A Phase 1a/b Study of IK-175 as a Single Agent and in Combination With Nivolumab in Patients With Locally Advanced or Metastatic Solid Tumors and Urothelial Carcinoma

Inclusion Criteria:

1. Adult patients ≥18 years of age.
2. Patients with confirmed solid tumors (including urothelial carcinoma) who have locallyrecurrent or metastatic disease that has progressed on or following all standard ofcare therapies or who is not a candidate for standard treatment.
3. For patients with urothelial carcinoma to be enrolled in the Combination Treatmentarm, patients must have confirmation of urothelial carcinoma and have unresectablelocally recurrent or metastatic disease that has progressed on or following allstandard of care therapies, or who is not a candidate for standard treatment.Checkpoint inhibitor therapy with anti-PD-1 or anti-PD-L1 does not necessarily need todirectly precede the study, but patients must have progressed on or within 3 months ofreceiving the last infusion/dose anti-PD-(L)1 therapy for inclusion in the CombinationTreatment arm only.
4. Have measurable disease.
5. Accessible tumor that can be safely accessed for multiple core biopsies and patient iswilling to provide tissue from newly obtain biopsies before and during treatment.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
7. Adequate organ function.
8. Highly effective birth control.
9. Time since the last dose of prior therapy to treat underlying malignancy (includingother investigational therapy): 9a. Systemic cytotoxic chemotherapy: ≥ the duration ofthe most recent cycle of the previous regimen (with a minimum of 2 weeks for all,except 6 weeks for systemic nitrosourea or systemic mitomycin-C). 9b. Biologic therapy (eg, antibodies): ≥ 3 weeks or their dosing interval if shorter than 3 weeks (e.g. q2wtherapy would require a 2-week washout). 9c. Small molecule therapies: ≥ 5 ×half-life. 9d. Investigational Agent: ≥4 weeks or ≥5 × half-life, whichever is shorter

Exclusion Criteria:

1. Untreated symptomatic central nervous system (CNS) tumors or brain metastasis.Patients are eligible if CNS metastases are asymptomatic and do not require immediatetreatment or have been treated and patients have neurologically returned to baseline (residual signs or symptoms related to the CNS treatment are permitted). In addition,patients must have been either off corticosteroids, or on a stable or decreasing doseof ≤10 mg daily prednisone (or equivalent) for at least 2 weeks prior to entering theTreatment period (Day 1).
2. Patients who have not recovered to ≤ Grade 1 or baseline from all adverse events (AEs)due to previous therapies
3. Has an active autoimmune disease that has required systemic treatment in past 2 yearswith the use of disease-modifying agents, corticosteroids, or immunosuppressive drugs;nonsteroidal anti-inflammatory drugs (NSAIDs) are permitted. Patients with type 1diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, orconditions not expected to recur in the absence of an external trigger are permittedto enroll.
4. Any condition requiring continuous systemic treatment with either corticosteroids (>10mg daily prednisone equivalents) or other immunosuppressive medications within 2weeks prior to first dose of study treatment (Inhaled or topical steroids andphysiological replacement doses of up to 10 mg daily prednisone equivalent arepermitted in the absence of active clinically significant [ie, severe] autoimmunedisease.).
5. Any other concurrent antineoplastic treatment or investigational agent except forallowed local radiation of lesions for palliation and hormone ablation.
6. Uncontrolled or life-threatening symptomatic concomitant disease (including knownsymptomatic human immunodeficiency virus (HIV) positive with an AIDS definingopportunistic infection within the last year, or a current CD4 count <350 cells/uL,symptomatic active hepatitis B or C checked at screening, or active tuberculosis).Patients with HIV are eligible if: 6a. they have received antiretroviral therapy (ART)for at least 4 weeks prior to entering the Treatment period as clinical indicatedwhile enrolled on study; 6b. they continue on ART as clinically indicated whileenrolled on study; 6c. CD4 counts and viral load are monitored per standard of care bya local health care provider.
7. Patients that have undergone a major surgery within 3 weeks of starting trialtreatment or has inadequate healing or recovery from complications of surgery prior tostarting trial treatment.
8. Prior radiotherapy within 2 weeks of start of study treatment. Subjects must haverecovered from all radiation-related toxicities, not require corticosteroids, and nothave had severe radiation pneumonitis. A 1-week washout is permitted for palliativeradiation [≤ 2 weeks of radiotherapy] to non-CNS disease.
9. Prior AHR inhibitor treatment without Sponsor permission.
10. Potentially life-threatening second malignancy requiring systemic treatment within thelast 3 years or which would impede evaluation of treatment response. Hormone ablationtherapy is allowed within the last 3 years. Patients with history of prior early stagebasal/squamous cell skin cancer or non-invasive or in situ cancers that have undergonedefinitive treatment at any time are eligible.
11. Recent or current significant cardiovascular disease (e.g. stroke, heart attack, heartfailure, or arrhythmia).
12. Medical issue that limits oral ingestion or impairment of gastrointestinal functionthat is expected to significantly reduce the absorption of IK-175.
13. Clinically significant (ie, active) cardiovascular disease: cerebral vascularaccident/stroke (<6 months prior to enrollment), myocardial infarction (<6 monthsprior to enrollment), unstable angina, congestive heart failure (≥ New York HeartAssociation Classification Class II), or the presence of any condition that canincrease proarrhythmic risk (eg, hypokalemia, bradycardia, heart block) including anynew, unstable, or serious cardiac arrhythmia requiring medication, or other baselinearrhythmia that might interfere with interpretation of ECGs on study (eg, bundlebranch block). Patients with QTcF >450 msec for males and >470 msec for females onscreening ECG are excluded. Any patients with a bundle branch block will be excludedwith QTcF >450 msec. Males who are on stable doses of concomitant medication withknown prolongation of QTcF (eg, Selective Serotonin Reuptake InhibitorAntidepressants) will only be excluded for QTcF >470 msec.
14. History of life-threatening toxicity related to prior immune therapy (eg. anti-CTLA-4or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targetingT-cell co-stimulation or immune checkpoint pathways) except those that are unlikely tore-occur with standard countermeasures (eg. hormone replacement after adrenal crisis).
15. Has an active infection requiring systemic therapy.
16. Treatment with any live/attenuated vaccine within 30 days of first study treatment.
17. A woman of child-bearing potential (WOCBP) who has a positive pregnancy test or isbreastfeeding prior to treatment.