A Phase 0/1 Clinical Trial With an Expansion Phase of GSK5764227, a B7-H3-Targeted Antibody-Drug Conjugate (ADC), in Patients With Recurrent Grade 4 Glioma and Patients With Brain Metastases
Overview
- Phase
- Early Phase 1
- Intervention
- Risvutatug rezetecan
- Conditions
- Not specified
- Sponsor
- Nader Sanai
- Enrollment
- 15
- Locations
- 1
- Primary Endpoint
- Phase 0: Total, Cleaved, and Unbound GSK5757810 Payload Concentration in Tumor Tissue
- Status
- Recruiting
- Last Updated
- last month
Overview
Brief Summary
This will be an open-label Phase 0/1 study that will enroll approximately 15 participants, 9 participants with recurrent WHO Grade 4 glioma (rGBM) and 6 participants with brain metastases, who will receive the investigational drug risvutatug rezetecan (GSK5764227), a B7-H3-targeted antibody-drug conjugate (ADC) with the GSK5757810 payload.
The trial will consist of a Phase 0 component (subdivided into Arms A and B) and an Expansion Phase 1 component. Participants with tumors demonstrating a positive pharmacokinetic (PK) response in the Phase 0 component will be eligible to enroll in the Expansion Phase to receive therapeutic dosing of risvutatug rezetecan.
Detailed Description
Phase 0: Patients with rGBM will enroll into Arm A. Arm A Cohort 1 will determine the optimal time interval (OTI) for surgery based on PK data assessed from two sub-cohorts (Cohort 1a and 1b). The OTI will be defined as the surgical time interval after dosing that corresponds to the highest median concentration of unbound risvutatug rezetecan payload in gadolinium (Gd) non enhancing rGBM tissue in either Cohort 1a or Cohort 1b. Arm A Cohort 2 will receive the IV infusion at the OTI schedule. Cohort 2 enrollment will begin once Arm A Cohort 1 enrollment is complete and the OTI has been determined. Patients with brain metastases will enroll into Arm B. Arm B will receive the IV infusion at the OTI schedule. Arm B enrollment will begin once Arm A Cohort 1 enrollment is complete and the OTI has been determined. After enrollment into Cohort 1 is complete, a written report will be submitted to the DSMB Chair (or qualified alternate) describing the time intervals, adverse events (AE) observed, and any safety reports. The DSMB Chair will review the report and provide written authorization to proceed with Arm A Cohort 2 and Arm B enrollment, or request more information within approximately two business days. Approval for enrollment initiation must be obtained prior to opening enrollment for Arm A Cohort 2 and Arm B. Only participants with tumors demonstrating positive PK response will proceed to the expansion Phase 1 component. Otherwise, participants will receive standard of care. Participants will complete the assessments and procedures noted for the End of Treatment (EOT) Visit. Participants will complete the 30-Day, 60-Day, and 90-Day Safety Follow-Up Visits and they will be monitored for survival as outlined in the "All Participants" section. To assess the PK and pharmacodynamic (PD) endpoints, blood, serum, cerebrospinal fluid (CSF), and brain tumor tissue will be collected intraoperatively (Gd enhancing and Gd non-enhancing tumor tissue will be collected and analyzed separately). Phase 1: Participants with tumors demonstrating positive PK response will continue risvutatug rezetecan treatment at the same dose received in Phase 0, administered once every three weeks (Q3W). Treatment will begin once the participant has recovered from surgery. Participants will receive risvutatug rezetecan until disease progression, unacceptable toxicity, death, withdrawal of consent, loss to follow-up, or study termination by the Sponsor. Participants will complete the assessments and procedures noted for the EOT Visit. Participants will complete the 30-day, 60-day, and 90-day Safety Follow-Up Visits and they will be monitored for survival as outlined in the "All Participants" section. All Participants: All participants will return to the clinic for safety monitoring per the schedule of activities following risvutatug rezetecan treatment discontinuation, and will be contacted approximately every 3 months for up to 12 months for survival data collection. Follow-up for long-term survival will begin after the final safety follow-up visit. MRI scans and RANO reviews will occur approximately every 2-3 months, per standard of care, to monitor disease progression. Participant Duration: Phase 0: The Phase 0 component will last up to approximately 2 months, starting at the 28-day screening window through the Post-Op Follow-Up Visit. Phase 1: Participants will take risvutatug rezetecan as long as the drug is tolerated and the Investigator believes the participant may be obtaining benefit. Treatment will continue until confirmed progression, unacceptable toxicity, death, withdrawal of consent, lost to follow-up, or end of treatment. All Participants: Participants will continue participating for 15 months following their last infusion of risvutatug rezetecan. Participants will return for a 30-day, 60-day, and 90 day Safety Follow-Up Visit. They will then be followed for survival for up to 12 months following the final Safety Follow-Up Visit.
