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Standard Chemoimmunotherapy (FCR/BR) Versus Rituximab + Venetoclax (RVe) Versus Obinutuzumab (GA101) + Venetoclax (GVe) Versus Obinutuzumab + Ibrutinib + Venetoclax (GIVe) in Fit Patients With Previously Untreated Chronic Lymphocytic Leukemia (CLL) Without Del(17p) or TP53 Mutation

NCT02950051

Description:

The aim of this study is to evaluate if standard chemoimmunotherapy (FCR, BR) in frontline treatment of physically fit CLL patients without del17p or TP 53 mutation can be replaced by combinations of targeted drugs (Venetoclax, Ibrutinib) with anti-CD20-antibodies (Rituximab, Obinutuzumab), which may induce extremely long lasting remissions.

Related Conditions:
  • Chronic Lymphocytic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Standard Chemoimmunotherapy (FCR/BR) Versus Rituximab + Venetoclax (RVe) Versus Obinutuzumab (GA101) + Venetoclax (GVe) Versus Obinutuzumab + Ibrutinib + Venetoclax (GIVe) in Fit Patients With Previously Untreated Chronic Lymphocytic Leukemia (CLL) Without Del(17p) or TP53 Mutation
  • Official Title: A Phase 3 Multicenter, Randomized, Prospective, Open-label Trial of Standard Chemoimmunotherapy (FCR/BR) Versus Rituximab Plus Venetoclax (RVe) Versus Obinutuzumab (GA101) Plus Venetoclax (GVe) Versus Obinutuzumab Plus Ibrutinib Plus Venetoclax (GIVe) in Fit Patients With Previously Untreated Chronic Lymphocytic Leukemia (CLL) Without Del(17p) or TP53 Mutation

Clinical Trial IDs

  • ORG STUDY ID: CLL13
  • SECONDARY ID: 2015-004936-36
  • NCT ID: NCT02950051

Conditions

  • Chronic Lymphocytic Leukemia

Interventions

DrugSynonymsArms
FludarabineFluduraStandard chemoimmunotherapy (SCIT)
CyclophosphamideEndoxanStandard chemoimmunotherapy (SCIT)
RituximabMabThera, RituxanStandard chemoimmunotherapy (SCIT)
BendamustineRibomustin, LevactStandard chemoimmunotherapy (SCIT)
VenetoclaxVenclexta, VenclyxtoRituximab + Venetoclax (RVe)
ObinutuzumabGazyva, GazyvaroObinutuzumab + Venetoclax (GVe)
IbrutinibImbruvicaObinutuzumab + Ibrutinib + Venetoclax (GIVe)

Purpose

The aim of this study is to evaluate if standard chemoimmunotherapy (FCR, BR) in frontline treatment of physically fit CLL patients without del17p or TP 53 mutation can be replaced by combinations of targeted drugs (Venetoclax, Ibrutinib) with anti-CD20-antibodies (Rituximab, Obinutuzumab), which may induce extremely long lasting remissions.

Detailed Description

      Chemoimmunotherapy is the standard of care in first-line treatment of CLL patients without
      del17p or TP 53 mutation; physically fit patients are treated with fludarabine,
      cyclophosphamide and rituximab (FCR)1. Due to the high risk of severe neutropenias and
      infections with FCR, bendamustine and rituximab (BR) must be considered in patients aged >65
      years.

      However, these conventional chemoimmunotherapies are associated with side effects caused by
      the rather unspecific mode of action of the chemotherapy. Therefore, there is an urgent need
      for alternatives, especially chemotherapy-free regimens.

      In first line treatment of elderly patients with CLL and coexisting conditions, the
      anti-CD20-antibody obinutuzumab is the new standard therapy. In the CLL11 trial the
      combination of obinutuzumab with chlorambucil proved to be safe and lead to markedly improved
      response rates as well as PFS times in comparison to chlorambucil alone or combined with
      rituximab.

      The BCL2 antagonist venetoclax (GDC-0199/ABT-199) showed striking activity with tumor lysis
      syndrome as dose limiting toxicity in patients with relapsed and refractory CLL. 400 mg
      venetoclax was determined to be a safe and efficacious dose. Several patients treated with
      the combination of venetoclax and rituximab in relapsed refractory CLL even achieved MRD
      negativity. The FDA approved Venetoclax for the treatment of relapsed CLL with 17p/TP53 on
      12th April 2016.

