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A Study Evaluating the Safety and Pharmacokinetics of Orally Administered SM08502 in Subjects With Advanced Solid Tumors

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ClinicalTrials.gov Identifier: NCT03355066
Recruitment Status : Recruiting
First Posted : November 28, 2017
Last Update Posted : June 3, 2021
Sponsor:
Information provided by (Responsible Party):
Biosplice Therapeutics, Inc.

Brief Summary:

This study is an open-label, multi-center, dose-escalation, dose-finding and expansion study in adult subjects with advanced solid tumors for whom no standard therapy is available. The study will evaluate the safety, tolerability, PK, PD, and preliminary anti-tumor efficacy of SM08502 administered orally, once daily, following a 28-day treatment cycle (Part 1A). Alternative dosing schedules will be explored in Part 1B and the recommended Part 2 dose and schedule will be further evaluated in Part 2.

Subjects will participate in a screening period of up to 14 days. Dosing in 28-day cycles will continue within each subject, unless treatment is discontinued due to toxicity, disease progression, initiation of a new anti-neoplastic therapy, withdrawal of consent, the Sponsor terminates the study, or the subject no longer meets retreatment criteria.


Condition or disease Intervention/treatment Phase
Solid Tumor, Adult Drug: SM08502 Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 180 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1, Open-Label, Dose-Escalation, Dose-Finding Study Evaluating the Safety and Pharmacokinetics of Orally Administered SM08502 in Subjects With Advanced Solid Tumors
Actual Study Start Date : November 6, 2017
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2022

Arm Intervention/treatment
Experimental: Part 1A: Dose Escalation
Cohorts of subjects with advanced solid tumors will receive increasing doses (10, 20, 40, 60, 80, 120, 160, or 200 mg) of SM08502, administered orally, once daily, following 28-day treatment cycles. If the maximum tolerated dose (MTD) is not determined at the 200 mg dose, dosing will continue at 50 mg/dose increments until an MTD is determined. Cohorts will include approximately 1 to 6 subjects according to an accelerated escalation design and safety requirements for expansion of subject numbers. For the purpose of dose escalation and de-escalation, the dose of SM08502 and regimen may be modified based on the type of dose limiting toxicities (DLTs) observed and following data review and discussions between the Sponsor and Investigators.
Drug: SM08502
SM08502 tablets to be administered orally.

Experimental: Part 1B: Dose Finding
Indications eligible for Part 1B include castration-resistant prostate cancer (CRPC), non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), colorectal cancer (CRC), endometrial cancer, or ovarian cancer for which histologic or cytologic confirmation of malignancy was obtained at diagnosis. Initially, two cohorts of 6-24 subjects will be evaluated comparing 2 different doses and schedules of SM08502 (30 mg daily and 40 mg 5 days on and 2 days off), administered orally following 28-day treatment cycles. If appropriate, alternative doses and schedules may be evaluated depending on the results.
Drug: SM08502
SM08502 tablets to be administered orally.

Experimental: Part 2: Expansion
Part 2 will evaluate the recommended Part 2 dose and schedule of SM08502, as determined in Part 1B, in 6 cohorts of subjects. The indications to be evaluated include subjects with advanced and/or metastatic CRPC, NSCLC, TNBC, CRC, endometrial cancer, and ovarian cancer for which histologic or cytologic confirmation of malignancy was obtained at diagnosis. Each cohort will enroll approximately 20 subjects.
Drug: SM08502
SM08502 tablets to be administered orally.




