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

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

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.

Study Overview

• Status: Terminated
• Conditions: Primary CNS Lymphoma
• Intervention / Treatment: Drug: Venetoclax; Drug: Obinutuzumab

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 Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Baden-Württemberg
    • Stuttgart, Baden-Württemberg, Germany, 70176
      • Klinikum Stuttgart

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics of venetoclax and obinutuzumab	Serum concentration and CSF concentration (μg/ml)	day 3, 15, and 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose limiting toxicities	Defined by CTCAE (version 5.0)	Within the first 6 weeks
Best lymphoma response achieved during induction	According to IPCG criteria	During induction (3 months)
Progression-free survival 1 (PFS1)	Time from the date of first dose until date of progression, relapse or death, whichever occurs first	Up to 15 months
Overall survival	Time from the date of first dose until date of death	Up to 15 months
Progression-free survival 2 (PFS2)	Time from the start of maintenance venetoclax treatment at week 12 until date of progression, relapse or death, whichever occurs first.	Up to 12 months
Mutational landscape of lymphoma	NGS test based on FoundationOne Heme® platform	At baseline

Collaborators and Investigators

• Sponsor: Klinikum Stuttgart
• Collaborators: University Hospital Freiburg
• Investigators: Study Chair: Gerald Illerhaus, Prof, Klinikum der Landeshauptstadt Stuttgart gKAö

Study record dates

Study Major Dates

• Study Start (Actual): May 12, 2020
• Primary Completion (Actual): November 25, 2021
• Study Completion (Actual): November 25, 2021

Study Registration Dates

• First Submitted: August 26, 2019
• First Submitted That Met QC Criteria: August 28, 2019
• First Posted (Actual): August 29, 2019

Study Record Updates

• Last Update Posted (Actual): January 19, 2022
• Last Update Submitted That Met QC Criteria: January 18, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: pharmacokinetics; venetoclax; obinutuzumab
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Antineoplastic Agents; Antineoplastic Agents, Immunological; Venetoclax; Obinutuzumab
• Other Study ID Numbers: ML40029

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: IPD will by made available on a data depository (e.g. https://datadryad.org/) after study completion and publication of results.
• IPD Sharing Time Frame: after study completion and publication of results.
• IPD Sharing Access Criteria: not decided yet
• IPD Sharing Supporting Information Type: Analytic Code

Drug and device information, study documents

• 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