AMP945 in Combination With Nab-paclitaxel and Gemcitabine for Treatment of Pancreatic Cancer

Study Overview
=================
Brief Summary
-----------------
This is a multicentre, open label, two-part study to determine whether the focal adhesion kinase (FAK) inhibitor AMP945, when given prior to dosing with gemcitabine and nab-paclitaxel, improves response to therapy in first-line patients with unresectable or metastatic pancreatic cancer. Part A is a phase 1b dose-escalation design that will enrol at least 3 participants in each of 4 dose-level cohorts, to determine the RP2D of AMP945 to be explored in Part B. Part B will determine the efficacy of the AMP945 regimen at the RP2D, and will be run as a Simon Two-stage design; Stage 1 will enrol 26 participants. If ≤5 of the 26 participants show an objective response, then recruitment will be paused and a detailed analysis of futility will be performed. If the study is deemed futile, recruitment will cease. If the study is determined to be not futile or >5 of the 26 participants show an objective response, recruitment will continue, and an additional 24 participants will be enrolled in Stage 2.

Official Title
-----------------
A Phase 1b/2a, Multicentre, Open Label Study of the Pharmacokinetics, Safety and Efficacy of AMP945 in Combination With Nab-paclitaxel and Gemcitabine in Pancreatic Cancer Patients

Conditions
-----------------
PDAC, Pancreatic Cancer, Pancreatic Ductal Adenocarcinoma

Intervention / Treatment
-----------------
* Drug: AMP945 ascending doses
* Drug: AMP945 RP2D


