CompletedPhase 2ACTRN12615000551594

A Phase II Study of Ibrutinib, Rituximab and mini-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy in very elderly patients with newly diagnosed Diffuse Large B-Cell Lymphoma (DLBCL)

A Phase II Study of Ibrutinib, Rituximab and mini-CHOP therapy in very elderly patients with newly diagnosed DLBCL

Sponsor

Australasian Leukaemia and Lymphoma Group

Enrollment

80 participants

Start Date

Nov 9, 2015

Study Type

Interventional

Conditions

elderly DLBCL

Summary

The study will evaluate the deliverability and efficacy of Ibrutinib-R-mini-CHOP chemotherapy in elderly patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Who is it for? You may be eligible to join this study if you are aged 75 years or above and have been newly diagnosed with DLBCL for which you have received no prior treatment (excluding prednisone). Study details All participants in this study will be treated with a chemotherapy regime known as Ibrutinib-R-mini-CHOP. This will include treatment with the drugs prednisone (orally), ibrutinib (orally), rituximab intravenously ((IV) - i.e. administered directly into the vein), cyclophosphamide IV, doxorubicin IV, vincristine IV and Pegfilgrastim G-CSF (subcutaneous injection). Treatment duration will be for up to 8 x 28 day cycles as tolerated. All participants will be regularly assessed for a minimum of 2 years in order to evaluate the safety, toxicity and effectiveness of treatment.

Eligibility

Sex: Both males and femalesMin Age: 75 Yearss

Inclusion Criteria17

Subject must be 75 years of age or older
No prior treatment for DLBCL excluding prednisone
Histologically confirmed de novo CD20+ DLBCL
Stage I bulky (largest dimension of lesion >/= 6cm), II, III or IV disease by the Ann Arbor Classification
At least 1 measurable site of disease according to the 2014 Recommendations for Initial Evaluation, Staging and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma – the Lugano Classification. The site of disease must be greater than 1.5 cm in the long axis regardless of short axis measurement. An extranodal lesion should have a longest diameter of > 1cm.
Eastern Cooperative Oncology Group performance status score of 0, 1, or 2 (this can be as measured after any pre-phase prednisone)
LVEF within institutional normal limits, as determined by Gated Heart Pool Scan, or if not available, echocardiogram
Minimum life expectancy of 3 months
Haematology values must be within the following limits:
a. Absolute neutrophil count (ANC) >=1.0 x10^9/Lindependent of growth factor support
b. Platelets >=100x10^9/L or >=50x10^9/L if bone marrow involvement independent of transfusion support in either situation
Biochemical values within the following limits:
a. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 3 x upper limit of normal (ULN)
b. Total bilirubin <= 1.5 x ULN unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin
c. Creatinine Clearance (as measured by Cockroft Gault) >/= 40 mL/min/1.73m2
Each subject (or their legally acceptable representative) must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study.
Men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree to not donate sperm during and after the study.

Exclusion Criteria23

History of treated lymphoma of any subtype
CNS or meningeal involvement
Contraindication to any drug in the chemotherapy regimen
Serious active co-morbid disease according to the investigator’s decision
Poor renal function, defined as a Creatinine Clearance Rate (as measured by Cockcroft Gault) < 40 mL/min/1.73m2
Poor hepatic function, defined as Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 3 x upper limit of normal (ULN) and/or total bilirubin > 1.5 x ULN unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin
Poor bone-marrow reserve, defined as absolute neutrophil count (ANC) < 1.0x10^9/L independent of growth factor support and/or platelet count < 100x10^9/L or < 50x10^9/L if bone marrow involvement independent of transfusion support in either situation
History of malignancy during the past 3 years, with the exception of non-melanoma skin cancers or stage 0 (in situ) carcinoma.
Treatment with any investigational drug within 30 days before the planned first cycle of chemotherapy
Requires anticoagulation with warfarin or equivalent vitamin K antagonists
Requires dual antiplatelet therapy with aspirin and a P2Y12 antagonist
Requires treatment with strong CYP3A inhibitors
Requires treatment with fish oil
Prior anthracycline use >= 150 mg/m2
History of stroke or intracranial haemorrhage within 6 months of enrolment
Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
Known bleeding disorders (e.g. von Willebrand’s disease)
Major surgery within 4 weeks of enrolment
Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk
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; RNA polymerase chain reaction [PCR]-positive) or active Hepatitis B Virus (HBV; DNA PCR-positive) infection. Only patients who are HBV surface antigen (HBVsAg) and/or HBV core antibody (HBVcAb) positive are required to undergo HBV DNA PCR testing. Subjects with PCR-negative HBV or who are HBV core antibody positive are permitted in the study but must be on HBV prophylaxis.
Any uncontrolled active systemic infection requiring intravenous (IV) antibiotics.
Vaccinated with live, attenuated vaccines within 4 weeks of enrolment.

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Interventions

Pre-phase prednisone at a dose of either 40mg/m2 IV or 100mg orally (depending on drug available IV or oral) daily for 5-7 days will be mandatory. All subjects will receive ibrutinib 560mg orally daily, rituximab 375mg/m2 IV (rounded up as per local investigator discretion to the nearest 100mg) on day 1, cyclophosphamide 400mg/m2 IV day 1, doxorubicin 25mg/m2 IV day 1, vincristine 1mg IV and prednisone 40mg/m2 IV or 100mg orally daily on a 21 day schedule aiming for a total of 6 cycles. This will be followed directly by 2 cycles of ibrutinib 560mg orally daily and rituximab 375mg/m2 IV on day 1 (rounded up as per local investigator discretion to the nearest 100mg) on a 21 day schedule. Pegfilgrastim G-CSF 6mg subcutaneous injection on day 4-5 of each cycle as tolerated.