Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Rare Diseases

Syndrome

Preleukemia

Myelodysplastic Syndromes

Bone Marrow Diseases

Hematologic Diseases

Precancerous Conditions

Antineoplastic Agents

All Drugs and Chemicals

Decitabine

Immunomodulating Agents

Antimetabolites

Enzyme Inhibitors

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.

Expansion of oral doses of SX-682 (study drug) at 200 mg twice daily (recommended phase 2 dose) in lower risk patients who have never received hypomethylating agents.

Expansion of oral doses of SX-682 (study drug) at 200 mg twice daily (recommended phase 2 dose) in lower risk patients who failed on hypomethylating agents.

Expansion of oral doses of SX-682 (study drug) at 100 mg twice daily with decitabine in lower risk patients who have never received hypomethylating agents.

Expansion of oral doses of SX-682 (study drug) at 100 mg twice daily with decitabine in lower risk patients who failed on hypomethylating agents.

Expansion of oral doses of SX-682 (study drug) at 200 mg twice daily (recommended phase 2 dose) in higher risk patients who failed on hypomethylating agents.

Expansion of oral doses of SX-682 (study drug) at 100 mg twice daily with decitabine in higher risk patients who have never received hypomethylating agents.

Expansion of oral doses of SX-682 (study drug) at 100 mg twice daily with decitabine in higher risk patients who failed on hypomethylating agents.

SX-682 is an oral small molecule selective inhibitor of C-X-C Motif Chemokine Receptor 1 (CXCR1) and CX-C Motif Chemokine Receptor 2 (CXCR2)

SX-682

Aaron D Schuler, PhD

Ali Brewer

Kaila Lopez

Hemant S Murthy, MD

Namrata S Chandhok, MD

Kristen Wing, RN,BSN,CCRP

Arlene Gayle, M.D.

Cyril Patra, MPH

Caroline Wagstaff

David A Sallman, MD

Shannon Gleason, MLS, CCRC

Anthony M Hunter, MD

Lisa A. Kelemen, RN, MSN

Amy E DeZern, MD, MHS

Mendel Goldfinger, MD

Anne Munoz, RN

This study will determine the safety profile, maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and recommended Phase 2 dose (RP2D) of SX-682 in the treatment of patients with Myelodysplastic Syndromes (MDS).

Participants will receive twice daily oral SX-682 for six 28 day cycles. If patients are responding well to the treatment they can continue SX-682 treatment. The first participants will be administered 25 mg orally twice daily. Unless dose limiting toxicities occur, participants will enroll and receive the following increasing twice daily doses of SX-682: 50 mg, 100 mg, 200 mg, and 400 mg.

After establishing the maximum tolerated dose 140 additional participants will be enrolled at the recommended phase 2 dose. Participants will receive continuous SX-682 twice daily oral therapy in 28-day cycles for a total of 6 cycles. The expansion dose cohort will be stratified into IPSS (a) low and intermediate-1 (N=20 SX-682 alone in HMA naive, N=20 SX-682 alone in HMA failure, N=20 SX-682 + DEC-C in HMA-naïve, N=20 SX-682 + DEC-C in HMA-failure) and (b) intermediate-2 and high risk (N=20 SX-682 alone in HMA failure, N=20 SX-682 + DEC-C in HMA-naive, N=20 SX-682 + DEC-C in HMA-failure) MDS. For patients responding well at the end of 6 cycles treatment may continue until disease progression or an adverse event leads to SX-682 discontinuation. Except for blood product transfusions, concurrent therapy for Myelodysplastic Syndromes is not permitted.

In this sequential model initially participant groups will enroll to receive SX-682 for six 28 day cycles in a dose escalation phase. A 3 + 3 participant design will be used to determine the safe dose. After 6 cycles at the specified dose of SX-682, SX-682 treatment can be continued. Once the safe dose level of SX-682 is determined, then participants will be enrolled at the this safe dose level of SX-682 in an expansion phase.

Study of SX-682 Alone and in Combination With Oral or Intravenous Decitabine in Subjects With Myelodysplastic Syndrome

A Phase 1, Open-Label, Dose-Escalation With Expansion Study of SX-682 Alone and in Combination With Oral or Intravenous Decitabine in Subjects With Myelodysplastic Syndrome

Participants cohorts will be enrolled at increasing doses of SX-682. The highest SX-682 dose tested at which no more than 1 of 6 participants experiences a dose limiting toxicity will define the SX-682 MTD

Number of participants experiencing DLTs.

The percentage of participants experiencing a complete remission, partial remission, or stable disease according to the International Working Group Response Criteria.

Number of delayed DLTs experienced by participants.

Number of participants experiencing adverse events (AEs).

Blood samples will be collected before and after the first dose of SX-682 on Day 1 of Cycle 1.

Blood samples will be collected before and after the first dose of SX-682 on Day 15 of Cycle 1.

H. Lee Moffitt Cancer Center and Research Institute

National Heart, Lung, and Blood Institute (NHLBI)

Johns Hopkins University

AdventHealth

Emory University

University of Miami

Mayo Clinic

Montefiore Medical Center

Syntrix Biosystems, Inc.

Skin and Connective Tissue Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antibodies

Pembrolizumab

Immunoglobulins

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

SX-682 will be administrated at the same dose the participant was administered in monotherapy and will be administered in a 6 week cycle that includes 2 i.v. infusions of pembrolizumab on days 1 and 22 of each cycle, for a total of up to 17 cycles. Once the highest safe dose of SX-682 in combination therapy with pembrolizumab is determined, participants will be enrolled in an expansion phase at that SX-682 dose with pembrolizumab 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)

Pembrolizumab is a humanized antibody that targets the programmed cell death 1 receptor (PD-1).

Aaron Schuler, PhD

Stuart Kahn

Millie Gedefa

Leonel F Hernandez-Aya, MD

Alisha Birgin

Renee Bradshaw

Anastasios Dimou, MD

Erin Reagan, RN

Sarah Cawley

Victor I Adrienne, MD

Youlia Petrova, BSN, RN

Katelyn Oliver, BSN, RN

Hussein Tawbi, MD

Stuart Kahn, M.D.

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.

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.

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.

SX-682 Treatment in Subjects With Metastatic Melanoma Concurrently Treated With Pembrolizumab

A Phase 1, Open-Label, Dose-Escalation With Expansion Study of SX-682 in Subjects With Metastatic Melanoma Concurrently Treated With Pembrolizumab

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.

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 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).

Duration of CR or PR according to RECIST v1.1 from the time of first documentation to radiologic progression or death.

The time from first SX-682 dose to documented disease progression according to RECIST v1.1 or death from any cause

During combination stage the time from first SX-682 dose to death from any cause.

Number of participants experiencing DLTs during monotherapy stage

Number of participants experiencing DLTs during combination therapy stage

Number of participants experiencing clinical or laboratory adverse events (AEs) including infections and neutropenia.

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.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Study of SX-682 Alone and in Combination With Oral or Intravenous Decitabine in Subjects With Myelodysplastic Syndrome	NCT04245397	Myelodysplastic...	SX-682 Decitabine	18 Years -	Syntrix Biosystems, Inc.
SX-682 Treatment in Subjects With Metastatic Melanoma Concurrently Treated With Pembrolizumab	NCT03161431	Melanoma Stage ... Melanoma Stage ...	SX-682 Pembrolizumab	18 Years -	Syntrix Biosystems, Inc.

Spots Global Cancer Trial Database for chemokine receptor blockade