Clinical trial NCT04116411: A Clinical Trial Evaluating the Efficacy of Valganciclovir in Glioblastoma Patients
Official title: A Multicenter Randomized Double-blinded Controlled Phase 2 Study Evaluating the Efficacy of Valganciclovir As Add-on Therapy in Glioblastoma Patients
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Glioblastoma Multiforme
Keywords: cytomegalovirus
valganciclovir
Lead sponsor: Karolinska Institutet
Sponsor class: OTHER
Collaborators: name: Karolinska University Hospital
name: Karolinska Institutet
First posted: 2019-10-04
Enrollment: 220
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A multicenter randomized double-blinded controlled phase 2 study evaluating the efficacy of valganciclovir as add-on therapy in glioblastoma patients. Patients will receive either placebo or valganciclovir according to a randomisation list, blinded to the sponsor and study team. Seven centers are aimed to include patients once approval is received for each respective study center.
Primary purpose: TREATMENT

Brief summary: This study is a multicenter randomized double-blinded controlled phase 2 study evaluating the efficacy and safety of the anti-CMV drug valganciclovir vs placebo as add-on therapy in patients with glioblastoma. Valganciclovir is approved for treatment of cytomegalovirus (CMV) infections, but may also have anti-tumoral effects. Current evidence imply that most glioblastomas are CMV positive and that the virus can affect tumor aggressiveness.

Detailed description: Adult patients will either be randomized to standard treatment (temozolomide and radiation therapy) + placebo tablets or to standard treatment + valganciclovir. Patients are randomized using 1 to 1 distribution of the patients between the treatment groups and are stratified according to methylation status of the MGMT promoter; equal proportion of patients are included in each group. A maximum of 30% of patients with methylated MGMT promoter are allowed into the study (to harmonise with current data used for statistical power calculation), as MGMT promotor methylation status is prognostic for patient survival. Patients must enter the study within 10 weeks after surgery.

Full dose treatment with 900mgs of Valganciclovir is given twice daily for 6 weeks, thereafter 900 mgs daily during 98 weeks (total treatment of 24 months). Valganciclovir is available in 450 mg tablets. The dose of Valganciclovir will be adjusted according to renal function.

This study will be performed in compliance with the protocol, ICH-GCP, the declaration of Helsinki and applicable Swedish regulatory requirements.

The study discontinuation criteria are as follows:

* Withdrawal of consent
* An adverse event which requires discontinuation of the trial medication or results in
* inability to continue to comply with trial procedures
* Disease progression which results in inability to continue to comply with trial
* procedures
* Major Protocol deviations
* Exclusion criteria met

Eligibility criteria: Inclusion Criteria:

1. Patients aged 18 years or older
2. Patients with newly diagnosed glioblastoma, IDH 1 wt, WHO grade IV
3. Radical resection
4. Concomitant treatment with temozolomide and radiation therapy
5. MGMT promoter methylation status
6. Patients with at least KPS 70 , ECOG/WHO 2
7. Patients providing written informed consent
8. Patients cooperative and able to complete all the assessment procedures.
9. Females of child-bearing age must have a negative pregnancy test at screening (all premenopausal women, or in case when menstrual status can not be ascertained in women under the age of 55). Female patient must agree to utilize a highly efficient birth control method throughout the study period (Pearl index \<1, e.g: oral contraception with gestagens, transdermal contraceptives, implants, injectables, intrauterine devices, bilateral tubal occlusion, sexual abstinence or vasectomised partner). The birth control method must be used at least 30 days after treatment end. Pregnancy testing should be performed at monthly intervals due to high teratogenic potential of valganciclovir. Men are recommended to use condoms with female partners during, and for at least 90 days following treatment with Valganciclovir.
10. Patients must be enrolled within 10 weeks after surgery

Exclusion Criteria:

