Laser Interstitial Thermal Therapy (LiTT) With Cemiplimab or Other Chemotherapy in Recurrent Glioblastomas

Official title

A Randomized Phase II Study of the Efficacy of Laser Interstitial Thermal Therapy (LiTT) Combined With Cemiplimab Versus Physician's Choice Chemotherapy in Recurrent Glioblastomas

Overview

This study will assess the therapeutic efficacy of the combination of Laser Interstitial Thermal Therapy (LiTT) with adjuvant cemiplimab compared to the therapeutic efficacy of the combination of LiTT with physician's choice of adjuvant chemotherapy in patients with recurrent glioblastoma. Patients will be enrolled and randomized on a 2:1 ratio to either the experimental arm (LiTT + cemiplimab) or the control arm (LiTT + physician/s choice chemotherapy).

Interventions

• Device NeuroBlate® Laser Ablation Laser Interstitial Thermal Therapy
  LiTT, or magnetic resource imaging (MRI)-guided laser ablation, is a minimally invasive surgery approved for cytoreductive treatment of brain tumors. It employs a small incision in the scalp and skull, through which a thin laser probe is inserted and guided by MRI imaging to the core of a tumor mass where it delivers hyperthermic ablation from the core to the rim.
• Drug Cemiplimab
  Cemiplimab is a programmed death receptor-1 (PD-1)-blocking antibody that is administered intravenously at 350mg over 30 minutes every 3 weeks on an outpatient basis.
• Drug Chemotherapy
  Adjuvant chemotherapy will be decided by the physician's choice of best fit by patient, including the agent(s), dosing, and schedule.

Primary outcome measures

• Progression-free survival (PFS) at Month 6 (PFS6) [Time frame: Start of treatment through 6 months after start of treatment (month 6)]
• Overall survival (OS) at Month 18 (OS18) [Time frame: Start of treatment through 18 months after start of treatment (month 18)]

Secondary outcome measures (8)

• Median Progression-Free Survival (PFS) as determined using the Kaplan-Meier method [Time frame: Start of treatment through 1 year after completion of treatment or progression (up to 3 years)]
• Median Overall Survival (OS) as determined using the Kaplan-Meier method [Time frame: Start of treatment through 1 year after completion of treatment or progression (up to 3 years)]
• Objective Response Rate (ORR) [Time frame: Start of treatment through completion of treatment or progression (up to 2 years)]
• Disease control rate (DCR) [Time frame: Start of treatment through 1 year after completion of treatment or progression (up to 3 years)]
• Duration of response (DoR) [Time frame: From first positive response (6 weeks after start of treatment) through 1 year after completion of treatment or progression (up to 3 years)]
• Number of participants with adverse events as defined by CTCAE v5.0 [Time frame: Start of treatment through 90 days after last dose of treatment (up to 27 months)]
• Changes in Health-related quality of life (HRQoL) as measured by the EORTC QLQ C30 [Time frame: Baseline through end of treatment (up to 3 years)]
• Changes in neurologic symptoms as measured by the EORTC QLQ BN20 [Time frame: Baseline through end of treatment (up to 2 years)]

Eligibility criteria

Inclusion criteria

• Histologically confirmed WHO grade 4 GBM (IDH-wt). Note: GBM variants, including histone-mutant and molecular-defined gliomas per WHO 2021 are allowed. Any number of recurrences are permitted.
• Unequivocal evidence of tumor progression as documented on the screening biopsy.
• At least 12 weeks post-completion of standard frontline therapy. Standard frontline therapy in this population includes maximal feasible surgical resection (biopsy alone is allowed), radiotherapy, and temozolomide chemotherapy. There is no restriction on the number of adjuvant temozolomide cycles.
• Candidate for LITT based on the size, location, and shape of the recurrent tumor as determined by the performing neurosurgeon. Surgical resection/debulking prior to LITT is allowed per standard of care but is not required; if the patient undergoes resection or debulking, it must have occurred at least 3 weeks prior to the start of any study treatment.
• At least 18 years of age.
• Karnofsky performance status ≥ 60%
• Adequate bone marrow and organ function as defined below:

