Venetoclax and Obinutuzumab for Relapsed/Refractory Primary CNS Lymphoma

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Primary CNS Lymphoma

Intervention / Treatment
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* Drug: Venetoclax
* Drug: Obinutuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Age at inclusion ≥ 18 to 80 years, in case of ECOG 0 to 1 age up to 85 years Eastern Cooperative Group performance status (ECOG) ≤ 3 Evaluable lymphoma manifestation in the CNS, either contrast-enhanced lesion in the brain parenchyma or measurable meningeal lesions. 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). At least one prior HD-MTX containing chemotherapy application (MTX dosed at ≥ 1 g/m2 body surface area) before progression or relapse. 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. Absolute neutrophil count (ANC) of at least 1'500/μl Platelet count of at least 50'000/μl 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) Written informed consent Recovery from toxicity from previous anti-lymphoma treatment to ≤ grade 2 Exclusion criteria: Known allergy to venetoclax or other components of the formulation Known allergy to obinutuzumab or other components of the formulation Primary ocular lymphomas without brain parenchymal involvement Lymphoma relapse outside the CNS; extra CNS relapse needs to be ruled out by body CT scans (neck till pelvis) or PET-CT scans. Contraindications for lumbar puncture at the discretion of the clinical investigator Prior exposure to obinutuzumab or venetoclax Other additional anti-lymphoma treatment, e.g. chemotherapy or radiotherapy Active hepatitis B or C HIV seropositivity Chronic use of immunosuppressive drugs, e.g. steroids for systemic autoimmune disease Active infections requiring treatment Other active malignancies (except non-melanoma skin cancer). Prior malignancies without evidence of disease for at least 5 years are allowed Patient is pregnant or breastfeeding, or expecting to conceive or father children within one year of finishing venetoclax and 18 months for obinutuzumab. Prior allogeneic haematopoietic stem cell or solid organ transplantation 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 Patient without legal capacity who is unable to understand the nature, significance and consequences of the trial Known or persistent abuse of medication, drugs or alcohol Person who is in a relationship of dependence/employment with the sponsor or the investigator Administration of moderate or strong CYP3A inhibitors or inducers within 1 week of initiation of venetoclax dosing.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional 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 2
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dosing group 1<br>Venetoclax 600mg + Obinutuzumab 1000mg | Drug: Venetoclax<br>* Venetoclax per os<br>* Other names: Venclyxto;Drug: Obinutuzumab<br>* ObintuzumabIV<br>* Other names: Gazyvaro;|
| Experimental: Dosing group 2<br>Venetoclax 800mg + Obinutuzumab 1000mg | Drug: Venetoclax<br>* Venetoclax per os<br>* Other names: Venclyxto;Drug: Obinutuzumab<br>* ObintuzumabIV<br>* Other names: Gazyvaro;|
| Experimental: Dosing group 3<br>Venetoclax 1000mg + Obinutuzumab 1000mg | Drug: Venetoclax<br>* Venetoclax per os<br>* Other names: Venclyxto;Drug: Obinutuzumab<br>* ObintuzumabIV<br>* Other names: Gazyvaro;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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venetoclax, obinutuzumab, pharmacokinetics