A Phase 1, Open-Label, Dose-Escalation With Expansion Study of SX-682 in Subjects With Metastatic Melanoma Concurrently Treated With Pembrolizumab
Cancers attract myeloid-derived suppressor cells (MDSCs) that prevent our own immune responses from destroying the cancer. This study will be the first study to begin to determine if the newly discovered drug SX-682 can block cancers from attracting MDSCs. This first study will enroll participants with melanoma, as melanoma cancer has been shown to be able to attract MDSCs. The study will begin to determine if SX-682 is a safe and effective treatment of melanoma. It is thought that SX-682 will block MDSCs from going to the cancer, and thus will allow a patient's own immune system to attack the cancer. The first participants enrolled in the study will receive for 21 days SX-682 as monotherapy. After 21 days participants will receive pembrolizumab therapy (an approved immunotherapy for melanoma) in combination with SX-682 for up to approximately 2 years. Once the safe dose level of SX-682 in combination with pembrolizumab is determined, the remaining participants will be enrolled at the highest safe dose level of SX-682, in combination with pembrolizumab. These participants will receive the combination therapy and be evaluated in the study for approximately 2 years.
• Written Informed Consent and HIPAA Authorization
‣ Subjects must have the nature of the study explained to them.
⁃ Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, pharmacokinetic collections, and other requirements of the study.
⁃ Subjects must provide a signed and dated IRB/IEC approved written informed consent form (ICF) in accordance with regulatory and institutional guidelines.
⁃ Subjects must provide a signed and dated Health Insurance Portability and Accountability Act (HIPAA) authorization.
⁃ The ICF and HIPAA authorization must be obtained before conducting any procedures that do not form a part of the subject's normal care.
⁃ After signing the ICF and HIPAA Authorization, subjects will be evaluated for study eligibility during the Screening Period (no more than 28 days before study drug administration) according to the following further inclusion/exclusion criteria:
• Target Population
‣ Histologically confirmed unresectable Stage III or Stage IV melanoma as per AJCC staging system. (mucosal melanoma is acceptable).
⁃ Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
⁃ Prior disease progression on anti-PD1 therapy (i.e., anti-PD1 or anti-PD-L1, including prior adjuvant). Prior anti-PD1 therapy must have been completed prior to first dose of SX-682, and all adverse events related to prior therapy have either returned to baseline or stabilized (other than endocrine toxicity for which medical replacement therapy is in place).
⁃ Must have at least measurable non-CNS disease with at least 1 unidimensional measurable lesion per RECIST v1.1.
⁃ Pre-treatment tumor tissue (i.e., archived paraffin-embedded) obtained in the metastatic setting or from an unresectable site of disease must be available for biomarker analyses. Biopsy should be excisional, incisional punch or core needle. Fine needle aspirates or other cytology samples are insufficient.
⁃ Prior radiotherapy must have been completed at least 2 weeks prior to study drug administration.
⁃ Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to first dose:
‣ WBC \> 3000/µL Neutrophils \> 1500/ µL Platelets \> 100,000/µL Hemoglobin \> 9.0 g/dL (may have been transfused) Creatinine \< 1.5 mg/dL AST/ALT \< 2.5 X ULN for subject with no liver metastases \< 5 X ULN for subjects with liver metastases Bilirubin \< 1.5 mg/dL (unless diagnosed with Gilbert's syndrome, who can have total bilirubin \< 3.0 mg/dL) INR or PT \< 1.5 X ULN unless the subject is receiving anticoagulant therapy aPTT or PTT \< 1.5 X ULN unless the subject is receiving anticoagulant therapy
⁃ Calculate and record creatinine clearance using the Cockcroft-Gault formula.
⁃ No known positivity for human immunodeficiency virus (HIV) (no laboratory testing is required), no active infection with Hepatitis B or Hepatitis C.
‣ Life expectancy \> 12 weeks.
‣ Subject Re-enrollment: This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment failure (i.e., subject has not been treated with SX-682) after obtaining agreement from the medical monitor prior to re-enrolling a subject. If re-enrolled, the subject must be re-consented.
• Age and Reproductive Status
‣ Men and women, ages \> 18 years of age.
⁃ Women of childbearing potential (WOCBP) must use method(s) of contraception (as will be explained in detail) while on study and for 4 months after the last dose of SX-682 or pembrolizumab. A WOCBP is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over age 45 in the absence of other biological or physiological causes.
⁃ Women under the age of 62 with a history of being postmenopausal must have a documented serum follicle stimulating hormone, (FSH) level \> 40 mIU/mL.
⁃ Women must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.
⁃ Women must not be breastfeeding.
⁃ Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year while on study and for a period at least 6 months after the last dose of study drug.
⁃ Women who are not of childbearing potential and azoospermic men do not require contraception.