Cullinan: This phase I study is evaluating the effectiveness of a new targeted therapy (CLN-619) alone, and in combination with immunotherapy (pembrolizumab), in people with advanced solid cancersA Phase 1 Dose-Escalation Study to Investigate the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamic Activity of CLN-619 (Anti-MICA/MICB Antibody) Alone and in Combination With Pembrolizumab in Patients With Advanced Solid Tumors

Exclusion

1. Currently participating/previously participated in an interventional study and received an investigational drug within 28 days (or five half-lives, whichever is longer) of dosing on C1D1.
2. Patients with concomitant second malignancies (except adequately treated non-melanomatous skin cancers, ductal carcinoma in situ, superficial bladder cancer, prostate cancer or in situ cervical cancer) are excluded unless in complete remission three years prior to study entry, and no additional therapy is required or anticipated to be required during study participation.
3. Patients with any active autoimmune disease or a history of known or suspected autoimmune disease, or history of a syndrome that requires systemic corticosteroids or immunosuppressive medications, except for patients with vitiligo, resolved childhood asthma/atopy or autoimmune thyroid disorders on stable thyroid hormone supplementation.

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

   1. Uncontrolled airway hyper-reactivity;
   2. Type 1 diabetes mellitus. Type 2 diabetes mellitus patients are allowed if they are under stable glycemic control as per Investigator assessment;
   3. Uncontrolled, clinically significant pulmonary disease;
   4. Requirement for supplemental oxygen to maintain a pulse ox > 93%;
   5. Symptomatic congestive heart failure as per Investigator assessment or documented cardiac ejection fraction less than 45%;
   6. Ejection fraction < 45% in patients with prior history of treatment with anthracycline chemotherapy or with a prior history of cardiac ventricular dysfunction. Patients with prior history of ventricular dysfunction or anthracycline therapy are required to have an echocardiogram for assessment of baseline cardiac function;
   7. History of unstable angina or myocardial infarction within six months of dosing on C1D1;
   8. Unstable cardiac arrhythmia;
   9. History of ventricular arrhythmia;
   10. Uncontrolled hypertension: patients with sustained systolic blood pressure readings greater than 150 or diastolic blood pressure greater than 100 should have documentation by treating physician that the finding is not consistent with uncontrolled hypertension;
   11. History of stroke or cerebral hemorrhage within one year of dosing on C1D1;
   12. Poorly controlled seizure disorder;
   13. Active diverticulitis within one year prior to dosing on C1D1;
   14. Recent major surgery within three months of dosing on C1D1 or major surgery with unresolved complications that could interfere with study treatment.
5. Treatment with systemic antiviral, antibacterial or antifungal agents for acute infection within ≤ 7 days of dosing on C1D1.
6. Has a history of, or a positive test for, HIV1/2 primary immunodeficiency disease such as Human Immunodeficiency Virus (HIV).
7. History of hepatitis B (with positive testing for either hepatitis B surface antigen [HBsAg] or hepatitis B core Ag) or hepatitis C (HCV) infection (with positive testing for HCV antibody and/or HCV ribonucleic acid [RNA] in serum). Acute hepatitis A (with positive testing for hepatitis A IgM).
8. Prior organ allograft or allogeneic hematopoietic transplantation.
9. History of the following events in conjunction with prior treatment with checkpoint inhibitor immunotherapy: Grade 3 or greater neurotoxicity, ocular toxicity, pneumonitis, myocarditis, or colitis; liver dysfunction meeting the laboratory criteria for Hy's Law.
10. Active central nervous system metastases and/or carcinomatous meningitis. Patients with brain metastases identified at Screening may be rescreened after they have been appropriately treated. Patients with treated brain metastases should be neurologically stable for 28 days post completion of treatment and prior to enrollment, and on a stable regimen of steroid dosing (prednisone <10 mg or the equivalent) for 14 days prior to dosing on C1D1.
11. 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 can be given to patients before initiation of treatment, and while on study therapy without restriction. Influenza vaccines containing live virus, or other clinically indicated vaccinations for infectious diseases (i.e. pneumovax, varicella) may be permitted, but must be discussed in advance with the Sponsor Medical Monitor and may require a study drug washout period before and/or after administration of the vaccine. Covid-19 vaccines may be administered according to institutional policy.

12. Active SARS-CoV-2 infection including history of positive SARS-CoV-2 testing without subsequent documentation of negative test results, patients with results that are pending but not yet known, or patients with suspected active infection based on clinical features.

    SARS-CoV-2 vaccination is permitted on treatment.

13. 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.

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

    a) A woman 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 alternative medical cause.

    Note: Women with amenorrhea for < two years and who are not surgically sterile i.e. tubal ligation, bilateral oophorectomy, or complete hysterectomy will only be considered not to be of reproductive potential if they have a documented follicle stimulating hormone (FSH) value in the postmenopausal range.

15. Male patient who plans to father a child or donate sperm within 120 days or 5 half-lives of CLN-619, whichever comes later, of last study drug administration, or who has a partner who is a WOCBP, and declines to use acceptable method to prevent pregnancy 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.
16. QT interval corrected for heart rate using Fridericia's formula (QTcF) of ≥ 500 milliseconds.
17. Patient has history of drug-related anaphylactic reactions to any components of CLN-619 (Module A and Module B patients) or pembrolizumab (Module B patients only). History of Grade 4 anaphylactic reaction to any monoclonal antibody therapy.
18. Known active alcohol or drug abuse.
19. Inability to comply with the protocol and/or not willing or not available for follow-up assessments.
20. Patients who are incapacitated or involuntarily incarcerated.
21. Patients who are unsuitable for participation based on the judgement of the Investigator.

22. Treatment with any of the following:

    1. Systemic anticancer treatment (excluding EGFR-TKIs as described above) within 14 days prior to the first dose of study drug on C1D1.
    2. Immunotherapy ≤ 28 days prior to the first dose of study drug on C1D1.
    3. Radiotherapy < 28 days and palliative radiation ≤ 14 days prior to the first dose of study drug on C1D1. If irradiated, lesions must have demonstrated clear-cut progression prior to being eligible for evaluation as target lesions.
    4. Major surgery (excluding placement of vascular access) ≤ 28 days of the first dose of study drug on C1D1.
23. Refractory disease will be defined as progressive disease at 16 weeks after receiving at least three doses of PD-1 therapy (Expansion B2 and Expansion B3 only).