Primary Outcome Measures :
  1. Part 1A: Maximum tolerated dose (MTD) of SM08502 based on the frequency and severity of dose-limiting toxicities (DLTs) [ Time Frame: DLT period of 28 days per dose level ]
  2. Part 1A, Part 1B and Part 2: Number of participants with treatment-emergent adverse events (TEAEs) as assessed by CTCAE v5.0 [ Time Frame: Approximately 5 years ]
  3. Part 1A, Part 1B and Part 2: Change from baseline in blood chemistry parameters: blood urea nitrogen [BUN], creatinine, glucose, potassium, sodium, calcium (micromoles per liter) [ Time Frame: Approximately 5 years ]
  4. Part 1A, Part 1B and Part 2: Change from baseline in blood chemistry parameters: aspartate aminotransferase [AST], alanine aminotransferase (ALT), alkaline phosphatase [ALP] (international units per liter) [ Time Frame: Approximately 5 years ]
  5. Part 1A, Part 1B and Part 2: Change from baseline in blood chemistry parameters: albumin (grams per day) [ Time Frame: Approximately 5 years ]
  6. Part 1A, Part 1B and Part 2: Change from baseline in blood chemistry parameters: chloride, bicarbonate (millimoles per liter) [ Time Frame: Approximately 5 years ]
  7. Part 1A, Part 1B and Part 2: Change from baseline in blood chemistry parameter: lactic acid dehydrogenase [LDH] (units per liter) [ Time Frame: Approximately 5 years ]
  8. Part 1A, Part 1B and Part 2: Change from baseline in hematology parameter: hemoglobin [Hb] (grams per liter) [ Time Frame: Approximately 5 years ]
  9. Part 1A, Part 1B and Part 2: Change from baseline in hematology parameter: hematocrit (proportion of red blood cells in blood) [ Time Frame: Approximately 5 years ]
  10. Part 1A, Part 1B and Part 2: Change from baseline in hematology parameter: red blood cells [RBC] count (trillion cells per liter) [ Time Frame: Approximately 5 years ]
  11. Part 1A, Part 1B and Part 2: Change from baseline in hematology parameters: neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count (giga cells per liter) [ Time Frame: Approximately 5 years ]
  12. Part 1A, Part 1B and Part 2: Change from baseline in prothrombin time [PT] (seconds) [ Time Frame: Approximately 5 years ]
  13. Part 1A, Part 1B and Part 2: Change from baseline in partial thromboplastin time [PTT] (seconds) [ Time Frame: Approximately 5 years ]
  14. Part 1A, Part 1B and Part 2: Change from baseline in urinalysis parameter: clarity [ Time Frame: Approximately 5 years ]
  15. Part 1A, Part 1B and Part 2: Change from baseline in urinalysis parameter: specific gravity (ratio) [ Time Frame: Approximately 5 years ]
  16. Part 1A, Part 1B and Part 2: Change from baseline in urinalysis parameter: urine pH [ Time Frame: Approximately 5 years ]
  17. Part 1A, Part 1B and Part 2: Change from baseline in urinalysis parameter: protein [ Time Frame: Approximately 5 years ]
  18. Part 1A, Part 1B and Part 2: Change from baseline in urinalysis parameter: glucose (millimole per liter) [ Time Frame: Approximately 5 years ]
  19. Part 1A, Part 1B and Part 2: Change from baseline in urinalysis parameter: ketones (millimoles per liter) [ Time Frame: Approximately 5 years ]
  20. Part 1A, Part 1B and Part 2: Change from baseline in urinalysis parameter: occult blood (10^9 cells per liter) [ Time Frame: Approximately 5 years ]
  21. Part 1A, Part 1B and Part 2: Change from baseline in urinalysis parameter: nitrite [ Time Frame: Approximately 5 years ]
  22. Part 1A, Part 1B and Part 2: Change from baseline in urinalysis parameter: leukocytes (counts per high power field) [ Time Frame: Approximately 5 years ]
  23. Part 1A, Part 1B and Part 2: Change from baseline in body temperature (degrees celsius) [ Time Frame: Approximately 5 years ]
  24. Part 1A, Part 1B and Part 2: Change from baseline in pulse rate (beats per minute) [ Time Frame: Approximately 5 years ]
  25. Part 1A, Part 1B and Part 2: Change from baseline in respiratory rate (breaths per minute) [ Time Frame: Approximately 5 years ]
  26. Part 1A, Part 1B and Part 2: Change from baseline in blood pressure (systolic and diastolic) (millimeters of mercury) [ Time Frame: Approximately 5 years ]
  27. Part 1A, Part 1B and Part 2: Change from baseline in electrocardiogram (ECG) parameters: PR interval, QRS interval, QT interval, QTcF (milliseconds) [ Time Frame: Approximately 5 years ]
  28. Part 1A and Part 1B: Cmax of SM08502 and its metabolite (SM08955) following single dose administration of SM08502 [ Time Frame: Approximately 5 years ]
  29. Part 1A and Part 1B: tmax of SM08502 and SM08955 following single dose administration of SM08502 [ Time Frame: Approximately 5 years ]
  30. Part 1A and Part 1B: AUC0-24 of SM08502 and SM08955 following single dose administration of SM08502 [ Time Frame: Approximately 5 years ]
  31. Part 1A and Part 1B: AUClast of SM08502 and SM08955 following single dose administration of SM08502 [ Time Frame: Approximately 5 years ]
  32. Part 1A and Part 1B: Cmax,ss of SM08502 and SM08955 following repeat dose administration of SM08502 [ Time Frame: Approximately 5 years ]
  33. Part 1A and Part 1B: Cmin,ss of SM08502 and SM08955 following repeat dose administration of SM08502 [ Time Frame: Approximately 5 years ]
  34. Part 1A and Part 1B: tmax,ss of SM08502 and SM08955 following repeat dose administration of SM08502 [ Time Frame: Approximately 5 years ]
  35. Part 1A and Part 1B: AUC0-24,ss of SM08502 and SM08955 following repeat dose administration of SM08502 [ Time Frame: Approximately 5 years ]
  36. Part 2: Tumor response as measured by RECIST 1.1 (Response Evaluation Criteria In Solid Tumors) or PCWG3 (Prostate Cancer Working Group 3) criteria where appropriate [ Time Frame: Approximately 5 years ]

