Idelalisib or Placebo in Combination with Bendamustine and
Rituximab in Patients with Relapsed/Refractory CLL - Interim
Results of a Phase 3 Randomized, Double-blind Placebo-
Controlled Trial
Andrew D. Zelenetz, MD, Prof
1
, Jacqueline C. Barrientos, MD
2
, Jennifer R. Brown, MD
3
,
Bertrand Coiffier, MD, Prof
4
, Julio Delgado, MD
5
, Miklós Egyed, MD, Prof
6
, Paolo Ghia, MD
7
,
Árpád Illés, MD, Prof
8
, Wojciech Jurczak, MD
9
, Paula Marlton, MBBS
10
, Marco Montillo,
MD
11
, Franck Morschhauser, MD, Prof
12
, Alexander S. Pristupa, MD
13
, Tadeusz Robak, MD,
Prof
14
, Jeff P. Sharman, MD
15
, David Simpson, MB, ChB
16
, Lukáš Smolej, MD
17
, Eugen
Tausch, MD
18
, Adeboye H. Adewoye, MD
19
, Lyndah K. Dreiling, MD
19
, Yeonhee Kim, PhD
19
,
Stephan Stilgenbauer, MD, Prof
18
, and Peter Hillmen, MB, ChB, Prof.
20
1
Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center and Weill
Cornell Medical College, 1275 York Avenue, New York, NY, USA
2
Hofstra Northwell School of
Medicine, Hofstra University, New Hyde Park, NY 11042, USA
3
Department of Medical Oncology,
450 Brookline Avenue, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
02215, USA
4
Department of Hematology, Centre Hospitalier Lyon Sud, 165 Chemin du Grand
Revoyet, 69310 Pierre-Bénite, France
5
Department of Hematology, Hospital Clínic, Villarroel, 170,
This manuscript version is made available under the CC BY-NC-ND 4.0 license.
Corresponding Author: Andrew D. Zelenetz, MD, PhD, Department of Medicine, Lymphoma Service, Memorial Sloan Kettering
Cancer Center, 1275 York Avenue, New York, NY, Telephone: (212) 639-2656, Fax: (212) 717-3036, zeleneta@mskcc.org.
Contributors
ADZ and AHA wrote the initial draft of the manuscript and ET and SS performed the genetic analyses. Employees of Gilead Sciences,
Inc., contributed to the study design, implementation, and data analyses. All authors critically reviewed each draft and provided
feedback and intellectual content, contributed to the data, reviewed the data analyses, and provided final approval to submit the
manuscript for publication.
Declaration of Interests
ADZ, AI, ASP, BC, ME, PH, and WJ have received institutional research grants from Gilead Sciences. AHA, LKD, XL, and YK are
employees of Gilead Sciences, Inc. DS received grants from Amgen; personal fees from Celgene, Janssen, and Roche; and non-
financial support from Celgene. FM received personal fees from Celgene, Genentech/Roche, Gilead, and Janssen. JCB received
research support from Gilead and participated in Gilead Advisory Boards. JD received consulting and lecturing fees from Gilead,
Janssen, Roche, and GSK-Novartis. JRB received personal fees from Sun Biopharma, Janssen, Gilead, Pharmacyclics, Infinity,
Celgene, Roche/Genentech and Pfizer. JPS has received research funding, honoraria, and speaking fees from Gilead. LS received
research support from Roche and also received honoraria, advisory boards fees, and travel grants from Gilead, Janssen, Novartis, and
Abbvie. MM received research grants, personal fees, and non-financial support from Gilead; and personal fees from Janssen, Roche,
and Novartis. PG has received personal fees from Adaptive Biotechnologies, AbbVie, Gilead, Janssen, and Pharmacyclics; and grants
from Gilead, Celgene, and Roche. ET received grants, personal fees and non-financial support from Gilead, non-financial support
from Celgene, and grants, personal fees and non-financial support from GlaxoSmithKline. SS have received grants and personal fees
from AbbVie, Amgen, Boehringer-Ingelheim, Celgene, Genentech, Genzyme, Gilead, GlaxoSmithKline, Janssen, Mundipharma,
Novartis, Pharmacyclics, Hoffmann La-Roche, and Sanofi. TR received research support and personal fees from Gilead. PM received
personal fees from Gilead, Pfizer and Amgen, and personal fees and non-financial support from Roche, Janssen, Novartis, and Takeda.
