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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT03980171
Registration number
NCT03980171
Ethics application status
Date submitted
5/06/2019
Date registered
10/06/2019
Titles & IDs
Public title
Study of Lenalidomide, Venetoclax and Obinutuzumab in Patients With Treatment-Naïve Follicular Lymphoma
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Scientific title
A Multicenter, Open Label, Phase Ib/II Study of Lenalidomide, Venetoclax and Obinutuzumab in Patients With Treatment-Naïve Follicular Lymphoma
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Secondary ID [1]
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19/45
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Universal Trial Number (UTN)
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Trial acronym
LEVERAGE
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Follicular Lymphoma
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Condition category
Condition code
Cancer
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Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
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Cancer
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Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Obinutuzumab
Treatment: Drugs - Venetoclax
Treatment: Drugs - Lenalidomide
Experimental: Obinutuzumab+venetoclax+lenalidomide - Patients in both dose escalation and dose expansion will receive 6 cycles of induction treatment consisting of obinutuzumab (flat dose of 1000mg) and protocol defined dose levels of venetoclax and lenalidomide.
Treatment: Drugs: Obinutuzumab
A flat dose of 1000mg IV will be given every cycle during induction. a cycle is 28 days.During maintenance 1000mg IV will be given every second cycle for upto 2 years.
Treatment: Drugs: Venetoclax
During dose escalation, the doses for venetoclax can be 400mg daily days 1-10, 800mg daily days 1-10, 400mg daily continuous or 800mg daily continuous. 6 cycles of treatment will be given during induction. Once the recommended phase 2 dose (RP2D) is established that dose will be used in dose expansion. A further 6 cycles of venetoclax will be given during maintenance if required based on response at the end of induction.
Treatment: Drugs: Lenalidomide
During dose escalation, the doses of lenalidomide can be 15mg for days 1-21 or 20mg for days 1-21. 6 cycles of treatment will be given during induction. During maintenance the dose of lenalidomide will be 10mg continuous for a further 6 cycles if required based on response at the end of induction.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Dose limiting toxicities (DLT)
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Assessment method [1]
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A toxicity that prevents further administration of the trial treatment at that dose level.
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Timepoint [1]
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During the first 2 cycles of induction during dose escalation which is expected to be completed in 1.5 years.
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Primary outcome [2]
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Recommended phase II dose (RP2D) of venetoclax in combination with lenalidomide and obinutuzumab
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Assessment method [2]
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The highest dose level at which the incidence of DLT was less than 2/6
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Timepoint [2]
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During dose escalation (1.5 years)
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Primary outcome [3]
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Complete response (CR) at the end of induction
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Assessment method [3]
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Investigator assessed CR rate by PET-CT after induction (end of cycle 6) by 2014 Lugano criteria
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Timepoint [3]
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3.5 years from first patient commencing treatment
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Primary outcome [4]
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Adverse events (AEs) of venetoclax, lenalidomide and obinutuzumab
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Assessment method [4]
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Type, grade and relationship to treatment of AEs, assessed according to Common Terminology of Coding of Adverse Events (CTCAE) v5.0.
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Timepoint [4]
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From signing consent until after completion of study treatment (6.75 years)
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Primary outcome [5]
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Rate of treatment-emergent AEs that require discontinuation or dose modification of study drug
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Assessment method [5]
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Type and grade of treatment-emergent AEs, assessed according to CTCAE v5.0, requiring discontinuation of study drug or dose reductions or interruptions
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Timepoint [5]
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From signing consent until after completion of study treatment (6.75 years)
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Primary outcome [6]
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Overall response rate (ORR)
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Assessment method [6]
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Investigator assessed ORR (complete response (CR) or partial response (PR)) by PET-CT assessed by 2014 Lugano criteria after 6 cycles of induction treatment (0.5 years)
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Timepoint [6]
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3.5 years from first patient commencing treatment
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Primary outcome [7]
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CR at 2.5 years from commencement of induction treatment
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Assessment method [7]
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CR based on 2014 Lugano criteria
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Timepoint [7]
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5.5 years from first patient commencing treatment
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Primary outcome [8]
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Progression free survival (PFS)
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Assessment method [8]
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PFS will be defined as the time from enrolment date to the first date of objectively documented progressive disease (PD) or date of death from any cause. Patients without documented progressive disease and who have not died by the end of the study will be censored at the date of last disease assessment.
