Status and phase
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About
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.
Full description
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.
Enrollment
Sex
Ages
Volunteers
Inclusion and exclusion criteria
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):
Adequate liver function:
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:
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:
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:
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.
Primary purpose
Allocation
Interventional model
Masking
80 participants in 2 patient groups
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Central trial contact
Avacta Life Sciences
Data sourced from clinicaltrials.gov
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