VENOBI-CNS: Venetoclax and Obinutuzumab for Relapsed/Refractory Primary CNS Lymphoma

Sponsor
Klinikum Stuttgart (Other)
Overall Status
Terminated
CT.gov ID
NCT04073147
Collaborator
University Hospital Freiburg (Other)
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Study Details

Study Description

Brief Summary

This is a phase IB study investigating the pharmacokinetics of the combination venetoclax and obinutuzumab in the cerebrospinal fluid of patient with relapsed primary CNS lymphoma.

Condition or Disease Intervention/Treatment Phase
Phase 1

Detailed Description

This is a phase IB study investigating the pharmacokinetics of the combination venetoclax and obinutuzumab in the cerebrospinal fluid of patient with relapsed primary CNS lymphoma. Three dosing groups of venetoclax (600mg, 800mg, and 1000mg) are planned; dosing of obinutuzumab will be 1000mg for each dosing group. 15 patients are planned being included from two centers in Germany.

Study Design

Study Type:
Interventional
Actual Enrollment :
4 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Intervention Model Description:
Three sequential dosing groups. Starting with dosing group 1 (5 patients), followed by dosing group 2 (5 patients) if no dose limiting toxicities occur during dosing group 1, and finally followed by dosing group 3 (5 patients) if no dose limiting toxicities occur in dosing group 2Three sequential dosing groups. Starting with dosing group 1 (5 patients), followed by dosing group 2 (5 patients) if no dose limiting toxicities occur during dosing group 1, and finally followed by dosing group 3 (5 patients) if no dose limiting toxicities occur in dosing group 2
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Chemotherapy Free Treatment With Venetoclax and Obinutuzumab for Relapsed / Refractory Primary CNS Lymphoma Patients (VENOBI-CNS Study) - A Phase IB Study to Assess the Pharmacokinetics in the Cerebrospinal Fluid
Actual Study Start Date :
May 12, 2020
Actual Primary Completion Date :
Nov 25, 2021
Actual Study Completion Date :
Nov 25, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: Dosing group 1

Venetoclax 600mg + Obinutuzumab 1000mg

Drug: Venetoclax
Venetoclax per os
Other Names:
  • Venclyxto
  • Drug: Obinutuzumab
    ObintuzumabIV
    Other Names:
  • Gazyvaro
  • Experimental: Dosing group 2

    Venetoclax 800mg + Obinutuzumab 1000mg

    Drug: Venetoclax
    Venetoclax per os
    Other Names:
  • Venclyxto
  • Drug: Obinutuzumab
    ObintuzumabIV
    Other Names:
  • Gazyvaro
  • Experimental: Dosing group 3

    Venetoclax 1000mg + Obinutuzumab 1000mg

    Drug: Venetoclax
    Venetoclax per os
    Other Names:
  • Venclyxto
  • Drug: Obinutuzumab
    ObintuzumabIV
    Other Names:
  • Gazyvaro
  • Outcome Measures

    Primary Outcome Measures

    1. Pharmacokinetics of venetoclax and obinutuzumab [day 3, 15, and 28]

      Serum concentration and CSF concentration (μg/ml)

    Secondary Outcome Measures

    1. Dose limiting toxicities [Within the first 6 weeks]

      Defined by CTCAE (version 5.0)

    2. Best lymphoma response achieved during induction [During induction (3 months)]

      According to IPCG criteria

    3. Progression-free survival 1 (PFS1) [Up to 15 months]

      Time from the date of first dose until date of progression, relapse or death, whichever occurs first

    4. Overall survival [Up to 15 months]

      Time from the date of first dose until date of death

    5. Progression-free survival 2 (PFS2) [Up to 12 months]

      Time from the start of maintenance venetoclax treatment at week 12 until date of progression, relapse or death, whichever occurs first.

