onyx, : Speakers Bureau. Elias:Pharmacyclics, Inc.: Employment. Clow:Pharmacyclics, Inc.: Employment. Fardis:Pharmacyclics: Employment. Graef:Pharmacyclics: Employment. Bilotti:Pharmacyclics: Employment. Richardson:Celgene, Millennium, Johnson&Johnson: Membership on an entity’s Board of Directors or advisory committees.
Abstract 904
Bruton's tyrosine kinase (BTK) is a central mediator of B-cell receptor (BCR) signaling which is essential for normal B-cell development. Ibrutinib is an orally administered inhibitor of ...BTK that induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells. MCL is an aggressive subtype of NHL, and despite high response rates to initial therapy, patients often relapse with acquired chemotherapy resistance and short response durations to conventional therapy. Preliminary results in 51 evaluable patients from the Phase 2 PCYC-1104 study demonstrated ibrutinib could achieve rapid nodal responses (including complete responses) in relapsed and refractory MCL patients (Wang et al, ASH 2011). Treatment with ibrutinib was associated with a transient increase in peripheral lymphocyte count representing a compartmental shift of cells with the CD19+/CD5+ phenotype from nodal tissues to peripheral blood (Chang et al, ASH 2011). Reported here are interim results of an international study of single-agent ibrutinib in previously treated MCL.
Subjects with relapsed or refractory MCL who were either bortezomib-naïve or bortezomib-exposed (prior treatment with at least 2 cycles of bortezomib) were enrolled. Ibrutinib was administered orally at 560mg daily (in continuous 28-day cycles) until disease progression. Bortezomib-naive and bortezomib-exposed cohorts were evaluated separately. Tumor response was assessed every 2 cycles according to the revised International Working Group for NHL criteria. The primary endpoint of the study is overall response rate (ORR). Secondary endpoints include: duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.
A total of 115 subjects (65 bortezomib-naïve and 50 bortezomib-exposed) were enrolled between February 15, 2011 and July 3, 2012. Of the 111 subjects treated, 109 subjects were evaluable for efficacy (received at least one dose of ibrutinib and underwent ≥ 1 tumor response assessment). Baseline characteristics include median age 68 years (40–84), median time since diagnosis 42 months, median number of prior treatments 3 (1–6), bulky disease (≥ 10 cm) 13%, Ann Arbor stage IV at screening 77.4%, prior stem cell transplant 9.6%, high risk by MIPI score at baseline assessment 48.7%, and refractory disease 44.3%.
Safety data are available for 111 subjects. Treatment-emergent AEs occurring in ≥ 15% of subjects: diarrhea (35%), fatigue (32%), upper respiratory tract infections (23%), nausea (21%), rash (21%), dyspnea (20%), and oedema peripheral (15%). Grade 3 or higher AEs occurring in ≥ 5% of subjects were neutropenia (11%), anemia (5%), diarrhea (5%), dyspnea (5%), pneumonia (5%), and thrombocytopenia (5%). Grade 4 treatment-related AEs were neutropenia (5%), hyperuricaemia (2%), and pancytopenia (1%). One grade 5 AE, pneumonia, was thought to be treatment-related. In the efficacy evaluable subjects, the ORR (complete + partial responses) is reported in Table 1. The median time on treatment was 6.0 months (0.7-16.6 months); 53% of subjects remain on treatment. Median DOR, PFS and OS have not been reached: 9 month DOR 65%, 12 month estimation of PFS 53% and OS 67%.Table 1:EfficacyBortezomib-naïve (n=63)Bortezomib-exposed (n=46)Total (n=109)ORR65.1%67.4%66.1%CR19%19.6%19.3%PR46%47.8%46.8%
Responses to ibrutinib increase with longer time on study treatment. Time to PR ranged from 1.4 – 8.3 months (median 1.9) and CR ranged from 1.7 – 11.2 months (median 3.9). This is seen with longer follow-up on the initial 51 subjects reported at ASH 2011: median time on study treatment was 3.8 months and is now 11.3 months; ORR was 69% and is now 74.5%; CR rate was 16% and is now 35.3%.
Longer follow up demonstrates the durability of responses and confirms the unprecedented single agent activity of ibrutinib in relapsed or refractory MCL in terms of ORR. The treatment- emergent AEs were consistent with safety data previously reported. A pivotal study in relapsed and refractory MCL patients following bortezomib treatment has been initiated.
