A First in Human Study of AdAPT-001 in Subjects With Refractory Solid Tumors

Study Overview
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Brief Summary
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This is the first clinical trial of AdAPT-001 for the treatment of cancer. AdAPT-001 is an oncolytic virus that is injected directly into the tumor. The purpose of this study is to find out the highest dose of AdAPT-001 that is safe and tolerable. This is the first step in studying whether it can be used to treat others with cancer in the future.

Detailed Description
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This is a dose escalation protocol to determine, first and foremost, the safety, tolerability and feasibility of intratumoral administration of AdAPT-001. The study has 3 parts. Different groups of patients will participate in each part. PART 1: Dose Escalation Safety Run-In (Enrollment Completed) During PART 1, all participants will be treated with AdAPT-001 as a single injection, one time. Participants will be assigned to different dose levels to find the highest dose of AdAPT-001 that is safe and tolerable. PART 2: Dose Expansion Single-Agent (Enrollment Completed) All participants in PART 2 will receive injections of AdAPT-001 on Days 1 and 15 of 28-day cycles. PART 3: Expansion Subjects will be assigned to the following two arms. If a checkpoint inhibitor is indicated for the subject, the subject may be enrolled on Arm 2 per investigator discretion, otherwise subjects may be enrolled on Arm 1. Arm 1: Intratumoral administration of AdAPT-001 (1.0 x 10¹² viral particles) on Day 1 and 15 of each 28-day cycle for up to 12 injections. Arm 2: Intratumoral administration of AdAPT-001 (1.0 x 10¹² viral particles) on Day 1 and 15 of each 28-day cycle for up to 12 injections plus a checkpoint inhibitor per investigator discretion.

Official Title
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A Phase 1/2, First in Human, Study to Evaluate the Safety and Tolerability of AdAPT-001 in Subjects With Refractory Solid Tumors

Conditions
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Cancer, Solid Tumor, Adult, Neoplasms

Intervention / Treatment
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* Biological: AdAPT-001
* Drug: Checkpoint Inhibitor, Immune


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is capable of understanding the purpose and risks of the study and has provided written Informed Consent. Subject is male or female, aged at least 18 years. Subject has a histologically or cytologically confirmed diagnosis of an advanced malignant solid tumor(s) who have received all conventional therapies considered appropriate by Investigator and have a tumor that is easily accessible and/or palpable for treatment. Ultrasound guidance may be used to aid administration. Subject's Eastern Cooperative Group (ECOG) performance status is 0-2 at Screening. Subject has acceptable liver function at Screening, as evidenced by: Bilirubin < 1.5 x ULN (upper limit of normal) AST (SGOT) and ALT (SGPT) < 3.0 x ULN (upper limit of normal) Alkaline Phosphatase < 2.5 x ULN (upper limit of normal) Subject has a Serum Creatinine < 1.5 x ULN (upper limit of normal) Subject has acceptable hematologic status at Screening, as evidenced by: Absolute neutrophil count > 1,500 cells/mm3; > 1.5 x 109/L, and Platelet count > 75,000/mm3; > 75.0 x 109/L, and Hemoglobin (HGB) ≥ 8.0 g/dL; ≥ 5.6 mmol/L Subject has an INR < 1.5 Female subjects of childbearing potential (i.e., women who have not been surgically sterilized or have not been post-menopausal for at least one year), and male subjects with partners of childbearing potential, must agree to use medically acceptable methods of contraception beginning on Study Day 1 and continuing until at least four weeks after administration of the subject's final dose of AdAPT-001. Medically acceptable contraception is defined as either: 1) usage by at least one of the partners of a barrier method of contraception, together with usage by the female partner, commencing at least three months prior to Study Day 1, of a stable regimen of any form of hormonal contraception or an intra-uterine device, or 2) usage by the couple of a double-barrier method of contraception. Use of a single-barrier method alone or abstinence alone is not considered adequate. Subject is willing and able to comply with all protocol procedures, evaluations and rescue measures. OPTIONAL: Archival formalin-fixed paraffin-embedded block(s) or previously cut archival tissue for at least 5 unstained slides (if available). Exclusion Criteria: Presence of a serious co-morbid medical condition, or a clinically significant laboratory finding(s) that, in the opinion of the Investigator, suggests the presence of an infectious, endocrine, and/or other inadequately treated systemic disorder. A known uncontrolled active bacterial, fungal, or viral infection. No subject with an active SARS-CoV-2 infection (within 14 days of a positive test) Known positive history of human immunodeficiency virus (HIV) test Subjects who have active hepatitis. If female, subject is pregnant and/or breastfeeding. Subjects with active autoimmune disease or history of autoimmune disease that might recur and may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded. Note: Subjects in any condition requiring systemic treatment with corticosteroids (prednisone > 10 mg/day or equivalent of the similar drug) or other immunosuppressive agents within 14 days before AdAPT-001), but currently or previously treated with any of the following steroid regimens were included: Topical, ophthalmic, intra-articular, intranasal, or inhaled corticosteroids with minimal systemic absorption; prophylactic short-term use of corticosteroids. Prior adenoviral therapy for any indication except vaccination against infectious disease. Subjects receiving COVID-19 or live vaccination, cannot start treatment until 7 days after completing the vaccination. Recommend waiting at least 28 days from AdAPT-001 dose prior to receiving COVID-19 vaccination. Concurrent treatment with Evusheld is allowed. Chemotherapy or immunotherapy within 14 days of study treatment. Hormonal therapy (including tamoxifen, aromatase inhibitors, and gonadotropin releasing hormone agonists) is allowed. Concurrent treatment with bisphosphonate and RANK ligand inhibitor is allowed.

