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Clinical picture: CLL (Chronical Lymfatic Leukemia)

Trial: HOVON-associated Murano study


News
1. Overview
2. Patient eligibility criteria
3. Registration (& randomization) of patients
4. Participating parties
5. Participating sites
6. Instruction videos
7. Download documentation / forms


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News


Murano study

The Murano study has been closed as of 25-08-2015.

1. Overview



Summary

A multicenter, phase III, open-label, randomized study in relapsed/refractory patients with chronic lymphocytic leukemia to evaluate the benefit of GDC-0199 (ABT-199) plus Rituximab compared with Bendamustine plus Rituximab.


Status

closed



Target number of patients

370


Study objectives

The primary efficacy objective for this study is as follows:
To evaluate the efficacy of GDC-0199 and rituximab (GDC-0199+R) compared with bendamustine and rituximab (BR) in patients with relapsed or refractory CLL as measured by investigator-assessed PFS.

The secondary efficacy objectives for this study are as follows:
To analyze Independent Review Committee (IRC)-assessed PFS in the subset of CLL patients with 17p deletion identified by fluorescence in situ hybridization (FISH) testing performed at a central laboratory.
To evaluate PFS as assessed by an IRC.
To analyze investigator-assessed PFS in the subset of CLL patients with 17p deletion identified by fluorescence in situ hybridization (FISH) testing performed at a central laboratory.
To evaluate rates of overall response (OR; defined as complete response [CR], complete response with incomplete marrow recovery [CRi], and partial response [PR]), PR, and CR and CRi at 12 weeks after Day 1 of the last cycle of multi-agent
therapy, as assessed by the investigator.
To evaluate OR, PR, CR, and CRi rates 12 weeks after Day 1 of the last cycle of multi-agent therapy, as determined by the IRC.
To evaluate PFS as assessed by the investigator and by the IRC.
To evaluate overall survival (OS).
To evaluate duration of response (DOR) for patients with a best overall response of CR, CRi, or PR.
To evaluate time to next anti-CLL treatment (TTNT).
To evaluate the proportion of patients with minimal residual disease (MRD)-negativity at the disease response assessment time points.

The safety objectives for this study are as follows:
To evaluate the safety of GDC-0199 and rituximab compared with BR in patients with relapsed or refractory CLL, focusing on serious adverse events, National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE, v4.0) Grade ≥ 3 adverse events, and Grade ≥ 3 laboratory toxicities.

The pharmacodynamic objective for this study is to assess changes in lymphocyte subset counts during the study (eg, T and B cells).

The PK objective for this study is to characterize the pharmacokinetics of GDC-0199 in patients with relapsed or refractory CLL.

The patient-reported outcome (PRO) objectives for this study are as follows:
- To compare treatment-related symptoms following treatment with GDC-0199 and rituximab compared with BR in patients with relapsed or refractory CLL, as measured by M. D. Anderson Symptom Inventory (MDASI) and European
Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and associated CLL module (QLQ-CLL16).
To evaluate changes from baseline CLL symptoms scores using MDASI and EORTC QLQ-C30 and QLQ-CLL16 questionnaires.
To evaluate time to disease-related symptom progression using EORTC QLQCLL16
health-related quality of life (HRQoL) using global health status/quality of life (QoL) and other functional subscales of QLQ-C30.
To assess interference of treatment and disease-related symptoms on QoL using the MDASI questionnaire.

The health economic objective for the study is to compare the health economic effects of GDC-0199 in combination with rituximab versus BR in patients with relapsed or refractory CLL as measured by the EuroQol 5 Dimension (EQ-5D) questionnaire (Rabin and deCharro 2001).

The exploratory objectives for this study are as follows:
To evaluate the relationship between efficacy outcome and potential biomarkers, including Bcl-2 expression, for patients treated with GDC-0199 and rituximab compared with BR.
To evaluate potential biomarkers that are prognostic and/or predictive of response and resistance to treatment with GDC-0199 and rituximab or with BR.