      Therefore, venetoclax plus CD20-antibody based combinations have the potential to induce
      higher rates of MRD negativity in frontline therapy of CLL and concomitantly induce lower
      rates of toxicities so that chemotherapy might be replaced. Furthermore, venetoclax and
      obinutuzumab demonstrated synergistic activity in a preclinical study of a murine Non-Hodgkin
      lymphoma xenograft model, and additive activity in a CLL lymph node model. The combination
      appears tolerable in the firstline treatment of CLL patients with coexisting conditions
      whilst the toxicity profile of both drugs compares favorably to those of the chemotherapies
      currently used in the treatment of CLL. Consequently, it should be tested if rituximab can be
      replaced by obinutuzumab in combination with venetoclax in this trial.

      Ibrutinib, a selective, irreversible small molecular inhibitor of Bruton´s Tyrosine Kinase
      (BTK), showed excellent responses and a safe toxicity profile9,10, even in combination with
      BR. Ibrutinib is approved for treatment of relapsed CLL as well as frontline therapy of CLL
      by the FDA and EMA (April 29th 2016).

      The combination of ibrutinib and venetoclax showed synergy in primary CLL cells.

      Consequently, the aim of the current trial is to evaluate if chemoimmunotherapy in the
      frontline treatment of physically fit patients in CLL can be replaced by combinations of
      these targeted drugs with anti-CD20-antibodies.
    

Trial Arms

NameTypeDescriptionInterventions
Standard chemoimmunotherapy (SCIT)Active ComparatorPatients up to age 65: 6 cycles (q28d) of Fludarabine + Cyclophosphamide + Rituximab (FCR) Patients older than 65 years: 6 cycles (q28d) of Bendamustine + Rituximab (BR)
  • Fludarabine
  • Cyclophosphamide
  • Rituximab
  • Bendamustine
Rituximab + Venetoclax (RVe)Experimental6 cycles (q28d) of RVe + 6 cycles (q28d) of Venetoclax (alone)
  • Rituximab
  • Venetoclax
Obinutuzumab + Venetoclax (GVe)Experimental6 cycles (q28d) of GVe + 6 cycles (q28d) of Venetoclax (alone)
  • Venetoclax
  • Obinutuzumab
Obinutuzumab + Ibrutinib + Venetoclax (GIVe)Experimental6 cycles (q28d) of GIVe + 6 cycles (q28d) of Ibrutinib plus Venetoclax. Administration of ibrutinib will be continued for a maximum of 36 months or until MRD negativity, start of new anti-CLL therapy or inacceptable toxicity, whatever occurs first.
  • Venetoclax
  • Obinutuzumab
  • Ibrutinib

Eligibility Criteria

        Inclusion Criteria:

          1. Documented CLL requiring treatment according to iwCLL criteria

          2. Age at least 18 years

          3. Life expectancy ≥ 6 months

          4. Ability and willingness to provide written informed consent and to adhere to the study
             visit schedule and other protocol requirements

          5. Adequate bone marrow function indicated by a platelet count >30 x10^9/l (unless
             directly attributable to CLL infiltration of the bone marrow, proven by bone marrow
             biopsy)

          6. Creatinine clearance ≥70ml/min directly measured with 24hr urine collection or
             calculated according to the modified formula of Cockcroft and Gault (for men: GFR ≈
             ((140 - age) x bodyweight) / (72 x creatinine), for women x 0, 85). For patients with
             creatinine values within the normal range the calculation of the clearance is not
             necessary. Dehydrated patients with an estimated creatinine clearance less than 70
             ml/min may be eligible if a repeat estimate after adequate hydration is > 70 ml/min

          7. Adequate liver function as indicated by a total bilirubin≤ 2 x, AST/ALT ≤ 2.5 x the
             institutional ULN value, unless directly attributable to the patient's CLL or to
             Gilbert's Syndrome

          8. Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative;
             patients positive for anti-HBc may be included if PCR for HBV DNA is negative and
             HBV-DNA PCR is performed every month until 12 months after last treatment cycle),
             negative testing for hepatitis C RNA within 6 weeks prior to registration

          9. Eastern Cooperative Oncology Group Performance Status (ECOG) performance status 0-2

        Exclusion Criteria:

          1. Any prior CLL-specific therapies (except corticosteroid treatment administere due to
             necessary immediate intervention; within the last 10 days before start of study
             treatment, only dose equivalents of 20 mg prednisolone are permitted).

