Melanoma Stage III, Melanoma Stage IV
Conditions
Keywords
Immunotherapy, Chemokine receptor blockade, Myeloid-derived suppressor cells
Brief summary
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.
Detailed description
Objectives The primary objective is to determine the safety profile of SX-682 alone and in combination with pembrolizumab in subjects with metastatic melanoma, including the maximum dose that can be administered until adverse effects prevent further dose increases, and the dose-limiting toxicity (DLT). The secondary objectives are to: 1) evaluate the efficacy of SX-682 in combination with pembrolizumab on the basis of the objective response rate, the duration of response, and the rate of progression; and 2) characterize the SX-682 single-dose and multidose PK profile. Exploratory objectives are to: 1) assess overall survival (OS); and 2) explore potential biomarkers associated with pharmacodynamic and clinical response to SX-682 alone and combined with pembrolizumab, where the biomarker measures include, but are not limited to, tumor myeloid-derived suppressor cells (MDSC), Tregs and CD69/CD8 T cells, and in the circulation, T- and B-cell subpopulations, neutrophils, the neutrophil-to-lymphocyte ratio (NLR), Tregs, the CD4:CD8 ratio, chemokines, cytokines, and LDH. Overview of Study Design This is a Phase 1, open-label, multi-center, dose-escalation with expansion study of twice-daily SX-682 in subjects with metastatic melanoma treated concurrently with pembrolizumab (Combination Stage) following a 21 day dose-escalation safety evaluation of SX-682 monotherapy (Monotherapy Stage). SX-682 is an oral small-molecule inhibitor of the CXCR1/2 chemokine receptors that are believed involved in MDSC-recruitment to tumor and other pro-tumoral mechanisms. Dosing of SX-682 in the Combination Stage is conditioned on ongoing concurrent treatment with pembrolizumab, and a subject who discontinues pembrolizumab may not receive further doses of SX-682.
Interventions
DRUGSX-682
SX-682 is an oral small molecule selective inhibitor of C-X-C Motif Chemokine Receptor 1 (CXCR1) and C-X-C Motif Chemokine Receptor 2 (CXCR2)
BIOLOGICALPembrolizumab
Pembrolizumab is a humanized antibody that targets the programmed cell death 1 receptor (PD-1).
Sponsors
Massachusetts General Hospital
National Cancer Institute (NCI)
Dana-Farber Cancer Institute
Mayo Clinic
University of Rochester
M.D. Anderson Cancer Center
University of Miami
Syntrix Biosystems, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
In this sequential model initially participant groups will enroll to receive SX-682 monotherapy for 21 days in a dose escalation phase. A 3 + 3 participant design will be used to determine the safe dose. After 21 days, at the specified dose of SX-682 monotherapy, subjects are administered combination therapy consisting of SX-682 at the same dose as used in monotherapy and standard pembrolizumab therapy. Again, a 3 + 3 participant design will be used to determine the safe dose of SX-682 in combination therapy with pembrolizumab. The next higher dose level will be enrolled only after subjects have received the current dose level safely for at least 6 weeks. Once the safe dose level of SX-682 in combination with pembrolizumab is determined, then participants will be enrolled at the highest safe dose level of SX-682, in combination with pembrolizumab, in an expansion phase.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Written Informed Consent and HIPAA Authorization 1. Subjects must have the nature of the study explained to them. 2. Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, pharmacokinetic collections, and other requirements of the study. 3. Subjects must provide a signed and dated IRB/IEC approved written informed consent form (ICF) in accordance with regulatory and institutional guidelines. 4. Subjects must provide a signed and dated Health Insurance Portability and Accountability Act (HIPAA) authorization. 5. The ICF and HIPAA authorization must be obtained before conducting any procedures that do not form a part of the subject's normal care. 6. 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