2. Patient eligibility criteria



Inclusion criteria

Signed informed consent.
Age ≥ 18 years.
Diagnosis of CLL that meets published diagnostic criteria (Hallek et al. 2008). Patients must have peripheral blood B-lymphocyte counts which clonally express CD5, CD19/20, and CD23 and are either kappa or lambda light-chain-restricted. Pro-lymphocytes may comprise no more than 55% of total circulating lymphocytes.
At initial diagnosis of CLL (ie, prior to front-line treatment), the peripheral lymphocyte count must have been > 5000/mm3. Patients must meet the following criteria for relapsed or refractory CLL (per the iwCLL guidelines [Hallek et al. 2008]):
– Relapsed disease: a patient who previously achieved a CR or PR, but after a period of 6 months or more demonstrates evidence of progression;
– Refractory disease: treatment failure or disease progression within 6 months of the last anti-leukemia therapy.
Previously treated with at least one but not more than three lines of therapy (a line of therapy is defined as completing at least two cycles of treatment for a given line of therapy), including at least one prior standard chemotherapy-containing regimen according to current guidelines (Appendix 8).
For patients with 17p deletion, previously treated with at least one but not more than three lines of therapy, including at least one prior standard chemotherapy-containing regimen according to current guidelines OR at least one prior alemtuzumab containing therapy.
Patients previously treated with bendamustine only if their duration of response was ≥ 24 months.
Patient requires treatment in the opinion of the investigator.
Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 1 (see Appendix 7).
Adequate BM function independent of growth factor or transfusion support, per local laboratory reference range at screening as follows:
- platelet count ≥ 75 000/mm3;
- absolute neutrophil count (ANC) ≥ 1000/mm3 unless cytopenia is clearly due to marrow involvement of CLL;
- total hemoglobin ≥ 9 g/dL (without transfusion support within 2 weeks of screening);
- if any of the above-mentioned cytopenias are present, there should be no evidence of myelodysplastic syndrome (MDS) or hypoplastic BM.
Adequate renal and hepatic function, per laboratory reference range at screening as
follows:
- Calculated creatinine clearance ≥ 50 mL/min using 24-hour creatinine clearance or modified Cockcroft − Gault equation (using ideal body mass [IBM] instead of mass (see protocol for formula).
- aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × the upper limit of normal (ULN) of the institution's normal range;
- bilirubin ≤ 1.5 × ULN. Patients with Gilbert's syndrome may have a bilirubin level > 1.5 × ULN, per discussion between the investigator and the Medical Monitor;
- prothrombin time (or international normalized ratio) and partial thromboplastin time not to exceed 1.2 × the institution’s normal range (patients with an elevated prothrombin time and known lupus anticoagulant may be eligible for
participation after consulting the Medical Monitor).
Female patients must be surgically sterile, postmenopausal (for at least 1 year), or have negative results for a pregnancy test performed as follows:
- at screening, on a serum sample obtained within 14 days prior to initiation of study treatment, and
- prior to dosing, on a urine sample obtained on Week 1 Day 1 if it has been > 7 days since obtaining the serum pregnancy test result.
Female patients who are not surgically sterile or postmenopausal (for at least 1 year) must practice at least one of the following methods of birth control throughout the duration of study participation and for at least 12 months after completing therapy with rituximab:
- total abstinence from sexual intercourse;
- a vasectomized partner;
- hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) that started at least 3 months prior to study drug administration;
- double-barrier method (condom + diaphragm or cervical cup with spermicidal contraceptive sponge, jellies, or cream).
Non-vasectomized male patients must practice at least one of the following methods of birth control throughout the duration of study participation and for at least 12 months after completing therapy with rituximab:
- a partner who is surgically sterile or postmenopausal (for at least 1 year) or who
is taking hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal)
for at least 3 months prior to study drug administration;
- total abstinence from sexual intercourse;
- double-barrier method (condom + diaphragm or cervical cup with spermicidal, contraceptive sponge, jellies, or cream).


