A Study Evaluating the Safety, Pharmacokinetics and Early Efficacy of AVA6000 in Solid Tumours

Study Overview
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Brief Summary
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This open-label, First-into-Human (FIH) study will evaluate the safety, tolerability, pharmacokinetics (PK) and early efficacy of AVA6000, a FAP-activated pro-drug of doxorubicin, in patients with locally advanced and/or metastatic solid tumours. In Phase Ia, using a 3+3 design, escalating doses of AVA6000 will be administered to patients with a range of solid tumour types to determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D). In Phase 1b, the selected RP2D dose will be assessed in one to three tumour types.

Detailed Description
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This study is a first-in-human (FIH), Phase 1, open-label, multicentre, dose-escalation study investigating AVA6000 monotherapy administered intravenously (IV) in patients with locally advanced (unresectable) and/or metastatic solid tumours. The study will be conducted in two parts: Phase 1a (Dose Escalation) and Phase 1b (Dose Expansion): Phase 1a (Dose Escalation): The dose-escalation phase is designed to evaluate the safety, tolerability and MTD and/or RP2D of AVA6000, administered as monotherapy Phase 1b (Dose Expansion): The dose-expansion phase will comprise 1 to 3 expansion arms in specific tumour types to evaluate the safety and tolerability of AVA6000 at the MTD or RP2D when administered as monotherapy. The tumour types to be explored in Phase 1b, will be determined based on evaluation of the Phase 1a data and the protocol will be amended accordingly.

Official Title
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A Phase 1, Open Label, Dose-Escalation and Expansion Study to Evaluate the Safety, Pharmacokinetics and Initial Therapeutic Activity of AVA6000, a Novel FAP-activated Doxorubicin Prodrug Administered Intravenously in Patients With Locally Advanced or Metastatic Selected Solid Tumours

Conditions
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Prostate Cancer, Pancreatic Cancer, Colorectal Cancer, Non-small Cell Lung Cancer, Head and Neck Cancer, Cancer of Unknown Primary Site, Ovarian Cancer, Breast Cancer, Soft Tissue Sarcoma, Bladder Cancer, Oesophageal Cancer, Biliary Tract Cancer

Intervention / Treatment
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* Drug: AVA6000


