A Study of Evaluating Dual Inhibitor of PAK4 and NAMPT ATG-019 in Advanced Solid Tumors or Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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This is a multi-center, open-label clinical study with separate Dose Escalation and Expansion Phases to assess preliminary safety, tolerability, and efficacy of ATG-019, a dual inhibitor of PAK4 and NAMPT, alone or co-administered with starting dose of 500 mg niacin ER in patients with advanced solid tumors or non-Hodgkin's lymphoma (NHL).

Detailed Description
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This is a multi-center, open-label clinical study with separate Dose Escalation and Expansion Phases to assess preliminary safety, tolerability, and efficacy of ATG-019, a dual inhibitor of PAK4 and NAMPT, alone or co-administered with starting dose of 500 mg niacin ER (may be titrated to 1,000 mg of daily dose, per label), in patients with advanced solid tumors or non-Hodgkin's lymphoma (NHL) for which all standard therapeutic options considered useful by the investigator have been exhausted and with PD at study entry. The MTD and RP2D will be determined.

Official Title
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A Phase I Open-Label Study of the Safety and Tolerability of ATG-019, a Dual Inhibitor of PAK4 and NAMPT, in Patients With Advanced Solid Tumors or Non-Hodgkin's Lymphoma

Conditions
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Solid Tumor, Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: ATG-019
* Combination Product: ATG-019 + Niacin ER


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent obtained prior to any screening procedures and in accordance with local and institutional guidelines. Age ≥18 years. Patients with histologically or cytologically confirmed, NHL or advanced solid tumors which have progressed despite standard therapy, for whom no standard therapy exists, or who have refused standard therapy. Patients must have objective evidence of PD on study entry: Advanced solid tumors: Measureable disease as defined by RECIST 1.11. NHL: Measureable disease including target lesion(s) as defined by the Cheson 2014 Classification2 for initial evaluation and staging. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1. Adequate hepatic function. Adequate renal function. Life expectancy of ≥ 3 months. Adequate hematopoietic function. Female patients of child-bearing potential must agree to use dual methods of contraception (including one highly effective and one effective method of contraception) and have a negative serum pregnancy test at Screening, and male patients must use an effective barrier method of contraception if sexually active with a female of child-bearing potential. Exclusion Criteria: Female patients who are pregnant or lactating. Time since the last prior therapy for treatment of advanced solid tumors or NHL**: Radiation, chemotherapy, immunotherapy or any other anticancer therapy, including investigational anti-cancer therapy ≤ 4 weeks prior to C1D1. Palliative steroids for disease related symptoms within 7 days prior to C1D1. Known central nervous system metastases. Major surgery within 4 weeks before C1D1. Impaired cardiac function or clinically significant cardiac diseases. Active infection with completion of therapeutic antibiotics, antivirals, or antifungals within 1 week prior to C1D1. Patients diagnosed with tuberculosis and had received treatment. Patients with a known history of human immunodeficiency virus (HIV). Known, active hepatitis A, B, or C infection. Serious psychiatric or medical conditions that, in the opinion of the Investigator, could interfere with treatment, compliance, or the ability to give consent.

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
Interventional Model Description: ATG-019 ATG-019+Niacin ER
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ATG-019 Alone<br>A starting does of 30 mg QoD×3 ATG-019 | Drug: ATG-019<br>* ATG-019 30 mg QoD×3 is selected as the staring dose. Oral ATG-019 will be taken three times a week every other day (Days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26) during each 28-day cycle.<br>* Other names: KPT-9274;|
| Experimental: ATG-019 + Niacin ER<br>A starting dose of 60 mg ATG-019 and 500 mg niacin ER | Combination Product: ATG-019 + Niacin ER<br>* ATG-019 60 mg is selected as starting dose. Oral ATG-019 will be taken three times a week every other day (Days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26) during each 28-day cycle. And a starting dose of 500 mg niacin ER (may be titrated up to 1,000 mg of daily dose, per label) co-administered with each dose of ATG-019.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine MTD* or RP2D* | MTD will be evaluated using the NCI-CTCAE, Version 5.0; RP2D will be determined by SMC for dose escalation phase. | 18 months | 
| To evaluate the Dose-Limiting Toxicity (DLT) for dose escalation phase | DLTs will be evaluated using the CTCAE, Version 5.0 for grading. | 18 months | 
| Overall Response Rate (ORR) | ORR analysis will be performed for both study phases by calculating the point estimate of the percentage of patients who have either CR or PR, presented as the number and percentage of patients, including a two-sided 95% CI. | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Plasma Concentration (Cmax) | To determine the maximum plasma concentration (Cmax) for dose escalation phase. | 18 months | 
| Time to Reach Cmax （Tmax） | To evaluate the time to reach Cmax after single and multiple doses for dose escalation phase. | 18 months | 
| To determine RP2D* | RP2D will be determined by SMC for dose escalation phase. | 18 months | 
| Duration of response (DOR) | The duration of time from first meeting CR or PR measurement criteria (whichever occurs first) until the first date that PD recurrence is objectively documented. | 18 months | 
| Disease control rate (DCR) | The analysis of DCR will be similar to that described for ORR, for patients who achieve CR, PR, or SD for ≥ 8 weeks. | 18 months | 
| Progression-free survival (PFS) | The duration of time from date of first dose of study treatment until the first date that PD is objectively documented or death due to any cause. | 18 months | 
| Overall Survival (OS) | The duration of time from date of first dose of study treatment until death from any cause. | 18 months | 
| Time to progression (TTP) | The duration of time from date of first dose of study treatment to date of PD. | 18 months |