A Phase 1 Trial of a Novel XPO1 Inhibitor in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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Study SL-801-0115 is a dose-escalation study evaluating multiple doses and schedules of orally administered SL-801 in patients with Advanced Solid Tumors

Detailed Description
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Study SL-801-0115 is a first-in-human, dose-escalation study in patients with advanced (i.e., metastatic or locally advanced and unresectable) solid tumors that are resistant to or relapsed following available standard systemic therapy or for which there is no standard systemic therapy and additional radiation therapy or other loco-regional therapies are not considered feasible. Eligible patients will be enrolled and receive treatment with SL-801 in a 28-day cycle. SL-801 will be administered orally and the dose regimen will depend on the cohort in which the patient is enrolled. The study plans to enroll approximately 70 adult patients at multiple study centers in the US.

Official Title
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A Phase 1 Trial of SL-801, a Novel Inhibitor of XPO1 Nuclear Export, in Patients With Advanced Solid Tumors

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: SL-801


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient must have histologic or cytologic evidence of a malignant solid tumor and must have disease that is resistant to or relapsed following available standard systemic therapy, or for which there is no standard systemic therapy or reasonable therapy likely to result in clinical benefit. The patient must have advanced disease, defined as cancer that is either metastatic, OR locally advanced and unresectable (and for which additional radiation therapy or other locoregional therapies are not considered feasible). The patient must have disease that is measurable by standard imaging techniques, per the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1), or evaluable per RECIST 1.1. (For patients with prior radiation therapy, measurable lesions must be outside of any prior radiation field[s], unless disease progression has been documented at that disease site subsequent to radiation.) The patient is ≥18 years old. The patient has an ECOG PS of 0-2. The patient has adequate baseline organ function, as demonstrated by the following: Serum creatinine ≤1.5 × institutional upper limit of normal (ULN) or calculated creatinine clearance >30 mL/min. Serum albumin ≥2.5 g/dL. Bilirubin ≤1.5 × institutional ULN. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × institutional ULN (patients with hepatic metastases must have AST/ALT ≤5 times ULN). International normalized ratio (INR) ≤1.5 or prothrombin time (PT) ≤1.5 × ULN; and either partial thromboplastin time or activated partial thromboplastin time (PTT or aPTT) ≤1.5 × ULN. The patient has adequate baseline hematologic function, as demonstrated by the following: Absolute neutrophil count (ANC) ≥1.5×10⁹/L Hemoglobin ≥8 g/dL, with no red blood cell (RBC) transfusions within the prior 14 days. Platelet count ≥100×10⁹/L, with no platelet transfusions within the prior 14 days. If the patient is a woman of child bearing potential (WOCBP), she has had a negative serum or urine pregnancy test within 1 week prior to treatment. The patient (male and female) agrees to use acceptable contraceptive methods for the duration of time on the study, and continue to use acceptable contraceptive methods for 1 month after the last dose of SL-801. The patient has signed informed consent prior to initiation of any study-specific procedures or treatment. The patient is able to adhere to the study visit schedule and other protocol requirements, including follow-up for survival assessment. Exclusion Criteria: The patient has persistent clinically significant ≥Grade 2 toxicities from previous anticancer therapy (excluding Grade 2 chemotherapy-related neuropathy which is permitted, and excluding Grade 2-3 laboratory abnormalities if they are not associated with symptoms, are not considered clinically significant by the Investigator, and can be managed with available medical therapies). The patient has received treatment with chemotherapy, external-beam radiation, or other systemic anticancer therapy within 28 days prior to study entry (Patients with advanced prostate cancer who are receiving luteinizing hormone releasing hormone [LHRH] agonists are permitted onto the study and should continue use of these agents during study treatment). The patient has received treatment with an investigational systemic anticancer agent within 28 days prior to C1D1. The patient has previously received treatment with SL-801 or another investigational agent that inhibits the XPO1/CRM1 pathway. The patient has an additional active malignancy that may confound the assessment of the study endpoints. Patients with a past cancer history (active malignancy within 2 years prior to study entry) with substantial potential for recurrence must be discussed with the Sponsor before study entry. Patients with the following concomitant neoplastic diagnoses are eligible: non-melanoma skin cancer, carcinoma in situ (including transitional cell carcinoma, cervical intraepithelial neoplasia), organ-confined prostate cancer with no evidence of progressive disease. The patient has clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association Class 3 or 4 congestive heart failure [Appendix 1], uncontrolled angina, history of myocardial infarction, unstable angina or stroke within 6 months prior to study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication). The patient has uncontrolled, clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease, pulmonary hypertension) that, in the Investigator's opinion, would put the patient at significant risk for pulmonary complications during the study. The patient has known active or suspected brain or leptomeningeal metastases. (Central nervous system [CNS] imaging is not required prior to study entry unless there is a clinical suspicion of CNS involvement). Patients with stable, treated brain metastases are eligible provided there is no evidence of CNS disease growth on imaging for at least 3 months following radiation therapy or other locoregional ablative therapy to the CNS. The patient is receiving immunosuppressive therapy for prophylaxis following a prior organ transplant (solid organ or allogeneic stem cell) or management of immune-mediated toxicities due to immunotherapy. Low-dose corticosteroid (defined as < 10mg/day of prednisone or equivalent) therapy is permitted. The patient has uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, disseminated intravascular coagulation, or psychiatric illness/social situations that would limit compliance with study requirements. The patient is pregnant or breast feeding. The patient has known positive status for human immunodeficiency virus active or chronic Hepatitis B or Hepatitis C. The patient is oxygen-dependent. The patient has any medical condition which in the opinion of the Investigator places the patient at an unacceptably high risk for toxicities.

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: SL-801<br>The starting dose regimen of SL-801 (i.e., the dose regimen in Cohort 1) is 5 mg/day on Days 1-4 and 8-11 every 21 days. In the 2nd portion of the dose escalation stage, patients receive SL-801 PO once daily on days 1-2, 8-9, 15-16 and 22-23 of a 28-day cycle. The starting dose will be 70 mg/day (the next planned dose level).The SL-801 dose regimen for a particular patient is dependent on the cohort in which the patient is enrolled | Drug: SL-801<br>* SL-801 is a small molecule inhibitor of the nuclear export protein Exportin-1 (XPO1).<br>* Other names: felezonexor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| safety and tolerability: percentage of patients experiencing treatment-related and treatment-emergent adverse events | The percentage of patients experiencing treatment-related and treatment-emergent adverse events | up to 5 years | 
| maximum tolerated dose | To identify the maximum tolerated dose (MTD) of SL-801 or determine the maximum tested dose at which multiple dose-limiting toxicities (DLTs) are not observed. | up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response | to evaluate the duration of response | up to 5 years | 
| Progression Free Survival | to evaluate progression free survive | up to 5 years | 
| Overall Response Rate | to evaluate overall response rate | up to 5 years | 
| Overall Survival | to evaluate overall survival | up to 5 years | 
| Pharmacokinetic Profile | Determine the maximum concentration of SL-801 in plasma | up to 5 years |