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

• ClinicalTrials.gov Identifier: NCT03355066
• Recruitment Status: Active, not recruiting
• First Posted: November 28, 2017
• Last Update Posted: October 19, 2022
• Sponsor: Biosplice Therapeutics, Inc.
• Information provided by (Responsible Party): Biosplice Therapeutics, Inc.

Study Description

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.

Approximately 10 subjects enrolled in Part 2, irrespective of the tumor type, will be included in a food effect substudy to assess the preliminary effect of a high-fat, high-calorie meal on the PK of SM08502. Subjects participating in the food effect substudy will continue on study and complete assessments as per the Part 2 schedule and receive SM08502 at the recommended Part 2 dose (or another previously assessed dose level and schedule).

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 82 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 2023
• Estimated Study Completion Date: December 2025

Arms and Interventions

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 3 cohorts of subjects. The indications to be evaluated include subjects with advanced and/or metastatic CRPC (two biomarker selection cohorts) and NSCLC for which histologic or cytologic confirmation of malignancy was obtained at diagnosis. Each cohort will enroll up to 20 subjects. Approximately 10 subjects of the total enrolled in Part 2, irrespective of cohort, will be included in a food-effect substudy to assess the preliminary effect of a high-fat, high-calorie meal on the PK of SM08502.	Drug: SM08502; SM08502 tablets to be administered orally.

Outcome Measures

Primary Outcome Measures :

1. Part 1A, Part 1B: 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 (cells/microliter) [ Time Frame: Approximately 5 years ]
12. Part 1A: Change from baseline in prothrombin time [PT] (seconds) [ Time Frame: Approximately 5 years ]
13. Part 1A: Change from baseline in partial thromboplastin time [PTT] (seconds) [ Time Frame: Approximately 5 years ]
14. Part 1A: Change from baseline in urinalysis parameter: clarity [ Time Frame: Approximately 5 years ]
15. Part 1A: Change from baseline in urinalysis parameter: specific gravity (ratio) [ Time Frame: Approximately 5 years ]
16. Part 1A: Change from baseline in urinalysis parameter: urine pH [ Time Frame: Approximately 5 years ]
17. Part 1A: Change from baseline in urinalysis parameter: protein [ Time Frame: Approximately 5 years ]
18. Part 1A: Change from baseline in urinalysis parameter: glucose (millimole per liter) [ Time Frame: Approximately 5 years ]
19. Part 1A: Change from baseline in urinalysis parameter: ketones (millimoles per liter) [ Time Frame: Approximately 5 years ]
20. Part 1A: Change from baseline in urinalysis parameter: occult blood (10^9 cells per liter) [ Time Frame: Approximately 5 years ]
21. Part 1A: Change from baseline in urinalysis parameter: nitrite [ Time Frame: Approximately 5 years ]
22. Part 1A: 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 1A, 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: Gene expression and splicing alterations in post-treatment compared to pre-treatment tumor specimens [ Time Frame: Approximately 5 years ]
12. Part 2 Food Effect substudy: Cmax of SM08502 and SM08955 following single dose administration of SM08502 in fed and fasted states. [ Time Frame: Approximately 5 years ]
13. Part 2 Food effect substudy: tmax of SM08502 and SM08955 following single dose administration of SM08502 in fed and fasted states. [ Time Frame: Approximately 5 years ]
14. Part 2: AUC0-24 of SM08502 and SM08955 following single dose administration of SM08502 in fed and fasted states. [ Time Frame: Approximately 5 years ]

Eligibility Criteria

• 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 in the Investigator's judgment). Histologic or cytologic confirmation of malignancy must have been obtained at diagnosis. The tumor types include: i. NSCLC (adenocarcinoma subtype) ii. TNBC iii. CRPC iv. CRC v. Endometrial cancer (endometrioid subtype) vi. Ovarian cancer (serous, mucinous, and endometrioid subtypes).
   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 no more than 2 prior lines of myelosuppressive chemotherapy. Additionally, CRPC subjects must have received no more than 4 total lines of treatment (including any hormonal therapies) in any setting. The tumor types include: i. NSCLC (adenocarcinoma subtype) ii. CRPC in two biomarker selected cohorts.
2. Measurable or evaluable disease per RECIST 1.1 (Part 1A). For Parts 1B and 2, at least 1 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 archived tumor specimens available for analysis (as specified in Section 7.2.2). Otherwise, a fresh tumor biopsy will be required at study entry. At the discretion of the Sponsor's Medical Monitor, a fresh tumor biopsy may not be required for eligibility if there are extenuating circumstances (e.g., inaccessible sites of disease or lack of subject suitability to undergo a fresh biopsy, or molecular profiling of archived tissue already performed).
4. 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 (Exceptions include subjects with: continuing alopecia regardless of any CTCAE grade, Grade 2 or lower neuropathy, and well-controlled hypothyroidism and/or adrenal insufficiency on chronic hormone replacement. All subjects with these exceptions are eligible).
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 corrected QT interval (QTc) using Fridericia's formula (QTcF) > CTCAE v5.0 Grade 1 (>480 msec) based on the mean of triplicate evaluation 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 parenteral antibiotic therapy.
8. Organ transplant recipients.
9. Subjects with known osteoporosis.
10. Subjects with a second malignancy unless adequately treated with no recurrence for 3 years. Subjects with 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.
11. 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
12. Subjects with known active human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection
13. Subjects with chronic liver disease or dysfunction and a Child-Pugh score of B or C
14. Subjects with untreated, progressing, or known symptomatic brain metastasis
15. Subjects with retinal abnormalities, specifically diabetic retinopathy, macular degeneration, other forms of retinal degenerative disease, or other retinal findings that may place the subject at risk

Contacts and Locations

Locations

United States, Arizona

Honor Health Research Institute

Scottsdale, Arizona, United States, 85258

University of Arizona Cancer Center

Tucson, Arizona, United States, 85724

United States, California

City of Hope Medical Center

Duarte, California, United States, 91010

UC Davis - Comprehensive Cancer Center

Sacramento, California, United States, 95817

United States, Colorado

Sarah Cannon Research Institute at HealthONE

Denver, Colorado, United States, 80218

United States, Florida

Florida Cancer Specialists

Sarasota, Florida, United States, 34232

United States, Georgia

Northside Hospital

Atlanta, Georgia, United States, 30342

United States, Massachusetts

Dana Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, Michigan

START Midwest

Grand Rapids, Michigan, United States, 49546

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

United States, New York

Memorial Sloan Kettering Cancer Center

New York, New York, United States, 10065

United States, North Carolina

Duke Cancer Institute

Durham, North Carolina, United States, 27710

United States, Ohio

Gabrail Cancer Center

Canton, