A Study of AP601 in Patients With Locally Unresectable Advanced or Metastatic Solid Tumors

Official title

A Phase 1, Open-label Study of the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Activity of AP601 in Patients With Solid Tumors.

Overview

A Phase 1, Open-Label Study of the Safety, Tolerability,Pharmacokinetics, Pharmacodynamics and Clinical Activity of AP601 in Patients with Solid Tumours.The study is designed to find the highest dose of AP601 that can be given safely. Participants will be assigned to one of six cohorts. Each cohort will receive a different dose of the study medication, AP601, based on the body weight. Each cohort will initially enrol 1-3 participants. If no serious side effects are seen in the first participant(s), the next cohort will receive the next dose level.

Detailed description

Participants will receive a single infusion of AP601 once every 2 weeks (14 days) (Q2W) for up to 12 months.

Part 1 (Dose Escalation):

Part 1 is a dose escalation part, using an accelerated 3+3 design. Up to 6 dose levels are planned to be evaluated in Part 1.

Cohort 1 - 0.5mg/kg (1-6 participants) Cohort 2 - 1.25 mg/Kg (1-6 participants) Cohort 3 - 2.5 mg/Kg (3-6 participants) Cohort 4- 5.0 mg/Kg (3-6 participants) Cohort 5- 7.5 mg/Kg (3-6 participants) Cohort 6- 10.0 mg/Kg. (3-6 participants) At the first dose level, a single participant will be enrolled and observed for dose-limiting toxicities (DLTs) and adverse events (AEs) for 28 days (2 treatment cycles). If the participant does not experience any DLTs, then a new participant may be dosed at the next higher dose level and observed for the DLT period (28 days). There will be a maximum of 2 single-patient cohorts.

If in any of the single-patient cohorts a patient experiences a DLT, an additional 2 patients will be enrolled at that dose level and evaluated using 3+3 design rules.

Cohorts 3 and above will all use a standard 3+3 design, even if toxicity was not seen in the single-patient Cohorts 1 and 2.

Part 2 (Dose Expansion):

A dose expansion part may be initiated following completion of the dose escalation cohorts.

Interventions

• Drug AP601
  AP601 is a fully human bispecific antibody designed for the treatment of CD73-expressing solid tumours. Participants will receive a single infusion of AP601 once every 2 weeks (14 days) (Q2W) for up to 12 months. All doses of AP601 will be admistered intraveneously. The infusion time for all doses of AP601 in each patient will be approximately 60 to 120 minutes.

Primary outcome measures

• To determine the tolerability (MTD and/or maximum administered dose [MAD] of AP601 in patients with solid tumours. [Time frame: Initial 28 days from the first dose of AP601 which is Cycle1Day1 (each cycle is 14 days) until Cycle2Day14 (each cycle is 14 days)]
• To determine the tolerability of Recommend Phase 2 Dose [RP2D])- MTD and/or maximum administered dose [MAD] of AP601 in patients with solid tumours. [Time frame: TEAEs and SAEs will be assessed at Screening until 90-day safety follow up visit.]
• To determine the tolerability of Recommend Phase 2 Dose [RP2D]) [Time frame: Cycle 1 - pre-dose, immediately following End of Infusion (EOI), 4 hours, 24 hours, 72 hours, 168 hours. Cycle 2- pre-dose, EOI, 4 hours, 24hours, 72hours, 168hours, Cycle 3 to Cycle 24- Predose (each cycle is 14 days), 0-6 hours, End of Trial Visit.]
• To determine the tolerability of Recommend Phase 2 Dose [RP2D]) [Time frame: PD will be assessed Cycle 1 - pre-dose, 24 hous, 72 hours, 168 hours. Cycle 2- pre-dose, 4 hours, 24hours, 72hours, 168hours, Cycle 3 to Cycle 24- Pre-dose (each cycle is 14days) and at End of Trial Visit.]
• To determine the tolerability of Recommend Phase 2 Dose [RP2D] [Time frame: Antitumour activity data will collected at End of Trial Visit , Safety Follow Up Visit (End of Trial + 30 days), Safety FUP Visit (End of Trial + 90 days) and at Survival Follow Up.]
• To determine the tolerability of RP2D - Number of Participants with a Change from baseline in clinical laboratory parameters (haematology) [Time frame: Assessed at Screening, Cycle1 Day1 , Cycle2 Day1, Cycle 3 Day1 to Cycle 24 Day 1(each cycle is of 14 days), End of Trial Visit (EOT) and Safety Follow Up (EOT+ 30 days)]
• To determine the tolerability of RP2D - Number of Participants with a Change from baseline in clinical laboratory parameters (clinical chemistry) [Time frame: Assessed at Screening, Cycle1 Day1 , Cycle2 Day1, Cycle3 Day1 until Cycle 24 Day 1 (each cycle is of 14 days), End of Trial Visit and Safety FUP (EOT+ 30 days)]
• To determine the tolerability of RP2D - Number of Participants with a Change from baseline in clinical laboratory parameters (Coagulation) [Time frame: Assessed at Screening, Cycle1 Day1 , Cycle2 Day1, Cycle3 Day1 to last Cycle 24 Day 1(each cycle is of 14 days), End of Trial Visit and Safety FUP (EOT+ 30 days)]
• To determine the tolerability of RP2D - Number of Participants with a Change from baseline in clinical laboratory parameters (Thyroid Function tests ) [Time frame: Assessed at Screening, Cycle1 Day1 , Cycle2 Day1, Cycle3 Day1 - until last Cycle 24 Day 1 (each cycle is of 14 days), End of Trial Visit and Safety FUP (EOT+ 30 days)]
• To determine the tolerability of RP2D - Number of Participants with a Change from baseline in clinical laboratory parameters (urinalysis) [Time frame: Assessed at Screening, Cycle1 Day1 , Cycle2 Day1, Cycle3 Day1 - until last Cycle 24 Day 1 (each cycle is of 14 days), End of Trial Visit and Safety FUP (End of Trial Visit+ 30 days)]

