Clinical trial NCT01646021: Study of Ibrutinib (a Bruton's Tyrosine Kinase Inhibitor), Versus Temsirolimus in Patients With Relapsed or Refractory Mantle Cell Lymphoma Who Have Received at Least One Prior Therapy
Official title: A Randomized, Controlled, Open-Label, Multicenter Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, Versus Temsirolimus in Subjects With Relapsed or Refractory Mantle Cell Lymphoma Who Have Received at Least One Prior Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Mantle Cell Lymphoma
Keywords: Mantle cell lymphoma
Relapsed mantle cell lymphoma
Refractory mantle cell lymphoma
Ibrutinib
Bruton's tyrosine kinase inhibitor
Temsirolimus
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
Collaborators: name: Pharmacyclics LLC.
First posted: 2012-07-20
Enrollment: 280
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 evaluate the efficacy and safety of ibrutinib versus temsirolimus in patients with relapsed or refractory mantle cell lymphoma who received at least 1 prior chemotherapy regimen.

Detailed description: This is a randomized (individuals assigned to study treatment by chance), open-label (identity of assigned study drug will be known), study to evaluate the efficacy and safety of ibrutinib when compared with temsirolimus in patients with relapsed or refractory mantle cell lymphoma (MCL) who have received at least 1 prior rituximab-containing chemotherapy regimen. Approximately 280 eligible patients will be randomly assigned in a 1:1 ratio and stratified (grouped) by the number of prior lines of therapy (1 or 2 versus \>=3) and simplified MCL International Prognostic Index criteria to receive either ibrutinib by mouth (Treatment Arm A) or temsirolimus intravenous infusion (Treatment Arm B). The study will consist of screening, treatment, and posttreatment phases. Data will be collected on disease response to the treatment, progression-free survival, overall survival, subsequent anti-MCL therapies, patient reported outcomes, and medical resource utilization. Tumor samples, blood collected at multiple time points, and a bone marrow aspirate will be evaluated to identify markers predictive of response or resistance to ibrutinib. Serial pharmacokinetic (study of what the body does to a drug) samples will be collected as detailed in the protocol. Safety will be monitored throughout the study. Disease evaluations will be performed every 9 weeks for up to 15 months from the start of study drug, and every 24 weeks thereafter, until disease progression, death, or the clinical cutoff, whichever comes first. Patients who receive treatment with temsirolimus and have disease progression (confirmed by an Independent Review Committee) may be eligible to crossover and receive treatment with ibrutinib 560 mg orally, daily, on a 21-day cycle until disease progression, unacceptable toxicity, or study end. Data will be analyzed up to 3 years after the last patient is enrolled for the final follow-up.

Eligibility criteria: Inclusion Criteria:

* Confirmed diagnosis of mantle cell lymphoma (MCL)
* Received at least 1 prior rituximab-containing chemotherapy regimen (separate lines of therapy are defined as single or combination therapies that are either separated by disease progression or by a \> 6 month treatment-free interval)
* Documented relapse or disease progression following the last anti-MCL treatment
* At least 1 measurable site of disease according to Revised Response Criteria for Malignant Lymphoma
* Eastern Cooperative Oncology Group performance status grade 0 or 1
* Protocol-defined hematology and biochemistry laboratory values

Exclusion Criteria:

* Prior nitrosoureas within 6 weeks, chemotherapy within 3 weeks, therapeutic anticancer antibodies within 4 weeks, radio- or toxin-immunoconjugates within 10 weeks, radiation therapy or other investigational agents within 3 weeks, or major surgery within 4 weeks of randomization
* Prior treatment with temsirolimus, other mTOR inhibitors, ibrutinib, or other Bruton's tyrosine kinase (BTK) inhibitors
* Known central nervous system lymphoma
* Received an allogeneic or autologous hematopoietic stem cell transplant \<=6 months from the date of randomization and on immunosuppressive therapy or have evidence of active graft versus host disease
* Diagnosed or treated for malignancy other than MCL, 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
* Requires anticoagulation with warfarin or equivalent vitamin K antagonist
* Requires treatment with strong CYP3A inhibitor
* Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification
* Known history of human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or active hepatitis B virus (HBV) infection or any uncontrolled active systemic infection requiring intravenous antibiotics
* Woman who is pregnant or breast-feeding
* 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