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
Interventional Model Description: The study is an exploratory open label single-arm interventional study using a 3 + 3 dose escalation safety run-in (PART 1) followed by a dose expansion single-agent (PART 2), followed by expansion (PART 3) single agent or single agent plus checkpoint inhibitor.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PART 1: Dose Escalation Safety Run-In (Enrollment Completed)<br>Subjects will be treated with AdAPT-001 as a single injection, one time. | Biological: AdAPT-001<br>* Oncolytic virus administered by intratumoral injection<br>|
| Experimental: PART 2: Dose Expansion Single-Agent (Enrollment Completed)<br>6 subjects will be enrolled in the Lead In Cohort. A Safety Analysis will be performed after 6 subjects have received at least 24 doses. Upon Safety team review as a continuous reassessment of safety, an additional 19 subjects may be enrolled. All subjects in PART 2 will receive injections of AdAPT-001 on Days 1 and 15 of 28-day cycles. | Biological: AdAPT-001<br>* Oncolytic virus administered by intratumoral injection<br>|
| Experimental: PART 3: Expansion<br>Up to 45 subjects will be enrolled in the expansion cohort to receive either AdAPT-001 on Days 1 and 15 of 28-day cycles or AdAPT-001 on Days 1 and 15 plus a checkpoint inhibitor of 28-day cycles. | Biological: AdAPT-001<br>* Oncolytic virus administered by intratumoral injection<br>Drug: Checkpoint Inhibitor, Immune<br>* Checkpoint Inhibitor per investigator discretion based on diagnosis and subject tolerability<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicities (DLT) | All subjects in PART 1 will be assessed for the development of dose-limiting toxicity (DLT) during treatment with AdAPT-001. The DLT assessment period is defined as: Day of Injection through 28 days post injection (Safety Follow Up). A DLT will be defined as any Grade 3 or higher adverse event, as assessed by the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0. | 28 days | 
| Maximum tolerated dose | In PART 1, A MTD is determined if any cohort experiences 2 subjects with DLT's. | 28 days | 
| Safety of a multiple dose regimen of AdAPT-001 | The safety data will include adverse events, serious adverse events, performance status, clinical laboratory tests, vital signs and physical examination results. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-tumor activity of AdAPT-001 | In PART 2 and PART 3, overall response rate (ORR) and best overall response rates per response evaluation criteria outlined in Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1), as well as progression-free survival (PFS), and duration of response will be assessed. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AdAPT-001, oncolytic virus, immunotherapy, adenovirus, intratumoral injection