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Willing and able to give written informed consent Male or female patients, ≥18 years of age Histological or cytological confirmation of a locally advanced (unresectable) and/or metastatic pancreatic (PDAC), CRC, NSCLC, HNSCC, CUP, ovarian, breast, soft tissue sarcoma, bladder, oesophageal, prostate, and biliary tract cancer, who have either relapsed or progressed on SoC treatment or are intolerant or nonamenable to SoC treatment In Phase 1b part of the study only: At least 1 lesion, not previously irradiated, that can be accurately measured at baseline as ≥10mm in the largest diameter (except lymph nodes, which must have a short axis ≥15 mm) with CT or MRI scan and that is suitable for accurate repeated measurements. Life expectancy of greater than 12 weeks, in the opinion of the investigator Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 Recovered from all acute toxic effects of any prior radiotherapy, chemotherapy, or surgical procedure (must have resolved to CTCAE grade ≤1 or returned to baseline, except alopecia and peripheral neuropathy, which can be up to CTCAE grade 2) Adequate haematological function (applies only to patients not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose): Neutrophil count of ≥1.5× 10^9 cells/L Haemoglobin ≥9g/dL (with or without transfusion support) Platelet count of ≥75,000/μL (without transfusion within 2 weeks prior to Cycle 1, Day 1) International normalised ratio (INR) and activated partial thromboplastin time (aPTT) ≤1.5 times the upper limit of normal (ULN) Adequate liver function: Total bilirubin ≤1.5 × ULN (in patients with Gilbert's Syndrome, <3 × ULN is allowed) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN (in patients with liver metastases, <5 × ULN is allowed) Alkaline phosphatase (ALP) <5 × ULN (patients with documented liver or bone metastases only) Adequate renal function: a. Serum creatinine ≤1.5 × ULN (in patients for whom, in the Investigator's judgment, serum creatinine levels do not adequately reflect renal function, creatinine clearance by Cockcroft-Gale formula ≥ 50 mL/min may be used) Women of childbearing potential (WOCBP) and women who have ≤ 2 years amenorrhea after start of menopause: has a negative serum pregnancy test within 7 days prior to Cycle 1, Day 1 Contraception requirements: Female patients of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use a highly effective contraceptive method (Pearl Index failure rate <1% per year) during the treatment period and for at least 6 months after the last dose of study drug Male patients with female partners of childbearing potential must agree to use 2 acceptable methods of contraception (Pearl Index failure rate <1% per year), including a barrier method (with or without spermicide) during the treatment period and for at least 6 months after the last dose of study drug Key Exclusion Criteria: Received trastuzumab within 7 months of the planned Cycle 1, Day 1 AVA6000 infusion Received a prior total cumulative anthracycline dose of >350mg/m^2 doxorubicin hydrochloride (or equivalent anthracycline dose) Clinically significant or untreated central nervous system (CNS) metastases requiring treatment, as determined by the Investigator. Has leptomeningeal disease Any history of an active (requiring treatment) other malignancy (except any in-situ carcinoma, non-melanoma skin carcinoma and early prostate cancer with a normal PSA) within 2 years of study entry Has a significant, uncontrolled, concomitant disease that could affect compliance with the protocol Has uncontrolled hypertension (systolic blood pressure [SBP] >150 mmHg and/or diastolic [DBP] >100 mm Hg), unstable angina, congestive heart failure (New York Heart Association (NYHA) Class >II), left ventricular ejection fraction (LVEF) <55% or the low limit of institutional normal limit (whichever is lower) by echocardiogram (ECHO), serious cardiac arrhythmia requiring treatment (exceptions include atrial fibrillation, paroxysmal supraventricular tachycardia), history of myocardial infarction within 6 months prior to Cycle 1, Day 1; history of uncontrolled cardiovascular disease or high-sensitivity troponin above normal at baseline Screening baseline mean QTcF interval (Fridericia's) of >470 msec, obtained from 3 electrocardiograms (ECGs). Has any clinically significant abnormalities in rhythm, conduction, or morphology of resting ECG (e.g., complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval >250msec). Has any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, known family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval, a baseline resting bradycardia <45 beats/min or a baseline resting tachycardia of >100 beats/min Known uncontrolled HIV infection Active hepatitis B (HBV) or hepatitis C (HCV) infection: Positive hepatitis B surface antigen (HBsAG) test at Screening. Patients with a past or resolved HBV infection (defined as having a negative HBsAG test and a positive antibody to hepatitis B core antigen [antiHBc] antibody test) are eligible. Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA Severe infection(requiring IV treatment)within 21 days prior to Cycle 1, Day 1 including, but not limited to, hospitalisation for complications of infection, bacteraemia, or severe pneumonia Any other clinically significant active disease, metabolic dysfunction, physical examination finding, clinical laboratory finding, or reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drugin the opinion of the investigator. Major surgery within 21 days prior to Cycle 1, Day 1 (excluding biopsies) or anticipates the need for major surgery during study treatment Has dementia or altered mental status that in the opinion of the investigator would preclude providing informed consent Pregnant or breastfeeding woman Known hypersensitivity to any of the components of AVA6000 or any excipient related to the product Received prior investigational therapy (defined as a treatment for which there is no Regulatory Authority-approved indication) within 21 or 42 days of Cycle 1 Day 1, for small molecule and biologic investigational therapies, respectively. Received any approved anticancer therapy, including chemotherapy or hormonal therapy, within 28 days prior to Cycle 1, Day 1, with the following exceptions: Hormone-replacement therapy or oral contraceptives Tyrosine kinase inhibitors (TKIs) that have been discontinued more than 7 days prior to Cycle1, Day 1 Is planned for on study treatment or has received within 21 days prior to Cycle 1, Day 1: St John's Wort, any strong inhibitor or inducer of CYP3A4, CYP2D6, narrow therapeutic index CYP1A2, CYP2B6, or P-glycoprotein (PGP) ̧ or any moderate OATP1B3 inhibitor (will include statins) Received systemic immunosuppressive medication (for any indication) at doses of >10mg prednisolone (or equivalent) within 28 days prior to Cycle 1, Day 1. Received radiotherapy within 28 days prior to Cycle 1, Day 1, except for limited field palliative radiotherapy. Patients who have received prior or concomitant radiotherapy to the mediastinal area are also excluded.