Secondary Outcome Measures :
  1. Part 1A and Part 1B: Tumor response as measured by RECIST 1.1 or PCWG3 criteria where appropriate [ Time Frame: Approximately 5 years ]
  2. Part 1B and Part 2: Gene expression profile of RNA isolated from whole blood [ Time Frame: Approximately 5 years ]
  3. Part 2: Cmax of SM08502 and SM08955 following single dose administration of SM08502 [ Time Frame: Approximately 5 years ]
  4. Part 2: tmax of SM08502 and SM08955 following single dose administration of SM08502 [ Time Frame: Approximately 5 years ]
  5. Part 2: AUC0-24 of SM08502 and SM08955 following single dose administration of SM08502 [ Time Frame: Approximately 5 years ]
  6. Part 2: AUClast of SM08502 and SM08955 following single dose administration of SM08502 [ Time Frame: Approximately 5 years ]
  7. Part 2: Cmax,ss of SM08502 and SM08955 following repeat dose administration of SM08502 [ Time Frame: Approximately 5 years ]
  8. Part 2: Cmin,ss of SM08502 and SM08955 following repeat dose administration of SM08502 [ Time Frame: Approximately 5 years ]
  9. Part 2: tmax,ss of SM08502 and SM08955 following repeat dose administration of SM08502 [ Time Frame: Approximately 5 years ]
  10. Part 2: AUC0-24,ss of SM08502 and SM08955 following repeat dose administration of SM08502 [ Time Frame: Approximately 5 years ]
  11. Part 2: Splicing perturbations in post-treatment tumor specimens compared to pre-treatment tumor specimens [ Time Frame: Approximately 5 years ]
  12. Part 2: Gene mutations in post-treatment tumor specimens compared to pre-treatment tumor specimens [ Time Frame: Approximately 5 years ]
  13. Part 2: Expression-function of genes in post-treatment tumor specimens compared to pre-treatment tumor specimens [ Time Frame: Approximately 5 years ]
  14. Part 2: Expression-function of transcripts in post-treatment tumor specimens compared to pre-treatment tumor specimens [ Time Frame: Approximately 5 years ]
  15. Part 2: Expression-function of proteins in post-treatment tumor specimens compared to pre-treatment tumor specimens [ Time Frame: Approximately 5 years ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  1. Subjects with advanced solid tumors (as defined below):

    1. Part 1A - Subjects with advanced solid tumors who are refractory to or intolerant of established therapy known to provide clinical benefit for their condition (i.e., subjects must not be candidates for regimens known to provide clinical benefit) and for which histologic or cytologic confirmation of malignancy was obtained at diagnosis, with the exception of hepatocellular carcinoma if it meets appropriate imaging-only diagnostic criteria [per the National Comprehensive Cancer Network (NCCN), Liver Imaging Reporting and Data System (LI-RADS), American Association for the Study of Liver Diseases (AASLD), Asian Pacific Association for the Study of the Liver (APASL), or European Association for the Study of the Liver - European Organisation for Research and Treatment of Cancer (EASL-EORTC)].
    2. Part 1B - Subjects with advanced and/or metastatic solid tumors who are refractory to or intolerant of established therapy known to provide clinical benefit for their condition (i.e., subjects must not be candidates for regimens known to provide clinical benefit). Histologic or cytologic confirmation of malignancy must have been obtained at diagnosis. The indications eligible for Part 1B include: i. NSCLC, ii.TNBC, iii. CRPC, iv. CRC, v. Endometrial cancer, vi. Ovarian cancer
    3. Part 2 - Subjects with advanced and/or metastatic solid tumors who are refractory to or intolerant of established therapy known to provide clinical benefit for their condition. Histologic or cytologic confirmation of malignancy must have been obtained at diagnosis. Subjects must have received at least two lines of prior therapy. The indications eligible for Part 2 include: i. NSCLC, ii. TNBC, iii. CRPC, iv. CRC, v. Endometrial cancer, vi. Ovarian cancer
  2. Measurable or evaluable disease per RECIST 1.1 (Part 1A). For Parts 1B and 2, at least one measurable lesion per RECIST 1.1 that has not been previously irradiated. In CRPC subjects (Parts 1B and 2) without measurable disease per RECIST 1.1, a PSA that is concordant with clinical disease progression (rising) is eligible. A PSA value of 2 ng/ml or greater is required for study entry.
  3. Subjects must have recovered (i.e., Grade 1 [or better] based on CTCAE v5.0) from all toxicity associated with previous chemotherapy, targeted therapy, experimental therapy, biological therapy, immuno-oncology therapy, surgery, radiotherapy, or other locoregional therapy. (Exception: Subjects may enter with continuing alopecia regardless of any CTCAE grade or with Grade 2 or better neuropathy.) The following intervals must elapse between end of last treatment and receiving the first dose of SM08502:

