Urothelial Cancer Clinical Trials

• Able to understand and willing to sign an informed consent.

• Age ≥ 18 years.

• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2.

• An archival, paraffin-embedded, formalin-fixed, tumor sample (see Laboratory Manual for details) that in Part A is no more than 30 months old at the time of screening or in Part B is no more than 30 months old at time of pre-screening. If an archival tumor sample is not available or is older than 30 months, then the patient must consent to provide a fresh biopsy during screening.

• Part A: Histologically or cytologically diagnosed, locally advanced (unresectable) or metastatic solid malignancies that have progressed after all available standard therapy for the specific tumor type, or for which no standard therapy exists. Patients for whom standard therapies are intolerable or considered inappropriate by the Investigator are eligible.

• Part B: Patients with histologically or cytologically confirmed, locally advanced (unresectable) or metastatic urothelial carcinoma exhibiting high levels of PPARG protein expression will be prospectively enrolled in this study. Eligibility will require a Tumor Positivity Score (TPS) of ≥ 60%, as determined by an investigational immunohistochemistry (IHC) assay for PPARG.

• • Treated with ≤ 4 prior therapies for advanced or metastatic disease Patients in Part B must have progressed after all available standard therapy, been unable to tolerate standard therapy, or be considered inappropriate for standard therapy by the Investigator.

• Part A: Patients with or without measurable disease (as defined by RECIST version 1.1) will be eligible for enrollment.

∙ Part B: Patients must have measurable disease per RECIST version 1.1 with ≥ 1 site of measurable disease that has not been previously irradiated or has progressed after radiation therapy.

∙ 7\. Screening laboratory values meet the criteria outlined in Table 8.

∙ 1\. Able to understand and willing to sign an informed consent 2. Aged 18 years or older on the day written informed consent is given 3. ECOG performance status 0 or 1 4. Histologically or cytologically confirmed, locally advanced (unresectable) or metastatic urothelial carcinoma by pathology report.

∙ 5\. Participants must have received and progressed after all available standard therapies known to confer clinical benefit, been unable to tolerate standard therapy, or be considered inappropriate for standard therapy by the Investigator.

∙ 6\. Must have progressed on treatment with an anti-PD-1/L1 mAb administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of the following criteria:

• Received at least 2 doses of an approved anti-PD-1/L1 mAb.

• Documented disease progression after anti-PD-1/L1 treatment (consistent with the principles of RECIST v1.1). The initial evidence of disease progression is to be confirmed by a second assessment no less than 4 weeks from the date of the first documented disease progression, in the absence of rapid clinical progression (as defined in 2.c).

• Progressive disease has been documented within 12 weeks from the last dose of anti-PD-1/L1 mAb.

‣ Progressive disease is determined consistent with the principles of RECIST v1.1.

⁃ This determination is made by the investigator. Once disease progression is confirmed, the initial date of disease progression documentation will be considered the date of disease progression.

• 7\. Measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been shown in such lesions.

• 8\. Archival tumor tissue sample within 30 months of enrollment or newly obtained \[core, incisional, OR excisional\] biopsy of a tumor lesion not previously irradiated has been provided.

• 9\. Participants who have AEs due to previous anticancer therapies (with the exception of alopecia or peripheral sensory neuropathy) must have recovered to ≤Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement are eligible, as are participants with ≤Grade 2 neuropathy, hearing loss, or alopecia.

• 10\. If male, agrees to use an adequate method of contraception starting with the first dose of study drug through 90 days after the last dose of study drug. Please see Section 10.3 for a list of acceptable birth control methods. Male participants must not donate sperm throughout the study period and for 90 days after the last dose of the study treatment.

• 11\. Female participants of childbearing potential must have a negative serum pregnancy test at screening within 7 days of the Cycle 1 Day 1 dosing. Female participants of childbearing potential must agree to use a highly effective form of contraception, as defined in the protocol (Section 10.3), during the study and for 120 days after the last dose of study drug. To be considered NOT of childbearing potential, female participants must have had a hysterectomy or bilateral oophorectomy or be 1-year post-menopause or have had amenorrhea for a period of 12 months or longer in the absence of chemotherapy, anti-estrogens, or ovarian suppression.

• 12\. HIV-infected participants must have well controlled HIV on ART, defined as:

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• Participants on ART must have a CD4+ T-cell count ≥350 cells/mm3 at the time of screening

• Participants on ART must have achieved and maintained virologic suppression, defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening

• It is advised that participants must not have had any AIDS-defining opportunistic infections within the past 12 months

• Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before study entry (Day 1) and agree to continue ART throughout the study.

• Participants with HIV should continue ongoing management by their health care provider(s), including monitoring of HIV viral load, CD4+ T-cell count, and appropriate supportive care measures.

• 13\. Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization.

∙ a. Hepatitis B screening tests are not required unless:

• Known history of HBV infection

• As mandated by local guidelines

∙ 14\. Participants with a history of HCV infection are eligible if HCV viral load is undetectable at screening.

∙ Note: Participants must have completed curative antiviral therapy at least 4 weeks prior to randomization.

• Hepatitis C screening tests are not required unless:

• 3\. Known history of HCV infection 4. As mandated by local guidelines 15. Adequate organ function as defined in Table 20.