SX-682 With Pembrolizumab for the Treatment of Metastatic or Recurrent Stage IIIC or IV Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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This phase II trial tests whether CXCR1/2 inhibitor SX-682 (SX-682) with pembrolizumab works to treat patients with stage IIIC or IV non-small cell lung cancer that has spread to other parts of the body (metastatic) or that has come back (recurrent). SX-682 is a drug that binds to receptors on some types of immune and cancer cells, inhibiting signaling pathways, reducing inflammation, and allowing other types of immune cells to kill and eliminate cancer cells. Pembrolizumab is a monoclonal antibody that binds to a receptor called PD-1 that is found on the surface of T-cells (a type of immune cell), activating an immune response against tumor cells. Giving SX-682 in combination with pembrolizumab may be more effective at treating patients with metastatic or recurrent non-small cell lung cancer than giving these treatments alone.

Detailed Description
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OUTLINE: Patients receive SX-682 orally (PO) twice daily (BID), starting 7 days prior to the start of pembrolizumab, and pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 3 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy and positron emission tomography (PET)/computed tomography (CT) or CT at screening and on study and undergo magnetic resonance imaging (MRI) and collection of blood samples at screening, throughout the study, and during follow up. After completion of study treatment, patients are followed up for up to 60 months.

Official Title
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A Phase 2 Trial of SX-682 and Pembrolizumab in Patients With Treatment Naive Stage IV or Recurrent Non-Small Cell Lung Cancer

Conditions
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Metastatic Lung Non-Small Cell Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Stage IIIC Lung Cancer AJCC v8, Stage IV Lung Cancer AJCC v8

Intervention / Treatment
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* Procedure: Biopsy
* Procedure: Biospecimen Collection
* Procedure: Computed Tomography
* Drug: CXCR1/2 Inhibitor SX-682
* Procedure: Magnetic Resonance Imaging
* Biological: Pembrolizumab
* Procedure: Positron Emission Tomography


