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.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and the dose limiting toxicities (DLT) of AOH1996.

II. To establish the recommended phase 2 dose of AOH1996.

III. To establish the recommended phase 2 dose of AOH1996 when given in conjunction with a TKI for NSCLC.

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.

Inclusion Criteria:

Informed Consent and Willingness to Participate

• 1. Documented informed consent by the participant
• 2. Willingness to permit study team to obtain and use archival tissue, if already existing

Age Criteria, Performance Status and Life Expectancy

• 3. Age: ≥ 18 years
• 4. ECOG performance status ≤ 2
• 5. Life expectancy of > 3 months

Nature of Illness and Treatment History __6. Patients with solid tumors failing standard therapies or patients refusing standard treatments (exception: Part B NSCLC combination (EGFR TKI + AOH1996) cohort: patients with stable disease or better on EGFR TKI for at least 2 months)

Contraception

__7. 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. See Appendix B for guidelines.

- Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only).

Laboratory Criteria (to be performed within 14 days prior to Day 1)

• 8. ANC ≥ 1,500/mm3
• 9. Platelets ≥ 100,000/mm3 :
• 10. Total serum bilirubin ≤ 1.5 x ULN
• 11. AST =< 1.5 x ULN or =< 3 x ULN with liver metastases
• 12. ALT =< 1.5 x ULN or =< 3 x ULN with liver metastases
• 13. Creatinine clearance of ≥ 60 mL/min per 24 hour urine or the Cockcroft-Gault
• 14. 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 __1. Dietary/herbal supplements

• 2. Other investigational products or chemotherapy. Exception: EGFR TKI in the NSCLC expansion cohort is allowed.
• 3. Warfarin
• 4. Current or planned use of agents contraindicated for use with strong CYP3A4 inducers
• 5. Strong inhibitors or inducers of CYP2C9
• 6. Strong inhibitors or inducers of CYP3A

Other Illnesses and Conditions

• 7. Issues with tolerating oral medication (e.g., inability to swallow pills, malabsorption issues, ongoing nausea or vomiting).
• 8. Women who are or are planning to become pregnant or breastfeed
• 9. Known allergy to any of the components within the study agents and/or their excipients.
• 10. 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.
• 11. 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).

Noncompliance

__12. 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).

**Eligibility should be confirmed per institutional policies.