Wang:Pharmacyclic: Research Funding. Off Label Use: Ibrutinib is a novel agent being studied in a clinical trial. Rule:Pharmacyclics: Research Funding. Martin:Pharmacyclics: Research Funding. Goy:Pharmacyclics: Research Funding. Auer:Pharmacyclics: Research Funding. Kahl:Pharmacyclics: Research Funding. Jurczak:Pharmacyclics: Research Funding. Advani:Pharmacyclics: Research Funding. McGreivy:pharmacyclics: Employment, Equity Ownership. Clow:Pharmacyclics: Employment, Equity Ownership. Stevens-Brogan:Pharmacyclics: Employment, Equity Ownership. Kunkel:Pharmacyclics: Employment, Equity Ownership. Blum:Pharmacyclics: Research Funding.
Bruton's Tyrosine Kinase (BTK) plays a critical role in chronic lymphocytic leukemia (CLL) cell survival by modulating B-cell receptor signaling. Ibrutinib (PCI-32765), a first-in-class oral ...inhibitor of BTK, inhibits proliferation, migration and adhesion in CLL cells. A total of 148 patients with CLL/SLL received ibrutinib monotherapy in a Phase 1 multiple ascending dose study (PCYC-04753) or Phase 1b/2 continuous dosing study (PCYC-1102-CA), after which a long-term extension study was available for continued follow-up for safety and efficacy with daily orally-administered ibrutinib monotherapy. The studies included patients with treatment-naïve (TN) and relapsed or refractory (RR) CLL/SLL. The aims of the present analysis were to evaluate safety based on time on ibrutinib therapy (≤ 1 year and > 1 year), summarize safety findings in the TN and RR patient populations, and assess duration of response (DOR).
Demographics and baseline characteristics were summarized according to parent study, comprising either TN patients or RR CLL/SLL patients who had received at least one dose of ibrutinib monotherapy. Patient disposition, treatment-emergent adverse events (AEs), best response, overall response rate (ORR), and DOR were determined for the time treated (beginning in the parent studies and extending into the long-term extension study).
At a median treatment duration of 21.5 months, 109 out of 148 patients continued treatment with ibrutinib for over a year. The percentage of patients who had a grade 3 or higher serious adverse event (SAE) declined over time from 43% within the first year of study treatment to 32% after the first year of treatment. With respect to side effects determined to be related to study drug, the number of grade 3 AEs and SAEs also declined from within the first year of treatment (24% and 8%, respectively) to after the first year of treatment (7% and 0%, respectively). AEs leading to ibrutinib discontinuation occurred in 12 patients within the first year of treatment for all 148 patients and in 6 out of 109 patients after the first year of treatment.
Overall, the most frequent AEs grade 3 or higher were pneumonia (16.9%), hypertension (13.5%), neutropenia (11.5%), thrombocytopenia (7.4%), and diarrhea (5.4%), regardless of relationship to study drug. Grade 3 or higher SAEs were reported in RR patients at 62% compared to TN patients at 29%. Pneumonia was reported in TN patients at 6.5% and in RR patients at 19.7%.
Within the efficacy population (n = 140), the ORR was 86.2% for TN patients and 88.3% for RR patients who achieved a partial response (PR) or better. The ORR combined with PR with lymphocytosis suggests that 93.1% of TN patients and 93.7% of RR patients achieved an objective response to ibrutinib therapy based on Cheson JCO 2012.
After a median follow up of 27.2 months (range 1.9-42 months) for TN and RR responders who achieved PR or better, the median DOR has not been reached. At landmark 30 months, 76.1% of the responders were alive without progression.
Ibrutinib as a single agent demonstrates long-term safety, tolerability, and durability of response in patients with TN and RR CLL/SLL. Indeed, a decrease in the number of patients experiencing SAEs or AEs grade 3 or higher after 1 year of treatment with ibrutinib resulted in low rates of treatment-related discontinuation after that time point. Grade 3 or higher SAEs were reported at a two-fold higher rate in patients who had received prior therapies, which may be reflective of disease state rather than relationship to ibrutinib. A majority of patients remain on ibrutinib monotherapy with the median DOR not yet reached in the ongoing extension study.
