Carmustine Wafers in Combination with Retifanlimab and Standard of Care Radiation with or without Temozolomide for the Treatment of Newly Diagnosed Glioblastoma or Gliosarcoma
This phase I trial tests the safety, side effects, and effectiveness of carmustine wafers in combination with retifanlimab and standard of care (SOC) radiation therapy with or without temozolomide in treating patients with newly diagnosed glioblastoma or gliosarcoma. Carmustine implants are a form of carmustine contained in a wafer. The wafer has a coating that dissolves slowly and releases carmustine directly into the area where the brain tumor was removed. This form may have fewer side effects and work better than other forms of carmustine. Carmustine wafers are a type of alkylating agent and a type of nitrosourea. Retifanlimab, a type of monoclonal antibody and a type of immune checkpoint inhibitor, binds to a protein called PD-1, which is found on T cells (a type of immune cell). Retifanlimab may block PD-1 and help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high-energy x-rays, particles, or radioactive seeds to kill tumor cells and shrink tumors. Temozolomide is in a class of medications called alkylating agents. It works by damaging the cell's deoxyribonucleic acid (DNA) and may kill tumor cells and slow down or stop tumor growth. Giving carmustine wafers in combination with retifanlimab and SOC radiation therapy with or without temozolomide may be safe, tolerable and/or effective in treating patients with newly diagnosed glioblastoma or gliosarcoma.
Inclusion Criteria
- Newly-diagnosed adults with World Health Organization (WHO) grade IV glioblastoma or gliosarcoma based on histopathological or molecular criteria who had carmustine wafers placed at resection
- No prior treatment for GBM other than surgical resection and carmustine wafer placement (patients who had a biopsy prior to resection are allowed)
- Post-operative magnetic resonance imaging (MRI) or computed tomography (CT) scan within 72 hours (preferably 24 hours) of surgical resection
- Substantial recovery from surgical resection
- On a stable or decreasing dose of steroids
- Karnofsky performance status of ≥ 60
- Clinically appropriate for concomitant temozolomide plus RT based on institutional guidelines
- Age ≥ 18 years
- Ensure that pregnant or lactating females are not enrolled and that contraceptive requirements are in accordance with applicable and recent requirements
- Men must agree to take appropriate precautions to avoid fathering children (with at least 99% certainty) from screening through 180 days after the last dose of retifanlimab
- Leukocyte count (WBC) ≥ 2,000/mcL
- Absolute neutrophil count ≥ 1,500/mcL
- Platelets ≥ 100,000/mcL
- Hemoglobin ≥ 8.0 g/dL
- Lymphocytes ≥ 500/mcL
- Ability to understand and the willingness to sign a written informed consent document
- Subjects must be willing and able to comply with scheduled visits, treatment schedule, study procedures, and other requirements of the study
- A standard of care lab order for MGMT promotor methylation and IDH mutation status has been placed, although results are not required at the time of enrollment
Exclusion Criteria
- Recurrent GBM or progression of lower grade tumor
- Central nervous system (CNS) hemorrhage of grade > 1 on baseline MRI scan, unless subsequently documented to have resolved
- Any known metastatic extracranial or leptomeningeal disease
- Intent to use other anti-neoplastic medications/treatments including the Optune® device
- Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results
- Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA-4 antibody or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
- Active, known or suspected autoimmune disease, with the following exceptions: Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis or alopecia) not requiring systemic treatment (subjects with a history of flares requiring systemic treatment are excluded), or other autoimmune conditions not expected to recur in the absence of an external trigger are permitted to enroll
- Subjects with history of life-threatening toxicity, including hypersensitivity reaction, related to prior immunoglobulin treatment for another condition (except those considered unlikely to re-occur, with written approval of study principal investigator [PI]) or any other study drug component
- History or evidence upon physical/neurological examination of other central nervous system condition (e.g., seizures, abscess) unrelated to cancer, unless adequately controlled by medication or considered not potentially interfering with protocol treatment
- Surgical procedure < 7 days prior to study treatment (no restriction for insertion of a central venous access device)
- Unable to swallow oral medication or any gastrointestinal disease or surgical procedure that may seriously impact the absorption of temozolomide
- Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, totally excised melanoma of stage IIA or lower, low or intermediate-grade localized prostate cancer (Gleason score ≤ 7), and curatively-treated carcinoma in situ of the cervix, breast, or bladder
- Known history of any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection, and/or detectable virus
- Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
- Evidence of interstitial lung disease, history of interstitial lung disease, or active, noninfectious pneumonitis
- Palliative radiation therapy administered within 1 week of first dose of study treatment or radiation therapy in the thoracic region that is > 30 Gy within 6 months of the first dose of study treatment. Note: Participants must have recovered from all radiation-related toxicities (to grade > 1 or baseline), not require corticosteroids for this purpose, and not have had radiation pneumonitis
- Toxicity of prior therapy that has not recovered to ≤ grade 1 or baseline (with the exception of any grade of alopecia and anemia not requiring transfusion support).
