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Leukemia, Lymphocytic, ChronicPhase 2CLL2-GiVeNCT02758665

Trial of Ibrutinib Plus Venetoclax Plus Obinutuzumab in Patients With CLL

A Phase 2 study testing ibrutinib, obinutuzumab and venetoclax in people with Leukemia, Lymphocytic, Chronic, run by University of Ulm at 11 sites in Germany.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

A prospective, open-label, multicentre phase-II trial of ibrutinib plus venetoclax plus obinutuzumab in physically fit (CIRS ≤ 6 \& normal creatinine clearance) and unfit (CIRS > 6 \& creatinine clearance ≥ 50 ml/min) patients with previously untreated chronic lymphocytic leukemia (CLL) with TP53 deletion (17p-)… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Leukemia, Lymphocytic, Chronic
What is being tested?
ibrutinib, obinutuzumab and venetoclax
Could I receive a placebo?
No, everyone receives an active treatment
How many people
41 participants
Where
11 sitesGermany
Study dates
Sep 2016to Mar 2022
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Have documented CLL according to iwCLL criteria, measurable disease (lymphocytosis > 5x109 and/or palpable and measurable lymph nodes by physical exam and/or organomegaly assessed by physical exam)
  • Subjects must have untreated CLL, i.e. no prior chemotherapy, antibody therapy or non-chemotherapeutic agent (BTK, PI3K, BCL2 inhibitor or similar). Local irradiation or short term (up to 1 month) corticosteroid treatment for autoimmune phenomena are allowed
  • Subjects must have TP53 deletion (17p-) and/or mutation (in bone marrow or peripheral blood), with pre-existing local test results confirmed by central laboratory in Ulm
  • CLL requiring treatment ("active disease") according to the iwCLL criteria
  • ECOG ≤ 2
  • Creatinine clearance ≥ 50 ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured after 24 h urine collection
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  • Adequate liver function as indicated by a total bilirubin ≤ 2 x, AST, and ALT ≤ 3 x the institutional ULN value, unless directly attributable to the patient's CLL or to Gilbert's Syndrome
  • No cardiovascular disability of New York Heart Association (NYHA) Class > 2. Class 2 is defined as comfortability at rest but moderate physical activity causes dyspnoea, angina pain or fatigue
  • Adequate bone marrow function (unless directly attributable to CLL, BM examination required):
  • ANC ≥ 1000/µl or
  • ANC < 1000/µl, if attributable to the underlying CLL (growth factor support may be administered after screening)
  • Platelets > 30.000/µl (unless directly attributable to the underlying CLL)
  • Hemoglobin ≥ 8g/dl (unless directly attributable to the underlying CLL)
  • Negative serological testing for hepatitis B (i.e. HBsAg negative and anti-HBc negative, patients positive for anti-HBc may be included if PCR for HBV DNA is negative) negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration.
  • [Patients who are HBsAg negative/anti-HBc positive with undetectable serum HBV DNA should be monitored closely (every month) for HBV DNA by a real-time PCR quantification assay with a lower limit of detection of the order of 10 WHO IU/mL until at least 24 months after the last treatment cycle with obinutuzumab. If the HBV DNA assay becomes positive, patients should pre-emptively be treated with a nucleoside analogue (i.e. lamivudine) for at 24 months after the last cycle of therapy with obinutuzumab or be referred to a gastroenterologist for management.]
  • Age at least 18 years
  • Life expectancy ≥ 6 months
  • Must be able to adhere to the study visit schedule and other protocol requirements
  • Able and willing to provide written informed consent and to comply with the study protocol procedures

Who cannot join

  • Transformation of CLL (i.e. Richter's transformation, prolymphocyctic leukemia)
  • One or more individual organ / system impairment score of 4 as assessed by the CIRS definition, excluding the Eyes, Ears, Nose, Throat and Larynx organ system
  • Known central nervous system (CNS) involvement
  • Patients with a history of PML
  • Active malignancies other than CLL within the past 2 years prior to study entry, with the exception:
  • Adequately treated in situ carcinoma of the cervix uteri
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  • Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin
  • Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent and in remission at time of screening
  • Use of agents which would interfere with the study drug within 28 days prior to registration
  • Uncontrolled infection requiring systemic treatment
  • History of severe infusion-related reaction to humanized or murine monoclonal antibodies, and/ or known sensitivity or allergy to murine products or allergy to xanthin oxidase and rasburicase or glucose-6-phosphate dehydrogenase deficiency
  • Requires treatment with the following drugs:
  • Within 7 days prior to the first dose of study drug: No steroid therapy higher than 20 mg Prednisolone for anti-neoplastic intent; No CYP3A inhibitors (e.g. fluconazole, ketoconazole, clarithromycin, warfarin or phenprocoumon); No potent CYP3A inducers (e.g., rifampin, phenytoin or carbamazepine);
  • Within 3 days prior to the first dose of study drug: Grapefruit or grapefruit products; Seville oranges (including marmalade); Star fruit.
  • History of stroke or intracranial hemorrhage within 6 months prior to registration
  • Pregnant women and nursing mothers
  • Fertile men or women of childbearing potential unless:
  • surgically sterile or ≥ 2 years after the onset of menopause
  • willing to use two highly effective contraceptive methods (Pearl Index <1) during study treatment and for 18 months after end of study treatment.
  • Vaccination with a live vaccine a minimum of 28 days prior to registration
  • Legal incapacity
  • Prisoners or subjects who are institutionalized by regulatory or court order
  • Persons who are in dependence to the sponsor or an investigator

