Clinical Trial of BMS-986504 in Recurrent GBM Patients

Description

PHASE 0

Eligible participants will enroll in the Phase 0 study and receive BMS-986504 in three dose escalation cohorts over 6 days prior to surgical resection. The final dose will be administered 3-5 hours before tumor resection on Day 6. Participants without histologically confirmed diagnosis of recurrent GBM after the craniotomy will be replaced.

Phase 0 Dose Escalation

An initial cohort of three participants will be enrolled at the starting dose level. If ≤1 of the participants experiences a dose-limiting toxicity (DLT) through the end of the Phase 0, the dose is escalated to the next level. Dose escalation continues to the next level if no more than one out of three participants experience a DLT. However, if two or more participants experience DLTs at any dose level, dose escalation stops.

A written report will be submitted to the DSMB Chair (or qualified alternate) describing the time intervals, dose levels, adverse events, safety reports and any DLTs observed after enrollment into each cohort is complete. The DSMB Chair will review the report and provide a written authorization to proceed or will request more information within approximately 2 business days. Approval for the initiation of enrollment must be obtained prior to implementation.

Phase 0 Dose Limiting Toxicity (DLT)

DLTs will be defined as any adverse event that is not clearly due to the underlying disease or extraneous causes, t and unrelated to disease, disease progression, intercurrent illness or concomitant medications from Phase 0 Day 1 through termination from the study or study completion. DLTs will include:

* ≥ Grade 3 thrombocytopenia with clinically significant bleeding
* > Grade 4 neutropenia for more than 7 days
* Neutropenic fever
* As determined by the investigator, any unacceptable toxicity which may include treatment-related death or grade 4 toxicity
* Any non-hematologic toxicity:

* Grade ≥ 3 regardless of relatedness to study treatment, duration, or baseline grade;
* Events that meet Hy’s law criteria;
* Excluding the following:

* Grade 3 nausea/vomiting or diarrhea for less than 72 hours with adequate antiemetic and other supportive care
* Grade 3 fatigue for greater than 1 week
* Grade 3 or higher electrolyte abnormality that lasts up to 72 hours, is not clinically complicated, and resolves spontaneously or responds to conventional medical interventions
* Any death not clearly due to the underlying disease or extraneous causes

Phase 0 PK/PD Assessments Tumor PK and PD analyses will be performed at IVY. To assess the PK and PD endpoints listed, blood, CSF and brain tumor tissue (Gd-enhancing and Gd-non-enhancing tumor tissue will be collected and analyzed separately) will be collected intraoperatively.

Retrospective genomic analysis of tissue from Phase 0 and subsequent resections at recurrence will be performed if positive PK/PD responses are observed.

Participants with tumors demonstrating negative PK will not proceed to the Expansion Phase 1 component but will receive standard of care. Participants will complete the end-of-treatment visit, safety follow-up, and survival monitoring as outlined in the “All Participants” section.

PHASE 1

Participants with tumors demonstrating PK response will continue treatment with the same dose that was received in Phase 0 once daily (QD) in a continuous regimen expressed in 3-week (21-day) cycles. Treatment will begin once the participant has recovered from surgery. Participants will receive BMS-986504 until the progression of disease, unacceptable toxicity or death, withdrawal of consent, loss to follow-up, or study termination by sponsor. Participants will complete the end-of-treatment visit, safety follow-up, and survival monitoring as outlined in the “All Participants” section.

Phase 1 Dose Modifications

Participants who experience a clinically significant Grade 2 toxicity considered related to study treatment, or a Grade 3 or 4 toxicity considered related to study treatment may temporarily suspend study treatment. Depending on the toxicity, study treatment may resume within 28 days after discussion with the Safety Officer.

Dosing of BMS-986504 during Phase 1 can be interrupted for approximately 28 days for medical events that are not associated with toxicity related to study treatment or disease progression.

Criteria for treatment modifications and suggested guidelines for the management of toxicities related to BMS-986504 are summarized in the protocol. These general guidelines may be modified at the discretion of the Investigator based on the best clinical judgement at that time. Any toxicities related to BMS-986504 should be managed according to standard medical practice.

A participant must discontinue study treatment, if, after treatment is resumed at a lower dose, the toxicity recurs with the same or worse severity.

ALL PARTICIPANTS

All participants will return to the clinic for safety monitoring per the schedule of activities following treatment discontinuation and will be contacted approximately every 3 months for up to 12 months for survival data collection. MRI scans and review to monitor progression in guidance with RANO criteria will occur approximately 2-3 month, per standard of care. The start of follow-up for long-term survival begins following completion of the Day 30 safety follow up call.

At treating physician’s discretion, longitudinal biomarker analysis through liquid biopsy will be conducted to characterize genomic and/or transcriptomic changes from tumor cells or cell-free DNA collected from CSF at Phase 0, at Expansion Phase, or recurrent craniotomy.

Additional biomarker analysis may be conducted using surgical tissue. If the participant undergoes repeat craniotomy for recurrence or progression of his/her brain tumor, IVY will request samples from the resected tumor, CSF or blood to enable longitudinal sample collection and analysis that will help identify possible resistance mechanisms.

STUDY STOPPING CRITERIA

Study stopping rules are:

* If < 1 of 3 participant shows positive PK at the highest dose level.
* If ≥ 2 participants have a ≥ 4-week delay to surgery due to BMS-986504 related toxicity at any dose level.
* Any unacceptable toxicity such as Grade 4 toxicity or death not clearly related to underlying disease or extraneous cause

The following options may occur as a result of any of the above:

* Halt participant dosing or study enrollment until the toxicity data can be further studied by the DSMB.
* Amend the protocol to address any of the below:

* Evaluate additional subjects in a particular dose cohort or in each dose cohort to make the study more sensitive to characterizing adverse events;
* Implementation of smaller dose increases between dose cohorts;
* Exclusion of certain participants thought to be more at-risk for a particular adverse event.
* Stop the study.

STUDY OBJECTIVES The Phase 0 Primary Objective is to evaluate concentration of BMS-986504 in Gd-non-enhancing tumor tissue, and the Expansion Phase Primary Objective is to assess safety and tolerability of BMS-986504 in participants who receive at least one dose.

The Phase 0 Secondary Objective is to evaluate concentration of BMS-986504 in CSF collected during Phase 0 surgery, and the Expansion Phase Secondary Objectives are to measure the rate of 6-month progression free survival (PFS6) and examine overall survival (OS) in participants.

STUDY DURATION The estimated total study length of around 15 months includes study initiation and accrual of 9 participants in 9 months, and follow-up for the participants for an additional 6 months to conclude the study.

The final trial report will be summarized and submitted for peer-review journals for publication

Phase 0 Participants: Up to approximately 2 months (screening window of 28 days through Day 30 phone call follow-up).

Phase 1 Participants: BMS-98604 will be taken by the participant as long as the drug is tolerated, and the investigator believes the participant may be obtaining benefit. Treatment will be taken by the participant until confirmed progression, unacceptable toxicity, death, withdrawal of consent, lost to follow-up, or end of treatment.

All Participants: Participants will be followed for survival for up to 12 months following end of treatment.