A Study of CLN-619 Alone and in Combination With Pembrolizumab in Advanced Solid Tumors

Inclusion Criteria:

1. Males or females aged ≥ 18 years.

2. Willing and able to give written informed consent and adhere to protocolrequirements; written informed consent and any locally required authorization mustbe obtained from the patient prior to performing any protocol-related procedures,including screening evaluations.

3. Module A Monotherapy Dose Escalation Cohort and Module B Combination Therapy DoseEscalation Cohorts: Histologically or cytologically-confirmed metastatic or locallyadvanced, unresectable solid tumors. For Module B, tumor type is listed as anapproved indication per the current prescribing information for pembrolizumab.

4. Module A Cohort Expansions:

5. Expansion A1: Histologically or cytologically-confirmed metastatic or locallyadvanced, unresectable NSCLC;

6. Expansion A2: Histologically or cytologically-confirmed metastatic or locallyadvanced, unresectable cervical cancer.

7. Expansion A3 and A4: Histologically or cytologically-confirmed metastatic orlocally advanced, unresectable endometrial cancer.

8. Eligibility for disease-specific expansion cohorts may be further refined byhistologic subtype, molecular features, or exposure to prior therapy based onclinical, pharmacodynamic, or biomarker data emerging from the study.

9. Module B Cohort Expansions:

10. Expansion B1: Histologically or cytologically-confirmed metastatic orlocally-advanced, unresectable NSCLC.

11. Expansion B2: Histologically or cytologically-confirmed metastatic orlocally-advanced, unresectable endometrial.

12. Eligibility for disease-specific expansion cohorts may be further refined byhistologic subtype, molecular features, or exposure to prior therapy based onclinical, pharmacodynamic, or biomarker data emerging from the study.

13. Module C CLN-619 + Chemotherapy Combination Therapy, Escalation and Expansion Cohort

14. C1: Histologically or cytologically confirmed metastatic or locally advanced,unresectable EGFRm NSCLC.

15. C2: Histologically or cytologically confirmed metastatic or locally advanced,unresectable endometrial cancer.

16. C3: Histologically or cytologically confirmed metastatic or locally advanced,unresectable, platinum-resistant epithelial ovarian cancer (including fallopiantube and primary peritoneal cancer).

17. Eligibility for disease-specific expansion cohorts may be further refined byhistologic subtype, molecular features, or exposure to prior therapy based onclinical, pharmacodynamic, or biomarker data emerging from the study.

18. Module D Loading Dose Cohort: a) Tumor types are restricted to epithelial ovarian (including fallopian tube andprimary peritoneal), breast, and gastrointestinal (esophageal, gastric, colorectal).

19. Module E CLN-619 + Dato-DXd Combination Therapy, Safety Run-in and ExpansionCohorts:

20. Histologically or cytologically confirmed recurrent metastatic or locallyadvanced, unresectable EGFRm NSCLC.

21. Local testing for determination of the mutation status is required.

22. Prior treatment history as follows:

23. Patients should have received any other approved standard therapy that isavailable to the patient, unless this therapy is contraindicated, intolerableto the patient, or is declined by the patient. In the case of a patientdeclining such therapy, documentation that the patient has been informed anddeclined should be documented in the medical record.

24. Patients eligible for Module E must meet the following criteria: Have receivedup to 4 prior lines of therapy, including i. Platinum-based chemotherapy ii. Atleast 1 EGFRm-directed targeted therapy iii. If EGFR T790M, must have receivedprior osimertinib iv. Prior treatment with topoisomerase I-targetedchemotherapeutic agent or TROP2-directed therapy not allowed

25. At baseline, patients are required to have one or more measurable lesions that meetRECIST v1.1 and meet the following conditions:

26. A non-lymph node lesion that has a longest unidimensional measurement of ≥ 10mm or a lymph node lesion that has a shortest unidimensional measurement of ≥ 15 mm;

27. Lesions that have received previous local treatment, such as radiotherapy orablation, can also be used as measurable target lesions if progression has beenconfirmed according to RECIST v1.1 prior to enrollment, and the longestunidimensional measurement is ≥ 10 mm.

