The primary objectives are to determine the safety profile of SX-682 alone and in combination
with nivolumab in subjects with refractory RAS mutated MSS mCRC, including the maximum dose
that can be administered until adverse effects prevent further dose increases (i.e., the MTD
or recommended phase 2 dose), and the dose-limiting toxicity (DLT). The secondary objectives
are to: 1) evaluate the efficacy of SX-682 in combination with nivolumab on the basis of the
objective response rate (ORR), the duration of response, and the rate of progression; and 2)
characterize the single-dose and multidose pharmacokinetic (PK) profile of SX-682.
This is a Phase Ib/II, open-label, dose-escalation with expansion study of twice-daily SX-682
in subjects with refractory RAS mutated MSS mCRC treated concurrently with nivolumab
(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. The combination of SX-682 with Nivolumab will demonstrate antitumor
activity, adequate safety and tolerability for patients with refractory mCRC. Refractory RAS
mutated (KRAS or NRAS) MSS mCRC represents an unmet medical need with non-response to immune
checkpoint blockade (ICB). MDACC preclinical models reveal that KRAS mutations drive the
CXCR2 axis and support an immune suppressive phenotype via upregulation of CXCL3 chemokines
increasing MDSC recruitment to the tumor microenvironment. Therefore, this proof of concept
study will investigate whether de novo immunotherapy resistance in MSS RAS mutated CRC can be
overcome by treatment with a small molecule CXCR2 antagonist in combination with anti-PD-1
- Written Informed Consent and HIPAA Authorization Written Informed Consent and HIPAA
1. Subjects must have the nature of the study explained to them.
2. Subjects must be willing and able to comply with scheduled visits, treatment
schedule, laboratory tests, pharmacokinetic collections, and other requirements
of the study.
3. Subjects must provide a signed and dated IRB approved written informed consent
form (ICF) in accordance with regulatory and institutional guidelines for both
the study and exploratory biomarker analyses (e.g., CMS4 and others) on archival
4. Subjects must provide a signed and dated Health Insurance Portability and
Accountability Act (HIPAA) authorization.
5. The ICF and HIPAA authorization must be obtained before conducting any procedures
that do not form a part of the subject's normal care.
6. 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: Target Population
1. Men and women, ages > 18 years of age.
2. Histologically or cytologically confirmed adenocarcinoma of the colon or the
rectum that is metastatic or unresectable.
3. Tumor is determined to be RAS-mutated (KRAS or NRAS) and microsatellite
stable/proficient in mismatch repair, as assessed by IHC and/or PCR/NGS in a CLIA
4. Received at least two prior regimens of therapy for unresectable or metastatic
CRC including fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens.
Patients who relapse within 6 months of adjuvant chemotherapy composed of
oxaliplatin and a fluoropyrimidine will have their adjuvant therapy count as one
5. For the expansion cohort, pre-treatment primary tumor tissue (i.e., archived
paraffinembedded) or from an unresectable metastatic site must be available for
biomarker analyses. Biopsy should be excisional or core needle. Fine needle
aspirates or other cytology samples are insufficient.
6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (Appendix
7. Must have measurable disease with at least 1 unidimensional measurable lesion per
RECIST v1.1 (see Appendix 2).
8. Prior radiotherapy must have been completed at least 2 weeks prior to study drug
9. 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
10. Glomerular filtration rate (GFR) calculated by Cockcroft-Gault formula >60
11. Life expectancy > 12 weeks as judged by the treating physician.
12. 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). If re-enrolled, the subject must be re-consented.
- Target Disease Exceptions
a) 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. An MRI is not required to rule out
brain metastases or leptomeningeal metastases. 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. 2. Medical History and Concurrent Diseases
a) 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:
1. Subjects with active, non-infectious pneumonitis.
2. Subjects with interstitial lung disease or a history of pneumonitis that required
oral or intravenous glucocorticoids to assist with management.
3. Subjects with clinically significant heart disease that affects normal
Clinically significant cardiovascular/ cerebrovascular disease as follows:
cerebral vascular accident / stroke / carotid artery disease / transient ischemic
attack (<6 months prior to enrollment), myocardial infarction (<6 months prior to
enrollment), unstable angina, congestive heart failure (New York Heart
Association Classification Class >II) or serious cardiac arrhythmia. b) 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. c) 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. d) Subjects with a condition
(including organ or bone marrow transplant) requiring systemic treatment with
either corticosteroids (> 10 mg daily prednisone equivalents) or other
immunosuppressive medications. Inhaled or topical steroids, and adrenal
replacement doses > 10 mg daily prednisone equivalents are permitted in the
absence of active autoimmune disease. e) Use of other investigational drugs
(drugs not marketed for any indication) or medications at immunosuppressive doses
within 28 days before study drug administration. f) Prior exposure to any immune
checkpoint blockade agent or any other immunomodulatory agent used for
antineoplastic therapy for mCRC. g) Anticancer treatment within 21 days before
the start of trial treatment [e.g., cytoreductive therapy, radiotherapy (with the
exception of palliative radiotherapy delivered in a normal organ-sparing
technique), immune therapy, or cytokine therapy]. 2019-1151: Version Major
surgery as determined by the investigator within 28 days before the start of
trial treatment (prior diagnostic biopsy is permitted). i) Subjects who have
received a live-virus vaccine within 30 days before study drug administration. j)
Treatment with botanical preparations (e.g., herbal supplements or traditional
Chinese medicines) intended for general health support or to treat the disease
under study within 2 weeks prior to randomization/treatment. k) Patients who are
taking any drug that is known to prolong QTc interval within at least 2 weeks
before the start of trial drug and during the conduct of the trial. 3. Physical
and Laboratory Test Findings
1. Any positive test for hepatitis B virus or hepatitis C virus indicating acute or
chronic infection (HBV surface antigen positive and HBV core antibody positive
with reflex to positive HBV DNA or HBV core antibody positive alone with reflex
to positive HBV DNA or positive HCV antibody with reflex to positive HCV RNA).
2. Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS).
3. Active tuberculosis (history of exposure or history of positive tuberculosis test
plus presence of clinical symptoms, physical or radiographic findings).
4. ECG demonstrating a QTc interval >470 msec or patients with congenital long QT
syndrome. 4. Allergies and Adverse Drug Reaction
a) History of allergy to study drug components (excipients:
hydroxpropylmethylcellulose phthalate (hypromellose phthalate or HPMCP),
microcrystalline cellulose, sodium croscarmellose, sodium lauryl sulfate, and silicon
dioxide). b) History of severe hypersensitivity reaction to any monoclonal antibody
(Grade ≥ 3 NCICTCAE v5).
c) History of anaphylaxis, or recent (within 5 months) history of uncontrolled asthma.
5. Sex and Reproduction Status
1. Women of childbearing potential (WOCBP) must use method(s) of contraception as
indicated in Appendix 4 while on study and for 5 months after the last dose of
SX-682 or nivolumab. 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.
2. 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.
3. 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
4. Women must not be breastfeeding.
5. 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. 2019-1151: Version 2.4 27 May 2020 48
6. Women who are not Women who are not of childbearing potential and azoospermic men
do not require contraception.