MK-3475 in Combination With MRI-guided Laser Ablation in Recurrent Malignant Gliomas

NCT02311582 | Completed Phase 1 Results DMC FDA Drug FDA Device

• 1 other identifier: 201501072
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 2

Brief Summary

The blood brain barrier (BBB) is a major obstacle to drug delivery in the treatment of malignant brain tumors including glioblastoma multiforme (GBM). MRI-guided laser ablation (MLA) has been noted to disrupt peritumoral the blood brain barrier (BBB), which may then lead to increased access of new tumor antigens to the lymphovascular system and vice versa of immune effector cells to the tumor for effective activation of the immune system, and tumor infiltration, respectively. Therefore, the combination of MK-3475 and MLA as proposed in this protocol is hypothesized to create a therapeutic combinatorial effect in which MLA increases material access to promote immune activation and then MK-3475 maximizes these tumor-specific immune reactions to impart effective tumor control.

Conditions

Malignant Glioma

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose (MTD) of MK-3475 When Combined With MLA - Phase I Only

  The MTD is defined as the dose level immediately below the dose level at which 2 patients of a cohort (of 2 to 6 patients) experienced dose-limiting toxicity during the first cycle. Dose escalations will proceed until the MTD has been reached, or failing that, 200 mg of MK-3475 every 3 weeks will be considered the MTD.

  Completion of Cycle 1 (each cycle is 3 weeks)

• Progression-free Survival (PFS) - Phase II Only

  PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.

  Through completion of follow-up (median length of follow-up 338 days, full range 43-2468 days).

Secondary Outcomes (7)

• Toxicity Profile of MK-3475 in Combination With MLA - Phase I Only

  Through 90 days after completion of treatment (up to 168 weeks)

• Overall Survival (OS) - Phase II Only

  Through completion of follow-up (median length of follow-up 338 days, full range 43-2468 days).

• Anti-glioma Immune Response Before and After MK-3475 With MLA - Phase II Only

  Up to 26 months

• Correlate Intratumoral Expression of PD-L1 and the Frequency of Glioma Cell-specific Cytotoxic T Cells With PFS - Phase II Only

  6 months

• Correlate Intratumoral Expression of PD-L1 and the Frequency of Glioma Cell-specific Cytotoxic T Cells With OS - Phase II Only

  Up to 2 years after completion of treatment (estimated to be up to 272 weeks)

Study Arms (5)

Phase I: MK-3475 + MLA Dose Level 1

EXPERIMENTAL

MK-3475 will be given at 100 mg intravenously (IV) every 3 weeks starting no more than 1 week after MLA until progression or unacceptable toxicity.

Biological: MK-3475; Device: MRI-guided laser ablation

Phase I: MK-3475 + MLA Dose Level 2

EXPERIMENTAL

MK-3475 will be given at 150 mg intravenously (IV) every 3 weeks starting no more than 1 week after MLA until progression or unacceptable toxicity.

Biological: MK-3475; Device: MRI-guided laser ablation

Phase I: MK-3475 + MLA Dose Level 3

EXPERIMENTAL

MK-3475 will be given at 200 mg intravenously (IV) every 3 weeks starting no more than 1 week after MLA until progression or unacceptable toxicity.

Biological: MK-3475; Device: MRI-guided laser ablation

Phase II: MK-3475 + MLA

EXPERIMENTAL

MK-3475 will be given at 200 mg intravenously (IV) every 3 weeks no more than 1 week after MLA, or no more than 1 week after biopsy (if no surgical debulking). This dose was determined in the Phase I portion of the trial.

Biological: MK-3475; Device: MRI-guided laser ablation

Phase II: MK-3475 Only

EXPERIMENTAL

MK-3475 will be given at 200 mg intravenously (IV) every 3 weeks beginning 3 weeks after surgical debulking or no more than 1 week after biopsy (if no surgical debulking). This dose was determined in the Phase I portion of the trial.

