A Phase 1, First-in-Human, Dose-Escalation and Expansion Study of FX-909 in Patients With Advanced Solid Malignancies, Including Advanced Urothelial Carcinoma

This is an open-label Phase 1 study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of FX-909 given orally (PO) in patients with advanced solid malignancies. Initially, FX-909 will be given in a dose-escalation phase (Part A) to determine the preliminary recommended phase 2 dose (RP2D). Part B will be a monotherapy expansion phase to further evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of FX-909 in patients with locally advanced (unresectable) and metastatic urothelial carcinoma. Throughout the study patients will be treated in 28-day cycles.

Inclusion Criteria:

1. Able to understand and willing to sign an informed consent.
2. Age ≥ 18 years
3. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
4. Part A (Dose Escalation): 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 (Expansion): Histologically or cytologically diagnosed, locally advanced (unresectable) or metastatic urothelial carcinoma with defined genetic alterations. Patients in Part B must have progressed after all available standard therapy (eg, anti- programmed cell death (ligand) 1 [PD(L)1], antibody-drug conjugate[s], and platinum-based doublet chemotherapy), been unable to tolerate standard therapy, or be considered inappropriate for standard therapy by the Investigator.

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

   Part B (Expansion): 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.

6. An archival, paraffin-embedded, formalin-fixed, tumor sample (see Laboratory Manual for details) that is no more than 30 months old at the time of screening must be provided unless the patient consents to provide a fresh biopsy during screening.
7. Screening laboratory values meet the criteria outlined in the protocol. Hematologic criteria may be met with transfusion of blood products or administration of G-CSF, provided they are not given within 7 days of C1D1.

Exclusion Criteria:

1. Female patients who are pregnant (confirmed with a positive pregnancy test) or breastfeeding.
2. Prior anticancer chemotherapy or small molecule targeted therapy, either investigational or commercially approved and available, within 2 weeks or 5 half-lives (whichever is shorter) prior to the start of study drug administration. When the most recent therapy was a biological therapy (including antibody-drug conjugates), an immune-checkpoint inhibitor (eg, anti-PD(L)1 or anti-CTLA4), or immune agonist, patients should wait 4 weeks before starting therapy with FX-909.
3. Prior therapy directly inhibiting PPARG or RXRA.
4. Adverse events from prior therapy that have not returned to baseline or stabilized at Grade 1 (except alopecia, hearing loss, vitiligo, endocrinopathy managed with replacement therapy, and Grade ≤ 2 neuropathy) prior to study drug administration.
5. Prior major surgery (excluding placement of vascular access) within 4 weeks before study drug administration.
6. Prior radiation therapy with an inadequate washout between the last dose and the start of study drug, defined as follows: 1) at least 2 weeks for palliative radiation to the extremities for osseous bone metastases is required; and 2) at least 4 weeks for radiation to non-extremity sites is required.
7. History of another malignancy in the previous 2 years, unless cured by surgery alone and continuously disease free. Exceptions include appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, melanoma in situ status-post full-thickness resection without recurrence, Stage 1 uterine cancer, localized prostate cancer that has been treated surgically with curative intent and presumed cured, or other malignancies with an expected curative outcome.
8. QT Interval Corrected Using Fridericia's Formula (QTcF) > 470 msec in screening, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first degree relatives.
9. Known active diagnosis of lipodystrophy/lipoatrophy, or an ongoing need to receive medications known to cause lipodystrophy/lipoatrophy
10. Any active uncontrolled systemic bacterial, viral, or fungal infection requiring treatment.
11. Known history of human immunodeficiency virus (HIV) seropositivity. Those who have no detectable viral load on highly active antiretroviral therapy (HAART) are permitted.
12. Patients with chronic hepatitis B virus (HBV) infection (indicated by a positive HBV surface antigen and/or hepatitis B core antibody), patients with a negative polymerase chain reaction (PCR) assay are permitted with either universal prophylaxis or a pre-emptive treatment approach consistent with regional or national guidelines for patients who receive anticancer therapies.
13. Active hepatitis C virus (HCV) infection. Those who have completed curative therapy for HCV and have no detectable viral load are permitted.
14. Prior diagnosis of chronic or recurrent (> 1 episode) pancreatitis at any time or a diagnosis of acute pancreatitis within the 6 months prior to screening
15. Significant impairment of lung function indicated by resting oxygen saturations below 92% or requiring chronic use of ambulatory supplemental oxygen.
16. Uncontrolled or symptomatic central nervous system (CNS) metastases, leptomeningeal disease, or carcinomatous meningitis. Asymptomatic brain metastasis is allowed if they have been stable after appropriate radiotherapy for 1 month.
17. Need for treatment with high doses of oral or intravenous steroids (> 10 mg/day prednisone or equivalent). Physiologic doses of corticosteroids for treatment of endocrinopathies may be continued if the patient is on a stable dose for at least 1 month.
18. Need or anticipated need for treatment with a prohibited therapy described in the protocol during the treatment phase of this study
19. Concurrent participation in any other investigational therapeutic study
20. History of any of the following cardiovascular diseases:
    • Recent history (within the 6 months prior to screening) of serious uncontrolled cardiac arrhythmia (including atrial fibrillation without adequate rate control) or clinically significant ECG abnormalities including second-degree (Type II) or third-degree atrioventricular node block
    • Documented cerebrovascular event (stroke or transient ischemic attack), cardiomyopathy, myocardial infarction, acute coronary syndromes (including unstable angina pectoris), coronary angioplasty, stenting, or bypass grafting within the 6 months prior to enrollment
    • Congestive heart failure (Class III or IV) as defined by the New York Heart Association functional classification system
    • Recent history (within the past 6 months) of symptomatic pericarditis
21. Thromboembolic events and/or bleeding disorders ≤ 28 days (eg, deep vein thrombosis or pulmonary embolism) prior to the first dose of study drug
22. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which, in the Investigator's opinion, makes it undesirable for the patient to participate in the study or would jeopardize compliance with the protocol.
23. Patients with type 1 diabetes mellitus, or type 2 diabetes mellitus that is not adequately controlled with diet and exercise or oral hypoglycemic agents (as defined by HbA1c and fasting plasma glucose criteria in Table 6; medication for type 2 diabetes mellitus should have remained stable for the past 14 days prior to screening).
24. Known hypersensitivity to FX-909 or any of its excipients (see Table 7 for the list of excipients)
25. Patients with gastrointestinal disorders that may interfere with the ability to swallow tablets or absorb study medication
26. Patient is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or child) who is a member of the study site or Sponsor staff directly involved with this study, unless prospective Institutional Review Board (IRB) or Ethics Committee (EC) approval (by chair or designee) is given allowing exception to this criterion for a specific patient.
27. Patients with any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before study entry.
28. Any condition that, in the opinion of the Investigator, would interfere with evaluation of the investigational product or interpretation of the patient's safety or study results.