          2. Transformation of CLL (Richter transformation)

          3. Decompensated hemolysis, defined as ongoing hemoglobin drop in spite of three more
             concurrent treatments being administered for hemolysis

          4. Detected del(17p) or TP53 mutation

          5. Patients with a history of PML

          6. Any comorbidity or organ system impairment rated with a single CIRS (cumulative
             illness rating scale) score of 4 (excluding the eyes/ears/nose/throat/larynx organ
             system), a total CIRS score of more than 6 or any other life-threatening illness,
             medical condition or organ system dysfunction that, in the investigator´s opinion,
             could comprise the patients safety or interfere with the absorption or metabolism of
             the study drugs (e.g, inability to swallow tablets or impaired resorption in the
             gastrointestinal tract)

          7. Urinary outflow obstruction

          8. Malignancies other than CLL currently requiring systemic therapies, not being treated
             in curative intention before (unless the malignant disease is in a stable remission
             due to the discretion of the treating physician) or showing signs of progression after
             curative treatment

          9. Uncontrolled or active infection

         10. Patients with known infection with human immunodeficiency virus (HIV)

         11. Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers

         12. Anticoagulant therapy with warfarin or phenoprocoumon, (rotation to alternative
             anticoagulation is allowed, but note that patients being treated with NOAKs can be
             included, but must be properly informed about the potential risk of bleeding under
             treatment with ibrutinib)

         13. History of stroke or intracranial hemorrhage within 6 months prior to registration

         14. Use of investigational agents which might interfere with the study drug within 28 days
             prior to registration

         15. Vaccination with live vaccines 28 days prior to registration

         16. Major surgery less than 30 days before start of treatment

         17. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal
             antibodies, known sensitivity or allergy to murine products

         18. Known hypersensitivity to any active substance or to any of the excipients of one of
             the drugs used in the trial

         19. Pregnant women and nursing mothers (a negative pregnancy test is required for all
             women of childbearing potential within 7 days before start of treatment; further
             pregnancy testing will be performed regularly)

         20. Fertile men or women of childbearing potential unless:

               1. surgically sterile or ≥ 2 years after the onset of menopause

               2. willing to use two methods of reliable contraception including one highly
                  effective contraceptive method (Pearl Index <1) and one additional effective
                  (barrier) method during study treatment and for 18 months after the end of study
                  treatment

         21. Legal incapacity

         22. Prisoners or subjects who are institutionalized by regulatory or court order

         23. Persons who are in dependence to the sponsor or an investigator
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Miminimal residual disease (MRD) negativity rate in peripheral blood (PB)
Time Frame:Month 15
Safety Issue:
Description:Proportion of MRD negative patients at month15 based on the intention-to-treat population (ITT population), that is the number of MRD negative patients divided by the number of the ITT population. MRD negativity is defined as <1 CLL-cell among 10,000 leukocytes analyzed [0.01%], i.e. < 10-4. Primary outcome measure for the comparison of GVe vs. SCIT

Secondary Outcome Measures

Measure:MRD negativity rate in PB
Time Frame:Month 15
Safety Issue:
Description:Time from randomization to the first occurrence of progression or relapse (determined using standard IWCLL guidelines [2008]), or death from any cause, whichever occurs first. Secondary outcome measure for all other comparisons with the exception of GVe vs. SCIT
Measure:MRD levels in PB
Time Frame:Month 2, 9, 13 and later time points according to the discretion of the treating physician at local laboratories
Safety Issue:
Description:
Measure:MRD levels in bone marrow (BM)
Time Frame:at final restaging (RE): 2 month after the end of the last treatment cycle
Safety Issue:
Description:
Measure:PFS
Time Frame:anticipated for January 2023 (after 213 events occured and 73 months after the first patient has been randomized)
Safety Issue:
Description:Time from randomization to the first occurrence of progression or relapse (determined using standard IWCLL guidelines [2008]), or death from any cause, whichever occurs first. Secondary outcome measure for all other comparisons with the exception of GIVe vs.SCIT
Measure:Overall response rate (ORR)
Time Frame:Month 3, 9, 13 and 15
Safety Issue:
Description:
Measure:Rate of complete responses (CR) / complete responses with incomplete bone marrow recovery(CRi)
Time Frame:Interim staging (IST: cycle 4 d1), cycle 9 d1 (or final restaging (RE) for patients in the SCIT arm), IR (or three month after RE for patients in the SCIT arm respectively) and Month 15, with regard to best response achieved
Safety Issue:
Description:Complete response (CR) rate is defined by the proportion of patients having achieved a CR/CRi defined by the IWCLL guidelines as best response until and including the response assessment at Month 6, 9, 12 and 15 (= number of patients with best response CR/CRi divided by the ITT population).

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:German CLL Study Group

Trial Keywords

  • CLL

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