Clinical trial NCT01611090: A Study of Ibrutinib in Combination With Bendamustine and Rituximab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
Official title: Randomized, Double-blind, Placebo-controlled Phase 3 Study of Ibrutinib, a Bruton's Tyrosine Kinase (BTK) Inhibitor, in Combination With Bendamustine and Rituximab (BR) in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Keywords: Chronic lymphocytic leukemia
Small lymphocytic lymphoma
Relapsed or refractory chronic lymphocytic leukemia
Relapsed or refractory small lymphocytic lymphoma
Ibrutinib
PCI-32765
JNJ-54179060
Bruton's tyrosine kinase inhibitor
Bendamustine
Rituximab
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
Collaborators: name: Pharmacyclics LLC.
First posted: 2012-06-04
Enrollment: 578
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to examine the safety and efficacy of Ibrutinib administered in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Detailed description: This is a randomized (patients will be assigned by chance to study treatments), double-blind (patients and study personnel will not know the identity of study treatments), placebo (an inactive substance that is compared with a drug to test whether the drug has a real effect in a clinical trial)-controlled study to determine the benefits and risks of combining ibrutinib with bendamustine and rituximab (BR) in patients with relapsed or refractory CLL/SLL following at least 1 line of prior systemic therapy. Approximately 580 patients will be randomized in a 1:1 ratio to either treatment arm A (placebo) or treatment arm B (ibrutinib 420 mg).

Study medication will be administered orally once daily on a continuous schedule. All patients will receive BR as the background therapy plus either ibrutinib or placebo for a maximum of 6 cycles, after which treatment with ibrutinib or placebo will continue until disease progression or unacceptable toxicity.

A treatment cycle will be defined as 28 days. The study will include a screening phase, a treatment phase, and a follow-up phase. Study end is defined as when either 80% of the patients have died or 5 years after the last patient is randomized into the study, whichever occurs first.

Patients in treatment arm A (placebo) who complete the treatment phase, with disease progression or (after interim analysis) meet International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria for treatment, may crossover to ibrutinib treatment (as in treatment arm B), at the investigators discretion. This open-label, next-line treatment with ibrutinib will continue until disease progression, unacceptable toxicity, withdrawal from study, or until the study end, whichever occurs earlier. One interim analysis is planned for the study. Efficacy evaluations will include computed tomography scans, laboratory testing, focused physical examinations, bone marrow biopsy and aspirate, and assessment of patient-reported outcomes. In both treatment arms, samples for the development of a population-based pharmacokinetic (PK; study of what the body does to a drug) approach will be collected. Safety will be assessed throughout the study.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that meets protocol-defined criteria
* Active disease meeting at least 1 of the International Workshop on Chronic Lymphocytic Leukemia 2008 criteria for requiring treatment
* Measurable nodal disease by computed tomography
* Relapsed or refractory CLL or SLL following at least 1 prior line of systemic therapy consisting of at least 2 cycles of a chemotherapy-containing regimen
* Eastern Cooperative Oncology Group Performance Status score of 0 or 1
* Hematology and biochemical values within protocol-defined limits
* Agrees to protocol-defined use of effective contraception
* Women of childbearing potential must have negative blood or urine pregnancy test at screening

Exclusion Criteria:

* Recent therapeutic interventions within 3 (chemotherapy/radiotherapy) to 10 weeks (immunotherapy)
* Prior treatment with ibrutinib or other Bruton's tyrosine kinase inhibitors or prior randomization in any other clinical study evaluating ibrutinib
* The presence of deletion of the short arm of chromosome 17
* Patients previously treated with a bendamustine-containing regimen who did not achieve a response or who relapsed and required treatment within 24 months of treatment with that regimen
* Patients for whom the goal of therapy is tumor debulking prior to stem cell transplant
* Received a hematopoietic stem cell transplant
* Known central nervous system leukemia/lymphoma or Richter's transformation
* Patients with uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia
* Chronic use of corticosteroids
* History of prior malignancy, except: malignancy treated with curative intent and with no known active disease present for \>=3 years before randomization; adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; adequately treated cervical carcinoma in situ without evidence of disease
* History of stroke or intracranial hemorrhage within 6 months prior to randomization; or clinically significant cardiovascular disease
* Requires anticoagulation with warfarin or equivalent vitamin K antagonists or treatment with strong CYP3A4/5 inhibitors
* Known history of human immunodeficiency virus or hepatitis C, or active infection with hepatitis B or C
* Any uncontrolled active systemic infection or any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the patient's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk
* A woman who is pregnant or breast feeding, or a man who plans to father a child while enrolled in this study or within 3 months after the last dose of study drug

