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Trial record 1 of 1 for:    NCT03161431
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SX-682 Treatment in Subjects With Metastatic Melanoma Concurrently Treated With Pembrolizumab

This study is not yet open for participant recruitment.
Verified May 2017 by Syntrix Biosystems, Inc.
Sponsor:
ClinicalTrials.gov Identifier:
NCT03161431
First Posted: May 19, 2017
Last Update Posted: May 19, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
Massachusetts General Hospital
The Wistar Institute
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Syntrix Biosystems, Inc.
  Purpose

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 Intervention Phase
Melanoma Stage Iii Melanoma Stage Iv Drug: SX-682 Biological: Pembrolizumab Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
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)
Primary Purpose: Treatment
Official Title: A Phase 1, Open-Label, Dose-Escalation With Expansion Study of SX-682 in Subjects With Metastatic Melanoma Concurrently Treated With Pembrolizumab

Resource links provided by NLM:


Further study details as provided by Syntrix Biosystems, Inc.:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Estimated Enrollment: 77
Anticipated Study Start Date: December 2017
Estimated Study Completion Date: December 2020
Estimated Primary Completion Date: August 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: SX-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)
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.
Drug: SX-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)
Biological: Pembrolizumab
Pembrolizumab is a humanized antibody that targets the programmed cell death 1 receptor (PD-1).
Other Name: KEYTRUDA

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, 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.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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:
  • Histologically confirmed unresectable Stage III or Stage IV melanoma as per AJCC staging system.
  • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
  • No prior systemic anticancer therapy for unresectable or metastatic melanoma. Note that prior adjuvant or neoadjuvant melanoma therapy is permitted if it was completed at least 6 weeks prior to first dose, and all related adverse events have either returned to baseline or stabilized.
  • Must have measurable 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.
  • Known BRAF V600 mutation status; subjects with either V600 wild-type or V600 mutation-positive status are eligible.
  • 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

    • 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.
    • 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.

Exclusion Criteria:

  • Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if these have been treated and there is no magnetic resonance imaging (MRI - except where contraindicated, in which CT scan is acceptable) evidence of progression for at least 8 weeks after treatment is complete and within 28 days prior to first dose of study drug administration. There must also be no requirement for high doses of systemic corticosteroids that could result in immunosuppression (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.
  • Ocular melanoma.
  • Subject was randomized into a prior pembrolizumab trial.
  • Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results. Specifically:

Subjects with active, non-infectious pneumonitis. Subjects with interstitial lung disease or a history of pneumonitis that required oral or intravenous glucocorticoids to assist with management.

Subjects with clinically significant heart disease that affects normal activities.

  • Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
  • Subjects with active, known or suspected autoimmune disease (Appendix 3). Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
  • Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
  • Prior treatment with an anti-PD1, anti-PD-L1, anti-PD-L2, anti-CTLA4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways.
  • Use of other investigational drugs (drugs not marketed for any indication) within 30 days before study drug administration.
  • Subjects who have had major surgery in the past 4 weeks.
  • Subjects who have received a live-virus vaccine within 30 days before study drug administration.
  • Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection.
  • Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
  • History of allergy to study drug components.
  • History of severe hypersensitivity reaction to any monoclonal antibody
  • Women of childbearing potential who are pregnant or breastfeeding.
  • Women with a positive pregnancy test at enrollment or prior to administration of study medication.
  • Prisoners or subjects who are involuntarily incarcerated, or other vulnerable populations (study is exempt from 45 CFR 46 Subparts B, C, and D).
  • Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness
  Contacts and Locations
Information from the National Library of Medicine

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


Contacts
Contact: Keith T Flaherty, M.D. 617-724-4000 kflaherty@mgh.harvard.edu

Locations
United States, Massachusetts
Massachusettes General Hospital Cancer Center
Boston, Massachusetts, United States, 02114
Sponsors and Collaborators
Syntrix Biosystems, Inc.
Massachusetts General Hospital
The Wistar Institute
National Cancer Institute (NCI)
Investigators
Principal Investigator: Keith T. Flaherty, M.D. Massachusettes General Hospital Cancer Center
  More Information

Responsible Party: Syntrix Biosystems, Inc.
ClinicalTrials.gov Identifier: NCT03161431     History of Changes
Other Study ID Numbers: Syntrix-SX682-Melanoma-101
1R44CA217591-01 ( U.S. NIH Grant/Contract )
First Submitted: May 16, 2017
First Posted: May 19, 2017
Last Update Posted: May 19, 2017
Last Verified: May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Syntrix Biosystems, Inc.:
Immunotherapy
Chemokine receptor blockade
Myeloid-derived suppressor cells

Additional relevant MeSH terms:
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Pembrolizumab
Antineoplastic Agents