SX-682 Treatment in Subjects With Metastatic Melanoma Concurrently Treated With Pembrolizumab
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|ClinicalTrials.gov Identifier: NCT03161431|
Recruitment Status : Not yet recruiting
First Posted : May 19, 2017
Last Update Posted : February 7, 2018
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) and will remain in the study for evaluations for 3 months.
After these participants complete the monotherapy stage, the next participants will receive SX-682 and pembrolizumab together as combination therapy. These participants will receive the combination therapy and be evaluated in the study for approximately 2 years.
|Condition or disease||Intervention/treatment||Phase|
|Melanoma Stage Iii Melanoma Stage Iv||Drug: SX-682 Biological: Pembrolizumab||Phase 1|
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, single-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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||77 participants|
|Intervention Model:||Sequential Assignment|
|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, SX-682 therapy will be stopped and participants will receive pembrolizumab therapy and continue to be evaluated for 90 days.
After the safe dose of SX-682 monotherapy has been determined, subjects will be enrolled to receive SX-682 and pembrolizumab combination therapy, in a SX-682 dose escalation phase. Again, a 3 + 3 participant design will be used to determine the safe dose. 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.
|Masking:||None (Open Label)|
|Official Title:||A Phase 1, Open-Label, Dose-Escalation With Expansion Study of SX-682 in Subjects With Metastatic Melanoma Concurrently Treated With Pembrolizumab|
|Anticipated Study Start Date :||May 2018|
|Estimated Primary Completion Date :||August 2020|
|Estimated Study Completion Date :||December 2020|
Experimental: Monotherapy: SX-682 dose escalation
Escalating oral doses of SX-682 (study drug) of 25, 50, 100, 200 and 400 mg twice-daily (i.e., 50, 100, 200, 400 and 800 mg total each day.
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)
Experimental: Combination therapy: SX-682 dose escalation and pembrolizumab
SX-682 will be initiated at an initial SX-682 dose no more than 50% of the single-agent MTD/RP2D and will be administered in a 6 week cycle that includes 2 i.v. infusions of pembrolizumab (2 mg/kg) on days 1 and 22 of each cycle, for a total of up to 17 cycles. Once the highest safe dose of SX-682 is determined participants will be enrolled at that dose for combination therapy.
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)Biological: Pembrolizumab
Pembrolizumab is a humanized antibody that targets the programmed cell death 1 receptor (PD-1).
Other Name: KEYTRUDA
- SX-682 Maximum Tolerated Dose (MTD) during Monotherapy Stage [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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
- Overall survival [ Time Frame: 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 dose limiting toxicities (DLTs) during monotherapy [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03161431
|Contact: Keith T Flaherty, M.D.||email@example.com|
|United States, Massachusetts|
|Massachusettes General Hospital Cancer Center|
|Boston, Massachusetts, United States, 02114|
|Principal Investigator:||Keith T. Flaherty, M.D.||Massachusettes General Hospital Cancer Center|