Exclusion criteria

Transformation of CLL to aggressive NHL (eg, Richter’s transformation, prolymphocytic leukemia, or DLBCL) or CNS involvement by CLL.
Undergone an allogeneic stem cell transplant.
Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia.
History of intolerance to prior bendamustine treatment (defined as toxicity requiring
permanent discontinuation of bendamustine) or other contraindication to bendamustine treatment.
History of severe (ie, requiring permanent discontinuation of prior rituximab therapy)
prior allergic or anaphylactic reactions to rituximab.
Known HIV-positivity.
Positive hepatitis serology (serology testing required at screening), as follows:
- Hepatitis B virus (HBV): Patients with positive serology for hepatitis B defined as positivity for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (anti-HBc).
- Hepatitis C virus (HCV): Patients with positive hepatitis C serology unless HCV (RNA) is confirmed negative. Note that patients with HCV- or hepatitis C virus core antibody (HCVcAB)-positivity who have received recent IV IgG should be evaluated further for risk of viral reactivation and may be eligible for the study after discussion with the Medical Monitor.
Requires the use of warfarin (due to potential drug − drug interactions that may potentially increase the exposure of warfarin). Patients may be eligible if able to be taken off warfarin and started on an alternative anticoagulant.
Received an anti-CLL monoclonal antibody within 8 weeks prior to the first dose of
study drug.
Received any of the following agents within 14 days prior to the first dose of study drug, or has not recovered to less than Grade 2 clinically significant adverse effect(s)/toxicity(s) of the previous therapy:
- any anti-cancer therapy including chemotherapy or radiotherapy and steroid
therapy for anti-neoplastic intent;
- investigational therapy, including targeted small-molecule agents.
Received potent CYP3A4 inhibitors (such as fluconazole, ketoconazole, and clarithromycin) within 7 days prior to the first dose of GDC-0199 (see Appendix 9).
Received potent CYP3A4 inducers (such as rifampin, carbamazepine, phenytoin, St. John’s Wort) within 7 days prior to the first dose of GDC-0199 (see Appendix 9).
History of prior GDC-0199 treatment.
Consumed grapefruit or grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of GDC-0199.
A cardiovascular disability status of New York Heart Association Class ≥ 3. Class 3
is defined as cardiac disease in which patients are comfortable at rest but marked limitation of physical activity due to fatigue, palpitations, dyspnea, or anginal pain.
A significant history of renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular, or hepatic disease that, in the opinion of the investigator, would adversely affect the patient’s participation in this study or interpretation of study outcomes.
Major surgery within 30 days prior to the first dose of GDC-0199.
A female patient who is pregnant or breast-feeding.
History of prior other malignancy that could affect compliance with the protocol or interpretation of results with the exception of the following:
- curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix at any time prior to study;
- other cancers not specified above which have been curatively treated by surgery and/or radiation therapy from which patient is disease-free for ≥ 5 years without further treatment.
Malabsorption syndrome or other condition that precludes enteral route of administration.
Known allergy to both xanthine oxidase inhibitors and rasburicase.
Evidence of other clinically significant uncontrolled condition(s) including, but not
limited to, uncontrolled systemic infection (viral, bacterial, or fungal).
Vaccination with a live vaccine within 28 days prior to randomization.


3. Registration (& randomization) of patients



Registration

An interactive voice response system (IxRS) will be used for patient registration, patient number, and
dose assignment.


4. Participating parties



Principal investigator

SPONSOR: F. Hoffmann-La Roche Ltd and AbbVie Inc will act as co-sponsors of this trial globally*


Coordinating investigator(s)

Organization - PI Name - City - email
VUMC - Dr. Chamuleau - Amsterdam - M.Chamuleau@vumc.nl
ErasmusMC - Dr. Lugtenburg - Rotterdam - p.lugtenburg@erasmusmc.nl
UMCG - Dr. Nijland - Groningen - m.nijland@umcg.nl
Antonius zkh - Dr. De Weerdt - Nieuwegein - o.weerdt@antoniusziekenhuis.nl
LUMC - Dr. Veelken - Leiden - j.h.veelken@lumc.nl
UMCU - Dr. Raymakers - Utrecht - r.raymakers@umcutrecht.nl
Albert Schweitzer zkh - Dr. Levin - Dordrecht - m-d.levin@asz.nl
Haga zkh - Dr. Kersting - Den Haag - s.kersting@hagaziekenhuis.nl
Orbis concern - Dr. van Kampen - Sittard-Geleen - r.vankampen@orbisconcern.nl
Meander MC - Dr. Regelink - Amersfoort - jc.regelink@meandermc.nl
Maxima MC - Dr. Nijziel - Eindhoven - m.nijziel@mmc.nl
Maasstadziekhuis - Dr. Leys - Rotterdam - leysm@maasstadziekenhuis.nl
Medisch Spectrum Twente - Dr. Schaafsma - Enschede - m.schaafsma@mst.nl


Other functions

MEDICAL MONITOR: Rebecca Elstrom, MD


5. Participating sites



6. Instruction videos



7. Download documentation / forms


 Protocol



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