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

Study Overview
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Brief Summary
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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 BBB, which could 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. Therefore the combination of MK-3475 and MLA as proposed in this protocol is hypothesized to create a therapeutic synergy 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.

Official Title
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A Phase I/II Study Testing the Safety, Toxicities, and Efficacy of MK-3475 in Combination With MRI-guided Laser Ablation in Recurrent Malignant Gliomas

Conditions
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Malignant Glioma

Intervention / Treatment
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* Biological: MK-3475
* Device: MRI-guided laser ablation
* Procedure: Surgical resection/debulking
* Procedure: Biopsy
* Procedure: Blood draw for research purposes
* Procedure: Cervical lymph node fine needle aspiration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L Serum creatinine ≤ 1.5 x IULN OR creatinine clearance by Cockcroft-Gault ≥ 60 mL/min for patients with serum creatinine > 1.5 x IULN Serum total bilirubin ≤ 1.5 x IULN OR direct bilirubin ≤ IULN for patients with total bilirubin > 1.5 x IULN AST (SGOT) and ALT (SGPT) ≤ 2.5 x IULN (or ≤ 5 x IULN for patients with liver metastases) 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 Sexually active women of childbearing potential and men must agree to use contraception (as described in the protocol) prior to study entry, for the duration of study participation, and for 120 days after last dose of MK-3475. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Patients with the ability to understand and willingness to sign an IRB approved written informed consent document will be enrolled into the trial. However, should a patient lose their ability to consent while participating in this study and s/he is still receiving clinical benefit from participation, s/he may continue on study with the consent of a Legally Authorized Representative. Exclusion Criteria: 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. A history of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-3475 or other agents used in the study. Dexamethasone > 4 mg at the time of registration 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). Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension, or psychiatric illness/social situations that would limit compliance with study requirements. 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. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease. Pregnant and/or breastfeeding. Patient must have a negative serum or urine pregnancy test within 72 hours of study entry. Known history of hepatitis B (e.g.,defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (e.g.,defined as HCV RNA [qualitative] is detected) infection. Known history of active TB (bacillus tuberculosis). Known history of HIV (HIV 1/2 antibodies).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I: MK-3475 + MLA<br>-In the phase I portion of this study, MK-3475 will be given every 3 weeks starting no more than 1 week after MLA until progression or unacceptable toxicity. | Biological: MK-3475<br>* -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).<br>* Other names: Keytruda;Device: MRI-guided laser ablation<br> <br> * Other names: AutoLITT;Procedure: Surgical resection/debulking<br>* Optional Standard of care<br>|
| Experimental: Phase II: MK-3475 Only (Arm B)<br>In the phase II portion of this study, MK-3475 will be given every 3 weeks beginning 3 weeks after surgical debulking or no more than 1 week after biopsy (if no debulking) The phase II dose was determined during the Phase I portion of the study. Patients enrolling in phase II will need to have tissue available for diagnostic purpose and for immunological monitoring. Surgical resection/debulking is per standard of care and optional for the purpose of this study and the performing neurosurgeon will determine whether each patient will undergo surgery. For those not undergoing surgical resection/debulking, a biopsy for tissue diagnosis and immune monitoring will only be performed when clinically warranted. | Biological: MK-3475<br>* -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).<br>* Other names: Keytruda;Procedure: Surgical resection/debulking<br>* Optional Standard of care<br>Procedure: Biopsy<br>* If no surgical resection/debulking Phase II patients only<br>Procedure: Blood draw for research purposes<br>* Phase II patients only Drawn prior to MLA or biopsy/surgical resection procedure, and immediately prior to each the first dose of MK-3475. Subsequently, research blood will be drawn at doses 2, 4, 6, 9, 18, 36, and at the end of treatment<br>Procedure: Cervical lymph node fine needle aspiration<br>* Optional Time of surgical procedure and 6 weeks +/- 1 week after surgical procedure<br>|