    1. Chemotherapy: 3 weeks
    2. Mitomycin C or a nitrosourea: 6 weeks
    3. Radiotherapy: 3 weeks
    4. Major surgery: 6 weeks
    5. Targeted therapy, including monoclonal antibodies and immuno-oncology therapies: 4 weeks or 5 half-lives, whichever is shortest
    6. Anti-hormonal therapy: 3 weeks. The exception is ADT for subjects with CRPC who are progressing on therapy, ADT may be continued in this study.
    7. Experimental therapy: 4 weeks or 5 half-lives, whichever is shortest
    8. Other locoregional therapy [e.g., radiofrequency ablation (RFA), TACE (transarterial chemoembolization), TARE (transarterial radioembolization), DEB-TACE (drug eluting bead transarterial chemoembolization)]: 6 weeks
  4. Subjects must meet the following laboratory criteria at Screening for study entry:

    1. Hepatic function: serum total bilirubin ≤ 1.5x upper limit of normal (ULN), AST/ALT ≤ 2.5x ULN. For subjects with Gilbert's syndrome, serum total bilirubin ≤ 3x ULN
    2. Renal function: measured or calculated creatinine clearance via Cockcroft-Gault formula >35 mL/min
    3. Hematology: absolute neutrophil counts ≥ 1500/mm3, platelet counts ≥ 100,000/mm3, hemoglobin ≥ 9.0 g/dL Subjects with values within 10% of these limits deemed not clinically significant by the Investigator may be entered with the approval of the Sponsor's Medical Monitor.
  5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1

Key Exclusion Criteria:

  1. Women who are pregnant or lactating
  2. Women of childbearing potential (WOCBP) who do not agree to follow the contraceptive guidelines as outlined in the study protocol
  3. Men of reproductive potential who do not agree to follow the contraceptive guidelines as outlined in the study protocol
  4. Subjects with a QTc (Fridericia's) prolongation > CTCAE v5.0 Grade 1 (>480 msec) at Screening
  5. Subjects with clinically significant ventricular tachycardia (VT), atrial fibrillation (AF), ventricular fibrillation (VF), second or third degree heart block
  6. Subjects with myocardial infarction (MI) within 1 year, Class II-IV congestive heart failure (CHF) per New York Heart Association (NYHA) classification, or clinically significant coronary artery disease (CAD)
  7. Subjects with active infection requiring antibiotic therapy
  8. Subjects with a second malignancy unless adequately treated with no recurrence for 3 years. Subjects with a history of previous or recent adequately treated skin basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ of any source are eligible.
  9. Subjects with active gastrointestinal (GI) disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of SM08502 per Investigator's opinion
  10. Subjects with known active human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection
  11. Subjects with chronic liver disease or dysfunction and a Child-Pugh score of B or C

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03355066


Contacts
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Contact: Biosplice Clinical Trials 1-855-222-0515 clinicaltrials@biosplice.com

Locations
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Sponsors and Collaborators
Biosplice Therapeutics, Inc.
Investigators
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Study Chair: Darrin Beaupre, MD, PhD, CMO Biosplice Therapeutics, Inc.
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Biosplice Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT03355066    
Other Study ID Numbers: SM08502-ONC-01
First Posted: November 28, 2017    Key Record Dates
Last Update Posted: June 3, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Biosplice Therapeutics, Inc.:
SM08502
pan Clk/Dyrk inhibitor
Additional relevant MeSH terms:
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Neoplasms