Safety and Preliminary Efficacy of ATG-017 Monotherapy or Combination Therapy With Nivolumab in Advanced Solid Tumors and Hematological Malignancies

Study Overview
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Brief Summary
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This is a Phase I, multi-center, open-label study of ATG-017 administered orally, alone or in combination with nivolumab in patients with advanced solid tumors and hematological malignancies. The study is composed of two modules: ATG-017 monotherapy (Module A) and ATG-017 in combination with nivolumab (Module B). Both Modules A and B will include Dose Escalation Phase and Dose Expansion Phase.

Detailed Description
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The dose escalation of ATG 017 will be conducted with intensive safety monitoring to ensure the safety of the patients with solid tumors (Module A and Module B) and hematological malignancies (Module A) harbouring activating alterations in the RAS-MAPK pathway, and will include the continuous and intermittent dosing schedules. The Dose Expansion Phase will start based on dose level and schedule (continuous or intermittent)

Official Title
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A Phase I, Open-Label, Multi-Center Dose Finding Study to Investigate the Safety, Pharmacokinetics, and Preliminary Efficacy of ATG-017 Monotherapy or Combination Therapy With Nivolumab in Patients With Advanced Solid Tumors and Hematological Malignancies

Conditions
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Solid Tumor, Hematological Malignancy

Intervention / Treatment
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* Drug: ATG-017
* Drug: ATG-017+Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses. Aged at least 18 years. Module A: Patient must have a documented activating alteration of the RAS-MAPK pathway. Module B: Dose Escalation Phase: Patient must have a documented activating alteration of the RAS-MAPK pathway; Dose Expansion Phase: Expansion cohorts will be further defined based on information from the Dose Escalation. Histological or cytological confirmation of a solid tumour. Patient with solid tumors must have at least 1 lesion, not previously irradiated. Estimated life expectancy of minimum of 12 weeks. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Ability to swallow and retain oral medication. Exclusion Criteria: Central nervous system metastatic disease, leptomeningeal disease, or metastatic cord compression. Prior ATG-017 administration in the present study. Prior treatment with an ERK1/2 inhibitor. Prior major surgery within 28 days of the first dose of study treatment or minor surgical procedures ≤7 days. Patients receiving unstable or increasing doses of corticosteroids. As judged by the investigator, any evidence of severe or uncontrolled systemic diseases. Active infection including hepatitis B, and/or hepatitis C. Known history of human immunodeficiency virus (HIV) infection. Inadequate bone marrow reserve or organ function -

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Module A (ATG-017 Monotherapy)<br>Dosing will begin at 5 mg QD ATG-017 as starting dose. A treatment cycle will be 21 days for continuous dosing and 28 days for 7 days on/7 days off intermittent dosing of ATG-017 treatment. | Drug: ATG-017<br>* Dosing will begin at 5 mg QD ATG-017 as starting dose. A treatment cycle will be 21 days for continuous dosing and 28 days for 7 days on/7 days off intermittent dosing of ATG-017 treatment.<br>* Other names: AZD0364 hemi-adipic acid;|
| Experimental: Module B (ATG-017+Nivolumab Combination Therapy in Solid Tumors)<br>With the combination with nivolumab, a cycle of study treatment will be defined as 28 days. ATG-017 is planned initially to be continuously given 28 days in each cycle. ATG-017 dosing schedule in combination therapy will follow a similar dose escalation principle as with monotherapy but starting at 5 mg BID. Nivolumab will be given at fixed dosing, 480 mg Q4W, on D1 of each cycle. | Drug: ATG-017+Nivolumab<br>* With the combination with nivolumab, a cycle of study treatment will be defined as 28 days. ATG-017 is planned initially to be continuously given 28 days in each cycle. ATG-017 dosing schedule in combination therapy will follow a similar dose escalation principle as with monotherapy but starting at 5 mg BID. Nivolumab will be specified dose on specified days.<br>* Other names: AZD0364 hemi-adipic acid+Opdivo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AEs/SAEs | Toxicity will be graded according to the NCI CTCAE, Version 5.0. | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentrations | Venous blood samples for determination of total concentrations of ATG 017 in plasma to characterise the PK profile of ATG-017 for a particular dose level | 18 months | 
| Overall Response Rate (ORR) | To determine the overall response rate according to RECIST1.1, Chenson 2014, IWG 2003 and 2006 | 18 months | 
| DOR | Duration of time from first occurrence of CR or PR until the first date that disease progression is objectively documented | 18 months | 
| Progression-Free Survival (PFS) | The time from the first dose date until disease progression or death from any cause | 18 months |