- EXCLUSIONARY LABORATORY VALUES FOR MONOTHERAPY: Alanine aminotransferase (ALT) > 2.5 x upper limit of normal (ULN)
- EXCLUSIONARY LABORATORY VALUES FOR MONOTHERAPY: Aspartate aminotransferase (AST) > 2.5 x ULN
- EXCLUSIONARY LABORATORY VALUES FOR MONOTHERAPY: Bilirubin ≥ 1.5 x ULN unless conjugated bilirubin ≤ ULN (conjugated bilirubin only needs to be tested if total bilirubin exceeds ULN). If there is no institutional ULN, then direct bilirubin must be < 40% of total bilirubin
- EXCLUSIONARY LABORATORY VALUES FOR MONOTHERAPY: Calculated creatinine clearance < 30 mL/min (glomerular filtration rate can also be used in place of creatinine clearance [CrCl])
- Active autoimmune disease requiring systemic immunosuppression in excess of physiologic maintenance doses of corticosteroids (> 10 mg/day of prednisone or equivalent) * Physiologic corticosteroid replacement therapy at doses ≤ 10 mg/day of prednisone or equivalent for adrenal or pituitary insufficiency and in the absence of active autoimmune disease is permitted * Participants with asthma that requires intermittent use of bronchodilators, inhaled steroids, or local steroid injections may participate * Participants using topical, ocular, intra-articular, or intranasal steroids (with minimal systemic absorption) may participate * Brief courses of corticosteroids for prophylaxis (e.g., contrast dye allergy) or study treatment–related standard premedication is permitted
- Has an active infection requiring systemic antibiotics or antifungal treatment
- History of organ transplant, including allogeneic stem cell transplantation
- Known allergy or hypersensitivity to any component of retifanlimab or formulation components
- Has received a live vaccine within 28 days of the planned start of study drug * Note: Examples of live vaccines include but are not limited to measles, mumps, rubella, chicken pox/zoster, yellow fever, rabies, bacillus Calmette-Guérin (BCG), and typhoid vaccine. Inactivated seasonal influenza vaccines and COVID-19 vaccine(s) are permitted and do not require a 4-week waiting period before starting study treatment; however, intranasal influenza vaccines are live attenuated vaccines and are not allowed
- Patients who are taking probiotic dietary supplements
- Patients with uncontrolled intercurrent illness
- Patients with psychiatric illness/social situations (e.g. prisoners/involuntarily incarcerated individuals) that would limit compliance with study requirements
Additional locations may be listed on ClinicalTrials.gov for NCT05083754.
Locations matching your search criteria
United States
District of Columbia
Washington
Maryland
Baltimore
Oregon
Portland
Tennessee
Nashville
PRIMARY OBJECTIVES:
I. To estimate overall survival rate at 2 years among newly diagnosed glioblastoma multiform (GBM) patients with unmethylated 06-methylguanine DNA methyltransferase treated with carmustine wafers + retifanlimab + radiation withholding temozolomide.
II. To compare quantified number and percent change of peripheral CD8+ T-cells defined by IFN+ expression in patients treated with carmustine wafers + retifanlimab + radiation with or without temozolomide versus carmustine + SOC.
SECONDARY OBJECTIVES:
I. To determine the safety of retifanlimab administered prior to and in combination with SOC in subjects with newly-diagnosed GBM after treatment with carmustine wafers.
II. To estimate overall survival of subjects who are treated with retifanlimab with or without temozolomide after carmustine placement.
III. To assess overall survival for patients with methylated or unmethylated MGMT independently.
IV. To assess an overall response rate in subjects who are treated with retifanlimab with or without temozolomide after carmustine placement.
V. To estimate progression-free survival (PFS) in subjects who are treated with retifanlimab with or without temozolomide after carmustine placement.
EXPLORATORY OBJECTIVES:
I. To characterize immune cell function during and after treatment in the peripheral blood and tumor tissue as measured by flow cytometry and immunohistochemistry.
II. To explore the potential association between biomarkers in the peripheral blood and tumor tissue, such as PD-L1 expression, and safety and efficacy for subjects with newly-diagnosed MGMT unmethylated GBM.
III. To assess tumor/treatment effect specimens from the first surgery and subsequent surgeries for inflammatory markers and genetic markers.
IV. To assess presence or absence of microsatellite instability (MSI) / mismatch repair deficiency in patients receiving retifanlimab and correlation with survival.
OUTLINE: Patients undergo surgical resection and receive carmustine wafer intratumorally per SOC and then are randomized to 1 of 2 groups.
GROUP I (INVESTIGATIONAL): Patients with MGMT promoter unmethylated GBM are assigned to Arm A and patients with MGMT promoter methylated GBM are assigned to Arm B.
ARM A: Patients receive retifanlimab intravenously (IV) over 30 minutes on day 1 of each cycle. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Within 42 days after surgery and at least 7 days after first dose of retifanlimab, patients undergo external- beam radiation therapy (RT) once daily (QD) Monday-Friday for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection throughout the study.
ARM B: Patients receive retifanlimab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Within 42 days after surgery and at least 7 days after first dose of retifanlimab, patients undergo external beam RT QD on Monday-Friday and receive temozolomide orally (PO) QD for 6 weeks per standard of care. Beginning 4 weeks after completing RT, patients receive temozolomide PO QD on days 1-5 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression. Patients may receive additional cycles of temozolomide as clinically warranted. Additionally, patients undergo blood sample collection throughout the study.
GROUP II (STANDARD OF CARE):
ARM C: Patients external beam RT QD on Monday-Friday and receive temozolomide PO QD for 6 weeks per standard of care. Beginning 4 weeks after completing RT, patients receive temozolomide PO QD on days 1-5 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression. Additionally, patients undergo blood sample collection throughout the study.
After completion of study treatment, patients are followed up at 30 and 90 days and then every 3 months until death or end of study.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationJohns Hopkins University/Sidney Kimmel Cancer Center
Principal InvestigatorLawrence R. Kleinberg
- Primary IDJ21103
- Secondary IDsNCI-2024-09191, IRB00291102
- ClinicalTrials.gov IDNCT05083754