Clinical Trials /

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

NCT03161431

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: SX-682 Treatment in Subjects With Metastatic Melanoma Concurrently Treated With Pembrolizumab
  • Official Title: A Phase 1, Open-Label, Dose-Escalation With Expansion Study of SX-682 in Subjects With Metastatic Melanoma Concurrently Treated With Pembrolizumab

Clinical Trial IDs

  • ORG STUDY ID: Syntrix-SX682-Melanoma-101
  • SECONDARY ID: 1R44CA217591-01
  • NCT ID: NCT03161431

Conditions

  • Melanoma Stage Iii
  • Melanoma Stage Iv

Interventions

DrugSynonymsArms
SX-682Monotherapy: SX-682 dose escalation
PembrolizumabKEYTRUDACombination therapy: SX-682 dose escalation and pembrolizumab

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Monotherapy: SX-682 dose escalationExperimentalEscalating 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
Combination therapy: SX-682 dose escalation and pembrolizumabExperimentalSX-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

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:SX-682 Maximum Tolerated Dose (MTD) during Monotherapy Stage
Time Frame:Up to 21 Days in 21 day Cycle 1 of Monotherapy Stage.
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:SX-682 dose limiting toxicities (DLTs) during monotherapy
Time Frame:Up to 21 Days in 21 day Cycle 1.
Safety Issue:
Description:Number of participants experiencing DLTs during monotherapy stage
Measure: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).
Safety Issue:
Description:Number of participants experiencing DLTs during combination therapy stage
Measure:Adverse events during Monotherapy Stage
Time Frame:Up to 21 Days in 21 day Cycle 1 of monotherapy stage.
Safety Issue:
Description:Number of participants experiencing clinical or laboratory adverse events (AEs) including infections and neutropenia.
Measure:Adverse events during combination Therapy Stage
Time Frame:Up to 42 Days in 42 day Cycle 1-17 of Combination Therapy Stage.
Safety Issue:
Description:Number of participants experiencing clinical or laboratory adverse events (AEs) including infections and neutropenia.
Measure: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.
Safety Issue:
Description: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.
Measure: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.
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Syntrix Biosystems, Inc.

Trial Keywords

  • Immunotherapy
  • Chemokine receptor blockade
  • Myeloid-derived suppressor cells

Last Updated

May 18, 2017