Phase II Study to Assess the Efficacy of the Combination of Trimipramine and Atezolizumab with Bevacizumab in Patients with Recurrent Glioblastoma. PHENIX (SAKK 70/24)

Switzerland (ICTRP)

ICTRP Trial ID
NCT07263438 (ICTRP)

Official title (approved by ethics committee)
CHUV- DO-Lundin-PHENIX (SAKK 70/24) Open-label phase II clinical trial to test the efficacy of the combination of trimipramine and atezolizumab with bevacizumab in patients with recurrent glioblastoma (BASEC)

Academic title
Open-label Phase II Clinical Trial to Test the Efficacy of the Combination of Trimipramine and Atezolizumab With Bevacizumab in Patients With Recurrent Glioblastoma (ICTRP)

Public title
Efficacy of the Combination of Trimipramine and Atezolizumab With Bevacizumab in Patients With Recurrent Glioblastoma: a Phase 2 Trial (ICTRP)

Disease under investigation
GlioblastomaRecurrence Tumor (ICTRP)

Intervention under investigation
Drug: TrimipramineBiological: Cohort 1: AtezolizumabBiological: BevacizumabBiological: Cohort 2: AtezolizumabBiological: Cohort 2: Bevacizumab (ICTRP)

Type of trial
Interventional (ICTRP)

Trial design
Allocation: Non-Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label). (ICTRP)

Inclusion/Exclusion criteria
Inclusion Criteria:

- Histologically or cytologically confirmed glioblastoma, according to World Health
Organization [WHO] 2021 with unequivocal first progression after standard (6 weeks
radiotherapy [RT]) with concurrent & adjuvant temozolomide [TMZ] chemotherapy.

- Patients must be at least 3 months off the concomitant part of chemo-radiotherapy.

- Stable or decreasing dose of steroids for 7 days prior to the baseline

- Magnetic Resonance Imaging [MRI] scan.

- Maximum dose of dexamethasone (or equivalent) 4 mg at time of inclusion.

- No surgery or other invasive procedures (major surgical procedure, open biopsy or
significant traumatic injury) within 4 weeks prior to registration.

- No core biopsy or other minor surgical procedure within 7 days prior to
registration. (Placement of a central vascular access device, if performed at least
2 days prior to trial treatment administration, is allowed).

- Patients who require anti-convulsant therapy must be taking non-enzyme inducing
antiepileptic drugs [non-EIAED]. Patients previously on EIAED must be switched to
non-EIAED at least 2 weeks prior to registration.

- Measurable disease per Response Assessment in Neuro-Oncology [RANO] version 2.0
criteria. Recurrent disease must be at least one bi-dimensionally measurable
contrast-enhancing lesion with clearly defined margins by MRI scan, with minimal
diameters of 10 mm, visible on 2 or more axial slices 5 mm apart, based on MRI scan
done within 28 days prior to registration.

- Karnofsky performance status 70-100.

- Adequate bone marrow function: neutrophil count = 1.5 x 10^9/L, platelet count = 100
x 109/L, hemoglobin = 90 g/L.

- Adequate hepatic function: total bilirubin = 1.5 x Upper Limit of Normal [ULN]
(except for patients with Gilbert's syndrome = 3.0 x ULN), aspartate
aminotransferase [AST] and alanine transaminase [ALT] and alkaline phosphatase [AP]
= 2.5 x ULN.

- Adequate renal function: estimated glomerular filtration rate [eGFR] = 45
mL/min/1.73 m2 (according to Chronic Kidney Disease Epidemiology Collaboration
[CKD-EPI] formula).

- Urine dipstick for proteinuria < 2+. Patients with = 2+ proteinuria on dipstick
urinalysis at baseline should undergo 24 hours urine collection and must demonstrate
= 1 g of protein/24 hours.

- Adequate coagulation function: International Normalized Ratio [INR] = 1.5 x ULN (the
ULN for INR is defined with the value 1.2 for all sites, in case no ULN is
documented in the laboratory certificates/sheets). Use of full-dose anticoagulants
is permitted as long as the INR is within therapeutic limits (according to the
medical standard in the institution) and the patient has been on a stable dose of
anticoagulants for at least two weeks before registration, as per American Society
for Clinical Oncology [ASCO] guidelines, low molecular weight heparin [LMWH] should
be the preferred approach. Concomitant anticoagulation with aspirin (up to 300
mg/day) and anticoagulation with LMWH is allowed.