Investigators
Nader Sanai
Director, Ivy Brain Tumor Center
St. Joseph's Hospital and Medical Center, Phoenix
Eligibility Criteria
Inclusion Criteria
- •1\. Diagnosed with: (a) GBM according to the 2021 WHO criteria, who have progressed on or following standard of care therapy, including maximal safe resection (biopsy allowed if resection was deemed unsafe) and concurrent chemoradiation; OR (b) Brain metastasis requiring surgical resection, whether treated or untreated, and must have well-controlled systemic disease or NED other than the brain metastases, in the opinion of the patient's primary oncologist.
- •2\. Has archival or biopsy brain tumor tissue available.
- •3\. Has measurable disease (preoperatively) defined as at least one contrast-enhancing lesion with two perpendicular measurements of at least 1 cm.
- •4\. Age ≥18 at time of consent.
- •5\. Has a performance status of ≤2 on the ECOG scale.
- •6\. Has adequate bone marrow and organ function as defined by the following laboratory values (as assessed by the local laboratory for eligibility):
- •Adequate Bone Marrow Function: Absolute neutrophil count ≥1500/μL (≥1.5 x 109/L), Platelets (at time of surgery) ≥100,000/μL (≥100 x 109/L), Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L (Criteria must be met without erythropoietin dependency and without pRBC transfusion within prior 2 weeks.)
- •Adequate Hepatic Function: Total Bilirubin ≤1.5x ULN (Participants with Gilbert's syndrome with a total bilirubin \>1.5x ULN and direct bilirubin ≤1.5x ULN will be permitted.), AST (SGOT) ≤2.5x institutional ULN, ALT (SGPT) ≤2.5x institutional ULN (Participants with liver metastases with ALT ≤5x ULN will be permitted.)
- •Adequate Renal Function: eGFR ≥50 mL/min/1.73 m2 (Calculated as individualized eGFR using the CKD-EPI formula \[2021\]); If measured or calculated GFR (e.g., creatinine clearance; mGFR) is required or used: ≥60 mL/min
- •Adequate Metabolic Function: Albumin ≥2.8 g/dL
Exclusion Criteria
- •1\. Evidence of leptomeningeal metastasis or spinal cord compression.
- •2\. Unable to undergo through MRI of the brain with IV contrast.
- •3\. Known active systemic bacterial infection (requiring IV antibiotics or fever \>38.5°C at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C \[for example, hepatitis B surface antigen positive\] (screening of viral infection is not required for enrollment).
- •4\. Serious infections within 4 weeks prior to the first infusion of study drug, including but not limited to infectious complications, bacteremia, severe pneumonia treated with IV antibiotics for ≥2 weeks; active infections with therapeutic IV antibiotics within 2 weeks prior to the first infusion of study drug. (Individuals who are receiving or have received prophylactic antibiotics \[e.g., prophylaxis against urinary infections\] are allowed).
- •5\. Known other concurrent severe psychiatric and/or an uncontrolled medical condition that, in the Investigator's judgement, would cause unacceptable safety risks, contraindicate participation in the clinical study, or compromise compliance with the protocol.
- •6\. Have any unresolved toxicities from prior therapy greater than NCI-CTCAE v5 Grade 1 at the time of starting study treatment (exceptions include: alopecia, hearing loss, vitiligo, endocrinopathy managed with replacement therapy, Grade 2 neuropathy, and any chronic Grade 2 toxicities following discussion with the Principal Investigator).
- •7\. Has received treatment with any of the following:
- •a. Orlotamab, enoblituzumab, I-Dxd, or otherB7-H3 targeted agents.
- •b. Investigational agent within 4 weeks prior to the first infusion of study drug.
- •c. Cytotoxic chemotherapy or anticancer drugs within 14 days prior to the first infusion of study drug.
Arms & Interventions
rGBM and Brain Mets
Group A will include participants with recurrent WHO Grade 4 glioma (rGBM) and group B will include participants with brain metastases (brain mets)
Intervention: Risvutatug rezetecan
Outcomes
Primary Outcomes
Phase 0: Total, Cleaved, and Unbound GSK5757810 Payload Concentration in Tumor Tissue
Time Frame: Intraoperatively
The total, cleaved, and unbound GSK5757810 payload concentration in Gd enhancing and Gd non-enhancing tumor tissue collected during Phase 0 surgery from participants with rGBM, and Gd enhancing tumor tissue collected during Phase 0 surgery from participants with brain metastases, will be determined.
Phase 1: Incidence of Adverse Events as Assessed by CTCAE v5.0
Time Frame: Date of first infusion until 90-days post last infusion
Incidence of the following will be summarized: AEs, SAEs, and AEs of Special Interest (AESIs); treatment discontinuations, dose interruptions, and dose reductions due to AEs; changes in vital signs, body weight, laboratory tests, ECG, and ECOG performance status
Secondary Outcomes
- Phase 1: Progression-Free Survival at 6 Months (PFS6)(Date of first infusion to the date of disease recurrence or death due to any cause (whichever occurs first), assessed up to 6 months)
- Phase 0: Total, Cleaved, and Unbound GSK5757810 Payload Concentration in CSF(Intraoperatively)
- Phase 0: pH2AX and B7-H3 Expression Change in Tumor Tissue(Intraoperatively, archival)
- Phase 1: Overall Survival (OS)(Date of first infusion to the date of death due to any cause, assessed up to 24 months)