28. Performance status of 0 or 1 based on the Eastern Cooperative Oncology Group (ECOG)performance scale.

29. Estimated life expectancy of 12 weeks or greater.

30. Prior palliative radiotherapy must have been completed 14 days prior to dosing onC1D1.

31. Toxicities related to prior study therapy should have resolved to Grade 1 or lessaccording to criteria of NCI CTCAE v5.0, except for alopecia. Peripheral neuropathyshould be clinically stable or improving and be Grade 2 or less in severity.Patients with chronic but stable Grade 2 toxicities may be allowed to enroll afteragreement between the Investigator and Sponsor.

32. Have adequate liver and kidney function and hematological parameters within a normalrange as defined by:

33. Total bilirubin ≤ 1.5x ULN. This does not apply for patients with confirmedGilbert's Syndrome, for whom total bilirubin must be less than 3.0 mg/dL with aconjugated bilirubin less than 0.5 mg/dL;

34. AST and ALT ≤ 2.5x ULN or ≤ 5x ULN for patients with liver metastases;

35. Creatinine clearance (CrCl) ≥ 45 mL/min as measured or estimated usingCockcroft-Gault formula or serum creatinine < 1.5 x ULN;

36. Hemoglobin ≥ 9 g/dL without blood transfusions for at least two weeks prior todosing on C1D1;

37. Absolute neutrophil count ≥ 1500 cells/mm3 without growth factor support, threedays for filgrastim, 14 days for pegfilgrastim;

38. Platelet count ≥ 100,000 cells/mm3.

39. Patients in the Module A, B, and C dose-escalation cohorts and Module D must havearchival tissue available for biomarker analysis. A fresh biopsy is required ifarchival tissue (e.g., all tumor blocks are exhausted) is unavailable.

40. Patients participating in the Module A or Module D dose-level cohortextension(s) must agree to provide a fresh biopsy and an on-treatment biopsy atCycle 2, Day 8.

41. Patients in the expansion cohorts for Modules A, B, and C must agree to providea fresh pretreatment biopsy and an on-treatment biopsy at Cycle 2, Day 8.

42. Patients participating in Module E safety run-in and expansion cohorts mustprovide archival tissue. Pre-treatment fresh biopsies are preferred but notrequired. On-treatment biopsies are not required.

Exclusion Criteria:

1. Currently participating/previously participated in an interventional study andreceived an investigational drug within 28 days (or five half-lives, whichever islonger) of dosing on C1D1.

2. Patients with concomitant second malignancies (except adequately treatednon-melanomatous skin cancers, ductal carcinoma in situ, superficial bladder cancer,prostate cancer or in situ cervical cancer) are excluded unless in completeremission three years prior to study entry, and no additional therapy is required oranticipated to be required during study participation.

3. Patients with any active autoimmune disease or a history of known or suspectedautoimmune disease, or history of a syndrome that requires systemic corticosteroidsor immunosuppressive medications, except for patients with vitiligo, resolvedchildhood asthma/atopy or autoimmune thyroid disorders on stable thyroid hormonesupplementation.

4. A serious uncontrolled medical disorder that would impair the ability of the patientto receive protocol therapy or whose control may be jeopardized by the complicationsof this therapy. These criteria include, but are not limited to the following:

5. Uncontrolled airway hyper-reactivity;

6. Type 1 diabetes mellitus. Type 2 diabetes mellitus patients are allowed if theyare under stable glycemic control as per Investigator assessment;

7. Uncontrolled, clinically significant pulmonary disease;

8. Requirement for supplemental oxygen to maintain a pulse ox > 93%;

9. Symptomatic congestive heart failure as per Investigator assessment ordocumented cardiac ejection fraction less than 45%;

10. Ejection fraction < 45% in patients with prior history of treatment withanthracycline chemotherapy or with a prior history of cardiac ventriculardysfunction;

11. History of unstable angina or myocardial infarction within six months of dosingon C1D1;

12. Unstable cardiac arrhythmia;

13. History of ventricular arrhythmia;

14. Uncontrolled hypertension: patients with sustained systolic blood pressurereadings greater than 150 or diastolic blood pressure greater than 100 shouldhave documentation by treating physician that the finding is not consistentwith uncontrolled hypertension;

15. History of stroke or cerebral hemorrhage within one year of dosing on C1D1;

16. Poorly controlled seizure disorder;

17. Active diverticulitis within one year prior to dosing on C1D1;

18. Recent major surgery within three months of dosing on C1D1 or major surgerywith unresolved complications that could interfere with study treatment.

