Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmocodynamics and Preliminary Antitumor Activity of AT-1965 in Patients With Advanced, Refractory or Recurrent Solid Tumors

1. The patient has an uncontrolled or life-threatening, symptomatic, current or recurrent disease (e.g., cardiovascular, renal, hepatic, endocrine) or other abnormality that could affect the action, absorption, or disposition of the study drug, may impact the ability of the patient to participate, may affect clinical or laboratory assessments, or otherwise has the potential to confound the study results.

2. Unstable or severe uncontrolled medical condition (e.g., unstable cardiac function, unstable pulmonary condition) or any important medical or psychiatric illness or abnormal laboratory finding that would, in the Investigator's judgment, increase the risk to the patient associated with his or her participation in the study.

3. Uncontrolled diabetes.

4. Patients with an active uncontrolled autoimmune disease. Excluded autoimmune conditions are listed in the Protocol Appendix 1.

1. Patients with history of transient autoimmune manifestations of an acute infectious disease that resolved upon treatment of the infectious agent are not excluded (e.g. acute Lyme arthritis).

2. Please contact the medical monitor regarding any uncertainty over autoimmune exclusions.

5. History of interstitial lung disease, idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on chest computed tomography scan in the last 6 months; NOTE: history of radiation pneumonitis in the radiation field (fibrosis) is permitted.

6. History of hemolysis or hemolytic anemia.

7. Evidence of ongoing subclinical hemolysis (high LDH and low serum haptoglobin with increased reticulocyte count).

8. History of adrenal gland disorders such as Cushing Syndrome, Congenital adrenal hyperplasia, Addison's Disease and hyperaldosteronism

9. Recipient of an allogeneic bone marrow transplantation or solid organ transplantation.

10. Endocrinopathy, unless on stable hormone replacement therapy.

11. History of known human immunodeficiency virus (HIV); unresolved viral hepatitis as documented by the detection of hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody at the time of the screening visit, and known quantitative HCV RNA results greater than the lower limits of detection of the assay.

12. Clinically significant cardiovascular disease including:

* Myocardial infarction or stroke within 6 months prior to the initiation of study treatment.

* LVEF \<50% on baseline assessment.

* If patient enrolled with cardiovascular disease, the LVEF must be confirmed at screening by and echocardiogram or MUGA.

* Unstable angina within 6 months prior to the initiation of study treatment.

* Congestive heart failure or cardiomyopathy with New York Heart Association Class 2, 3 or 4 by clinical assessment or by imaging studies within 6 months prior to the initiation of study treatment.

* Coronary or peripheral artery bypass graft surgery, transient ischemic attack, or pulmonary embolism (in past 3 months).

* History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes).

* Uncontrolled hypertension where the Systolic is ≥150 mmHg and the diastolic blood pressure ≥110 mm Hg despite ongoing antihypertensive therapy.

* QT interval corrected by the Fridericia correction formula (QTcF) ≥470 msec on the Screening ECG.

* The patient requires the use of concomitant medications that prolong QT/QTc interval (except the patients who have normal ECG but are taking medications that prolong QT/QTc interval) unless approved by medical monitor.

13. Recent anticancer treatment, including the following (patient may be started earlier within these timeframes if considered by the Investigator to be safe and within the best interest of the patient and with approval from the Sponsor):

* Systemic antineoplastic therapy within 21 days or 5 half-lives prior to initiation of study treatment. (6 weeks for nitrosoureas or mitomycin C and 8 weeks for platinum based drugs) and/or has not recovered from acute toxicity for the most recent antitumor treatment to CTCAE Grade 1 or baseline, except for alopecia, prior to the first dose of study drug, whichever is shorter. (6 weeks for nitrosoureas or mitomycin C and 8 weeks for platinum-based drugs) and/or has not recovered from acute toxicity for the most recent antitumor treatment to CTCAE Grade 1 or baseline, except for alopecia, prior to the first dose of study drug.

* Radiation therapy within 2 weeks prior to the initiation of study treatment

* Patient received chemoembolization or radioembolization within 4 weeks prior to the initiation of study treatment.

14. The patient has received any investigational agents that have not received regulatory approval within 30 days or 5 half-lives prior to the first dose of study drug, whichever is shorter. This includes the FDA approved for all Emergency Authorization Use (EAU) drugs or therapies.

15. Major surgery within 4 weeks of starting study treatment or not recovered from any effects of prior major surgery (uncomplicated central line placement or fine needle aspirate are not considered major surgery).

16. Primary tumor type:

* Central nervous system (CNS) malignant disease not previously treated, active leptomeningeal disease, uncontrolled symptomatic CNS involvement, or CNS malignant disease requiring steroid or other therapeutic intervention.

* Liquid/hematological tumors

* Lymphoma

* Uveal melanoma

17. Patients with a history of secondary malignancy(ies) that is currently clinically significant and has potential for metastases or currently requires active intervention (except for gonadotropin-releasing hormone (GnRH) or luteinizing hormone-releasing hormone (LH-RH) agonists in prostate cancer or hormonal therapy in breast cancer).

* Secondary malignancies exceptions include basal cell or squamous cell skin cancer

18. Requires systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to Day 1 of treatment. Inhaled, intranasal, intra-articular and topical (including ocular) steroids are allowed. Adrenal replacement (i.e., physiologic replacement) doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.

19. History of severe immune-related AE (irAE) that led to permanent discontinuation of prior immunotherapy.

20. History of Grade ≥ 3 irAE within the past 16 weeks or any Grade 4 life threatening irAE (regardless of duration) or neurologic or ocular AE of any grade while receiving prior immunotherapy; NOTE: Patients with endocrine AEs of any grade are permitted to enroll if they are stably maintained on appropriate replacement therapy but must have no history of adrenal crisis and be asymptomatic.

21. Has, within 28 days prior to screening, received a live, attenuated or mRNA based vaccine against infectious disease.

22. Nursing women not willing to stop breastfeeding while on study and for 3 months thereafter.

23. Uncontrolled active infection requiring intravenous (IV) antibiotic, antiviral, or antifungal medications within 14 days prior to first dose of study treatment. Patients on chronic suppressive antibiotics may be allowed after discussion with the Sponsor.

24. Patient is \<18 years of age at the time of informed consent.

25. Life expectancy of \<3 months.

26. Known current drug or alcohol abuse.

27. The patient is not an appropriate candidate for participation in this clinical study for any other reason as deemed by the investigator.

What this study is about