Protocol Summary

Protocol No.: OCR14627

Sponsor Protocol No.: 201501072

Study Title
A Phase I and Open Label, Randomized, Controlled Phase II Study Testing the Safety, Toxicities, and Efficacy of MK-3475 in Combination with MRI-guided Laser Ablation in Recurrent Malignant Gliomas

Principal Investigator(s)
Tran, David

Objective
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.

Phase: Phase I/II

Age Group: Adult

Scope: National

Treatment
Phase I: MK-3475 + MLA
- Patients will receive MK-3475 every 3 weeks, with the dose to be determined. The first dose of MK-3475 will be given no more than 1 week after MLA, and it will be administered every 3 weeks thereafter until progression or unacceptable toxicity.
- MK-3475 will be given intravenously over the course of 30 minutes
- MK-3475 will be given up to 24 months after MLA

Phase II: MK-3475 Only
- In the phase II portion of this study, MK-3475 will be given every 3 weeks beginning 3-6 weeks after surgical debulking
- MK-3475 will be given intravenously over the course of 30 minutes
- MK-3475 will be given up to 24 months after surgical debulking

Phase II: MK-3475 + MLA
- In the phase II portion of this study, MK-3475 will be given every 3 weeks no more than 1 week after MLA
- MK-3475 will be given intravenously over the course of 30 minutes
- MK-3475 will be given up to 24 months after surgical debulking

Detailed Eligibility
Inclusion Criteria:
1. Ages 18 years old and older
2. Phase I: Histologically confirmed grade III or IV malignant glioma.
3. Phase II: Histologically confirmed grade IV malignant glioma (GBM). *Note: GBM variants and secondary GBM are allowed for both phase I and phase II.
4. Unequivocal evidence of tumor progression as documented by biopsy or brain MRI scan per RANO criteria.
5. 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 but more than 4 weeks from the completion of radiotherapy, 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.
6. 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.

** Contact study team for full listing of Inclusion and Exclusion criteria.

Applicable Disease Sites

Brain and Nervous System

Participating Institutions
UF Gainesville : Sonisha Warren

Contact
Sonisha Warren, PhD
Phone: +1 352-294-8737
Email: sonisha.warren@neurosurgery.ufl.edu

More Information:
View study listing on ClinicialTrials.gov
http://www.clinicaltrials.gov/ct2/show/
NCT02311582