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A Clinical Trial Evaluating the Efficacy of Valganciclovir in Glioblastoma Patients (VIGAS2)

Primary Purpose

Glioblastoma Multiforme

Status

Recruiting

Phase

Phase 2

Locations

Sweden

Study Type

Interventional

Intervention

Valganciclovir Tablets

Temozolomide 120 mg

Radiotherapy 60 Gy

Placebo oral tablet

About this trial

This is an interventional treatment trial for Glioblastoma Multiforme focused on measuring cytomegalovirus, valganciclovir

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients aged 18 years or older
Patients with newly diagnosed glioblastoma, IDH 1 wt, WHO grade IV
Radical resection
Concomitant treatment with temozolomide and radiation therapy
MGMT promoter methylation status
Patients with at least KPS 70 , ECOG/WHO 2
Patients providing written informed consent
Patients cooperative and able to complete all the assessment procedures.
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.
Patients must be enrolled within 10 weeks after surgery

Exclusion Criteria:

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

Sites / Locations

SE01 Karolinska University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Active Comparator

Arm Label

Placebo

Valganciclovir

Arm Description

Patients will receive placebo tablets with similar appearance as the active drug. Patients receive two 450 mg tablets twice daily taken per orally for 6 weeks, thereafter two 450 mg tablet once daily for an additional 22.5 months; a total treatment time of 24 months.

Patients will receive valganciclovir tablets with similar appearance as the placebo tablets. Patients receive two 450 mg valganciclovir tablets twice daily taken per orally for 6 weeks, thereafter two 450 mg valganciclovir tablets once daily for an additional 22.5 months; a total treatment time of 24 months.

Outcomes

Primary Outcome Measures

Impact of valganciclovir on median overall survival of glioblastoma patients

Median overall survival will be analyzed using Cox regression analysis and presented by Kaplan-Meier graphs. Proportion of patients alive at 12 or 24 months, respectively, in each study arm and will be analyzed using Fisher exact test.

Baseline and demographic data

All baseline and demographic data will be analysed using descriptive statistics such as mean, medians, standard deviations etc. for all variables which are continuous. Variables that are categorical will be analysed using frequency tables with number of patients and percent. All these analyses will be divided by treatment group. No formal hypothesis testing will be performed for the demographic and baseline variables.

Secondary Outcome Measures

Progression free survival at 12 and 24 months

Tumor recurrence is estimated as clinical and radiological determination (RANO criteria and NANO criteria). The progression free survival will be calculated as the (date of progression - date of first dose of study drug). Patients who are alive without progression at end of follow-up will be censored. Patients who are withdrawn from the study during the follow-up for other reason than dead will be censored at time of withdrawal. Patients who dies for any reason during the follow-up without any progression will be classified as progression using date of death as date of progression. Patients are analysed for stable disease, surgical interventions and treatment failure. Progression free survival will be analysed using Cox regression analysis and presented by Kaplan-Meier graphs. The difference in 12 and 24 months progression free survival rates for patients treated with valganciclovir or placebo will be analysed using Fisher exact test.

Incidence of valganciclovir treatment related adverse events

Number of patients with treatment related adverse events, as assessed by CTCv4. Vital signs: blood pressure (mmHg), heart rate (beats per minute), temperature (degree Celsius), clinical laboratory (total blood counts and differential analyses, liver transaminases and bilirubin, and renal function (creatinine and GFR) and physical exam. Adverse events will be analyzed using a chi-square test without continuity correction.

Health related Quality of Life using EORTC QLQ30 module

Quality of Life measures are recoreded according to EORTC QLQ30 and BN20 module, that are validated for brain tumor patients and measured as a unit of scale. There will be a comparison of scores for patients receiving valganciclovir versus placebo treatment. These are standard tools for assessing patients reported quality of Life along time during treatment. The change from baseline will be analysed using Wilcoxon Rank Sum test.

Cognitive functions

MMSE (Mini Mental State Examination) tests are made with a questionary form and will be assesses every three months during the study. The change from baseline will be analysed using Wilcoxon Rank Sum test.

Health related Quality of Life using the EORTC BN20 module

Quality of Life measures are recoreded according to BN20 module, that are validated for brain tumor patients and measured as a unit of scale. There will be a comparison of scores for patients receiving valganciclovir versus placebo treatment. These are standard tools for assessing patients reported quality of Life along time during treatment. The change from baseline will be analysed using Wilcoxon Rank Sum test.

Full Information

NCT ID

NCT04116411

First Posted

August 29, 2019

Last Updated

September 3, 2021

Sponsor

Cecilia Soderberg-Naucler

Collaborators

Karolinska University Hospital, Karolinska Institutet

1. Study Identification

Unique Protocol Identification Number

NCT04116411

Brief Title

A Clinical Trial Evaluating the Efficacy of Valganciclovir in Glioblastoma Patients

Acronym

VIGAS2

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

2. Study Status

Record Verification Date

September 2021

Overall Recruitment Status

Recruiting

Study Start Date

September 4, 2019 (Actual)

Primary Completion Date

August 31, 2024 (Anticipated)

Study Completion Date

August 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Cecilia Soderberg-Naucler

Collaborators

Karolinska University Hospital, Karolinska Institutet

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Glioblastoma Multiforme

Keywords

cytomegalovirus, valganciclovir

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

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.

