CLINICAL TRIAL / NCT05095376
Testing the Addition of the Chemotherapy Drug Lomustine (Gleostine®) to the Usual Treatment (Temozolomide and Radiation Therapy) for Newly Diagnosed MGMT Methylated Glioblastoma
- Interventional
- Recruiting
- NCT05095376
Contact Information
A Phase III Trial of Gleostine® (Lomustine)-Temozolomide Combination Therapy Versus Standard Temozolomide in Patients With Methylated MGMT Promoter Glioblastoma
This phase III trial compares the effect of adding lomustine to temozolomide and radiation therapy versus temozolomide and radiation therapy alone in shrinking or stabilizing newly diagnosed MGMT methylated glioblastoma. Chemotherapy drugs, such as lomustine and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy photons to kill tumor cells and shrink tumors. Adding lomustine to usual treatment of temozolomide and radiation therapy may help shrink and stabilize glioblastoma.
PRIMARY OBJECTIVE:
I. To determine if the regimen with the two alkylating agents temozolomide and lomustine
with radiotherapy (RT) significantly prolongs overall survival (OS) versus (vs.) standard
chemoradiotherapy with temozolomide in patients with newly diagnosed glioblastoma (GBM)
with MGMT promoter methylation.
SECONDARY OBJECTIVES:
I. To determine if the regimen with the two alkylating agents temozolomide and lomustine
with radiotherapy (RT) significantly prolongs progression-free survival (PFS) vs.
standard chemoradiotherapy with temozolomide in patients with newly diagnosed GBM with
MGMT promoter methylation.
II. To compare the two different chemotherapy regimens on patient-reported outcomes
(PROs), as measured by the MD Anderson Symptom Inventory - Brain Tumor (MDASI-BT) in
patients with newly diagnosed GBM with MGMT promoter methylation.
III. To determine if the regimen with the two alkylating agents temozolomide and
lomustine with radiotherapy (RT) is associated with inferior short-term change in patient
reported outcomes (PROs) as measured by MDASI-BT vs. standard chemoradiotherapy with
temozolomide in patients with newly diagnosed GBM with MGMT promoter methylation.
IV. To assess toxicity in the two different chemotherapy regimens.
EXPLORATORY OBJECTIVES:
I. To assess the association between absolute lymphocyte counts and outcomes. II. To
assess the association between CD4+ lymphocyte counts and outcomes. III. To compare the
two different chemotherapy regimens in terms of long-term PROs as measured by MDASI-BT at
years 1 and 2.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients undergo radiation therapy 5 days per week and receive temozolomide orally
(PO) once daily (QD) for 6 weeks in the absence of disease progression or unacceptable
toxicity. Patients then receive temozolomide PO QD on days 1-5. Treatment repeats every
28 days for 6 cycles in the absence of disease progression or unacceptable toxicity.
ARM II: Patients undergo radiation therapy 5 days per week for 6 weeks in the absence of
disease progression or unacceptable toxicity. Patients also receive lomustine PO on day 1
and temozolomide PO QD on days 2-6. Treatment repeats every 42 days for 6 cycles in the
absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for year 1,
every 4 months for year 2, and then every 6 months thereafter.
Gender
All
Age Group
18 Years to 70 Years
Accepting Healthy Volunteers
No
Inclusion Criteria:
- STEP 1 REGISTRATION: No known IDH mutation. (If tested before step 1 registration,
patients known to have IDH mutation in the tumor on local or other testing are
ineligible and should not be registered)
- STEP 1 REGISTRATION: Availability of formalin-fixed paraffin-embedded (FFPE) tumor
tissue block and hematoxylin and eosin (H&E) stained slide to be sent for central
pathology review for confirmation of histology and MGMT promoter methylation status.