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Provide written informed consent prior to any study procedures and agree to adhere to all protocol requirements. Aged at least 18 years at the time of consent. Confirmed histological or cytological diagnosis of advanced pancreatic adenocarcinoma that is: Part A: metastatic or not surgically resectable. Part B: metastatic, with initial diagnosis of metastatic disease ≤6 weeks prior to Baseline. Has measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques or as >10 mm with spiral CT scan. Eligible for treatment with nab-paclitaxel and gemcitabine as standard of care therapy. Eastern Cooperative Oncology Group (ECOG) Performance Score of 0-1, sustained on two separate assessments: the first at least 2 weeks prior to the 1st dose of AMP945 and the 2nd within 72 hours prior to the 1st dose of AMP945. Participants not maintaining an ECOG Performance Score of 0-1 at the second assessment will be excluded from participation. Has a life expectancy of >3 months. Adequate organ function, as defined by the laboratory results below (samples must be obtained ≤14 days prior to study drug administration): a) Haematology: (i) Absolute neutrophil count (ANC) ≥1.5 × 109/L; (ii) Platelet count ≥100,000/mm3 (100 × 109/L); (iii) Haemoglobin (Hgb) ≥9 g/dL. b) Serum chemistry: (i) Aspartate transaminase (AST) (SGOT), ALT (SGPT) ≤2.5 × upper limit of normal range (ULN), unless liver metastases are clearly present, then ≤5 × ULN is allowed; (ii) Total bilirubin ≤ULN; (iii) Creatinine <1.5 x upper limit of normal (ULN) or estimated glomerular filtration rate (eGFR) >60 mL/min/1.73m2 (calculated using the Cockcroft-Gault equation). c) No clinically significant abnormalities in coagulation results. d) No clinically significant abnormalities in urinalysis results. Agree to use contraception according to protocol Exclusion Criteria: Pregnant or breast-feeding, or plans to become pregnant during the study. Has received any investigational medicinal product (IMP) within 30 days or 5 half-lives (whichever is longer) prior to Day -8. Known brain metastases, unless previously treated and well-controlled for at least 3 months (defined as clinically stable, no oedema, no steroids and stable in 2 scans at least 4 weeks apart). Gastrointestinal condition that could interfere with the swallowing or absorption of study medication. Part A: Has received prior systemic treatments for pancreatic cancer, except those given in the adjuvant setting, and with recurrence more than 6 months after completion of curative/adjuvant treatment. Part B: Has received no previous radiotherapy, surgery, chemotherapy, or investigational therapy for the treatment of metastatic disease. Prior treatment with 5-FU or gemcitabine administered as a radiation sensitizer in the adjuvant setting is allowed, provided at least 6 months have elapsed since completion of the last dose and no lingering toxicities are present. Participants having received cytotoxic doses of gemcitabine or any other chemotherapy in the adjuvant setting are not eligible for this study. History of malignancy other than in situ cancer or basal or squamous cell skin cancer in the last 5 years. Major surgery, other than diagnostic surgery (i.e., surgery done to obtain a biopsy for diagnosis without removal of an organ), within 4 weeks prior to Day -8. Known human immunodeficiency virus (HIV) and/or history of Hepatitis B or C infections or known to be positive for Hepatitis B surface antigen (HBsAg) or Hepatitis C Antibody. Known history of myocardial infarction, coronary stenting, stroke, or cerebrovascular accident within 6 months prior to the first dose of study drug. Focal palliative radiotherapy (e.g., to a bony metastasis) within the 14 days prior to Run-in, or more extensive radiotherapy within 28 days prior to Run-in. History of chronic leukemias (e.g., chronic lymphocytic leukemia). History of interstitial lung disease, history of slowly progressive dyspnoea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis or multiple allergies. History of connective tissue disorders (e.g., lupus, scleroderma, arteritis nodosa). Clinical signs of active infection and/or a temperature of > 38.0°C at the time of Screening or Baseline. Study entry may be deferred at the discretion of the Principal Investigator (PI). Currently using warfarin. Administration of a live virus vaccine in the 4 weeks prior to Day -8 or plans to receive a live virus vaccine during the study. Clinically significant allergies to AMP945, nab-paclitaxel or gemcitabine (or any of their excipients), including hypersensitivity reactions to human albumin, that are not likely to be well controlled with premedication or other supportive measures. Exhibiting any of the conditions or events outlined in the Contraindications or Special Warnings and Precautions sections of the nab-paclitaxel and/or gemcitabine package inserts. Peripheral neuropathy > Grade 1. Corrected QT interval using Fridericia's correction (QTcF) > 460 ms for males and >480 ms for females. Any clinically relevant medical, social, or psychiatric conditions, or any finding during Screening, which in the Investigator's opinion may put the participant at unacceptable risk or interfere with the study objectives. Prior treatment with AMP945.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Single arm study but 2 parts; Part A is dose escalation Part B is open label single dose level
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AMP945<br>Part A: AMP945 administered in dose escalating cohorts Part B: AMP945 recommended phase 2 dose | Drug: AMP945 ascending doses<br>* Part A is a phase 1b dose-escalation design that will enrol at least 3 participants in each of 4 dose-level cohorts, to determine the RP2D of AMP945 to be explored in Part B. Dose escalation decisions will be made using a standard 3+3 dose-escalation phase 1 oncology study design.<br>Drug: AMP945 RP2D<br>* Part B will determine the efficacy of the AMP945 priming regimen at the recommended phase 2 dose (RP2D) determined in Part A.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Treatment-Emergent Adverse Events (TEAEs) from Baseline to End of Study | TEAEs during study treatment and follow up periods | From first dose of study drug to end of study, an expected average of 6 months | 
| Part A: Determination of RP2D | The RP2D of AMP945 will be determined based on either the maximum tolerated dose or maximum pharmacodynamic effect, which ever is reached first | After Cycle 1 (28 days) for each Part A cohort | 
| Part B: efficacy of AMP945 | Overall response rate based on RECIST 1.1 | Imaging every 56 days per participant, with an expected average duration of 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: efficacy of AMP945 | Overall response rate based on RECIST 1.1 | Imaging every 56 days per participant, with an expected average duration of 6 months | 
| AMP945 levels in plasma | Measurement of maximum concentration (cmax) of AMP945 | Days -8, -7, 1, 3, 4, 8 and 10 | 
| AMP945 levels in plasma | Measurement of time to cmax (tmax) | Days -8, -7, 1, 3, 4, 8 and 10 | 
| AMP945 levels in plasma | Measurement of clearance (CL) | Days -8, -7, 1, 3, 4, 8 and 10 |