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Author manuscript
Lancet Oncol
. Author manuscript; available in PMC 2018 March 01.
Published in final edited form as:
Lancet Oncol
. 2017 March ; 18(3): 297–311. doi:10.1016/S1470-2045(16)30671-4.
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
08036 Barcelona, Spain
6
Department of Hematology, Somogy County Kaposi Mor Hospital,
Kaposvar, Tallián Gyula utca 20-32 -7400 Hungary
7
Division of Experimental Oncology and
Department of Onco-Hematology, IRCCS Ospedale San Raffaele and Università Vita-Salute San
Raffaele, Via Olgettina, 60, 20132 Milan, Italy
8
Department of Hematology, Institution of Internal
Medicine Building B, University of Debrecen, Debrecen, Nagyerdei krt 98, 4032 Hungary
9
Department of Hematology, Jagiellonian University, ul. Kopernika 17, 31-501 Krakow, Poland
10
Department of Hematology, Princess Alexandra Hospital, University of Queensland, School of
Medicine, 199 Ipswich Rd Woolloongabba QLD 4102, Brisbane, Australia
11
Department of
Hematology, Niguarda Cancer Center, Niguarda Hospital, Piazza Ospedale Maggiore, 3, 20162
Milan, Italy
12
CHRU Lille, Unité GRITA, Department of Hematology, Université de Lille, EA 4481
GRIIOT, Lille, France
13
Department of Hematology, Ryazan Regional Clinical Hospital, Ryazan,
Russia
14
Department of Hematology, Medical University of Lodz and Copernicus Memorial
Hospital, Ciolkowskiego 2, Lodz, 93-510 Poland
15
US Oncology Research, Willamette Valley
Cancer Institute and Research Center, 520 Country Club Parkway, Eugene, OR 97401, USA
16
North Shore Hospital, 124 Shakespeare Rd, Takapuna, Auckland 0620, New Zealand
17
4th
Department of Internal Medicine-Hematology, University Hospital and Charles University in
Prague, Faculty of Medicine in Hradec Králové, Sokolská 581, 500 05 Hradec Králové, Czech
Republic
18
Department of Internal Medicine III, Ulm University, Albert-Einstein-Allee 23, 89081
Ulm, Germany
19
Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA
20
Department of Hematology/Oncology, St. James's University Hospital, Beckett Street, Leeds
LS9 7TF, UK
Summary
Background—Bendamustine and rituximab (BR) has been a standard of care for the
management of patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). We
evaluated the efficacy and safety of adding idelalisib, a first-in-class targeted PI3Kδ inhibitor, to
BR in patients with R/R CLL
Methods—This trial was a global, multicenter, double-blind, placebo -controlled trial in adult
patients (≥18 years) with R/R CLL requiring treatment for their disease. Patients had to have
measurable lymphadenopathy (≥1 nodal lesion ≥2.0 cm in the longest diameter and ≥1.0 cm in the
longest perpendicular diameter) by computer tomography or magnetic resonance imaging, disease
progression within <36 months since last prior therapy, a Karnofsky Performance Status score ≥60
and adequate bone marrow, liver and kidney function. Key exclusion criteria included histological
transformation to an aggressive lymphoma (eg, Richter transformation) or disease refractory to
bendamustine. Patients were randomised 1:1 using a central interactive web response system that
assigned a unique treatment code for each patient, to receive intravenous BR infusions for a
maximum of 6 cycles in addition to blinded study drug matching the assigned treatment of either
twice-daily oral idelalisib 150 mg or placebo administered continuously until disease progression
or intolerable study drug-related toxicity. Randomisation was stratified based on high-risk features
(
IGHV
, del(17p)/
TP53
mutation) and refractory vs relapsed disease. The primary endpoint was
progression-free survival (PFS) assessed by an independent review committee in the intent-to-treat
population. Overall survival was a key secondary endpoint. Crossover was not permitted to the
idelalisib arm at progression. The trial is ongoing (ClinicalTrials.gov # NCT01569295).