| Experimental: Phase II: MK-3475 + MLA (Arm A)<br>In the phase II portion of this study, MK-3475 will be given every 3 weeks no more than 1 week after MLA, or no more than 1 week after biopsy (if no debulking). The phase II dose will be determined during the phase I portion of this study and is 200 mg. Patients enrolling in phase II will need to have tissue available for diagnostic purpose and for immunological monitoring. Surgical resection/debulking is per standard of care and optional for the purpose of this study and the performing neurosurgeon will determine whether each patient will undergo surgery. --For those not undergoing surgical resection/debulking, a biopsy for tissue diagnosis and immune monitoring will be performed during MLA MLA will take place at least 3 weeks but not more than 6 weeks after surgical resection/debulking or if no surgical resection/debulking will start on day 1 | Biological: MK-3475<br>* -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).<br>* Other names: Keytruda;Device: MRI-guided laser ablation<br> <br> * Other names: AutoLITT;Procedure: Surgical resection/debulking<br>* Optional Standard of care<br>Procedure: Biopsy<br>* If no surgical resection/debulking Phase II patients only<br>Procedure: Blood draw for research purposes<br>* Phase II patients only Drawn prior to MLA or biopsy/surgical resection procedure, and immediately prior to each the first dose of MK-3475. Subsequently, research blood will be drawn at doses 2, 4, 6, 9, 18, 36, and at the end of treatment<br>Procedure: Cervical lymph node fine needle aspiration<br>* Optional Time of surgical procedure and 6 weeks +/- 1 week after surgical procedure<br>|
| Experimental: Phase II (after amendment #12): MK-3475 + MLA<br>After amendment 12, all patients will be enrolled in this arm MK-3475 will be given every 3 weeks no more than 1 week after MLA The phase II dose will be determined during the phase I portion of this study and is 200 mg. Patients enrolling in phase II will need to have tissue available for diagnostic purpose and for immunological monitoring. Surgical resection/debulking is per standard of care and optional for the purpose of this study and the performing neurosurgeon will determine whether each patient will undergo surgery. For those not undergoing surgical resection/debulking, a biopsy for tissue diagnosis and immune monitoring will be performed during MLA MLA will take place at least 3 weeks but not more than 6 weeks after surgical resection/debulking or if no surgical resection/debulking will start on day 1 | Biological: MK-3475<br>* -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).<br>* Other names: Keytruda;Device: MRI-guided laser ablation<br> <br> * Other names: AutoLITT;Procedure: Surgical resection/debulking<br>* Optional Standard of care<br>Procedure: Biopsy<br>* If no surgical resection/debulking Phase II patients only<br>Procedure: Blood draw for research purposes<br>* Phase II patients only Drawn prior to MLA or biopsy/surgical resection procedure, and immediately prior to each the first dose of MK-3475. Subsequently, research blood will be drawn at doses 2, 4, 6, 9, 18, 36, and at the end of treatment<br>Procedure: Cervical lymph node fine needle aspiration<br>* Optional Time of surgical procedure and 6 weeks +/- 1 week after surgical procedure<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal tolerated dose (MTD) of MK-3475 when combined with MLA - Phase I only | DLT (dose limiting toxicity) is defined as any of the following that occur during the time frame between the first dose of MK-3475 and 3 weeks after the second dose of MK-3475 that are attributed as possibly, probably, or definitely related to the study treatment: Grade 2 or greater diarrhea Autoimmune hypophysitis Grade 3 or greater hepatitis Grade 2 or greater pneumonitis Significant intracranial edema requiring high-dose steroid (defined as > 16 mg/day and/or inability to taper steroids to ≤ 8 mg/day within 4 weeks due to recurrent symptoms attributable to excessive intracranial edema) Grade 3 or greater non-hematologic toxicity Grade 3 or greater hematologic toxicity | Completion of DLT monitoring for Phase I (approximately 8 months) | 
| Progression-free survival (PFS) of patients being treated with MK-3475 plus MLA - Phase II only | PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. | Up to 2 years after completion of treatment (estimated to be up to 272 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity profile of MK-3475 in combination with MLA - Phase I only | The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting The only toxicities that will not be collected are those that are clearly related to MLA and/or surgery AND ASLO not related to MK-3475 Adverse events will be tracked from start of treatment through 30 days following the last day of study treatment. Serious adverse events will be tracked for 90 days following the last dose of study treatment. | Through 90 days after completion of treatment (up to 168 weeks) | 
| Overall survival (OS) of MK-3475 plus MLA - Phase II only | OS is defined as the duration of time from start of treatment to time of death. | Up to 2 years after completion of treatment (estimated to be up to 272 weeks) | 
| 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) | 
| Identify PD-1-dependent biomarkers in glioma cell-specific T cells that negatively correlate with the frequency of glioma cell-specific cytotoxic T cells and PFS - Phase II only |  | Up to 2 years after completion of treatment (estimated to be up to 272 weeks) | 
| Identify PD-1-dependent biomarkers in glioma cell-specific T cells that negatively correlate with the frequency of glioma cell-specific cytotoxic T cells and OS - Phase II only |  | Up to 2 years after completion of treatment (estimated to be up to 272 weeks) |