Regorafenib With Temozolomide With or Without RT in MGMT-Methylated, IDH Wild-type GBM Patients

NCT06095375 | Completed Phase 1

• 2 other identifiers: IOV-GB-1-2021-REGOMA22021-001604-15
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 2

Brief Summary

This study will evaluate the addition of regorafenib to standard of care treatment with TMZ as adjuvant therapy, and in combination with TMZ+RT as concomitant therapy. The standard of care for newly diagnosed GBM (ndGBM) includes surgical resection to the extent that is safely feasible, followed by RT plus concomitant TMZ chemotherapy, and up to 6 months of adjuvant TMZ. The dose escalation will be explored following a "3+3" design, escalating oral doses of regorafenib in combination with adjuvant (maintenance) TMZ (cohort A) to estimate the MTD of regorafenib as adjuvant (maintenance) therapy. After finding the MTD in the Adjuvant Therapy dose escalation, the Concomitant Therapy (cohort B) dose escalation will start, exploring escalating oral doses of regorafenib in combination with concomitant TMZ+RT, to estimate the MTD of regorafenib as concomitant therapy.

Conditions

Glioblastoma, IDH-wildtype; MGMT-Methylated Glioblastoma

Outcome Measures

Primary Outcomes (3)

• Number of patients with a Dose Limiting Toxicity (DLT)

  During dose escalation, the DLT evaluation period will be two cycles from Day -1 of Cycle 1 of adjuvant phase (cohort A) or from Day 1 to last day of the concomitant RT phase (Cohort B). (each cycle is 28 days)

• Number of patients with ≥1 adverse event (AE) using the NCI CTCAE v5.0

  * Grade 3 diarrhea, nausea, vomiting, and loss of appetite if lasting for ≥ 7 consecutive days; * Grade 3 electrolyte imbalance if lasting for ≥ 7 consecutive days; * Grade 3 dermal toxicity if lasting for ≥ 7 consecutive days; * Grade 3 fatigue for ≥ 7 consecutive days; * Grade 4 T-Bil, AST (GOT) and/or ALT (GPT) elevations,

  evaluation period will be two cycles from Day -1 of Cycle 1 of adjuvant phase (cohort A) or from Day 1 to last day of the concomitant RT phase (Cohort B). (each cycle is 28 days)

• Number of patients discontinuing study treatment due to an AE

  Number of patients discontinuing study treatment due to an AE

  evaluation period will be two cycles from Day -1 of Cycle 1 of adjuvant phase (cohort A) or from Day 1 to last day of the concomitant RT phase (Cohort B). (each cycle is 28 days)

Secondary Outcomes (8)

• Pharmacokinetics parameters - AUC

  evaluation period will be two cycles from Day -1 of Cycle 1 of adjuvant phase (cohort A) or from Day 1 to last day of the concomitant RT phase (Cohort B). (each cycle is 28 days)

• Best response to treatment according to RANO criteria

  from date of randomization until the date of first occurrence of disease progression or death, whichever come first,assessed up to 32 months

• Progression-free survival

  from the start of radiotherapy until the date of first occurrence of disease progression or death whichever come first,assessed up to 32 months

• EORTC QLQ-C30

  from the start of radiotherapy until the date of first occurrence of disease progression or death whichever come first,assessed up to 32 months

• Pharmacokinetics parameters - Tmax

  evaluation period will be two cycles from Day -1 of Cycle 1 of adjuvant phase (cohort A) or from Day 1 to last day of the concomitant RT phase (Cohort B). (each cycle is 28 days)

Study Arms (2)

Cohort A (Adjuvant/Maintenance Phase)

EXPERIMENTAL

Drug: Regorafenib; Drug: Temozolomide

Cohort B (Concomitant Phase)

EXPERIMENTAL

Drug: Regorafenib; Drug: Temozolomide

Interventions

Regorafenib DRUG

Cohort A (Adjuvant/Maintenance Phase). The Adjuvant (Maintenance) Therapy dose escalation will explore three dose levels of regorafenib (e.g., 80 mg, 120 mg and 160 mg; level-1: regorafenib 40 mg will be evaluated in case of DLT during regorafenib 80 mg) administered in combination with adjuvant TMZ to evaluate the initial toxicity of regorafenib and TMZ Cohort B (Concomitant Phase) Therapy dose escalation will explore three dose levels of regorafenib (e.g., 80 mg, 120 mg and 160 mg; level -1: regorafenib 40 mg will be evaluated in case of DLT during regorafenib 80 mg) administered in combination with TMZ and RT.