- Women of childbearing potential must use highly effective contraception , are not
pregnant or breast-feeding and agree not to become pregnant during trial treatment
and until 6 months after the last dose of investigational drug. A negative pregnancy
test before inclusion into the trial is required for all women of childbearing
potential.

- Men agree not to donate sperm or to father a child during trial treatment and until
6 months after the last dose of investigational drug.

- Patient is able and willing to swallow trial drug as whole tablet.

Only for Cohort 2:

- Consent to giving access of part of the tumor tissue and Cerebrospinal Fluid [CSF]
obtained during the routine neurosurgical procedure for pharmacology and
translational studies. Tumor tissue will only be made available once it is
established that enough tumor tissue is available for standard neuropathological
analysis.

- Patients that have a medical indication for a neurosurgical resection from first
recurrent tumor.

Exclusion Criteria:

- Patient must be in first progression/recurrence and have not received more than one
line of chemotherapy (concurrent and adjuvant temozolomide). Treatment of Time to
Treatment Failure [TTF] fields (Optune) is allowed during first line but will be
stopped at registration.

- Patients must not have prostate enlargement with urinary retention or angle-closure
glaucoma at registration.

- Any other experimental drug must be discontinued at least 30 days prior to
registration

- Patients under ongoing treatment with an antidepressant must be eligible for a
switch to trimipramine. Patients currently under TriCyclic Antidepressant [TCAs]
(amitriptyline, clomipramine, nortriptyline, imipramine), selective serotonin
reuptake inhibitors (sertraline, paroxetine, fluvoxamine, citalopram, escitalopram)
or serotonin and norepinephrine reuptake inhibitors (venlafaxine, duloxetine) must
be weaned off these medications for at least 14 days before the introduction of
trimipramine.

Note: Patients treated with fluoxetine prior to enrollment will only be eligible for this
trial after a two-month washout period before starting the study treatment.

- Prior treatment with atezolizumab or any other immune checkpoint inhibitors.

- Prior treatment with bevacizumab or other Vascular Endothelial Growth Factor [VEGF]
inhibitors or VEGF-receptor signaling inhibitors.

- Concomitant or prior use of immunosuppressive medication within 5 half-lives before
registration, with the exceptions of intranasal and inhaled corticosteroids.

- Life expectancy of less than 12 weeks.

- Active systemic prior malignancy. Patients with a prior malignancy (basal cell
carcinoma of the skin, squamous carcinoma of the skin or carcinoma in situ of the
cervix) and treated with curative intention are eligible if all treatment of that
malignancy was completed at least 2 years before registration and the patient has no
evidence of disease at registration.

- Blood pressure combination treatment with more than two antihypertensive medications
or uncontrolled blood hypertension under properly antihypertensive medications.

- Severe or uncontrolled cardiovascular disease (congestive heart failure New York
Heart Association [NYHA] III or IV unstable angina pectoris, history of myocardial
infarction within the last six months, serious arrhythmias requiring medication
(with exception of atrial fibrillation or paroxysmal supraventricular tachycardia).

- Have a heart rate corrected QT interval using Fridericia's formula [QTcF] (QTc = QT
/ RR^1/3) = 450 msec or other factors that increase the risk of QT prolongation or
arrhythmic events (e.g. heart failure, hypokalaemia, familial history of long QT
interval syndrome). Patients with bundle branch block and prolonged QTcF are
permitted with approval of the sponsor investigator.

- Presence of a grade 3 atrioventricular [AV] block on electrocardiogram [ECG].

- History of cerebrovascular accident or intracranial haemorrhage within 6 months
prior to registration.

- Known h (ICTRP)

not available

Primary and secondary end points
Cohort 1: Progression-free survival rate [PFSR];Cohort 2: Level of trimipramine in the tumor tissue and cerebrospinal fluid [CSF] (ICTRP)

not available

Registration date
not available

Incorporation of the first participant
not available

Secondary sponsors
not available

Additional contacts
Andreas Hottinger, MD, PhD, andreas.hottinger@chuv.ch, 0041 79 556 52 71 (ICTRP)

Secondary trial IDs
CHUV- DO-Lundin-PHENIX (ICTRP)

Results-Individual Participant Data (IPD)
not available

Further information on the trial
https://clinicaltrials.gov/study/NCT07263438 (ICTRP)