Note that tissue for central pathology review and central MGMT assessment must be
received by the NYU Center for Biospecimen Research and Development (CBRD) on or
before postoperative calendar day 30. If tissue cannot be received by postoperative
calendar day 30, then patients may NOT enroll on this trial as central pathology
review will not be complete in time for the patient to start treatment no later than
8 weeks following surgery. Results of central pathology review and central MGMT
analysis will generally be conveyed to NRG Oncology within 10 business days of
receipt of tissue. Note: In the event of an additional tumor resection(s), tissue
must be received within 30 days of the most recent resection and the latest
resection must have been performed within 30 days after the initial resection.
Surgical resection is required; stereotactic biopsy alone is not allowed because it
will not provide sufficient tissue for MGMT analysis
- STEP 1 REGISTRATION: Contrast-enhanced brain MRI after surgery
- STEP 1 REGISTRATION: Willing to use highly effective method of contraception for
participants of childbearing potential (participants who may become pregnant or who
may impregnate a partner) during therapy and for 6 months after completing
treatment; this inclusion is necessary because the treatment in this study may be
significantly teratogenic
- STEP 1 REGISTRATION: The patient or a legally authorized representative must provide
study-specific informed consent prior to study entry and, for patients treated in
the United States (U.S.), authorization permitting release of personal health
information
- STEP 2 REGISTRATION: Histopathologically proven diagnosis of glioblastoma (or
gliosarcoma as a subtype of glioblastoma) confirmed by central pathology review
- STEP 2 REGISTRATION: MGMT promoter with methylation confirmed by central pathology
review (See Section 10 for details). Note: Patients with tissue that is insufficient
or inadequate for analysis, fails MGMT testing, or has indeterminate or unmethylated
MGMT promoter are excluded.
- STEP 2 REGISTRATION: IDH mutation testing by at least one method (such as
immunohistochemistry for IDH1 R132H) must be performed as part of standard of care
and no mutation must be found (i.e IDH wildtype). (If a mutation is identified then
the patient will be ineligible and must be registered as ineligible at Step 2.)
- STEP 2 REGISTRATION: History/physical examination within 28 days prior to Step 2
registration
- STEP 2 REGISTRATION: Karnofsky performance status (KPS) >= 70 within 28 days prior
to Step 2 registration
- STEP 2 REGISTRATION: Neurologic function assessment within 28 days prior to Step 2
registration
- STEP 2 REGISTRATION: Age 18-70 years
Adequate hematologic, renal, and hepatic function within 14 days prior to STEP 2
REGISTRATION defined as follows:
- STEP 2 REGISTRATION: Hemoglobin >= 10 g/dl (Note: the use of transfusion or other
intervention to achieve hemoglobin (Hgb) >= 10.0 g/dl is acceptable)
- STEP 2 REGISTRATION: Leukocytes >= 2,000/mm^3
- STEP 2 REGISTRATION: Absolute neutrophil count >= 1,500/mm^3
- STEP 2 REGISTRATION: Platelets >= 100,000/mm^3
- STEP 2 REGISTRATION: Total bilirubin =< 1.5 x institutional/lab upper limit of
normal (ULN)
- STEP 2 REGISTRATION: Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic
transaminase [SGOT]) =< 2.5 x ULN
- STEP 2 REGISTRATION: Alanine aminotransferase (ALT) (serum glutamate pyruvate
transaminase [SGPT]) =< 2.5 x ULN
- STEP 2 REGISTRATION: Serum creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >=
50 mL/min (if using the Cockcroft-Gault formula
- STEP 2 REGISTRATION: For patients with evidence of chronic hepatitis B virus (HBV)
infection, the HBV viral load must be undetectable on suppressive therapy, if
indicated
- Note: Known positive test for hepatitis B virus surface antigen (HBV sAg)
indicating acute or chronic infection would make the patient ineligible unless
the viral load becomes undetectable on suppressive therapy. Patients who are