Patient CharacteristicsTreatment-Naïve CLL/SLL (≥ 65 years)Relapsed/Refractory CLL/SLLTotal CLL/SLLNumber of patients31117148Median age (range)71 (65, 84)65 (37, 82)68 (37, 84)Age ≥ 65 years31 (100%)60 (51%)91 (61%)≥ 3 Prior therapies083 (71%)83 (56%)Rai Stage III or IV17 (54%)62 (53%)79 (53%)Median time on study treatment, months (range)26.7 (0.3, 34.0)20.5 (0.3, 42.0)21.5 (0.3, 42.0)Patients continuing study treatment25/ 31 (81%)68/ 117 (58%)93/ 148 (63%)Treatment discontinuation due to disease progression1 (3%)21 (18%)22 (15%)Death within 30 days of last dose011 (9%)11 (7%)
O'Brien:Pharmacyclics: Research Funding. Furman:Genentech: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy; Gilead: Consultancy. Fowler:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Coutre:Pharmacyclics: Consultancy, Research Funding. Burger:Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jones:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wierda:Abbott Laboratories: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Research Funding, Speakers Bureau; Genentech/Roche: Consultancy, DSMB, DSMB Other, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tragara: Research Funding. Flinn:Pharmacyclics: Research Funding. Advani:Pharmacyclics: Research Funding; Janssen: Research Funding. Kolibaba:Pharmacyclics: Research Funding. Shaw:Pharmacyclics: Employment, Equity Ownership. Clow:Pharmacyclics: Employment, Equity Ownership. James:Pharmacyclics: Employment, Equity Ownership. Chu:Pharmacyclics: Employment, Equity Ownership. Byrd:Celgene: Consultancy; Johnson and Johnson: Consultancy; Pharmacyclics: Research Funding.
Abstract 189
BTK is an essential mediator of B-cell receptor signaling in normal and transformed B-cells. Ibrutinib (PCI-32765), an oral inhibitor to BTK, promotes apoptosis and inhibits ...proliferation, migration and adhesion in CLL cells. Chemoimmunotherapy (CIT) treatment approaches such as fludarabine, cyclophosphamide and rituximab have markedly improved outcomes of younger, fit patients (pts) as initial or second-line therapy. While effective, fludarabine-based therapy is less well tolerated in the elderly and carries significant risk of cellular immune suppression and myelosupression that limit protracted use. Additionally, virtually all pts eventually relapse after fludarabine-based CIT and effective salvage regimens that induce durable remissions are lacking. Herein, we present mature data from a large (n=116 pts) multi-cohort Phase Ib/II trial of ibrutinib in treatment-naive (TN) or relapsed/refractory (RR) CLL/SLL. Pts experienced a high frequency of disease control extending beyond 22 months in both TN and RR CLL/SLL including those with high risk genomic features.
Pts who were TN (all age >=65 years), RR (>= 2 prior therapies including a purine analog), or high-risk (HR) (relapse within 2 years following combination CIT or del 17p) were enrolled into 5 cohorts evaluating oral ibrutinib at fixed doses of 420mg or 840mg daily until disease progression (PD).CohortPopulationDose mg/dayGroup Size1relapsed/refractory420272treatment-naïve; aged ≥ 65 years420263relapsed/refractory840344High Risk - relapsed or refractory420245treatment-naïve; aged ≥ 65 years8405aaCohort closed prior to full accrual after comparable activity and safety between doses was shown in R/R pts.
Primary objective was to determine the safety of the two dosing regimens. Secondary objectives were to assess efficacy, PK/PD and long-term safety. Overall Response rate (ORR) inclusive of complete and partial responses (CR and PR respectively) was assessed per IWCLL guidelines. In addition, those pts who achieved a PR with the exception of lymphocytosis were categorized as PR with lymphocytosis.
Study PopulationTreatment naive, age >= 65yrs (cohort 2 & 5)Relapsed or Refractory (cohort 1 & 3)High risk (cohort 4)(N=116)Number of pts316124Median f/u, months (range)16.6 (1.4, 23.2)17.3 (0.3, 22.4)10.3 (1.1, 11.5)Age (range)71 (65, 84)64 (40, 81)68 (37, 82)Median # prior Tx (range)04 (1,12)4 (1,11)Hgb <11 g/dl OR Plt <100,000 μL61%57%63%b2M >3 mg/L8/31 (26%)30/57 (53%)9/23 (39%)IgVH unmutated (UM)17/31 (55%)50/58 (86%)19/23 (83%)del 17p2/30 (7%)21/57 (37%)7/23 (30%)del 11q1/30 (3%)23/57 (40%)8/23 (35%)Best Response by Cohort:IWCLL ORR (CR + PR)71%67%50%CR10%3%0PR61%64%50%PR with lymphocytosis10%20%29%SD13%5%8%PD02%4%Not evaluable6%7%8%
The majority of AEs have been Gr ≤ 2 in severity, most commonly diarrhea (54%), fatigue (29%), upper respiratory tract infection (29%), rash (28%), nausea (26%) and arthralgias (25%). Hematologic toxicity ≥ Gr 3 was relatively infrequent. There was no evidence of cumulative toxicity or long-term safety concerns with a median follow-up of 16 months for the 116 treated pts. Treatment discontinuation for AE occurred in 7/116 pts across cohorts. Serial evaluation of serum immunoglobulins revealed a significant increase in IgA at 3, 6, and 12 months (P < 0.005 at each time point) with no decline in IgG or IgM.
