A Study to Evaluate the Safety, Tolerability and Efficacy of RZ-001 With Valganciclovir (VGCV) in Subjects With Glioblastoma

Study Overview
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Brief Summary
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This is a Phase 1/2a, open-label study to evaluate the safety, tolerability, immunogenicity, and preliminary clinical activity of RZ-001 administered in combination with VGCV in subjects with hTERT-positive GBM.

Detailed Description
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The study consists of 2 parts: a dose-escalation part (Part 1) and a dose-expansion part (Part 2). Part 1 consists of dose escalation exploring MTD/RP2D for intratumoral (IT) injection. Part 2 will consist of dose expansion exploring clinical activity for the optimal fixed dose based on the results of Part 1.

Official Title
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A Phase 1/2a, Open-label, Multicenter, Dose Escalation and Dose Expansion Study Evaluating the Safety, Tolerability, and Efficacy of RZ-001 in Combination With Valganciclovir in Subjects With Glioblastoma

Conditions
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Glioblastoma

Intervention / Treatment
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* Drug: RZ-001
* Combination Product: VGCV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult males and females Histologically-confirmed grade 4 astrocytoma, GBM, per The 2021 WHO Classification of CNS Tumors. hTERT positive expression confirmed during the screening period ECOG score of ≤ 2 KPS ≥ 60 Life expectancy ≥ 3 months Exclusion Criteria: Diagnosis of other malignant tumors within 5 years prior to RZ-001 administration. Have extracranial metastases of the tumor cells Current or history of HIV positive Not suitable for inclusion judged by the investigator

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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Cohort 1<br>RZ-001 Dose 1 and VGCV | Drug: RZ-001<br>* Recombinant adenovirus harboring the modified ribozyme construct with HSV-tk as a therapeutic transgene<br>* Other names: Ad-ECRT-122T;Combination Product: VGCV<br>* VGCV, used in a subject after RZ-001 administration, is a nucleoside analog that is metabolized by HSV-tk and other cellular kinases to form the cytotoxic nucleotide analog ganciclovir triphosphate. An approved oral VGCV will be used in the proposed clinical study of RZ-001.<br>* Other names: Valganciclovir;|
| Experimental: Part 1 Cohort 2<br>RZ-001 Dose 2 and VGCV | Drug: RZ-001<br>* Recombinant adenovirus harboring the modified ribozyme construct with HSV-tk as a therapeutic transgene<br>* Other names: Ad-ECRT-122T;Combination Product: VGCV<br>* VGCV, used in a subject after RZ-001 administration, is a nucleoside analog that is metabolized by HSV-tk and other cellular kinases to form the cytotoxic nucleotide analog ganciclovir triphosphate. An approved oral VGCV will be used in the proposed clinical study of RZ-001.<br>* Other names: Valganciclovir;|
| Experimental: Part 1 Cohort 3<br>RZ-001 Dose 3 and VGCV | Drug: RZ-001<br>* Recombinant adenovirus harboring the modified ribozyme construct with HSV-tk as a therapeutic transgene<br>* Other names: Ad-ECRT-122T;Combination Product: VGCV<br>* VGCV, used in a subject after RZ-001 administration, is a nucleoside analog that is metabolized by HSV-tk and other cellular kinases to form the cytotoxic nucleotide analog ganciclovir triphosphate. An approved oral VGCV will be used in the proposed clinical study of RZ-001.<br>* Other names: Valganciclovir;|
| Experimental: Part 1 Cohort 4<br>RZ-001 Dose 4 and VGCV | Drug: RZ-001<br>* Recombinant adenovirus harboring the modified ribozyme construct with HSV-tk as a therapeutic transgene<br>* Other names: Ad-ECRT-122T;Combination Product: VGCV<br>* VGCV, used in a subject after RZ-001 administration, is a nucleoside analog that is metabolized by HSV-tk and other cellular kinases to form the cytotoxic nucleotide analog ganciclovir triphosphate. An approved oral VGCV will be used in the proposed clinical study of RZ-001.<br>* Other names: Valganciclovir;|
| Experimental: Part 1 Cohort 5<br>RZ-001 Dose 5 and VGCV | Drug: RZ-001<br>* Recombinant adenovirus harboring the modified ribozyme construct with HSV-tk as a therapeutic transgene<br>* Other names: Ad-ECRT-122T;Combination Product: VGCV<br>* VGCV, used in a subject after RZ-001 administration, is a nucleoside analog that is metabolized by HSV-tk and other cellular kinases to form the cytotoxic nucleotide analog ganciclovir triphosphate. An approved oral VGCV will be used in the proposed clinical study of RZ-001.<br>* Other names: Valganciclovir;|
| Experimental: Part 2<br>RZ-001 Dose 6 and VGCV | Drug: RZ-001<br>* Recombinant adenovirus harboring the modified ribozyme construct with HSV-tk as a therapeutic transgene<br>* Other names: Ad-ECRT-122T;Combination Product: VGCV<br>* VGCV, used in a subject after RZ-001 administration, is a nucleoside analog that is metabolized by HSV-tk and other cellular kinases to form the cytotoxic nucleotide analog ganciclovir triphosphate. An approved oral VGCV will be used in the proposed clinical study of RZ-001.<br>* Other names: Valganciclovir;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of dose limiting toxicities (DLTs) |  | Day 1 to Day 28 | 
| Maximum tolerated dose (MTD) or maximum administered dose (MAD) dose(MAD) and select the recommended Phase 2 dose (RP2D) of RZ-001 in combination with VGCV |  | Day 1 to Day 28 | 
| Number of participants with treatment-related adverse events as assessed by NCI-CTCAE | Adverse events (AEs) as characterized by type, number, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE]), timing, seriousness, and relationship to RZ-001 | Day 1 to Day 28 | 
| Number of participants with significant laboratory abnormalities as assessed by NCI-CTCAE | Clinically significant laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI-CTCAE), timing, and relationship to RZ-001 | Day 1 to Day 28 | 
| Overall survival (OS) |  | Day 1 to Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in concentration of serum vascular endothelial growth factor (VEGF) |  | Day 1 to Day 28 | 
| Change in concentration of serum anti-adenovirus antibody |  | Day 1 to Day 28 | 
| Overall response rate (ORR) |  | Day 1 to Day 15 | 
| Duration of response (DOR) |  | Day 1 to Day 15 | 
| Progression-free survival (PFS) per modified Response Assessment for Neuro-Oncology (mRANO) |  | Day 1 to Day 15 | 
| Overall survival (OS) |  | Day 1 to Day 15 | 
| Neurologic function assessment using the Neurologic Assessment in Neuro-Oncology (NANO) scale ranging from 0 to 3 in each assessment domain |  | Day 1 to Day 15 |