Secondary outcome measures (12)

• To assess the PK of AP601 in patients with solid tumours - Serum PK concentration of AP601. [Time frame: Cycle 1 - Pre-dose, immediately following End of Infusion (EOI), 4 hours, 24 hours, 72 hours, 168 hours. Cycle 2- pre-dose, EOI, 4 hours, 24hours, 72hours, 168hours, Cycle 3 to Cycle 24 - Predose (each cycle is 14 days), 0-6 hours and End of Trial Visit.]
• To assess the PK of AP601 in patients with solid tumours - Individual maximum concentration values, directly determined from the serum concentration time profiles for each participant (Cmax) [Time frame: Cycle 1 - pre-dose, immediately following End of Infusion (EOI), 4 hours, 24 hours, 72 hours, 168 hours. Cycle 2- pre-dose, EOI, 4 hours, 24hours, 72hours, 168hours, Cycle 3 to Cyle 24- Predose(each cycle is 14 days), 0-6 hours and End of Trial Visit.]
• To assess the PK of AP601 in patients with solid tumours -Serum clearance following IV administration (CL) [Time frame: Cycle 1 - Pre-dose, immediately following End of Infusion (EOI), 4 hours, 24 hours, 72 hours, 168 hours. Cycle 2- pre-dose, EOI, 4 hours, 24hours, 72hours, 168hours, Cycle 3 -to Cycle 24- Predose(each cycle is 14days), 0-6 hours and End of Trial Visit.]
• To assess the PK of AP601 in patients with solid tumours -Area under the serum concentration-time curve (AUC) from time zero to 168 hours post-dose (AUC0-168) [Time frame: Cycle 1 - Pre-dose, immediately following End of Infusion (EOI), 4 hours, 24 hours, 72 hours, 168 hours. Cycle 2- pre-dose, EOI, 4 hours, 24hours, 72hours, 168hours, Cycle 3 to Cycle 24 Predose(each cycle is 14days), 0-6 hours and End of Trial Visit.]
• To assess the PK of AP601 in patients with solid tumours - AUC from time zero to the last time point with measurable concentration using the linear trapezoidal rule (AUClast) [Time frame: Cycle 1 - Pre-dose, immediately following End of Infusion (EOI), 4 hours, 24hours, 72 hours, 168 hours. Cycle 2- pre-dose, EOI, 4 hours, 24hours, 72hours, 168hours, Cycle 3 to Cycle 24- Predose(each cycle is 14days), 0-6 hours and End of Trial Visit.]
• To assess the PK of AP601 in patients with solid tumours - The time to attain maximum concentration (Tmax) [Time frame: Cycle 1 - pre-dose, immediately following End of Infusion (EOI), 4 hours, 24 hours, 72 hours, 168 hours. Cycle 2- pre-dose, EOI, 4 hours, 24hours, 72hours, 168hours, Cycle 3 to Cycle 24- Predose (each cycle is 14days), 0-6 hours and End of Trial Visit.]
• To assess the PK of AP601 in patients with solid tumours - Terminal elimination half-life (T1/2) [Time frame: Cycle 1 - Pre-dose, immediately following End of Infusion (EOI), 4 hours, 24 hours, 72 hours, 168 hours. Cycle 2- pre-dose, EOI, 4 hours, 24hours, 72hours, 168hours, Cycle 3 to Cycle 24- Predose(each cycle is 14days), 0-6 hours and End of Trial Visit.]
• To assess the PK of AP601 in patients with solid tumours - Volume of distribution (Vz) [Time frame: Cycle 1 - pre-dose, immediately following End of Infusion (EOI), 4 hours, 24 hours, 72 hours, 168 hours. Cycle 2- pre-dose, EOI, 4 hours, 24hours, 72hours, 168hours, Cycle 3 to Cycle 24- Predose(each cycle is 14days), 0-6 hours and End of Trial Visit.]
• To assess the PK of AP601 in patients with solid tumours - Trough concentration (Ctrough) [Time frame: Cycle 1 - pre-dose, immediately following End of Infusion (EOI), 4 hours, 24 hours, 72 hrs, 168 hours. Cycle 2- pre-dose, EOI, 4 hours, 24hours, 72hours, 168hours, Cycle 3 to Cycle 24- Predose(each cycle is 14days), 0-6 hours and End of Trial Visit.]
• To assess the Immunogenicity of AP601 in patients with solid tumours. [Time frame: Assessed at Cycle1 Day1 - Pre-dose, Cycle2 Day1 - Predose, Cycle3 Day1- Predose until Last Cycle 24 Day 1 (each cycle is of 14 days) and End of Trial Visit.]
• To assess the antitumor activity of AP601 in patients with solid tumours. [Time frame: Antitumour activity data will collected at End of Trial(EOT) Visit , Safety FUP Visit (EOT + 30 days), Safety Follow Up Visit (EOT + 90 days) and at Survival Follow Up.]
• To evaluate the preliminary efficacy of AP601 in patients with solid tumours- Objective Response Rate (ORR) [Time frame: Upto 2 years]

