AOH1996 for the Treatment of Refractory Solid Tumors

Study Overview
=================
Brief Summary
-----------------
This phase I trial studies the side effects and best dose of AOH1996 in treating patients with solid tumors that do not respond to treatment (refractory). AOH1996 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) and the dose limiting toxicities (DLT) of PCNA inhibitor AOH1996 (AOH1996). II. To establish the recommended phase 2 dose (RP2D) of AOH1996. SECONDARY OBJECTIVES: I. To determine the pharmacokinetics of AOH1996. II. To evaluate for preliminary efficacy of AOH1996. III. To evaluate response rate and disease control rate in solid tumors. EXPLORATORY OBJECTIVE: I. To determine pharmacodynamics parameters (alteration of gammaH2AX, downregulation of Myc) of AOH1996. OUTLINE: This is a dose-escalation study. Patients receive AOH1996 orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days.

Official Title
-----------------
First in Human Phase 1 Study of AOH1996 in Patients With Refractory Solid Tumors

Conditions
-----------------
Refractory Malignant Solid Neoplasm

Intervention / Treatment
-----------------
* Drug: PCNA Inhibitor AOH1996


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Documented informed consent by the participant Willingness to permit study team to obtain and use archival tissue, if already existing Age: >= 18 years Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Life expectancy of > 3 months Patients with solid tumors failing standard therapies or patients refusing standard treatments Agreement by females and males of childbearing potential to use an adequate method of birth control (hormonal contraception is inadequate) or abstain from heterosexual activity for the course of the study through 30 days after the last dose of study medication Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only) Absolute neutrophil count (ANC) >= 1,500/mm^3 (performed within 14 days prior to day 1) Total serum bilirubin =< 1.5 x upper limit of normal (ULN) (performed within 14 days prior to day 1) Aspartate aminotransferase (AST) =< 1.5 x ULN or =< 3 x ULN with liver metastases (performed within 14 days prior to day 1) Alanine aminotransferase (ALT) =< 1.5 x ULN or =< 3 x ULN with liver metastases (performed within 14 days prior to day 1) Creatinine clearance of >= 60 mL/min per 24 hour urine or the Cockcroft-Gault (performed within 14 days prior to day 1) Women of childbearing potential (WOCBP): negative urine or serum pregnancy test If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required Exclusion Criteria: Concomitant medications/therapies Dietary/herbal supplements Other investigational products Warfarin Current or planned use of agents contraindicated for use with strong CYP3A4 inducers Strong inhibitors or inducers of CYP2C9 Strong inhibitors or inducers of CYP3A Issues with tolerating oral medication (e.g. inability to swallow pills, malabsorption issues, ongoing nausea or vomiting) Women who are or are planning to become pregnant or breastfeed Known allergy to any of the components within the study agents and/or their excipients No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years Intercurrent or historic medical condition that increases subject risk in the opinion of the Investigator. Eligibility may be revisited for intercurrent medical conditions once resolution/recovery is deemed adequate by the investigator (e.g. recovery from major surgery, completion of treatment for severe infection) Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (PCNA inhibitor AOH1996)<br>Patients receive PCNA inhibitor AOH1996 PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: PCNA Inhibitor AOH1996<br>* Given PO<br>* Other names: Proliferating Cell Nuclear Antigen Inhibitor AOH1996;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AEs) | Toxicity and adverse events will be recorded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. All toxicities/AEs will be recorded from the initiation of protocol therapy through the follow-up period. | Up to 30 days after last study drug is given | 
| Dose limiting toxicities | Toxicities will be graded according to NCI CTCAE version 4.0. | Up to 28 days (cycle 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | Will be assessed using Response Evaluation Criteria in Solid Tumors version 1. Response rate will be estimated in the overall population and 95% exact confidence intervals will be estimated. | Up to 2 years | 
| Progression-free survival | Time to disease progression/ relapse or death as a result of any cause. | Assessed up to 2 years | 
| Overall survival | Time to death as a result of any cause. | Assessed up to 2 years | 
| Time to treatment failure | Time to treatment termination for any reason (progression, toxicity, death, patient preference). | Assessed up to 2 years |