Responses were observed independent of poor-risk factors including advanced stage disease, prior lines of therapy, b2M, or cytogenetics (e.g. ORR in del 17p R/R (cohorts 1 & 3) 67%). Interestingly, 56/69 relapsed pts with UM IgVH developed treatment related lymphocytosis compared to 11/11 pts with mutated (M) IgVH that resolved more rapidly (median time to normalization 6.2 vs 14.8 months) and normalized more frequently (86% vs 55% P<0.04) compared to those with M IgVH.
Estimated 22 month PFS for the 85 RR and HR pts is 76% and for the 31 TN pts is 96%. Estimated 22 month OS for 85 R/R and HR pts is 85% and for the 31 TN pts is 96%. Median PFS and OS have not been met for any of the cohorts including pts with high-risk factors (see Figure- PFS by 17p del status).
Ibrutinib monotherapy is highly active, well tolerated, and induces durable remissions in pts with RR CLL including those with high-risk disease and in older TN pts warranting phase III evaluation in these populations. Display omitted Display omitted
Byrd:Pharmacyclics: Research Funding. Off Label Use: Ibrutinib is not approved for the treatment of NHL. Burger:Pharmacyclics: Consultancy, Research Funding. Sharman:Celgene: Consultancy; Pharmacyclics: Honoraria; Calistoga: Honoraria; Portola pharmaceuticals: Consultancy. Tran:pharmacyclics: Employment, Equity Ownership. Clow:Pharmacyclics: Employment, Equity Ownership. Kunkel:Onyx Pharmaceuticals: Consultancy. James:Pharmacyclics: Employment, Equity Ownership. O'Brien:Pharmacyclics: Research Funding.
To evaluate the safety profile, pharmacokinetics, and thrombolytic activity of alfimeprase, a novel direct-acting thrombolytic agent, in patients with chronic peripheral arterial occlusion (PAO).
In ...this multicenter, open-label, single-dose, dose-escalation study, 20 patients with worsening symptoms of lower extremity ischemia within 6 months of enrollment were treated with alfimeprase in five escalating dose cohorts (0.025 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.3 mg/kg, and 0.5 mg/kg) by means of intraarterial and sometimes intrathrombic pulsed infusion. The primary endpoint was safety assessed by adverse event rates. Additional safety assessments included vital sign monitoring, serum chemistry testing, hematologic testing, and coagulation testing for 28 days after the procedure, as well as alpha2-macroglobulin and antialfimeprase antibody testing for as long as 3 months after treatment. Pharmacokinetic parameters were evaluated with use of an assay that measures free and alpha2-macroglobulin-bound (ie, total) alfimeprase.
No patient experienced a hemorrhagic adverse event. Mean plasminogen and fibrinogen concentrations were not substantially altered by treatment. Three transient treatment-related adverse events were reported in the same patient: one incidence each of increased blood fibrinogen level, skin rash, and headache. All three adverse events were graded as mild. The pharmacokinetic profile of alfimeprase suggested that the half-life for total alfimeprase ranges from 11 to 54 minutes (median, 25 min) in patients with PAO. The serum alpha2-macroglobulin concentrations decreased transiently in a dose response-like manner between 12 and 24 hours and returned to within normal limits approximately 14 days after alfimeprase exposure.
Alfimeprase in doses as high as 0.5 mg/kg was generally well-tolerated in patients with chronic PAO. No bleeding complications were noted. The stable fibrinogen concentrations suggest that the activity of alfimeprase may be limited to the target thrombus. Alfimeprase holds the potential to achieve dissolution of thrombus with a diminished risk of hemorrhage.
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