Zelenetz et al. Page 2
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Findings—Between 26 June 2012 and 21 August 2014, 416 patients with R/R CLL were
enrolled; 207 patients were randomised to the idelalisib and 209 to the placebo arm. After the
prespecified interim analysis, the Independent Data Monitoring Committee (IDMC) recommended
discontinuation and unblinding of the trial due to efficacy. Updated data are presented in this
manuscript with a cutoff date of 07 October 2015. Median (95% CI) PFS was 20·8 (16·6, 26·4)
and 11·1 (8·9, 11·1) months in the idelalisib and placebo arms, respectively (hazard ratio [HR],
0·33; 95% CI, 0·25, 0·44; P<0·0001) at a median (Q1, Q3) follow-up of 14 (7, 18) months. The
most frequent grade 3 or greater AEs were neutropenia (124/207 [60%]) and febrile neutropenia
(48/207 [23%]) in the idelalisib arm and neutropenia (99/209 [47%]) and thrombocytopenia
(27/209 [13%]) in the placebo arm. Serious AEs included febrile neutropenia, pneumonia and
pyrexia and were common in both treatment arms. An increased risk of infection was observed in
the idelalisib vs placebo arm.
Interpretation—Idelalisib plus BR is superior to BR alone, improving PFS and OS. This
regimen represents an important new treatment option for patients with R/R CLL.
Introduction
Most patients with chronic lymphocytic leukemia (CLL) will suffer disease relapse
following standard frontline chemoimmunotherapy.
1
Relapse risk is increased in patients
with high-risk features (eg, unmutated immunoglobulin heavy chain variable region [
IGHV
]
genes,
TP53
mutation [
TP53mut
], deletions of the short arm of chromosome 17 [del(17p)])
or disease refractory to therapy.
1–4
Treatment choice at relapse is dependent on the interval
since completion of last therapy, presence of high-risk features, previously administered
agents, and patient fitness.
1,5
For most patients, the goals of therapy are to maximize durable
disease control and relief of symptoms; however, disease control becomes increasingly
difficult at relapse due to toxicities from pre-existing therapies and clonal evolution resulting
in resistance to therapy.
Phosphoinositide 3-kinase (PI3K) cellular signaling pathways mediate key cellular functions
including cell growth, proliferation, differentiation, motility, and survival.
6
Expression of the
PI3K delta isoform (PI3Kδ) is largely restricted to leucocytes. In CLL, cellular trafficking
via chemokine receptor type 4/5 and B-cell receptor responses involve PI3Kδ signaling,
making it an attractive target for therapy.
6
Idelalisib, a first-in-class PI3Kδ inhibitor, is
approved for use in combination with rituximab for patients with relapsed CLL who are not
candidates for chemotherapy.
7,8
We hypothesized that idelalisib in combination with
bendamustine and rituximab (BR) would improve efficacy as defined by progression-free
survival (PFS) with tolerable toxicity in patients with relapsed/refractory (R/R) CLL.
Methods
Study design and participants
In this phase 3, randomized, multicenter, double-blind, placebo-controlled study, patients
were enrolled at total of 110 sites in the following 19 countries: Australia, Belgium, Canada,
Croatia, Czech Republic, France, Greece, Hungary, Ireland, Italy, New Zealand, Poland,
Portugal, Romania, Russia, Spain, Turkey, United Kingdom, and United States (Appendix
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page 3). The trial was conducted according to the principles of Good Clinical Practice and
the Declaration of Helsinki. Institutional review boards at each study site approved the
protocols. All patients provided written informed consent.
Eligible were male and female patients ≥18 years of age who had a diagnosis of CLL
requiring treatment according to International Workshop on Chronic Lymphocytic Leukemia
(IWCLL) criteria,
9
measurable lymphadenopathy (≥1 nodal lesion that measures ≥2.0 cm in
the longest diameter and ≥1.0 cm in the longest perpendicular diameter) by computer
tomography (CT) or magnetic resonance imaging (MRI), had received prior therapy
containing a purine analog or bendamustine and an anti-CD20 monoclonal antibody,
experienced CLL progression less than 36 months since completion of the last prior therapy,
and were fit to receive cytotoxic therapy and had Karnofsky Performance Status score of
≥60. Although not an eligibility requirement, an average life expectancy of the patients was
≥120 days.
Disease progression at inclusion was assessed by the investigator and was based on IWCLL
criteria that included indications for treatment.
9
Required baseline laboratory values
included serum bilirubin ≤1·5 x upper limit of normal (ULN, unless due to Gilbert’s
syndrome or hemolysis) and serum transaminases up to 2·5 x ULN. Grade 2 neutropenia,
thrombocytopenia, or anemia were permitted only if deemed related to bone marrow
involvement with CLL, documented by bone marrow biopsy. Whether patients were deemed
fit to receive the BR regimen depended on the protocol eligibility requirements such as
performance status, creatinine clearance ≥40 ml/min (calculated using the Cockcroft-Gault
equation), and the medical judgment of the investigator with consideration for the number
and severity of comorbid conditions in each patient.