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: Time from the date of randomization until the date of first documented evidence of progressive disease (or relapse for subjects who experience CR during the study) or death, whichever occurred first (approximately 48 months)
Secondary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: Approximately up to 48 months
measure: Overall Survival (OS)
timeFrame: Approximately up to 48 months
measure: Duration of Response
timeFrame: Approximately up to 48 months
measure: Time-to-Next Treatment
timeFrame: Approximately up to 48 months
measure: Progression-Free Survival 2
timeFrame: Approximately up to 48 months
measure: Time to Worsening in the Lymphoma Sub Scale of Functional Assessment of Cancer Therapy- Lymphoma (FACT-Lym)
timeFrame: Approximately up to 48 months
measure: Number of Participants Affected With Treatment-emergent Adverse Events
timeFrame: Time from first dose of study drug until the last dose date + 30 days or the start of a subsequent anti-neoplastic therapy, whichever occur earlier (Approximately up to 4 years)
Other outcomes:
measure: Time to Response
timeFrame: Approximately up to 2.8 years
measure: Extent of Exposure of Time
timeFrame: Approximately up to 46.8 months
measure: One Year Survival Rate
timeFrame: Month 12
measure: Area Under the Plasma Concentration of Ibrutinib During Steady State (AUC-ss)
timeFrame: Cycle 1 and 2 (Day 1): Predose, 1, 2, 4 hr. postdose; Cycle 3 (day 1): Predose (Each cycle is of 21 days)
measure: Number of Participants With Biomarkers That Alter B-cell Receptor (BCR) Signaling or Activate Alternative Signaling Pathways and to Explore Their Association With Response or Resistance to Ibrutinib
timeFrame: Approximately up to 28.2 months
measure: Number of Hospitalizations Reported Related Medical Resource Utilization Information (MRUI)
timeFrame: Approximately up to 28.2 months
measure: Number of Emergency Room Visits Reported Related Medical Resource Utilization Information (MRUI)
timeFrame: Approximately up to 28.2 months
measure: Days of Hospitalization and Emergency Room Visits Reported Related Medical Resource Utilization Information (MRUI)
timeFrame: Approximately up to 28.2 months
measure: The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment
timeFrame: Baseline, Cycle 2, 3, 4, 5, 6, 7, 8, 11, 14, 17, 20, 28, 36 and End of treatment (approximately up to 23 months)
Locations:
city: Antwerpen
country: Belgium
city: Brugge
country: Belgium
city: Brussels
country: Belgium
city: Edegem
country: Belgium
city: Gent
country: Belgium
city: Leuven
country: Belgium
city: Wilrijk
country: Belgium
city: Goiânia
country: Brazil
city: Porto Alegre
country: Brazil
city: Ribeirão Preto
country: Brazil
city: Rio De Janeiro
country: Brazil
city: Sao Paulo
country: Brazil
city: Edmonton
country: Canada
state: Alberta
city: Ottawa
country: Canada
state: Ontario
city: Montreal
country: Canada
state: Quebec
city: Temuco
country: Chile
city: Bogota
country: Colombia
city: Medellin
country: Colombia
city: Brno
country: Czechia
city: Praha 10
country: Czechia
city: Praha 2
country: Czechia
city: Mulhouse
country: France
city: Paris Cedex 15
country: France
city: Paris
country: France
city: Pessac
country: France
city: Villejuif
country: France
city: Berlin
country: Germany
city: Essen
country: Germany
city: Heidelberg
country: Germany
city: Homburg
country: Germany
city: Kiel
country: Germany
city: Koln
country: Germany
city: Mainz
country: Germany
city: Munchen
country: Germany
city: Ulm
country: Germany
city: Budapest
country: Hungary
city: Debrecen
country: Hungary
city: Pécs N/A
country: Hungary
city: Szeged
country: Hungary
city: Dublin
country: Ireland
city: Goyang-Si
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Monterrey
country: Mexico
city: Oaxaca
country: Mexico
city: Queretaro
country: Mexico
city: Amsterdam
country: Netherlands
city: Rotterdam
country: Netherlands
city: Brzozow
country: Poland
city: Chorzow
country: Poland
city: Gdansk
country: Poland
city: Krakow
country: Poland
city: Opole
country: Poland
city: Slupsk
country: Poland
city: Wroclaw
country: Poland
city: Coimbra
country: Portugal
city: Lisboa
country: Portugal
city: Lisbon
country: Portugal
city: Porto
country: Portugal
city: Chelyabinsk
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: Nizhny Novgorod
country: Russian Federation
city: Obninsk
country: Russian Federation
city: Rostov-Na-Donu
country: Russian Federation
city: Saint Petersburg
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: Madrid
country: Spain
city: Palma De Mallorca
country: Spain
city: Salamanca
country: Spain
city: Valencia
country: Spain
city: Göteborg
country: Sweden
city: Lund
country: Sweden
city: Stockholm
country: Sweden
city: Umeå
country: Sweden
city: Uppsala
country: Sweden
city: Tainan
country: Taiwan
city: Taipei
country: Taiwan
city: Taoyuan
country: Taiwan
city: Cherkassy
country: Ukraine
city: Dnepropetrovsk
country: Ukraine
city: Donetsk
country: Ukraine
city: Khmelnitskiy
country: Ukraine
city: Kiev
country: Ukraine
city: Lviv
country: Ukraine
city: Birmingham
country: United Kingdom
city: Harrow
country: United Kingdom
city: Leeds
country: United Kingdom
city: Liverpool
country: United Kingdom
city: London
country: United Kingdom
city: Manchester
country: United Kingdom
city: Plymouth
country: United Kingdom
city: Southampton
country: United Kingdom
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References:
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: Dreyling M, Jurczak W, Jerkeman M, Silva RS, Rusconi C, Trneny M, Offner F, Caballero D, Joao C, Witzens-Harig M, Hess G, Bence-Bruckler I, Cho SG, Bothos J, Goldberg JD, Enny C, Traina S, Balasubramanian S, Bandyopadhyay N, Sun S, Vermeulen J, Rizo A, Rule S. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet. 2016 Feb 20;387(10020):770-8. doi: 10.1016/S0140-6736(15)00667-4. Epub 2015 Dec 7.