Biological: MK-3475

Interventions

MK-3475 BIOLOGICAL

Patients currently on pembrolizumab beyond the 2 year/35 cycle limit at the time of the approval of Amendment 13 (approved 07/28/2021) may continue to receive pembrolizumab unless there is progression, toxicity or agreement by the patient and PI to come off therapy. Participants who discontinue pembrolizumab after receiving 35 doses are eligible for retreatment with pembrolizumab if they progress during follow-up provided they meet the requirements. Participants may receive an additional 17 cycles (12 months) of pembrolizumab during the Second Course Phase (Retreatment).

Also known as: Pembrolizumab, Keytruda

Phase I: MK-3475 + MLA Dose Level 1; Phase I: MK-3475 + MLA Dose Level 2; Phase I: MK-3475 + MLA Dose Level 3; Phase II: MK-3475 + MLA; Phase II: MK-3475 Only

MRI-guided laser ablation DEVICE

MLA is a minimally invasive laser surgery, which employs a small incision in the scalp and skull, through which a thin laser probe is inserted and guided by MR imaging to the core of the tumor mass where it delivers hyperthermic ablation from the core to the rim.

Also known as: MLA, NeuroBlate, AutoLITT

Phase I: MK-3475 + MLA Dose Level 1; Phase I: MK-3475 + MLA Dose Level 2; Phase I: MK-3475 + MLA Dose Level 3; Phase II: MK-3475 + MLA

Eligibility Criteria

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

You may qualify if:

• Phase I: Histologically confirmed grade III or IV malignant glioma.
• Phase II: Histologically confirmed grade IV malignant glioma (GBM).
• \*Note: GBM variants and suspected secondary GBM are allowed for both phase I and phase II.
• Unequivocal evidence of tumor progression as documented by biopsy or brain MRI scan per RANO criteria.
• There must be an interval of at least 12 weeks from the completion of standard front-line therapy to study registration unless there is unequivocal evidence for tumor recurrence per RANO criteria. When the interval is less than 12 weeks, the use of perfusion imaging and/or PET scan is allowed to differentiate between unequivocal evidence of tumor recurrence and pseudoprogression. Standard front-line therapy is as described below:
• For grade IV malignant gliomas (GBM): Standard front line therapy for newly diagnosed GBM must include maximal feasible surgical resection (biopsy alone allowed), radiotherapy, and temozolomide chemotherapy. If the tumor was initially diagnosed as either a grade II or III tumor and now has recurred or progressed as a grade IV GBM, it will be considered a secondary recurrent grade IV GBM and will be eligible for this study as long as prior treatment included maximal feasible surgical resection (biopsy alone allowed), radiotherapy, and temozolomide chemotherapy.
• For grade III malignant gliomas with 1p 19q codeletions: Standard front line therapy for newly diagnosed grade III malignant gliomas must include maximal feasible surgical resection (biopsy alone allowed), radiotherapy, and chemotherapy (PCV or temozolomide). If the patient did not receive any or all components of the standard front line therapy as detailed above for newly diagnosed grade III gliomas and the tumor then recurred or progressed, s/he must first receive at least one prior standard therapy or any appropriate combination of the components of standard therapy as detailed above and must experience further recurrence or progression before s/he is deemed eligible for this study. If the tumor was initially diagnosed as a grade II glioma with 1p 19q codeletions and now has recurred or progressed as a grade III tumor, it will be considered a secondary recurrent grade III glioma with 1p 19q codeletions and will be eligible for this study as long as prior treatment included maximal feasible surgical resection (biopsy alone allowed), radiotherapy, and chemotherapy (PCV or temozolomide).
• For grade III malignant gliomas without 1p 19q codeletions: Standard front-line therapy for newly diagnosed grade III malignant gliomas must include maximal feasible surgical resection (biopsy alone allowed), radiotherapy, and temozolomide chemotherapy. If the tumor was initially diagnosed as a grade II glioma without 1p 19q codeletions and now has recurred or progressed as a grade III tumor, it will be considered a secondary recurrent grade III glioma without 1p 19q codeletions and will be eligible for this study as long as prior treatment included maximal feasible surgical resection (biopsy alone allowed), radiotherapy, and temozolomide chemotherapy.
• Candidate for MLA based on the size, location, and shape of the recurrent tumor as determined by the performing neurosurgeon. Surgical resection/debulking prior to MLA 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 first dose of MK-3475. For Phase II: if surgical resection/debulking prior to MLA is not indicated, a biopsy of the tumor will be done at the same time of MLA to obtain tumor tissue for both diagnostic purposes and immune monitoring.
• Patients who have undergone a resection for recurrence will be eligible. In those who have undergone a gross total resection, the MLA will be directed at treating a peritumoral margin of 0.5-1cm surrounding the resection cavity to disrupt the BBB and potentially increase access of MK-3475 to the peritumoral infiltrating glioma cells.
• At least 18 years of age.
• Karnofsky ≥ 60%
• Normal bone marrow and organ function as defined below:
• ANC ≥ 1,500/mcL
• Platelets ≥ 100,000/mcL

You may not qualify if:

• Prior treatment with any anti-angiogenic agent (including bevacizumab).
• Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
• Prior treatment with a monoclonal antibody within 4 weeks prior to the first dose of MK-3475 or has not recovered (i.e. ≤ grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to the first dose of MK-3475 or has not recovered (i.e. ≤ grade 1 or at baseline) from adverse events due to a previously administered agent.
• Note: patients with ≤ grade 2 neuropathy are an exception to this criterion and may qualify for the study.
• Note: if a patient underwent major surgery, s/he must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Candidates for curative resection or urgent surgical procedure(s) needed.
• Presence of infratentorial lesions, brainstem lesions, or lesions that are less than 5 mm from the hyophysis or cranial nerves.
• Multifocal gliomas that are bilateral. Patients with unilateral multifocal gliomas may be eligible if their multifocal disease can be treated effectively and safely in a single MLA procedure.
• 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 MLA.
• Requires therapeutic doses of anticoagulants unless anticoagulation can be safely discontinued before surgery per standard practice (e.g. first DVD for which anticoagulation has been at least 3 months and repeat imaging demonstrates resolution of DVT) or an IVC filter can be used in place of anticoagulation. Subjects are permitted to resume anticoagulation following surgery per discretion of treating physician and/or site SOPs
• Received prior local therapy (stereotactic radiosurgery, brachytherapy, or carmustine wafers) to the proposed area of MLA treatment.
• Received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of MK-3475. Administration of killed vaccines is allowed.
• Currently receiving any other investigational agents or has participated in a study of an investigational agent or using an investigational device within 3 weeks of the first dose of MK-3475.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (2)

University of Florida

Gainesville, Florida, 32611, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Publications (1)

• Hwang H, Huang J, Khaddour K, Butt OH, Ansstas G, Chen J, Katumba RG, Kim AH, Leuthardt EC, Campian JL. Prolonged response of recurrent IDH-wild-type glioblastoma to laser interstitial thermal therapy with pembrolizumab. CNS Oncol. 2022 Mar 1;11(1):CNS81. doi: 10.2217/cns-2021-0013. Epub 2022 Jan 19.

  PMID: 35043686 DERIVED

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Glioma

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Milan G. Chheda, M.D.
• Organization: Washington University School of Medicine

mchheda@wustl.edu

314-747-2712

Study Officials

• Milan G Chheda, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

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

Model Details: As of Amendment 12, patients enrolled in the phase II portion of this trial will no longer be randomized. These patients will undergo MLA followed by MK-3475 treatment.

Study Record Dates

• First Submitted: December 4, 2014
• First Posted: December 8, 2014
• Study Start: August 5, 2015
• Primary Completion: April 15, 2024
• Study Completion: April 15, 2024
• Last Updated: May 29, 2025
• Results First Posted: May 29, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)