Cohort A (Adjuvant/Maintenance Phase); Cohort B (Concomitant Phase)

Temozolomide DRUG

Following a "3+3" design, in cohort A three patients will be administered temozolomide 150-200 mg/m2 for 5 consecutive days every 28 days until 6-12 cycles and regorafenib daily for 21 days, with a 1-week washout period at dose of 80 mg (level 1), 120 mg (level 2), or 160 mg (level 3) (regorafenib 40 mg- level -1). As a general rule, one cycle will last 28 days (day 1-28); however, in the event of treatment prolongation, the cycle period will be extended. In cohort B,During concomitant therapy phase: temozolomide 75 mg/m2/die for 42 (max 49 days) consecutive days (concomitant with radiation therapy).

Cohort A (Adjuvant/Maintenance Phase); Cohort B (Concomitant Phase)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Males and females of ≥ 18 years of age at the time of signing the informed consent form (ICF).
• Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
• Patients capable of taking oral medication
• Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
• Histologically confirmed Grade IV GBM/gliosarcoma (WHO criteria; non-IDH R132Hmutant by immunohistochemistry \[IHC\] or, sequencing for IDH1 and 2 in case of patients \>55 years) established following either a radical or partial surgical resection. This includes treatment naïve (chemotherapy and RT) patients with prior histologically diagnosis of lower-grade astrocytoma that has been upgraded to a histologically verified glioblastoma after a subsequent definitive surgery.
• NOTE: Patients with known isocitrate dehydrogenase (IDH) 1 and 2 are to be excluded.
• Methylated MGMT according to local laboratory (in case of pyrosequencing, methylation \>10%)
• Subject must have recovered from the effects of surgery, including post-operative infections or complications. Toxicities resulting from surgery must have resolved to NCI CTCAE (v5.0) Grade ≤ 1 prior to starting regorafenib treatment (with the exception of Grade 2 alopecia).
• For Concomitant Therapy Cohort: Prior tumor resection up to 7 weeks prior to the first dose of regorafenib.
• For Adjuvant Therapy Cohort: Subject must have recently completed standard course of radiotherapy with TMZ chemotherapy, and then have an MRI documenting stable disease prior to the first dose of regorafenib (In case of "pseudoprogression" the patient will not be eligible)
• For Adjuvant Therapy:
• All AEs resulting from prior RT+TMZ chemotherapy must have resolved to NCI CTCAE (v5.0) Grade 1 (except for laboratory parameters outlined below).
• Subject must have not experienced significant toxicity to prior RT+TMZ (i.e., Grade 4 hematological toxicity)
• Subjects must have life expectancy of at least 6 months
• Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1 (or KPS 70)

You may not qualify if:

• Received any prior treatment for glioma including:
• Prior prolifeprospan 20 with carmustine wafer.
• Prior intracerebral agent.
• Prior radiation treatment for GBM or lower-grade glioma.
• Prior chemotherapy or immunotherapy for GBM or lower-grade glioma.
• NOTE: 5-aminolevulinic acid-mediated photodynamic therapy and Flourcrescein administered prior to surgery to aid in optimal surgical resection is not considered a chemotherapy agent.
• Patients who performed biopsy as surgical approach of glioblastoma.
• Patients who are taking strong cytochrome P (CYP) CYP3A4 inhibitors (eg, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole) or strong CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifampin, St. John's Wort).
• Patients who are receiving additional, concurrent, active therapy for GBM outside of the trial.
• Disease located outside of the brain (e.g. brainstem and leptomeningeal disease).
• Candidate for urgent palliative intervention for primary disease (e.g., impending herniation) as judged by the Investigator
• History of allergy or hypersensitivity to any of the study treatments or any of their excipients.
• In the presence of therapeutic intent to anticoagulate the patient: INR or PT and aPTT not within therapeutic limits (according to the medical standard in the institution). NOTE: Per American Society of Clinical Oncology (ASCO) guidelines, use of low-molecular-weight heparin (LMWH) should be the preferred approach.
• Unable or unwilling to undergo brain MRI scans with intravenous (IV) gadolinium.
• History of another malignancy in the previous 3 years, with a disease-free interval of\< 3 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible.

Sponsors & Collaborators

• Istituto Oncologico Veneto IRCCS: lead
• Bayer S.p.A: collaborator

Study Sites (2)

Istituto Oncologico Veneto IRCCS

Padua, 35128, Italy

Location

Humanitas Research Hospital

Rozzano, 20089, Italy

Location

MeSH Terms

Conditions

Glioblastoma

Interventions

regorafenib; Temozolomide

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 10, 2023
• First Posted: October 23, 2023
• Study Start: July 4, 2022
• Primary Completion: October 9, 2024
• Study Completion: December 22, 2025
• Last Updated: January 9, 2026

Record last verified: 2026-01

Locations

IT (2)