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.
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.
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.
- 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 at least 3 weeks
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).
- 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.
- 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
- Glomerular filtration rate (GFR) calculated by Cockcroft-Gault formula >60
ml/min.
- 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 (mucosal melanoma is acceptable).
- 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.
- 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).
- ECG demonstrating a QTc interval >470 msec or patients with congenital long QT
syndrome.
- 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
