Clinical Trials /

SX-682 and Nivolumab for RAS Mutated Microsatellite Stable Metastatic Colorectal Cancer (mCRC) (STOPTRAFFIC-1)

NCT04599140

Description:

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.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: SX-682 and Nivolumab for RAS Mutated Microsatellite Stable Metastatic Colorectal Cancer (mCRC) (STOPTRAFFIC-1)
  • Official Title: Phase Ib/II Trial of SX-682 in Combination With Nivolumab for Refractory RAS Mutated (RAS) Microsatellite Stable (MSS) Metastatic Colorectal Cancer (mCRC) (STOPTRAFFIC-1)

Clinical Trial IDs

  • ORG STUDY ID: 2019-1151
  • NCT ID: NCT04599140

Conditions

  • Metastatic Colorectal Cancer

Interventions

DrugSynonymsArms
CXCR1/2 Inhibitor SX-682SX 682, SX-682, SX682Treatment (SX-682, nivolumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (SX-682, nivolumab)

Purpose

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.

Detailed Description

      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
      therapy (nivolumab).
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (SX-682, nivolumab)ExperimentalMONOTHERAPY STAGE: Patients receive SX-682 orally PO BID on days 1-21 in the absence of disease progression or unacceptable toxicity. COMBINATION STAGE: Patients receive SX-682 PO BID on days 1-56 and nivolumab IV over 30 minutes on days 1 and 29. Treatment repeat every 56 days weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
  • CXCR1/2 Inhibitor SX-682
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Written Informed Consent and HIPAA Authorization Written Informed Consent and HIPAA
             Authorization

               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
                  tissue.

               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
                  environment.

               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
                  prior regimen.

               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

                    1. .

               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
                  administration.

               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
                  ml/min.

              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.

        Exclusion Criteria:

          -  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
                  activities.

                  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
                  drug.

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

Primary Outcome Measures

Measure:Incidence of adverse events (AEs)
Time Frame:Up to 2 years
Safety Issue:
Description:For each system organ class and preferred term, summaries will be made with respect to the number and proportion of subjects having at least 1 occurrence of an adverse event during the study. The incidence of AEs will be presented overall, by system organ class and preferred term, intensity (based on National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0), immune-related adverse events, treatment-emergent adverse events, and additional grouping by severity and relationship to study drug. Individual listings of adverse events will be provided. Dose limiting toxicities and study drug-related grade >= 2 adverse events will be listed individually.

Secondary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:Up to 2 years
Safety Issue:
Description:Patient response will be determined using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Unconfirmed responses will not be used in the final analysis. ORR is defined by the number of (partial response + complete response)/ (total number of treated patients) in the cohort. Will estimate the response rate along with the two-sided exact 95% confidence interval.
Measure:Progression-free survival (PFS)
Time Frame:Up to 2 years
Safety Issue:
Description:Assessed according to RECIST 1.1. Median PFS and 95% confidence intervals will be estimated using the Kaplan-Meier method.
Measure:Overall survival (OS)
Time Frame:Up to 2 years
Safety Issue:
Description:OS time will be presented using the Kaplan-Meier method. Median OS with 95% confidence interval will be estimated using the Kaplan-Meier method.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • metastatic colorectal cancer
  • microsatellite stable
  • KRAS mutation
  • NRAS mutation

Last Updated

October 22, 2020