19. Clinically significant corneal disease (Module E).

20. Treatment with systemic antiviral, antibacterial or antifungal agents for acuteinfection within ≤ 7 days of dosing on C1D1.

21. Has known human immunodeficiency virus (HIV) infection that is not well controlled.

22. Diagnosed with hepatitis B (with positive testing for either hepatitis B surfaceantigen [HBsAg] or hepatitis B core Ab) or hepatitis C virus (HCV) infection (withpositive testing for HCV antibody and/or HCV ribonucleic acid [RNA] in serum) underany of the following conditions:

23. Active disease for hepatitis B or hepatitis C and received antiretroviraltherapy within 4 weeks.

24. Blood hepatitis B DNA or HCV RNA are detectable.

25. Prior organ allograft or allogeneic hematopoietic transplantation.

26. History of the following events in conjunction with prior treatment with checkpointinhibitor immunotherapy: Grade 3 or greater neurotoxicity, ocular toxicity,pneumonitis, myocarditis, or colitis; liver dysfunction meeting the laboratorycriteria for Hy's Law.

27. Symptomatic uncontrolled brain metastases, known or suspected leptomeningealmetastases and/or carcinomatous meningitis.

28. Receipt of live vaccine < 28 days prior to study start. Treatment with non-oncologyrecombinant or inactivated vaccines for the control of infectious diseases may beadministered according to institutional policy.

29. Active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection basedon positive SARS-CoV-2 testing or patients with suspected active infection based onclinical features, including patients with history of SARS-CoV-2-related pneumonitiswith 28 days prior to enrollment or patients who have clinically significantpulmonary symptoms related to prior pneumonitis.

30. Has received immunosuppressive medications including but not limited to cellcept,methotrexate, infliximab, anakinra, tocilizumab, cyclosporine or corticosteroids (≥10 mg/day of prednisone or equivalent), within 14 days of dosing on C1D1.

31. Woman of child-bearing potential (WOCBP) who is pregnant or breast-feeding, plans tobecome pregnant within 120 days of last study drug administration, or declines touse an acceptable method to prevent pregnancy during study treatment and for 120days after the last dose of study drug administration.

32. Male patient who plans to father a child or donate sperm within 120 days or 5half-lives of CLN-619, whichever comes later, of last study drug administration, orwho has a partner who is a WOCBP, and declines to use acceptable method to preventpregnancy during study treatment and for 120 days or 5 half-lives of CLN-619,whichever comes later, after the last dose of study drug administration.

33. QT interval corrected for heart rate using Fridericia's formula (QTcF) of ≥ 500milliseconds.

34. Patient has history of drug-related anaphylactic reactions to any components ofCLN-619 or combination agent, including hypersensitivity of drugs with similarstructure or class. History of Grade 4 anaphylactic reaction to any monoclonalantibody therapy.

35. Known active alcohol or drug abuse.

36. Inability to comply with the protocol and/or not willing or not available forfollow-up assessments.

37. Patients who are incapacitated or involuntarily incarcerated.

38. Patients who are unsuitable for participation based on the judgement of theInvestigator.

39. Treatment with any of the following:

40. Systemic anticancer treatment within 14 days prior to the first dose of studydrug on C1D1.

41. Immunotherapy ≤ 28 days prior to the first dose of study drug on C1D1.

42. Systemic radiotherapy ≤28 days and local and palliative radiation ≤ 14 daysprior to the first dose of study drug on C1D1. I

43. Major surgery (excluding placement of vascular access) ≤ 28 days of the firstdose of study drug on C1D1.