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: This Phase I study will follow a standard 3+3 design in Part 1a to determine the maximum tolerated dose (MTD) and/or recommended dose of AVA6000, given as an intravenous infusion, to be used in Part 1b in the dose-expansion phase in up to 3 tumour types.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AVA6000 Phase 1a<br>Patients in Phase Ia will receive escalating doses of AVA6000 following a 3+3 design, commencing with a starting dose of 80mg/m2, once every 3 weeks (Q3W) starting on Cycle 1, Day 1 (C1D1), until disease progression, unacceptable toxicities, withdrawal from treatment for other reasons, reaching maximum lifetime cumulative exposure to doxorubicin (or other anthracyclines), or death, whichever occurs first. | Drug: AVA6000<br>* AVA6000 is a FAP-activated prodrug of doxorubicin. AVA6000 will be administered via IV infusion every 3 weeks. Dosing will occur based on the calculated patient's BSA on the day of dosing.<br>|
| Experimental: AVA6000 Phase 1b<br>Patients in Phase Ib will receive the RP2D dose of AVA6000, once every 3 weeks (Q3W) starting on Cycle 1, Day 1 (C1D1), until disease progression, unacceptable toxicities, withdrawal from treatment for other reasons, reaching maximum lifetime cumulative exposure to doxorubicin (or other anthracyclines), or death, whichever occurs first. One to three tumour types will be selected based on the assessment of Phase 1a data. | Drug: AVA6000<br>* AVA6000 is a FAP-activated prodrug of doxorubicin. AVA6000 will be administered via IV infusion every 3 weeks. Dosing will occur based on the calculated patient's BSA on the day of dosing.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with dose-limiting toxicities (DLTs) |  | Cycle 1, 21 days | 
| Percentage of patients with Dose-Limiting toxicities (DLTs) of AVA6000 during the DLT period |  | Cycle 1, 21 days | 
| Maximum-tolerated dose (MTD) or Recommended Phase 2 dose (RP2D) |  | Cycle 1, 21 days | 
| Percentage of patients with Adverse Events (AEs) at RP2D AVA6000 dose level in tumour-specific expansion arms. |  | Cycle 1, 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum drug concentration (Cmax) of AVA6000 & Doxorubicin | Cmax (maximum plasma concentration) of AVA6000 and Doxorubicin after administration after Cycle 1 and 2 for 72 hours post-dose. | Cycle 1 and Cycle 2, 0-72 hours post dose (Dose Escalation) | 
| Area under the concentration versus time curve (AUC) of AVA6000 & Doxorubicin | AUC (Area under the concentration versus time curve) of AVA6000 and Doxorubicin after administration after Cycle 1 and 2 for 72 hours post-dose. | Cycle 1 and Cycle 2, 0-72 hours post dose (Dose Escalation) | 
| Elimination half-life (t1/2) of AVA6000 & Doxorubicin | t1/2 (Elimination half-life) of AVA6000 and Doxorubicin after administration after Cycle 1 and 2 for 72 hours post-dose. | Cycle 1 and Cycle 2, 0-72 hours post dose (Dose Escalation) | 
| Renal clearance (CLr) of AVA6000 & Doxorubicin | CLr (Renal clearance) of AVA6000 and Doxorubicin after administration after Cycle 1 and 2 for 72 hours post-dose. | Cycle 1 and Cycle 2, 0-72 hours post dose (Dose Escalation) | 
| Objective response rate (ORR) | ORR is defined as the proportion of patients achieving a best overall response of confirmed partial responses (PR) or complete response (CR), per Response Evaluation Criteria in Solid Tumors (RECIST 1.1). | Up to one year | 
| Duration of Response (DoR) | DoR is defined as the duration of time from date of first response to date of disease progression, as per RECIST v1.1 | Up to one year | 
| Progression-free-survival (PFS) | PFS is defined as the time from the date of the first dose to the date of the first documentation of confirmed disease progression or death, whichever occurs first, as per RECIST v1.1 | Up to one year | 
| Overall survival (OS) | Overall survival (OS), defined as the date of first dose) to the occurrence of death from any cause | Up to one year |