Trial locations and contacts

11 sites in 1 country.

11 sites in 1 country

Germany11 sites

  • Universitätsklinikum Köln

    Cologne, 50937

  • BAG Onkologische Gemeinschaftspraxis

    Dresden, 01307

  • Universitätsklinikum Essen

    Essen, 45147

  • Universitätsklinikum Freiburg

    Freiburg im Breisgau, 79106

  • Universitätsklinikum Heidelberg

    Heidelberg, 69120

  • Universitätsklinikum des Saarlandes

    Homburg / Saar, 66421

  • Universitätsklinikum Schleswig-Holstein

    Kiel, 24105

  • Universitätsmedizin der Johannes Gutenberg-Universität Mainz

    Mainz, 55131

  • Klinikum Schwabing

    München, 80804

  • Unimedizin Rostock

    Rostock, 18057

  • Universitätsklinikum Ulm

    Ulm, 89081

Other trials in Germany

About this study

Official title: A Prospective, Open-label, Multicentre Phase-II Trial of Ibrutinib Plus Venetoclax Plus Obinutuzumab in Physically Fit or Unfit Patients With Previously Untreated Chronic Lymphocytic Leukemia (Cll) With tp53 Deletion (17p-) and/or Mutation

A prospective, open-label, multicentre phase-II trial of ibrutinib plus venetoclax plus obinutuzumab in physically fit (CIRS ≤ 6 \& normal creatinine clearance) and unfit (CIRS > 6 \& creatinine clearance ≥ 50 ml/min) patients with previously untreated chronic lymphocytic leukemia (CLL) with TP53 deletion (17p-) and/or mutation

Read the detailed description

Chronic lymphocytic leukemia (CLL) with TP53 deletion (17p-) and/or mutation has a poor prognosis. Different therapeutic strategies have been tested over the last decade such as fludarabine-based regimens, alemtuzumab, bendamustine alone or with rituximab, lenalidomide, or ofatumumab, but all without compelling evidence for success. For example, with the FCR regimen as the standard 1st line treatment for fit CLL patients, only 5% (1 of 22) of patients with 17p deletion had a complete response (CR) and 40% of patients were free of disease progression at 12 months in the CLL8 Trial. New agents like Bruton's Tyrosin Kinase (BTK) inhibitors such as ibrutinib have shown promising results in patients with relapsed or refractory CLL, however, outcome of CLL patients with 17p deletion is inferior to other subgroups. The CLL11 trial revealed an impressive improvement in efficacy with GA-101 (obinutuzumab) as compared to rituximab when combined with Chlorambucil. Moreover, the BCL2 antagonist venetoclax (previously GDC-0199/ABT-199), tested as a single agent in relapsed / refractory CLL patients, showed striking activity with tumor lysis syndrome as dose limiting toxicity. Consequently, the current trial will test a combination regimen consisting of obinutuzumab, ibrutinib and venetoclax (the "GIVe" regimen) as first line treatment in CLL patients with TP53 deletion (17p-) and/or mutation with the aim to demonstrate efficacy in this population at highest unmet medical need.

The primary objective of the study is to evaluate the efficacy of the GIVe regimen in patients with TP53 deletion (17p-) and/or mutation and previously untreated CLL requiring treatment.

For this, the CR rate at cycle 15 (d1; final restaging) will be used as primary parameter for efficacy. The CR rate is defined as the proportion of patients having achieved a CR or a CR with incomplete recovery of the bone marrow (CRi) as best response (according to iwCLL criteria) until cycle 15 (d1; final restaging) from start of therapy.

Efficacy of the regimen will be further assessed by evaluation of the proportion of patients free of disease progression (PD-free rate) after 12 cycles of therapy, overall response rate (ORR), minimal residual disease (MRD) and overall survival as well as other time to event endpoints as outlined below.

