IRB Study Number 23-1181
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objective
• To assess safety and tolerability of FX-909
Secondary Objectives
• To define the preliminary recommended phase 2 dose of FX-909, and/or maximum tolerated dose (MTD)
• To characterize the pharmacokinetic profile of FX-909 in patients with advanced solid malignancies
• To evaluate preliminary antitumor activity of FX-909 in patients with advanced solid malignancies
Inclusion Criteria
1) Able to understand and willing to sign an informed consent. A legally authorized representative (eg, parent or legal guardian) may consent on behalf of a patient who is otherwise unable to provide informed consent, if acceptable to and approved by the site and/or site’s Institutional Review Board (IRB) or Ethics Committee (EC).
2) Age ≥ 18 years
3) Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 (see Section 20.1.1)
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 that include any of the following (see Section 20.6, Appendix F, for recommendations on appropriate tests):
o Amplification of PPARG
o A PPARG fusion (TSEN2-PPARG, MKRN2-PPARG, CASC15-PPARG, or NR2C2-PPARG)
o An activating mutation in PPARG (T475M, M280I, I290M, S249L, R168K, R164W, P113S, R164W, or E3K; other PPARG mutations may be eligible following a discussion with the Sponsor)
o An activating mutation in RXRA (S427F or S427Y)
o Mutations or fusions of FGFR3 (including FGFR3:BAIAP2L1, FGFR3:TACC3v1, FGFR3:TACC3v3, and any fusions with sufficient read depth, which preserve the kinase domain and are predicted to generate a functional oncoprotein, and FGFR3 missense variants including G370C, R248C, S249C, and/or Y373C, and other FGFR3 single nucleotide variants or small insertions or deletions that are known or suspected to be gain-of-function based on somatic classification rulesets).
Eligible genetic alterations within urothelial carcinoma may be refined by the Sponsor based on emerging data as the study progresses.
Patients in Part B must have progressed after all available standard therapy (eg, anti-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. (Note: Patients whose cancers harbor molecular alterations for which targeted therapy is standard of care [eg, FGFR3 genetic alterations] should have received local health-authority approved appropriate therapy for their tumor type prior to enrollment, unless this is considered inappropriate by the Investigator or refused by the patient).
5) Part A (Dose Escalation): Patients with and without measurable disease (as defined by Response Evaluation Criteria in Solid Tumors [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. Tumor lesions planned for biopsy must not be followed as target lesions for disease assessments.
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. Biopsies must be collected from a tumor lesion that has not been previously irradiated (or has progressed following radiation therapy) and tumor lesions planned for biopsy must not be followed as target lesions for disease assessments unless the biopsy occurred prior to the baseline/screening tumor assessment evaluation.
7) Screening laboratory values meet the criteria outlined in Table 6.
o 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. Female patients of childbearing potential who engage in heterosexual intercourse and males who are sexually active with female partners of childbearing potential must agree to use a highly effective form of contraception (eg, females: male partner sterilization, estrogen/progestogen, or progestogen-only hormonal contraceptives associated with inhibition of ovulation [oral, intravaginal, transdermal, depot, or implant], intrauterine devices, intrauterine hormone-releasing systems; males: male condoms, vasectomy) throughout the study, starting at the time of consent and for at least 90 days after the last dose of the study drug. Female patients of childbearing potential are those who have begun menstruating. To be considered NOT of childbearing potential, female patients 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. Male patients must not donate sperm throughout the study period and for 90 days after the last dose of FX-909.
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. (See Exclusion Criterion 6 for required radiotherapy windows.)
3) Prior therapy directly inhibiting PPARG or RXRA. Note: Prior treatment with rosiglitazone or pioglitazone for type 2 diabetes would not preclude participation in this study, provided there is not a need for ongoing treatment with a thiazolidinedione during the study. If given, these agents must have been discontinued at least 2 weeks prior to the start of study drug administration.
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. Patients must have fully recovered from surgery or its complications prior to the start of study treatment.
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. (Note for patients enrolled in Part B: Patients must have ≥ 1 site of measurable disease for assessment via RECIST version 1.1. Patients with ≥ 1 site of measurable disease per RECIST version 1.1. who have previously irradiated lesions that have progressed after radiation therapy are eligible.)
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 (see Sections 11.6.2 and 20.3 for additional information regarding concomitant medication and the impact on QTc). QTcF is QT corrected for heart rate according to Fridericia’s correction formula (QTcF = QT/RR0.33) and can be machine calculated or manually over-read.
9) Known active diagnosis of lipodystrophy/lipoatrophy, or an ongoing need to receive medications known to cause lipodystrophy/lipoatrophy (see Section 11.6.3 for agents known to cause lipodystrophy/lipoatrophy). Screening for lipodystrophy/lipoatrophy without a known prior diagnosis is not necessary for enrollment in the study.
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 (Note: Elevations of amylase or lipase in the absence of clinical signs and symptoms that are consistent with a diagnosis of pancreatitis do not meet the criteria for exclusion.)
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 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 Section 11.6.2 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 (see Section 20.1.2)
• 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 (systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg) 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. Screening for chronic conditions is not required.
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 IRB/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.