immune to hepatitis B (anti-hepatitis B surface antibody positive) are eligible
(e.g. patients immunized against hepatitis B)
- STEP 2 REGISTRATION: For patients with a history of hepatitis C virus (HCV)
infection must have been treated and cured. For patients with HCV infection who are
currently on treatment, they are eligible if they have an undetectable HCV viral
load
- Note: Known positive test for hepatitis C virus ribonucleic acid (HCV
ribonucleic acid [RNA]) indicating acute or chronic infection would make the
patient ineligible unless the viral load becomes undetectable on suppressive
therapy
- STEP 2 REGISTRATION: Known human immunodeficiency virus (HIV) infected patients on
effective anti-retroviral therapy with undetectable viral load within 6 months prior
to step 2 registration are eligible for this trial. Testing is not required for
entry into protocol
- STEP 2 REGISTRATION: Negative serum or urine pregnancy test (in persons of
childbearing potential) within 14 days prior to Step 2 registration
- Childbearing potential is defined as any person who has experienced menarche
and who has not undergone surgical sterilization (hysterectomy or bilateral
oophorectomy) or who is not postmenopausal
Exclusion Criteria:
- STEP 2 REGISTRATION: Prior therapy for tumor, except for resection or prior laser
interstitial thermal therapy (LITT). For example, prior chemotherapy, immunotherapy,
or targeted therapy for GBM or lower grade glioma is disallowed (including but not
limited to temozolomide, lomustine, bevacizumab, any viral therapy, ipilimumab or
other CTLA-4 antibody, PD-1 antibody, CD-137 agonist, CD40 antibody, PDL-1 or 2
antibody, vaccine therapy, polio or similar viral injection as treatment for the
tumor, and/or any other antibody or drug specifically targeting T-cell
co-stimulation or immune checkpoint pathways) as is Gliadel wafer, radiotherapy,
radiosurgery, vaccine or other immunotherapy, brachytherapy, or convection enhanced
delivery
- Note: 5-aminolevulinic acid (ALA)-mediated fluorescent guided resection (FGR)
photodynamic therapy (PDT) or fluorescein administered prior to/during surgery
to aid resection is not exclusionary and is not considered a chemotherapy or
intracerebral agent. Prior laser interstitial thermal therapy (LITT) is
allowed.
- STEP 2 REGISTRATION: Current or planned treatment with any other investigational
agents for the study cancer
- STEP 2 REGISTRATION: Definitive clinical or radiologic evidence of metastatic
disease outside the brain
- STEP 2 REGISTRATION: Prior invasive malignancy (except non-melanomatous skin cancer,
cervical cancer in situ and melanoma in situ) unless disease free for a minimum of 2
years
- STEP 2 REGISTRATION: Prior radiotherapy to the head or neck that would result in
overlap of radiation therapy fields
- STEP 2 REGISTRATION: Pregnancy and individuals unwilling to discontinue nursing due
to the potential teratogenic effects and potential risk for adverse events in
nursing infants
- STEP 2 REGISTRATION: History of allergic reactions attributed to compounds of
similar chemical or biologic composition to temozolomide or lomustine
- STEP 2 REGISTRATION: History of pulmonary fibrosis
- STEP 2 REGISTRATION: Uncontrolled intercurrent illness including, but not limited
to:
- Ongoing or active infection requiring IV antibiotics, IV antiviral, or IV
antifungal treatment
- Symptomatic congestive heart failure, defined as New York Heart Association
Functional Classification III/IV (Note: Patients with known history or current
symptoms of cardiac disease, or history of treatment with cardiotoxic agents,
should have a clinical risk assessment of cardiac function using the New York
Heart Association Functional Classification)
- Unstable angina pectoris within 6 months prior to Step 2 registration
- Uncontrolled cardiac arrhythmia
- Psychiatric illness/social situations that would limit compliance with study
requirements
- STEP 2 REGISTRATION: No evidence of diffuse leptomeningeal disease that requires
whole brain irradiation.
- Glioblastomas