Eligibility criteria

Inclusion Criteria: 1. Patients with histologically or cytologically proven locally unresectable advanced or metastatic solid tumors. Patients must be relapsed or refractory to at least one standard-of-care therapy, and/or have refused standard-of-care therapy.

2\. Eastern Cooperative Oncology Group performance status of 0 to 1 at Screening, with an estimated life expectancy of at least 3 months.

3\. Disease must have at least 1 assessable (long diameter ≥1 cm) lesion for evaluation of response by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.

4\. Patients with adequate organ and bone marrow function, in the absence of growth factors, including the specific laboratory findings of Absolute neutophil count, platelet count, Haemoglobin, AST, ALT, Serum total Bilirubin, Alkaline phosphatase, prothrombin time, INR or activated partial thromboplastin time, creatinine and albumin.

5\. Female Volunteers must be of nonchild bearing potential i.e, surgically sterilised at least 6 weeks before Screening Visit or postmenopausal.

6\. Females of childbearing potential must have a negative pregnancy test, agree not to attempt to become pregnant or donate Ova and agree to use contraception from one month prior to Screening until at least 90 days after last dose of study drug, if not exclusively in a same-sex relationship or abstinent as a committed lifestyle.

Male Vonuteers:

• Must agree not to donate sperm from signing the ICF until at aleast 90 days after the last dose of the study drug.
• If engaging in sexual intercourse with a female partner who could become pregnant, must agree to use adequate contraception.
• Willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions.

Exclusion criteria

• Has received concurrent antitumor treatment or IPs within 28 days of C1D1. The antitumor treatments include chemotherapy, radiotherapy, immunotherapy, targeted therapy, hormonal therapy, or cytokine therapy.
• Has received prior CD73-targeted and/or CD137-targeted therapeutics.
• Has had major surgery within 28 days prior to C1D1 (excluding prior diagnostic biopsy).
• Any unresolved toxicity (except alopecia) from prior therapy of ≥CTCAE Grade 1, prior to the day of the first dose of IP. Participants with Grade 2 toxicity that is not CS (e.g., alopecia, vitiligo), or that is deemed stable or irreversible (e.g., peripheral neuropathy) can be enrolled.
• History of any other malignancy, which has been active or treated within the past 2 years, with the exception of thyroid cancer, cervical intraepithelial neoplasia, basal cell carcinoma and squamous cell carcinoma.
• Prior history of an irAE with immunotherapy-related toxicities that resulted in discontinuation of prior immunotherapy.
• Current symptomatic leptomeningeal disease or uncontrolled, untreated brain metastasis.
• Has received any organ transplantation including allogeneic stem cell transplantation.
• Has received blood transfusions or growth factor support ≤ 14 days prior to screening.
• Has any significant acute or chronic infections including:

• Infection requiring systemic antibacterial, antifungal, or antiviral therapy within 14 days before first dose of AP601.
• Known active hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection.
• Current active, or history of, any autoimmune disease that may relapse or immunodeficiencies.
• Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before first dose of AP601.
• Known severe hypersensitivity reactions to monoclonal antibodies.
• Breastfeeding (or planning to breastfeed) at any time during the study, and for 90 days following study completion.
• Participants with a current or recent (within the past 12 months) diagnosis of alcohol or non-prescribed drug abuse, as defined by local guidelines.
• Evidence of cardiac dysfunction (defined as myocardial infarction within the last 6 months, New York Heart Association Class II/III/IV heart failure, unstable angina, unstable cardiac arrhythmias, or known left ventricular ejection fraction \[LVEF\] <55%) or other CS cardiac pathology likely to impair the participants ability to participate in the study.
• Uncontrolled intercurrent illness including, but not limited to, uncontrolled hypertension, uncontrolled diabetes, uncontrolled endocrinopathy, severe active peptic ulcer disease or gastritis.
• Has received a live (or live attenuated) vaccination within 28 days of the first dose of AP601 and during the study period.
• Any other condition or prior therapy that in the opinion of the PI (or delegate) would make the volunteer unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance with any study requirements.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

Australia · 3 centers

• Calvary Mater Newcastle — Waratah
• Pindara Private Hospital — Brisbane
• Epworth HealthCare — Melbourne

Identifiers

NCT: NCT07165067 · AP601-101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