Clinical trial NCT04073147: Venetoclax and Obinutuzumab for Relapsed/Refractory Primary CNS Lymphoma
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Primary CNS Lymphoma
Keywords: venetoclax
obinutuzumab
pharmacokinetics
Lead sponsor: Klinikum Stuttgart
Sponsor class: OTHER
Collaborators: name: University Hospital Freiburg
First posted: 2019-08-29
Enrollment: 4
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
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 2
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Pharmacokinetics of venetoclax and obinutuzumab
timeFrame: day 3, 15, and 28
Secondary outcomes:
measure: Dose limiting toxicities
timeFrame: Within the first 6 weeks
measure: Best lymphoma response achieved during induction
timeFrame: During induction (3 months)
measure: Progression-free survival 1 (PFS1)
timeFrame: Up to 15 months
measure: Overall survival
timeFrame: Up to 15 months
measure: Progression-free survival 2 (PFS2)
timeFrame: Up to 12 months
measure: Mutational landscape of lymphoma
timeFrame: At baseline
Other outcomes:
Locations:
city: Stuttgart
country: Germany
facility: Klinikum Stuttgart
state: Baden-Württemberg
Study officials:
affiliation: Klinikum der Landeshauptstadt Stuttgart gKAö
name: Gerald Illerhaus, Prof
role: STUDY_CHAIR
References: