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Pembrolizumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients will have intravenous pembrolizumab 7 days before surgery with Laser Interstitial Thermotherapy

Patients will have intravenous pembrolizumab 14 days after surgery with Laser Interstitial Thermotherapy

Patients will have intravenous pembrolizumab 35 days after surgery with Laser Interstitial Thermotherapy

Pembrolizumab injections 7 days before surgery

Pembrolizumab at 7 days prior

Pembrolizumab injections 14 days after surgery

Pembrolizumab at 14 days post

Pembrolizumab injections 35 days after surgery

Pembrolizumab at 35 days post

surgical procedure to heat hard to reach tumors with a laser beam

Laser Interstitial Thermotherapy

Tiffany Hodges, MD

The purpose of this study is to test the side effects and efficacy of using Laser Interstitial Thermotherapy (LITT) combined with Pembrolizumab. LITT is a minimally invasive surgical technique that uses a laser to heat brain tumors.

Pembrolizumab is an investigational (experimental) drug that works by helping participants' immune system work correctly to detect and fight cancer cells. Pembrolizumab is experimental because it is not approved by the Food and Drug Administration (FDA), for this use, though it is approved to treat other cancers.

Primary Objectives:

1. Phase I: To determine the optimal timing for combining LITT and pembrolizumab in patients with rGBM:

   • To determine the feasibility, safety, tolerability and side effect profiles for combining LITT and pembrolizumab at various time points pre-LITT vs. post-LITT (Phase I).
2. Phase II: To estimate the response to pembrolizumab combined with LITT in patients with rGBM;

   • To estimate the response rate after treatment with LITT combined with pembrolizumab in patients with rGBM (Phase II).
3. To collect and record the side effect profiles for combining LITT and pembrolizumab (Phase I and Phase II).

Secondary Objectives:

1. To determine the effect of pembrolizumab on systemic immune microenvironment in patients with rGBM.
2. To determine the effect of pembrolizumab on the intra-tumoral immunosuppressive microenvironment within rGBM.
3. Secondary for Phase II, to estimate progression free survival (PFS) and overall survival (OS) after treatment with LITT combined with pembrolizumab in patients with rGBM (Phase II).
4. Measure radiological response using both conventional RANO criterion, a modified RANO (RANOi) designed specifically for immunotherapy response assessment, as well as MRI fingerprinting (MRF), recently demonstrated by the PI and collaborators to accurately and precisely distinguish recurrent GBM from radiation injury.
5. Correlate clinical and radiological response to known biomarkers of GBM such as Isocitrate Dehydrogenase 1 (IDH-1) mutations, Isocitrate Dehydrogenase 2 (IDH-2) mutations, Methyl-Guanine Methyl Transferase (MGMT) promoter methylation, Phosphatase and tensin homologue (PTEN) loss and KI-67.

Study Design:

The Phase I component will involve up to two of a possible 3 cohorts of 3-4 patients each for a total of 6-8 evaluable patients. Each patient will undergo a stereotactic biopsy. If GBM or Gliosarcoma is confirmed by frozen section, patients will undergo LITT then treatment with 200 mg pembrolizumab IV. Cohort I will receive pembrolizumab on post operative day 14 and every 3 weeks thereafter. In the event that one patient suffers non-hematologic toxicity of grade 3 or more, or if hematologic toxicity is grade 4 or higher, the investigators will delay the 2nd dose of pembrolizumab by 3 weeks and a 4th patient will be accrued. If there are two patients in the initial cohort with non-hematologic toxicities grade 3, or if hematological toxicity in two patients is grade 4 or higher, the second cohort will delay initiation of pembrolizumab until post operative day 35 after LITT. Conversely, if there are no non-hematologic adverse events (AEs) of grade 3 or higher, the investigators will proceed to cohort IB using the same dose of pembrolizumab given 7 days prior to surgery, then every 3 weeks. Similarly, feasibility and safety will be addressed as above in deciding whether or not to proceed to the next cohort.

The Phase II component of the study will consist of additional patients receiving pembrolizumab at the earliest tolerated time post LITT:

* 14 days post-op
* -7 days pre-op;
* 35 days post-opto achieve a total of 23 evaluable patients at the earliest tolerated dose.

Three parallel groups given Pembrolizumab injections at different timepoints

Because this is an open-label, safety and tolerability study in which all enrolled subjects will receive Pembrolizumab in Combination with LITT, this study is unblinded.

Laser Interstitial Thermotherapy (LITT) Combined With Checkpoint Inhibitor for Recurrent GBM (RGBM)

Phase I/II Study of Laser Interstitial Thermotherapy (LITT) Combined With Checkpoint Inhibitor for Recurrent GBM (RGBM)

Optimal timing of LITT with pembrolizumab

Response rates for the Phase II component will be calculated and compared to historical controls using chi-square tests or Fishers exact tests.

PFS, defined as time from diagnosis to documented progression

OS, defined as time from diagnosis to death

PFS6, Proportion of patients who do not progress at 6 months

PFS12, Proportion of patients who do not progress at 12 months

PFS24, Proportion of patients who do not progress at 24 months

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Laser Interstitial Thermotherapy (LITT) Combined With Checkpoint Inhibitor for Recurrent GBM (RGBM)	NCT03277638	Glioblastoma, A...	Pembrolizumab a... Pembrolizumab a... Pembrolizumab a... Laser Interstit...	18 Years -	Case Comprehensive Cancer Center
Laser Interstitial Thermotherapy (LITT) Combined With Checkpoint Inhibitor for Recurrent GBM (RGBM)	NCT03277638	Glioblastoma, A...	Pembrolizumab a... Pembrolizumab a... Pembrolizumab a... Laser Interstit...	18 Years -	Case Comprehensive Cancer Center
Laser Interstitial Thermotherapy (LITT) Combined With Checkpoint Inhibitor for Recurrent GBM (RGBM)	NCT03277638	Glioblastoma, A...	Pembrolizumab a... Pembrolizumab a... Pembrolizumab a... Laser Interstit...	18 Years -	Case Comprehensive Cancer Center

Spots Global Cancer Trial Database for pembrolizumab at 7 days prior