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

VIGAS 2 is conducted under a randomised double blinded protocol. The study team and the patients are blinded to the randomisation list. Randomisation is performed by the contracted Clinical Cancer Center Unit at the Karolinska University Hospital by an unblinded person, Claudia Maes who holds responsibility to select out number codes for coded cans of the study drug. Claudia Maes is unrelated to the sponsor and the study team.

Allocation

Randomized

Enrollment

220 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Arm Title

Valganciclovir

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Valganciclovir Tablets

Other Intervention Name(s)

Valcyte, ValGANcilovir, Valganciclovir 450 mg, J05AB14, Valganciclovir oral

Intervention Description

Valganciclovir treatment of glioblastoma

Intervention Type

Drug

Intervention Name(s)

Temozolomide 120 mg

Other Intervention Name(s)

Temozolomide pill, Temozolomide tablet

Intervention Description

Chemotherapy

Intervention Type

Radiation

Intervention Name(s)

Radiotherapy 60 Gy

Other Intervention Name(s)

Radiation

Intervention Description

Radiation therapy

Intervention Type

Drug

Intervention Name(s)

Placebo oral tablet

Other Intervention Name(s)

Placebos

Intervention Description

Placebo treatment of glioblastoma

Primary Outcome Measure Information:

Title

Impact of valganciclovir on median overall survival of glioblastoma patients

Description

Time Frame

Study closure at 30 months follow up. Survival analyses will be analysed at 12 and 24 months.

Title

Baseline and demographic data

Description

Time Frame

At 30 months follow up

Secondary Outcome Measure Information:

Title

Progression free survival at 12 and 24 months

Description

Time Frame

12 and 24 months

Title

Incidence of valganciclovir treatment related adverse events

Description

Time Frame

30 months follow up time

Title

Health related Quality of Life using EORTC QLQ30 module

Description

Time Frame

Base line and at every 3 months until 24 months follow up.

Title

Cognitive functions

Description

Time Frame

up to 24 months

Title

Health related Quality of Life using the EORTC BN20 module

Description

Time Frame

Base line and at every 3 months until 24 months follow up.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients aged 18 years or older Patients with newly diagnosed glioblastoma, IDH 1 wt, WHO grade IV Radical resection Concomitant treatment with temozolomide and radiation therapy MGMT promoter methylation status Patients with at least KPS 70 , ECOG/WHO 2 Patients providing written informed consent Patients cooperative and able to complete all the assessment procedures. 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. Patients must be enrolled within 10 weeks after surgery Exclusion Criteria: Patients allergic to, or who do not tolerate Valganciclovir, aciclovir or valaciclovir treatment Patients with decreased cognitive function (below 24 in MMSE test) Pregnant or lactating females Patients not signing informed consent Patient is simultaneously participating in another experimental drug therapy trial Neutrophil count < 1,5 cells/ 109/L Platelet count < 150 cells/ 109/L HGB < 80 g/L Abnormal renal function (GFR < 30) Secondary glioblastoma, or glioblastoma IDH1 mutated. Unfit for any other reason judged by investigator

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Cecilia Soderberg-Naucler, MD, PhD

Phone

+46702427471

cecilia.naucler@ki.se

First Name & Middle Initial & Last Name or Official Title & Degree

Afsar Rahbar, PhD

Phone

+46769496980

afsar.rahbar@ki.se

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Giuseppe Stragliotto, MD, PhD

Organizational Affiliation

Karolinska University Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

SE01 Karolinska University Hospital

City

Solna

State/Province

Stockholm

ZIP/Postal Code

SE17164

Country

Sweden

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Giuseppe Stragliotto, MD, PhD

Phone

+46723161644

giuseppe.stragliotto@sll.se

First Name & Middle Initial & Last Name & Degree

Eva Hamberg, Nurse

Phone

+46-708776885

eva.hamberg@sll.se

First Name & Middle Initial & Last Name & Degree

Giuseppe Stragliotto, MD, PhD

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

When approval from authorities in Sweden allows data sharing, these will be available for other researchers.

IPD Sharing Time Frame

When data is available and permissions to share these are approved, data will be available for other researchers.

IPD Sharing Access Criteria

Access will be given by the sponsor upon request.

Citations:

PubMed Identifier

26670887

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.

Results Reference

background

PubMed Identifier

23391370

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.

Results Reference

background

PubMed Identifier

24523453

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.

Results Reference

background

PubMed Identifier

23404447

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.

Results Reference

result

PubMed Identifier

24256396

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.

Results Reference

result

PubMed Identifier

35194187

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.

Results Reference

derived

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A Clinical Trial Evaluating the Efficacy of Valganciclovir in Glioblastoma Patients

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