• Absolute neutrophil count ≥ 1.5 K/cumm
• Platelets ≥ 100 K/cumm
• Hemoglobin ≥ 9.0 g/dL
• Total bilirubin ≤ 1.5 x IULN
• AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN
• Creatinine clearance > 30 mL/min by Cockcroft-Gault
• INR or PT ≤ 1.5 x IULN (unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants)
• aPTT ≤ 1.5 x IULN (unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants)
• The effects of cemiplimab on the developing human fetus are unknown. For this reason, people of childbearing potential and people able to father a child must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 4 months after completion of study participation (for patients in the Experimental Arm) OR 14 days after completion of study participation (for people of childbearing potential in the Control Arm) or 4 months (for people able to father a child in the Control Arm).
• Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Exclusion criteria

• Received prior treatment with any anti-angiogenic agent (including bevacizumab) within 3 months of date of surgery (LITT). (Note: bevacizumab is otherwise permitted when used outside this window for cerebral edema.)
• Received prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD127, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
• Received prior treatment with a monoclonal antibody within 4 weeks prior to the first day of study treatment.
• Received prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to the first day of study treatment.
• Has not recovered (i.e., grade 1 or baseline) from adverse events caused by anti-cancer agents administered no more than 4 weeks prior to consent. Note: patients with ≤ grade 2 neuropathy are an exception to this criterion. Note: if a patient underwent major surgery, they must have recovered adequately from the toxicity and/or complications prior to the first day of study treatment.
• Candidate for curative resection or urgent surgical procedure(s) needed.
• Presence of brainstem lesions or lesions that are < 5 mm from the hypophysis or cranial nerves.
• Multifocal glioma that is bilateral. Patients with unilateral multifocal gliomas may be eligible if their multifocal disease can be treated effectively and safely in a single LITT procedure. Note: Corpus callosal tumors are eligible even if they are bilateral as long as they satisfy the size and shape limits of LITT as determined by the performing neurosurgeon.
• Presence of leptomeningeal metastases.
• Recent (within 8 weeks) history of CNS hemorrhage unless the hemorrhage is located within the tumor that will be removed en total during surgical debulking or ablated during LITT.
• Requires therapeutic doses of anticoagulants unless anticoagulation can be safely discontinued before surgery per standard practice or an IVC filter can be used in place of anticoagulation. Patients are permitted to resume anticoagulation following LITT at the discretion of their treating physician.
• Received prior local therapy (stereotactic radiosurgery, brachytherapy, or carmustine wafers) to the proposed area of LITT.
• Received a live vaccine or live-attenuated vaccine within 28 days prior to the first day of study treatment. Received COVID-19 vaccine within 7 days of first dose.
• Currently receiving any other investigational agents or has participated in a study of an investigational agent or device within 3 weeks of the first day of study treatment.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agents used in the study.
• Dexamethasone > 4 mg at the time of consent.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment (with the exception of daily dexamethasone ≤ 4 mg).
• History of immune related pneumonitis or (non-infectious) interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease in the last 5 years.
• Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection or infection requiring hospitalization or treatment with IV anti-infectives within 14 days of first dose, myocardial infarction within 12 months of first dose, symptomatic congestive heart failure, unstable angina pectoris, acute coronary syndrome within 12 months of first dose, transient ischemic attack or stroke within 12 months of first dose, or cardiac arrhythmia. New York Heart Association Function Classification of class II, II, or IV are exclusionary.
• Has an active autoimmune disease requiring systemic treatment within the past 2 years (i.e. with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Pregnant and/or breastfeeding. People of childbearing potential must have a negative pregnancy test within 14 days of study entry and again within 72 hours of initiation of cemiplimab (if applicable).
• Active or latent tuberculosis.
• History of HIV infection if not on effective anti-retroviral therapy with undetectable viral load for 6 months. Patients with HIV who are receiving effective anti-retroviral therapy and have had an undetectable viral load for at least 6 months are eligible. HIV testing not required in the absence of known history of infection.
• Evidence of chronic hepatitis B virus (HBV) that is detectable on suppressive therapy. Patients with evidence of chronic HBV infection with undetectable HBV viral load on suppressive therapy are eligible. HBV testing not required in the absence of known history of infection.
• History of hepatitis C virus (HCV) infection that has not been cured or that has a detectable viral load. Patients with a history of HCV that has been treated and cured are eligible. Patients with HCV infection who are currently on treatment and have an undetectable HCV viral load are eligible. HCV testing not required in the absence of known history of infection.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 2 centers

• Mayo Clinic — Rochester
• Washington University School of Medicine — St Louis

Identifiers

NCT: NCT07620548 · 26-x027

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