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Timepoint [8]
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From commencement of treatment to end of study (6.75 years)
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Primary outcome [9]
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Duration of response (DOR)
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Assessment method [9]
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DOR will be measured in the subset of patients who achieved CR or PR and it is defined as the time from the first documented disease response to the earliest recurrence or progressive disease. Deceased patients without recurrence or progressive disease will be censored at the date of death.
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Timepoint [9]
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From commencement of treatment to end of study (6.75 years)
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Primary outcome [10]
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Time to next anti-lymphoma treatment (TTNT)
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Assessment method [10]
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TTNT will be measured from enrolment date to date of initiation of next anti-cancer therapy (for follicular lymphoma) or date of death from any cause. Patients who do not start next anti-cancer therapy by the end of the study will be censored at the date of last contact.
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Timepoint [10]
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From commencement of treatment to end of study (6.75 years)
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Primary outcome [11]
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Overall survival (OS)
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Assessment method [11]
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OS will be measured from enrolment date to the date of death from any cause. Patients who have not died by the study close-out date will be censored at their last visit date. Patients who are lost to follow-up before the close-out date and who are not known to have died will be censored at the date they were last known to be alive.
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Timepoint [11]
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From commencement of treatment to end of study (6.75 years)
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Primary outcome [12]
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Quality of life (QoL)
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Assessment method [12]
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QoL will be measured using Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym).
The FACT-Lym is a disease-specific 42-item questionnaire that has been validated for the purpose of assessing health-related quality of life (HRQoL) in patients with various forms of lymphoma.The FACT-Lym consists of FACT-G subscales: Physical Well-Being (7 items), Social/Family Well-Being (7 items), Emotional Well-Being (6 items), Functional Well-Being (7 items), and the Lymphoma subscale: Additional Concerns (15 items). FACT-Lym questions are scored on a 5-point Likert scale from 0 to 4 (0 being not at all and 4 being very much).
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Timepoint [12]
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From commencement of treatment to end of treatment (5.5 years)
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Eligibility
Key inclusion criteria
1. Patient has provided written informed consent.
2. Patient has histologically confirmed follicular lymphoma WHO grade 1-3A and non-contiguous or bulky (>7cm) stage II and stage III or IV according to Lugano criteria 2014, irrespective of FLIPI score
3. Patient meets =1 Groupe d'Etude des Lymphomes Folliculaires (GELF) criterion for treatment.
4. Bi-dimensionally measurable disease, with at least one mass lesion = 2 cm in longest diameter.
5. Male or female age = 18 years at signing consent
6. Eastern Cooperative Oncology Group (ECOG) performance status = 2.
7. Adequate organ and haematologic function within 10 days prior to registration, defined by:
* Haemoglobin =80g/L
* ANC =1 x 109/L and platelet count =75 x 109/L; unless due to marrow infiltration or hypersplenism (in which case ANC = 0.5 x 109/L and platelets = 50 x 109/L)
* Serum aspartate transaminase (AST) or alanine transaminase (ALT) <2.5 x upper limit of normal (ULN)
* International normalized ratio >1.5 x ULN for patients not receiving therapeutic anticoagulation
* Partial thromboplastin time (PTT) or activated PTT (aPTT) =1.5 x ULN unless due to the presence of an inhibitor (e.g. lupus anticoagulant)
* Bilirubin <2.0 x ULN unless due to Gilbert's syndrome, documented liver involvement with lymphoma, or of non-hepatic origin
* Creatinine clearance =50ml/min(Cockcroft-Gault)
8. Able to comply with protocol requirements and follow-up procedures.
9. Female patients of childbearing potential (FCBP) must be willing to use two methods of birth control simultaneously or be surgically sterile, or abstain from heterosexual activity for at least 28 days before starting lenalidomide and for the course of the study through to 18 months after the last dose of obinutuzumab, 28 days after the last dose of lenalidomide and 30 days after the last dose of venetoclax, whichever is longer. Patients of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 24 consecutive months (Refer to Appendix 4).
