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

Inclusion Criteria:

1. The patient has a histologically or cytologically confirmed unresectable ormetastatic solid tumor that is refractory to standard therapy or for which in theopinion of the investigator no standard therapy is suitable.

2. Patient should have at least 1 measurable lesion per RECIST version 1.1 as assessedby the investigator. For Part A only, patients with radiographically evaluable butnon-measurable disease are allowed after discussion with the sponsor.

3. Recovered from AEs (except irAEs) of prior chemotherapy (per NCI CTCAE version 5.0)to Grade ≤ 1 or return to baseline status (except for alopecia) as perInvestigator's discretion.

4. The patient has an ECOG performance status of 0 to 2.

5. The patient has adequate bone marrow, renal, and hepatic function, defined asfollows:

6. Hemoglobin ≥9.5 g/dL (without transfusion in the prior 3 weeks).

7. Platelets ≥100 × 109 cells/L (may be achieved with transfusion as per PIdiscretion)

8. ANC ≥1.5 ×109 cells/L (without the use of hematopoietic growth factors within 4weeks prior to dosing).

9. Creatinine Clearance ≥60 mL/min (by using Cockcroft-gault equation)

10. Total bilirubin ≤1.5 × ULN, unless the patient has a prior history of Gilbert'ssyndrome, in which case ≤3.0 × ULN is acceptable.

11. AST and ALT ≤2.5 × ULN; or ≤5 × ULN if due to liver involvement by tumor

12. Female patients of child-bearing potential must have a negative serum pregnancy testwithin 72 hours prior to the first dose of study drug and before each start of a newtreatment cycle. NOTE: Women are considered of childbearing potential unless theyare surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, orbilateral oophorectomy) or are postmenopausal (at least 12 consecutive months withno menses without an alternative medical cause) and have an elevatedfollicle-stimulating hormone (FSH) at screening.

13. Female patients of childbearing potential must agree to use a highly effectivemethod of contraception during the study and for a minimum of 3 months followingadministration of study drug, which includes a barrier method plus 1 or more of thefollowing:

14. Hormonal contraceptives (e.g., birth control pills, skin patches, vaginalrings, or the Depo-Provera® shot)

15. Intrauterine device (IUD)

16. Male or female condoms with spermicide

17. Diaphragm with spermicide

18. Permanent tubal occlusive birth control system

19. Male patients with female partners of childbearing potential must be vasectomized orbe willing to use an acceptable method of birth control or to practice abstinenceduring the study and for 3 months after the last dose of IMP.

20. Must be 30 days since participation in any other interventional clinical trial.

21. Must be 28 days since mRNA Covid 19 vaccine injection.

22. Willing to avoid sun exposure, wear protective clothing, and/or apply broad spectrum (ultraviolet A [UVA] and ultraviolet B [UVB] protection) sunscreen if sun exposureis unavoidable.

23. The patient is capable of understanding the written informed consent, providessigned and witnessed written informed consent and authorization permitting use ofcollected tissue and personal health information, and agrees to comply with protocolrequirements.

For Part B Dose Expansion in TNBC only:

1. Histologically or cytologically confirmed metastatic triple-negative breast cancer (mTNBC) who had received at least two prior treatments (a taxane and sacituzumabgovitecan-hziy) for metastatic disease, for advanced disease.

2. In addition, patients with TNBC with either Low HER2 (IHC 1+ or IHC 2+/in situhybridization-negative), PD-L1 (CPS>10) or BRCA mutation need to have prior FDAapproved available therapies before participation in this expansion arm.

Exclusion Criteria:

1. The patient has an uncontrolled or life-threatening, symptomatic, current orrecurrent disease (e.g., cardiovascular, renal, hepatic, endocrine) or otherabnormality that could affect the action, absorption, or disposition of the studydrug, may impact the ability of the patient to participate, may affect clinical orlaboratory assessments, or otherwise has the potential to confound the studyresults.

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

3. Uncontrolled diabetes.

4. Patients with a history of autoimmune disease. Excluded autoimmune conditions arelisted in Appendix 1.

5. Patients with history of transient autoimmune manifestations of an acuteinfectious disease that resolved upon treatment of the infectious agent are notexcluded (e.g. acute Lyme arthritis).

6. Please contact the medical monitor regarding any uncertainty over autoimmuneexclusions.

7. 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 chestcomputed tomography scan in the last 6 months; NOTE: history of radiationpneumonitis in the radiation field (fibrosis) is permitted.

8. History of hemolysis or hemolytic anemia.

9. Evidence of ongoing subclinical hemolysis (high LDH and low serum haptoglobin withincreased reticulocyte count).

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

11. Recipient of an allogeneic bone marrow transplantation or solid organtransplantation.

12. Endocrinopathy, unless on stable hormone replacement therapy.

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

14. Clinically significant cardiovascular disease including:

• Myocardial infarction or stroke within 6 months prior to the initiation ofstudy treatment.

• LVEF <50% on baseline assessment.

• If patient enrolled with cardiovascular disease, the LVEF must be confirmed atscreening 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 AssociationClass 2, 3 or 4 by clinical assessment or by imaging studies within 6 monthsprior 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., ventriculartachycardia, ventricular fibrillation, torsades de pointes).

• Uncontrolled hypertension where the Systolic is ≥150 mmHg and the diastolicblood pressure ≥110 mm Hg despite ongoing antihypertensive therapy.

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

• The patient has cardiac dysrhythmias.

• The patient requires the use of concomitant medications that prolong QT/QTcinterval (except the patients who have normal ECG but are taking medicationsthat prolong QT/QTc interval).

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

• Systemic antineoplastic therapy within 21 days or 5 half-lives prior toinitiation of study treatment. (6 weeks for nitrosoureas or mitomycin C and 8weeks for platinum based drugs) and/or has not recovered from acute toxicityfor the most recent antitumor treatment to CTCAE Grade 1 or baseline, exceptfor 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 tothe initiation of study treatment.

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

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

16. Primary tumor type:

• Central nervous system (CNS) malignant disease not previously treated, activeleptomeningeal disease, uncontrolled symptomatic CNS involvement, or CNSmalignant 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 clinicallysignificant and has potential for metastases or currently requires activeintervention (except for gonadotropin-releasing hormone (GnRH) or luteinizinghormone-releasing hormone (LH-RH) agonists in prostate cancer or hormonal therapy inbreast cancer).

• Secondary malignancies exceptions include basal cell or squamous cell skincancer

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

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

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

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

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

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

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 studyfor any other reason as deemed by the investigator.