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. Prior treatment history as follows: a) Patients should have received any other approved standard therapy that isavailable to the patient, unless this therapy is contraindicated, intolerable to thepatient, or is declined by the patient. In the case of a patient declining suchtherapy, documentation that the patient has been informed and declined should bedocumented in the medical record.

14. Baseline measurable disease based on RECIST v1.1 for Module A escalation, Module Bescalation; and, both Module A and Module B expansion cohorts. Patients are requiredto have one or more measurable lesions that meet RECIST v1.1 and meet the followingconditions:

15. 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;

16. 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.

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

18. Estimated life expectancy of 12 weeks or greater.

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

20. 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.

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

22. 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;

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

24. Creatinine clearance (CrCl) ≥ 45 mL/min as measured or estimated usingCockcroft-Gault formula;

25. Hemoglobin ≥ 8 g/dL without blood transfusions for at least two weeks prior todosing on C1D1;

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

27. Platelet count ≥ 75,000 cells/mm3.

28. Patients in the Module A and Module B dose escalation cohorts must have archivaltissue for biomarker analysis. A fresh biopsy is required if archival tissue isunavailable.

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. Patients with prior history of ventricular dysfunction oranthracycline therapy are required to have an echocardiogram for assessment ofbaseline cardiac function;

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

20. Has a history of, or a positive test for, HIV1/2 primary immunodeficiency diseasesuch as Human Immunodeficiency Virus (HIV).

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

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

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

24. Prior organ allograft or allogeneic hematopoietic transplantation.

25. 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.

26. Active central nervous system metastases and/or carcinomatous meningitis. Patientswith brain metastases identified at Screening may be rescreened after they have beenappropriately treated. Patients with treated brain metastases should beneurologically stable for 28 days post completion of treatment and prior toenrollment, and on a stable regimen of steroid dosing (prednisone <10 mg or theequivalent) for 14 days prior to dosing on C1D1.

27. Treatment with non-oncology vaccines for the control of infectious diseases (i.e.HPV vaccine) within 28 days of C1D1. The inactivated seasonal influenza vaccine canbe given to patients before initiation of treatment, and while on study therapywithout restriction. Influenza vaccines containing live virus, or other clinicallyindicated vaccinations for infectious diseases (i.e. pneumovax, varicella) may bepermitted, but must be discussed in advance with the Sponsor Medical Monitor and mayrequire a study drug washout period before and/or after administration of thevaccine. Covid-19 vaccines may be administered according to institutional policy.

28. Active SARS-CoV-2 infection including history of positive SARS-CoV-2 testing withoutsubsequent documentation of negative test results, patients with results that arepending but not yet known, or patients with suspected active infection based onclinical features. SARS-CoV-2 vaccination is permitted on treatment.

29. 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 28 days of dosing on C1D1.

30. Female of child-bearing potential (FOCBP) who is pregnant or breast-feeding, plansto become 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. a) A female of childbearing potential is defined as: i) Not surgically sterile, i.e.bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy, or; ii)Not post-menopausal, defined as amenorrhea for ≥ two years without an alternativemedical cause. Note: Females with amenorrhea for < two years and who are not surgically sterilei.e. tubal ligation, bilateral oophorectomy, or complete hysterectomy will only beconsidered not to be of reproductive potential if they have a documented folliclestimulating hormone (FSH) value in the postmenopausal range.

31. 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 FOCBP, 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.

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

33. Patient has history of drug-related anaphylactic reactions to any components ofCLN-619 (Module A and Module B patients) or pembrolizumab (Module B patients only).History of Grade 4 anaphylactic reaction to any monoclonal antibody therapy.

34. Known active alcohol or drug abuse.

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

36. Patients who are incapacitated or involuntarily incarcerated.

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

38. Treatment with any of the following:

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

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

41. Radiotherapy < 28 days and palliative radiation ≤ 14 days prior to the firstdose of study drug on C1D1. If irradiated, lesions must have demonstratedclear-cut progression prior to being eligible for evaluation as target lesions.

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

43. Refractory disease will be defined as progressive disease at 16 weeks afterreceiving at least three doses of PD-1 therapy (Expansion B2 and Expansion B3 only).