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects aged 18 years and older Pathologically or cytologically confirmed non-small cell lung cancer with no known oncogenic EGFR mutation, ALK rearrangement, ROS1 rearrangement or RET fusions Tumoral PD-L1 expression >=1% by any Clinical Laboratory Improvement Act (CLIA)-certified assay Metastatic or recurrent non-small cell lung cancer (NSCLC). Stage IIIC per 8th edition TNM stage classification is allowed if not amenable to curative surgery or radiation per investigator judgment At least one site of measurable disease as determined by the Investigator, using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. Subjects must have ECOG PS 0 or 1 at the time of informed consent and at the time of treatment initiation Must be willing to provide pre-treatment archived specimen or undergo a biopsy procedure if archived specimen is not available Must be willing to provide an on-treatment biopsy, if deemed safe by the treating physician Platelet count >= 100,000/uL Absolute neutrophil count >= 1,500/uL Hemoglobin >= 8g/dL Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 times upper limit of normal Creatinine =< 2.0 mg/dL Women of child-bearing potential and sexually active men must agree to use adequate contraception (hormonal or barrier method) prior to treatment initiation, during treatment and for three months after completing treatment Negative beta-human chorionic gonadotropin (hCG) pregnancy test at screening for patients of childbearing potential. Pregnant or breast feeding women are not eligible Signed and dated informed consent document indicating that the patient has been informed of all the pertinent aspects of the trial prior to enrollment Exclusion Criteria: Prior chemotherapy or immune checkpoint inhibitor or immune-modulatory therapy (e.g. anti-PD[L]1, anti-CTLA4, anti-TIM3, anti-GITR, anti-TIGIT, anti-LAG3), for metastatic or recurrent disease Prior chemotherapy and immune checkpoint inhibitor and immune modulatory therapy in the curative setting is allowed as long as treatment was completed > 6 months prior to consenting For patients with NSCLC harboring an oncogenic alteration other than listed may have received prior small molecule inhibitor therapy (e.g. MET inhibitor for MET exon 14 mutated NSCLC). A wash-out period of at least 5 half-lives is required prior to start of study treatment Presence of other active cancers within the last 2 years. Patients with stage I cancer who have received definitive local treatment at least 2 years previously and no evidence of recurrence are eligible. All patients with previously treated in situ carcinoma are eligible, as patients with history of non-melanoma skin cancer Symptomatic central nervous system (CNS) metastases; participants with known brain metastasis must be asymptomatic with no steroids or antiepileptics within 7 days prior to start of study treatment Patients with untreated CNS metastases may be enrolled as long as they meet the above criteria. Patients with bulky CNS metastases should consider receiving radiation prior to study entry per investigator judgment Participants with spinal cord compression must have received local treatment and must have been symptomatically stable with no use of steroids for at least 7 days prior to start of study treatment Participants must not have an active autoimmune disease that has required immune modulating treatment within 1 year prior to consenting (i.e., disease modifying agents, corticosteroids). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is allowed Inability to discontinue corticosteroid therapy; steroids must be tapered off 7 days prior to first dose of SX-682 Known history of primary immunodeficiency History of organ transplant that requires use of immunosuppressives Current symptomatic pneumonitis and any past history of immune checkpoint inhibitor related pneumonitis regardless of steroid treatment history History of non-infectious pneumonitis (e.g. radiation pneumonitis) that required steroids within 6 months of start of study treatment Radiotherapy within 7 days of start of study treatment Major surgery within 21 days of start of study treatment. Minor surgery within 2 weeks of start of study treatment. Placement of vascular access device and biopsies are not considered major or minor surgery and are allowed Electrocardiogram (EKG) demonstrating a corrected QT (QTc) interval > 480 msec on three consecutive EKGs or patients with congenital long QT syndrome Severe lung disease (e.g. chronic obstructive pulmonary disease [COPD]) who cannot stop steroids 7 days prior to start of study treatment Serious cerebrovascular and cardiac disease defined as: Active unstable angina pectoris Congestive heart failure NYHA (New York Heart Association) > grade 3 Acute myocardial infarction within 3 months of consenting Stroke or transient ischemic attack within 3 months of consenting Known active chronic infections: Active hepatitis B, hepatitis C and tuberculosis. Testing is not required for assessment of eligibility. Active infection requiring IV antibiotics within 7 days of study treatment initiation Hepatitis C virus (HCV) infection: Patients with known history of HCV infection are eligible if HCV viral load is below the limit of quantification per local assay Hepatitis B virus (HBV) infection: Patients with known history of HBV infection are eligible if HBV viral load is below the limit of quantification and negative hepatitis B virus surface antigen (HBsAg) per local assay Known uncontrolled HIV (human immunodeficiency virus) infection Participants with known HIV infection are allowed if they are receiving anti-retroviral therapy, have CD4+ T-cell count >= 350 cells/uL within 6 months prior to study treatment initiation and no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection Any serious or uncontrolled concomitant disorder that, in the opinion of the investigator, would compromise the patient's ability to complete the study Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (SX-682, pembrolizumab)<br>Patients receive SX-682 PO BID, starting 7 days prior to the start of pembrolizumab, and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 3 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy and PET/CT or CT at screening and on study and undergo MRI and collection of blood samples at screening, throughout the study, and during follow up. | Procedure: Biopsy<br>* Undergo biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo PET/CT or CT<br>* Other names: tomography;Drug: CXCR1/2 Inhibitor SX-682<br>* Given PO<br>* Other names: SX682;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Nuclear Magnetic Resonance Imaging;Biological: Pembrolizumab<br>* Given IV<br>* Other names: Pembrolizumab Biosimilar BCD-201;Procedure: Positron Emission Tomography<br>* Undergo PET/CT<br>* Other names: proton magnetic resonance spectroscopic imaging;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best objective response rate | Response is defined as a complete response (CR) or partial response (PR) as best objective response. For the primary analyses, binary proportions will be estimated along with 90% confidence intervals (consistent with 1-sided 5% level testing). | Up to 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate within cohorts | Evaluated within the cohorts separately (>= 50% and 1-49% PD-L1 tumor proportion score). Will evaluate the response rate within the cohorts separately. Within each cohort, the response rates and associated 80% confidence intervals will be estimated. | Up to 6 years | 
| Disease control rate |  | Up to 6 years | 
| Duration of response | Will be estimated using the method of Kaplan-Meier. Confidence intervals about medians will be estimated using the Brookmeyer-Crowley method. | Date of first documentation of confirmed response (CR or PR) to date of first documentation of progression, assessed up to 6 years | 
| Progression-free survival | Will be estimated using the method of Kaplan-Meier. Confidence intervals about medians will be estimated using the Brookmeyer-Crowley method. | Date of study registration to date of first documentation of progression, assessed up to 6 years | 
| Overall survival | Will be estimated using the method of Kaplan-Meier. Confidence intervals about medians will be estimated using the Brookmeyer-Crowley method. | Date of study registration to date of death due to any cause, assessed up to 6 years | 
| Frequency and severity of adverse events | Toxicity frequencies will be estimated with 95% confidence. | Up to 6 years |