    6. Mutational landscape of lymphoma [At baseline]

      NGS test based on FoundationOne Heme® platform

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 85 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion criteria:
    1. Age at inclusion ≥ 18 to 80 years, in case of ECOG 0 to 1 age up to 85 years

    2. Eastern Cooperative Group performance status (ECOG) ≤ 3

    3. Evaluable lymphoma manifestation in the CNS, either contrast-enhanced lesion in the brain parenchyma or measurable meningeal lesions.

    4. Biopsy proven CD20 positive PCNSL at initial diagnosis or previous relapse/progression (re-biopsy at study inclusion is not mandatory for inclusion, but strongly recommended if time in remission is longer than 24 months).

    5. At least one prior HD-MTX containing chemotherapy application (MTX dosed at ≥ 1 g/m2 body surface area) before progression or relapse.

    6. Confirmed relapsed or refractory PCNSL according to the IPCG response criteria with the following definition: Evidence of disease recurrence following PR/CR or uCR or no radiological response (SD or PD) as per the IPCG criteria to prior chemotherapy regimen(s), at least one of them containing high-dose methotrexate.

    7. Absolute neutrophil count (ANC) of at least 1'500/μl

    8. Platelet count of at least 50'000/μl

    9. Adequate liver (alanine aminotransferase [ALAT] and AST ≤ 3.0 x upper limit of normal [ULN] and total bilirubin ≤ 1.5 x ULN) and kidney function (estimated ≥ 30ml/min creatinine clearance according to Cockgroft-Gault formula)

    10. Written informed consent

    11. Recovery from toxicity from previous anti-lymphoma treatment to ≤ grade 2

    Exclusion criteria:
    1. Known allergy to venetoclax or other components of the formulation

    2. Known allergy to obinutuzumab or other components of the formulation

    3. Primary ocular lymphomas without brain parenchymal involvement

    4. Lymphoma relapse outside the CNS; extra CNS relapse needs to be ruled out by body CT scans (neck till pelvis) or PET-CT scans.

    5. Contraindications for lumbar puncture at the discretion of the clinical investigator

    6. Prior exposure to obinutuzumab or venetoclax

    7. Other additional anti-lymphoma treatment, e.g. chemotherapy or radiotherapy

    8. Active hepatitis B or C

    9. HIV seropositivity

    10. Chronic use of immunosuppressive drugs, e.g. steroids for systemic autoimmune disease

    11. Active infections requiring treatment

    12. Other active malignancies (except non-melanoma skin cancer). Prior malignancies without evidence of disease for at least 5 years are allowed

    13. Patient is pregnant or breastfeeding, or expecting to conceive or father children within one year of finishing venetoclax and 18 months for obinutuzumab.

    14. Prior allogeneic haematopoietic stem cell or solid organ transplantation

    15. Therapeutic intervention in setting of other former interventional clinical trial within 30 days before the first IMP administration in VENOBI study; simultaneous participation in registry and diagnostic studies or follow up of an interventional trial is allowed

    16. Patient without legal capacity who is unable to understand the nature, significance and consequences of the trial

    17. Known or persistent abuse of medication, drugs or alcohol

    18. Person who is in a relationship of dependence/employment with the sponsor or the investigator

    19. Administration of moderate or strong CYP3A inhibitors or inducers within 1 week of initiation of venetoclax dosing.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Klinikum Stuttgart Stuttgart Baden-Württemberg Germany 70176

    Sponsors and Collaborators

    • Klinikum Stuttgart
    • University Hospital Freiburg

    Investigators

    • Study Chair: Gerald Illerhaus, Prof, Klinikum der Landeshauptstadt Stuttgart gKAö

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Klinikum Stuttgart
    ClinicalTrials.gov Identifier:
    NCT04073147
    Other Study ID Numbers:
    • ML40029
    First Posted:
    Aug 29, 2019
    Last Update Posted:
    Jan 19, 2022
    Last Verified:
    Jan 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    No
    Keywords provided by Klinikum Stuttgart
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Jan 19, 2022