10. Sexually active males must agree to use a condom during sexual contact with a pregnant female or a female of child-bearing potential (FCBP) for the course of the study through to 18 months after the last dose of obinutuzumab, 28 days after the last dose of lenalidomide and 30 days after the last dose of venetoclax, whichever is longer, even if he has undergone a successful vasectomy.
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
1. WHO grade 3B follicular lymphoma, biopsy proven or clinically suspected histologic transformation to diffuse large B-cell lymphoma
2. Known central nervous system lymphoma or leptomeningeal disease.
3. History of other malignancy that could affect compliance with the protocol or interpretation of results Patients with a history of curatively treated basal or squamous cell carcinoma or Stage 1 melanoma of the skin or in situ carcinoma of the cervix are eligible.
Patients with a malignancy that has been treated with curative intent may be included provided they remain in remission without treatment for = 2 years prior to enrollment
4. Has had prior systemic therapy for follicular lymphoma (with the exception of corticosteroid monotherapy to control disease related symptoms).
5. Major surgery or a wound that has not fully healed within 4 weeks prior to registration.
6. Patient is unable to swallow tablets.
7. 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 venetoclax or lenalidomide capsules, or put the study outcomes at undue risk.
8. Known hypersensitivity to any of the study drugs or their components (obinutuzumab, L-histidine, L-histidine hydrochloride monohydrate, Trehalose dehydrate, Poloxamer 188), humanized or murine monoclonal antibodies, xanthine oxidase inhibitors or rasburicase.
9. Has received the following agents within 7 days prior to registration:
* Steroid therapy with anti-neoplastic intent (with the exception of =7 days of prednisolone or equivalent at doses of =100mg daily to control lymphoma symptoms prior to cycle 1 day 1)
* Strong CYP3A inhibitors (See section 7.10.3)
* Strong CYP3A inducers (See section 7.10.3)
* Consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days of registration
10. Has a history of stroke or intracranial hemorrhage within 6 months prior to registration.
11. Has a known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment.
12. Requires the use of vitamin K antagonists (because of potential drug-drug interactions that may potentially increase the exposure of warfarin).
13. Presence of positive test results for hepatitis B virus (HBV), hepatitis B surface antigen (HBsAg), or hepatitis C (HCV) antibody.
Patients who are positive for HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation Patients with occult or prior HBV infection (defined as positive total hepatitis B core antibody [HBcAb] and negative HBsAg) may be included if HBV DNA is undetectable. These patients must be willing to receive prophylactic lamivudine or entecavir and undergo monthly DNA testing during (and for 6 months following completion of) treatment.
14. Receipt of live-virus vaccines within 28 days prior to registration or need for live-virus vaccines at any time during study treatment.
15. Pregnant or lactating, or intending to become pregnant during the study.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
NA
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Active, not recruiting
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
19/08/2019
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
1/11/2026
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Actual
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Sample size
Target
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Accrual to date
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Final
50
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Recruitment in Australia
Recruitment state(s)
QLD,VIC,WA
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Recruitment hospital [1]
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Townsville Hospital and Health Services - Townsville
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Recruitment hospital [2]
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Peter MacCallum Cancer Centre - Melbourne
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Recruitment hospital [3]
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Sir Charles Gairdner Hospital - Nedlands
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Recruitment postcode(s) [1]
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- Townsville
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Recruitment postcode(s) [2]
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3000 - Melbourne
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Recruitment postcode(s) [3]
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6009 - Nedlands
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Funding & Sponsors
Primary sponsor type
Other
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Name
Peter MacCallum Cancer Centre, Australia
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
The trial will investigate the combination of venetoclax, obinutuzumab and lenalidomide in patients with treatment-naïve follicular lymphoma. Patients will receive induction treatment for 0.5 years with venetoclax, obinutuzumab and lenalidomide followed by maintenance treatment for upto 2 years. Maintenance treatment will be determined by the response at the end of induction. Following completion of treatment patients will be followed up for 3 years after the last patient completes induction treatment.
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Trial website
https://clinicaltrials.gov/study/NCT03980171
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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John Seymour, MBBS, FRACP, PhD
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Address
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Country
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Phone
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+613 855 97262
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Fax
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Email
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[email protected]
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Contact person for scientific queries
Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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No/undecided IPD sharing reason/comment
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What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results not provided in
https://clinicaltrials.gov/study/NCT03980171