2. Target Population 1. Histologically confirmed unresectable Stage III or Stage IV melanoma as per AJCC staging system. (mucosal melanoma is acceptable). 2. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. 3. 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). 4. Must have at least measurable non-CNS disease with at least 1 unidimensional measurable lesion per RECIST v1.1. 5. 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. 6. Prior radiotherapy must have been completed at least 2 weeks prior to study drug administration. 7. 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 8. Calculate and record creatinine clearance using the Cockcroft-Gault formula. 9. No known positivity for human immunodeficiency virus (HIV) (no laboratory testing is required), no active infection with Hepatitis B or Hepatitis C. 10. Life expectancy \> 12 weeks. 11. 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. 3. Age and Reproductive Status 1. Men and women, ages \> 18 years of age. 2. 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. 3. 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. 4. 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. 5. Women must not be breastfeeding. 6. 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. 7. Women who are not of childbearing potential and azoospermic men do not require contraception.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival | Combination Stage cycle (Cycles 1-17) and the 90 day follow-up period after the last SX-682 dose. | During combination stage the time from first SX-682 dose to death from any cause. |
| SX-682 Maximum Tolerated Dose (MTD) during Monotherapy Stage | Up to 21 Days in 21 day Cycle 1 of Monotherapy Stage. | During the Monotherapy Stage participant cohorts will be enrolled at increasing doses of SX-682. The highest SX-682 dose tested at which no more than 1 of 6 cohort participants experiences a DLT will define the SX-682 monotherapy MTD. |
| SX-682 Maximum Tolerated Dose during Combination Therapy Stage | Up to 42 Days in 42 day Cycle 1 of Combination Therapy Stage. | During the Combination Therapy Stage participant cohorts will be enrolled at increasing doses of SX-682 and a fixed pembrolizumab dose level. The highest SX-682 dose tested at which no more than 1 of 6 cohort participants experiences a DLT will define the SX-682 combination therapy MTD. |
| The observed tumor response rate | Days 38-42 of each 42 day Combination Stage cycle (Cycles 1-17) | The percentage of participants with their best response (a complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). |
| The observed tumor response duration | Days 38-42 of each 42 day Combination Stage cycle (Cycles 1-17) | Duration of CR or PR according to RECIST v1.1 from the time of first documentation to radiologic progression or death. |
| Progression free survival | Days 38-42 of each 42 day Combination Stage cycle (Cycles 1-17) | The time from first SX-682 dose to documented disease progression according to RECIST v1.1 or death from any cause |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| SX-682 dose limiting toxicities (DLTs) during monotherapy | Up to 21 Days in 21 day Cycle 1. | Number of participants experiencing DLTs during monotherapy stage |
| SX-682 dose limiting toxicities (DLTs) during combination therapy stage | Days 38-42 of each 42 day Combination Stage cycle (Cycles 1-17). | Number of participants experiencing DLTs during combination therapy stage |
| Adverse events during Monotherapy Stage | Up to 21 Days in 21 day Cycle 1 of monotherapy stage. | Number of participants experiencing clinical or laboratory adverse events (AEs) including infections and neutropenia. |
| Adverse events during combination Therapy Stage | Up to 42 Days in 42 day Cycle 1-17 of Combination Therapy Stage. | Number of participants experiencing clinical or laboratory adverse events (AEs) including infections and neutropenia. |
| SX-682 single dose pharmacokinetic parameters during SX-682 monotherapy and SX-682 and pembrolizumab combination therapy | SX-682 dose on Day 1 of Cycle 1 of Monotherapy Stage and Combination Therapy Stage. | Blood samples will be collected before and after the first dose SX-682 during Monotherapy Stage and Combination Therapy Stage. The Cmax will be determined. |
| SX-682 steady-state pharmacokinetic parameters during SX-682 monotherapy and SX-682 and pembrolizumab combination therapy | Morning dose of day 15 of Cycle 1 of monotherapy stage and combination therapy stage. | Blood samples will be collected before and after the morning dose of SX-682 on Day 15 of cycle 1 during monotherapy and combination therapy. The Cssmax will be determined. |
Countries
United States
Outcome results
None listed