1. Patients allergic to, or who do not tolerate Valganciclovir, aciclovir or valaciclovir treatment
2. Patients with decreased cognitive function (below 24 in MMSE test)
3. Pregnant or lactating females
4. Patients not signing informed consent
5. Patient is simultaneously participating in another experimental drug therapy trial
6. Neutrophil count \< 1,5 cells/ 109/L
7. Platelet count \< 150 cells/ 109/L
8. HGB \< 80 g/L
9. Abnormal renal function (GFR \< 30)
10. Secondary glioblastoma, or glioblastoma IDH1 mutated.
11. Unfit for any other reason judged by investigator

Primary outcomes:
measure: Impact of valganciclovir on median overall survival of glioblastoma patients
timeFrame: Study closure at 30 months follow up. Survival analyses will be analysed at 12 and 24 months.
measure: Baseline and demographic data
timeFrame: At 30 months follow up
Secondary outcomes:
measure: Progression free survival at 12 and 24 months
timeFrame: 12 and 24 months
measure: Incidence of valganciclovir treatment related adverse events
timeFrame: 30 months follow up time
measure: Health related Quality of Life using EORTC QLQ30 module
timeFrame: Base line and at every 3 months until 24 months follow up.
measure: Cognitive functions
timeFrame: up to 24 months
measure: Health related Quality of Life using the EORTC BN20 module
timeFrame: Base line and at every 3 months until 24 months follow up.
Other outcomes:
Locations:
city: Oslo
country: Norway
facility: Oslo University Hospital
city: Stavanger
country: Norway
facility: Stavanger University Hospital
city: Solna
country: Sweden
facility: SE01 Karolinska University Hospital
state: Stockholm
Study officials:
affiliation: Karolinska University Hospital
name: Giuseppe Stragliotto, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Stragliotto G, Rahbar A, Solberg NW, Lilja A, Taher C, Orrego A, Bjurman B, Tammik C, Skarman P, Peredo I, Soderberg-Naucler C. Effects of valganciclovir as an add-on therapy in patients with cytomegalovirus-positive glioblastoma: a randomized, double-blind, hypothesis-generating study. Int J Cancer. 2013 Sep 1;133(5):1204-13. doi: 10.1002/ijc.28111. Epub 2013 Mar 13.
citation: Soderberg-Naucler C, Peredo I, Stragliotto G. Valganciclovir in patients with glioblastoma. N Engl J Med. 2013 Nov 21;369(21):2066-7. doi: 10.1056/NEJMc1312413. No abstract available.
citation: Peredo I, Hellden A, Wolmer-Solberg N, Pohanka A, Stragliotto G, Rahbar A, Stahle L, Bellander BM, Soderberg-Naucler C. Ganciclovir concentrations in the cerebral extracellular space after valganciclovir treatment; a case study. BMJ Case Rep. 2015 Dec 15;2015:bcr2014207694. doi: 10.1136/bcr-2014-207694.
citation: Rahbar A, Orrego A, Peredo I, Dzabic M, Wolmer-Solberg N, Straat K, Stragliotto G, Soderberg-Naucler C. Human cytomegalovirus infection levels in glioblastoma multiforme are of prognostic value for survival. J Clin Virol. 2013 May;57(1):36-42. doi: 10.1016/j.jcv.2012.12.018. Epub 2013 Feb 4.
citation: Cobbs CS. Does valganciclovir have a role in glioblastoma therapy? Neuro Oncol. 2014 Mar;16(3):330-1. doi: 10.1093/neuonc/nou009. No abstract available.
citation: Merchut-Maya JM, Bartek J Jr, Bartkova J, Galanos P, Pantalone MR, Lee M, Cui HL, Shilling PJ, Brochner CB, Broholm H, Maya-Mendoza A, Soderberg-Naucler C, Bartek J. Human cytomegalovirus hijacks host stress response fueling replication stress and genome instability. Cell Death Differ. 2022 Aug;29(8):1639-1653. doi: 10.1038/s41418-022-00953-w. Epub 2022 Feb 22.