Primary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: Up to 5 years
Secondary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: Up to 5 years
measure: Overall Survival (OS)
timeFrame: Up to 5 years
measure: Percentage of Participants With Minimal Residual Disease (MRD)-Negative Response
timeFrame: Up to 5 years
measure: Percentage of Participants With Sustained Hematologic Improvement
timeFrame: Up to 5 years
measure: Median Time to Clinically Meaningful Improvement in FACIT-Fatigue Scale
timeFrame: Up to 2 years
measure: Number of Participants With Clinically Relevant Shifts in Disease-Related Symptoms
timeFrame: From the date of randomization to disease progression (Up to 2 years)
measure: Number of Participants Who Received Subsequent Antineoplastic Therapy
timeFrame: Up to 5 years
measure: Change From Baseline in Beta2 Microglobulin at End of Treatment (EOT)
timeFrame: Baseline to EOT (Up to 2 years)
measure: Change From Baseline in FACIT-Fatigue Scale at End of Treatment
timeFrame: Baseline to EOT (up to 2 years)
measure: Change From Baseline in EORTC QLQ-C30 Physical Functioning Score at End of Treatment
timeFrame: Baseline to EOT (up to 2 years)
measure: Change From Baseline in EORTC QLQ-CLL 16 Domain Scores at End of Treatment
timeFrame: Baseline to EOT (up to 2 years)
measure: Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) Visual Analog Scale at End of Treatment
timeFrame: Baseline to EOT (up to 2 years)
measure: Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) Utility Score Scale at End of Treatment
timeFrame: Baseline to EOT (up to 2 years)
Other outcomes:
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city: Brugge
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city: Salvador
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city: Petah Tikva
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city: Tel Aviv
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city: Seoul
country: Korea, Republic of
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country: Mexico
city: Monterrey
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city: Oaxaca
country: Mexico
city: Brzozow
country: Poland
city: Chorzów
country: Poland
city: Krakow
country: Poland
city: Opole
country: Poland
city: Slupsk
country: Poland
city: Coimbra
country: Portugal
city: Lisboa
country: Portugal
city: Ponta Delgada
country: Portugal
city: Porto
country: Portugal
city: Arkhangelsk
country: Russian Federation
city: Dzerzhinsk
country: Russian Federation
city: Ekaterinburg
country: Russian Federation
city: Krasnodar
country: Russian Federation
city: Moscow N/a
country: Russian Federation
city: Moscow
country: Russian Federation
city: Nizhniy Novgorod
country: Russian Federation
city: Obninsk
country: Russian Federation
city: Perm
country: Russian Federation
city: Rostov-Na-Donu
country: Russian Federation
city: Ryazan
country: Russian Federation
city: Saint Petersburg
country: Russian Federation
city: Samara
country: Russian Federation
city: Sochi
country: Russian Federation
city: St. Petersburg
country: Russian Federation
city: St.-Petersburg
country: Russian Federation
city: Syktyvkar
country: Russian Federation
city: Barcelona
country: Spain
city: L'hospitalet De Llobregat
country: Spain
city: Madrid
country: Spain
city: Salamanca
country: Spain
city: Valencia
country: Spain
city: Göteborg
country: Sweden
city: Huddinge
country: Sweden
city: Stockholm
country: Sweden
city: UMEå
country: Sweden
city: Ankara
country: Turkey
city: Istanbul
country: Turkey
city: Izmir
country: Turkey
city: Kayseri
country: Turkey
city: Cherkassy
country: Ukraine
city: Dnepropetrovsk
country: Ukraine
city: Donetsk
country: Ukraine
city: Khakhiv
country: Ukraine
city: Khmelnitskiy
country: Ukraine
city: Kiev
country: Ukraine
city: Lviv
country: Ukraine
city: Vinnitsa
country: Ukraine
city: Birmingham
country: United Kingdom
city: Harrow
country: United Kingdom
city: Plymouth
country: United Kingdom
city: Sheffield Yorks
country: United Kingdom
city: Sutton
country: United Kingdom
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References:
citation: Fraser GAM, Chanan-Khan A, Demirkan F, Santucci Silva R, Grosicki S, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Loscertales J, Avigdor A, Rule S, Samoilova O, Pavlovsky MA, Goy A, Mato A, Hallek M, Salman M, Tamegnon M, Sun S, Connor A, Nottage K, Schuier N, Balasubramanian S, Howes A, Cramer P. Final 5-year findings from the phase 3 HELIOS study of ibrutinib plus bendamustine and rituximab in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Leuk Lymphoma. 2020 Dec;61(13):3188-3197. doi: 10.1080/10428194.2020.1795159. Epub 2020 Aug 6.
citation: Lavezzi SM, de Jong J, Neyens M, Cramer P, Demirkan F, Fraser G, Bartlett N, Dilhuydy MS, Loscertales J, Avigdor A, Rule S, Samoilova O, Goy A, Ganguly S, Salman M, Howes A, Mahler M, De Nicolao G, Poggesi I. Systemic Exposure of Rituximab Increased by Ibrutinib: Pharmacokinetic Results and Modeling Based on the HELIOS Trial. Pharm Res. 2019 May 1;36(7):93. doi: 10.1007/s11095-019-2605-8.
citation: Brown JR, Moslehi J, O'Brien S, Ghia P, Hillmen P, Cymbalista F, Shanafelt TD, Fraser G, Rule S, Kipps TJ, Coutre S, Dilhuydy MS, Cramer P, Tedeschi A, Jaeger U, Dreyling M, Byrd JC, Howes A, Todd M, Vermeulen J, James DF, Clow F, Styles L, Valentino R, Wildgust M, Mahler M, Burger JA. Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. Haematologica. 2017 Oct;102(10):1796-1805. doi: 10.3324/haematol.2017.171041. Epub 2017 Jul 27.
citation: Chanan-Khan A, Cramer P, Demirkan F, Fraser G, Silva RS, Grosicki S, Pristupa A, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Pylypenko H, Loscertales J, Avigdor A, Rule S, Villa D, Samoilova O, Panagiotidis P, Goy A, Mato A, Pavlovsky MA, Karlsson C, Mahler M, Salman M, Sun S, Phelps C, Balasubramanian S, Howes A, Hallek M; HELIOS investigators. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016 Feb;17(2):200-211. doi: 10.1016/S1470-2045(15)00465-9. Epub 2015 Dec 5.