Key exclusion criteria included known histological transformation to an aggressive
lymphoma (eg, Richter transformation); disease refractory to bendamustine (ie, no response
or progression less than six months from last dose of bendamustine); chronic active hepatitis
B or C; pneumonitis; or prior therapy with inhibitors of AKT, BTK, JAK, mTOR, PI3K
(including idelalisib), or SYK. All patients provided written informed consent.
Randomisation and masking
A central Interactive Web Response System (IWRS) was used to assign a unique treatment
code for each patient, as well as bottle numbers and instructions for dispensing of blinded
study drug matching the assigned treatment. Patients were randomized in a 1:1 ratio based
on a computer-generated randomisation schedule prepared by Triangle Biostatistics
(Wilmington, NC, USA) to receive either idelalisib or placebo in combination with BR. The
randomisation was balanced by randomly permuted blocks with a block size of four. Patients
were stratified based on the presence or absence of del(17p) and/or
TP53
mutation: either vs
neither (or indeterminate),
IGHV
mutation status: unmutated or
IgHV3-21
) vs mutated (or
indeterminate) and by disease status: refractory (CLL progression <6 months from
completion of prior therapy) or relapsed (CLL progression ≥6 months from completion of
prior therapy) disease.
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Blinding was achieved through the use of a placebo that was well matched to the active drug
in appearance, packaging, labeling, and schedule of administration. During the study, both
patients and study personnel remained blinded to the identity of the treatment assignments,
which were available only to the IWRS, the Independent Data Monitoring Committee
(IDMC), and drug safety personnel. Following an interim analysis, the final study
unblinding occurred upon recommendation by the IDMC.
Procedures
Study treatment consisted of twice-daily oral idelalisib 150 mg or matching placebo. In both
treatment arms, bendamustine 70 mg/m
2
was administered intravenously on days 1 and 2 for
six 28-day cycles. Rituximab was administered intravenously with each cycle of
bendamustine at 375 mg/m
2
on day 1 of cycle 1 and 500 mg/m
2
on day 1 of cycles 2 to 6.
Bendamustine and rituximab were administered up to a maximum of 12 and six infusions,
respectively. Idelalisib/placebo was administered continuously until disease progression,
death, intolerable toxicity, pregnancy, substantial noncompliance with study procedures,
study discontinuation, or withdrawn consent (Appendix page 6). Detailed guidelines for
modifications of all study treatments can be found in our protocol online. Briefly, in case an
AE was deemed related to study drug (either idelalisib/placebo), the administration of the
drug was held or modified. After the AE had resolved, the study drug could be reinstituted at
either the starting dose level (150 mg/dose twice daily) or at the reduced dose level (100 mg/
dose twice daily).
Clinic/laboratory visits occurred every two weeks through week 24, every six weeks
between weeks 24 and 48, and every 12 weeks thereafter. At each visit, safety and CLL
disease status were assessed by physical and laboratory examinations. Imaging by CT or
MRI was performed every 12 weeks and evaluated by the Independent Review Committee
(IRC) for evidence of response or disease progression, according to IWCLL criteria.
9
At the
time of discontinuation from the study, an end-of-study CT/MRI tumor assessment was
performed unless the patient already had radiographic confirmation of definitive disease
progression. This assessment was followed by a safety visit 30 days thereafter. Patients who
permanently discontinued the study treatment for a reason other than disease progression
could continue on study with regular assessments until disease progression or another
anticancer or experimental therapy was initiated. Long-term follow-up for survival was
conducted at approximately six-month intervals for five years. Data had been collected
longitudinally for peripheral blood CD4 count, serum immunoglobulin and health-related
quality of life (FACT-Leu, EuroQoL-5 Dimensions [EQ-5D]), but were not analysed at the
time of this publication. The data for del 11q had also been collected but have not yet been
fully collated and analysed.
Overall safety profile of each treatment was characterized by the type, frequency, severity,
timing of onset, duration, and relationship to study therapy of any adverse events (AEs) or
abnormalities of laboratory tests. Adverse events were classified using the Medical
Dictionary for Regulatory Activities (MedDRA) version 18.0. The severity of AEs was
graded by the investigator according to the Common Terminology Criteria for Adverse
Events (CTCAE), Version 4.03.
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