A further secondary objective of the study is to evaluate the safety of ibrutinib, venetoclax and obinutuzumab.

Keywords
CLL, chronic lymphocytic leukemia, ibrutinib, venetoclax, obinutuzumab, TP53 Deletion
Medical subject headings
Leukemia, Lymphocytic, Chronic, B-Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT02758665
Study groupRoleWhat they receive
Obinutuzumab, Ibrutinib, VenetoclaxExperimentalObinutuzumab i.v.: Cycle 1 (3000 mg), Cycle 2-6 (1000 mg) Ibrutinib (tablet): Cycle 1-15 (420 mg daily) Venetoclax (tablet): Cycle 1 (last 7 days 20 mg daily), Cycle 2 (ramp up 50 mg to 400 mg) Cycle 3-12 (400 mg daily)
Receives: Drug: ibrutinib; Drug: obinutuzumab; Drug: venetoclax

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Complete response (CR) rate

    Measured: at day 1 of cycle 15 (1 cycle = 28 days) after start of induction therapy

Secondary outcomes (13)

  1. PD-free rate

    Proportion of patients free of disease progression (PD-free rate) after 12 cycles of therapy

    Measured: up to 336 days

  2. Overall Response rate

    Overall response rate (ORR) (including all patients achieving a complete response (CR), a complete response with incomplete recovery of the bone marrow (CRi), a partial response (PR) and a PR with lymphocytosis)

    Measured: up to 1176 days

  3. ORR

    ORR after end of maintenance treatment

    Measured: at 1008 days (=end of maintenance treatment)

  4. MRD levels

    MRD levels (measured in peripheral blood after cycle 9, after cycle 12, at the beginning of cycle 15 (d1), at the beginning of cycle 36 (d1), as well as in bone marrow at the beginning of cycle 15)

    Measured: at the following days: 252, 336, 393, 381 as well as in bone marrow at day 393

  5. Progression-free survival (PFS)

    Progression-free survival (PFS)

    Measured: up to 1176 days

  6. Event-free survival (EFS)

    Event-free survival (EFS)

    Measured: up to 1176 days

  7. Overall survival (OS)

    Overall survival (OS)

    Measured: up to 1176 days

  8. Duration of response in patients with (clinical) CR/CRi, PR

    Duration of response in patients with (clinical) CR/CRi, PR

    Measured: up to 1176 days

  9. Time to next CLL treatment (TTNT)

    Time to next CLL treatment (TTNT)

    Measured: up to 1176 days

  10. Treatment-free survival (TFS)

    Treatment-free survival (TFS)

    Measured: up to 1176 days

  11. Subsequent Treatment for CLL

    Evaluation of subsequent treatment for CLL (including proportion receiving allogeneic SCT as consolidation or in relapse) including response to treatment

    Measured: up to 1176 days

  12. Safety Parameters (Type, frequency, and severity of adverse events (AEs) and adverse events of special interest (AESI) and their relationship to study Treatment)

    Measured: up to 1176 days

  13. Incidence of Richter's transformation

    Incidence of Richter's transformation

    Measured: up to 1176 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 May 2016 (estimated)
  2. Study startSep 2016
  3. Primary completionJan 2022
  4. Study completionMar 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
41 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02758665
Sponsor's protocol ID
CLL2-GIVe
Acronym
CLL2-GiVe
Status last verified
Jan 2023
First submitted
6 Apr 2016
Last updated
17 Jan 2023
Results posted
No
Data monitoring committee
No
Individual data sharing
Yes

Publications

  • Langerbeins P, Giza A, Robrecht S, Cramer P, von Tresckow J, Al-Sawaf O, Fink AM, Furstenau M, Kutsch N, Simon F, Goede V, Hoechstetter M, Niemann CU, da Cunha-Bang C, Kater A, Dubois J, Gregor M, Staber PB, Tausch E, Schneider C, Stilgenbauer S, Eichhorst B, Fischer K, Hallek M. Reassessing the chronic lymphocytic leukemia International Prognostic Index in the era of targeted therapies. Blood. 2024 Jun 20;143(25):2588-2598. doi: 10.1182/blood.2023022564.

    PubMed 38620092

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing ibrutinib, obinutuzumab and venetoclax in people with Leukemia, Lymphocytic, Chronic, run by University of Ulm at 11 sites in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 19 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 17 Jan 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 11 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Complete response (CR) rate (time frame: at day 1 of cycle 15 (1 cycle = 28 days) after start of induction therapy). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02758665, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Jan 2023.

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