MC# 16-09 - A Phase I Study of SL-801, a Reversible Inhibitor of Nuclear Export, in Patients with Advanced Solid Tumors

  • Agent(s): SL-801
  • Disease Type(s): Bladder, Breast, Cervical, Colorectal, Endometrial, Esophageal, Gastric, Head and Neck, Hepatocellular, Lung-NSCLC, Lung-SCLC, Melanoma, Mesothelioma, Neuroendocrine, Ovarian, Pancreatic, Prostate, Renal, Sarcoma, Solid Tumor, Squamous Cell, Thyroid
  • Phase(s): I
  • Drug Classification(s): Targeted Therapy, Small Molecule
  • Molecular Target(s): XPO1

Mechanism of Action

SL-801 is a new class of an anti-cancer drug that has begun testing in cancer subjects.  This new class of drugs, termed XPO1 inhibitors, can block  XPO1, which is a protein responsible for transporting various tumor-suppressing proteins (such as p53) out of the cell nucleus.  In normal cells, these tumor-suppressing proteins are located in the nucleus to monitor cell growth and sense any DNA damage, and provide protection against damage or mutations to the cell’s DNA.  When these tumor-suppressing proteins are transported out of the nucleus by XPO1, they are unable to perform their protective function, possibly leading to unchecked cell growth or malignancy.  By blocking XPO1 in tumor cells, the drug SL-801  is designed to keep tumor-suppressing proteins in the nucleus, where they can respond to damage within the nucleus and regulate harmful cell growth.  The anti-cancer effect of SL-801 has been demonstrated in various scientific studies using both cancer cells and animal models of cancer in laboratories.  This study is the first time SL-801 will be tested in human cancer subjects.

Purpose

In this study, the sponsor and investigators want to learn:

  • How much of the study drug SL-801 can be given with an acceptable level of side effects;
  • How much SL-801, taken orally, is absorbed into the blood, how it is distributedand transformed in the human body, and how fast it is removed;
  • What anti-cancer benefits SL-801 will have for cancer subjects;
  • If research tests related to this study can predict who will benefit from SL-801.
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 times 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 and no red blood cell (RBC) transfusions during the prior 14 days
    • Platelet count ≥100×109/L and no platelet transfusions during 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 treatment with 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 toxicities Grade ≥2 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 14 days prior to study entry (28 days for prior nitrosourea or mitomycin-C). (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 14 days prior to study entry
  • 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 opinion of the Investigator 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). Corticosteroid 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

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT02667873?term=SL-801&rank=1

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Re: MC# 16-09