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

• ClinicalTrials.gov Identifier: NCT04116411
• Recruitment Status: Recruiting
• First Posted: October 4, 2019
• Last Update Posted: September 13, 2021
• Sponsor: Cecilia Soderberg-Naucler
• Collaborators: Karolinska University Hospital; Karolinska Institutet
• Information provided by (Responsible Party): Cecilia Soderberg-Naucler, Karolinska Institutet

Tracking Information

• First Submitted Date: August 29, 2019
• First Posted Date: October 4, 2019
• Last Update Posted Date: September 13, 2021
• Actual Study Start Date: September 4, 2019
• Estimated Primary Completion Date: August 31, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 3, 2019)

• Impact of valganciclovir on median overall survival of glioblastoma patients [ Time Frame: Study closure at 30 months follow up. Survival analyses will be analysed at 12 and 24 months. ]
  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 [ Time Frame: At 30 months follow up ]
  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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 3, 2019)

• Progression free survival at 12 and 24 months [ Time Frame: 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 Patients who are withdrawn from the study during the follow-up for other reason than dead will be censored at time of withdrawal.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 [ Time Frame: 30 months follow up time ]
  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 [ Time Frame: Base line and at every 3 months until 24 months follow up. ]
  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 [ Time Frame: up to 24 months ]
  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 [ Time Frame: Base line and at every 3 months until 24 months follow up. ]
  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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
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.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes 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.

Primary Purpose: Treatment

• Condition: Glioblastoma Multiforme

Intervention

• Drug: Valganciclovir Tablets
  Valganciclovir treatment of glioblastoma
  Other Names:

  • Valcyte
  • ValGANcilovir
  • Valganciclovir 450 mg
  • J05AB14
  • Valganciclovir oral
• Drug: Temozolomide 120 mg
  Chemotherapy
  Other Names:

  • Temozolomide pill
  • Temozolomide tablet
• Radiation: Radiotherapy 60 Gy
  Radiation therapy
  Other Name: Radiation
• Drug: Placebo oral tablet
  Placebo treatment of glioblastoma
  Other Name: Placebos

Study Arms

• Placebo Comparator: Placebo
  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.
  Interventions:

  • Drug: Temozolomide 120 mg
  • Radiation: Radiotherapy 60 Gy
  • Drug: Placebo oral tablet
• Active Comparator: Valganciclovir
  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.
  Interventions:

  • Drug: Valganciclovir Tablets
  • Drug: Temozolomide 120 mg
  • Radiation: Radiotherapy 60 Gy

Publications *

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 3, 2019): 220
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: August 31, 2024
• Estimated Primary Completion Date: August 31, 2024 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Cecilia Soderberg-Naucler, MD, PhD; +46702427471; cecilia.naucler@ki.se

Contact: Afsar Rahbar, PhD; +46769496980; afsar.rahbar@ki.se

• Listed Location Countries: Sweden

Administrative Information

• NCT Number: NCT04116411
• Other Study ID Numbers: Eudra CT: 2019-001083-30
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: When approval from authorities in Sweden allows data sharing, these will be available for other researchers.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Supporting Materials: Analytic Code
• Time Frame: When data is available and permissions to share these are approved, data will be available for other researchers.
• Access Criteria: Access will be given by the sponsor upon request.

• Current Responsible Party: Cecilia Soderberg-Naucler, Karolinska Institutet
• Original Responsible Party: Same as current
• Current Study Sponsor: Cecilia Soderberg-Naucler
• Original Study Sponsor: Same as current

Collaborators

• Karolinska University Hospital
• Karolinska Institutet

Investigators

• Principal Investigator: Giuseppe Stragliotto, MD, PhD; Karolinska University Hospital

• PRS Account: Karolinska Institutet
• Verification Date: September 2021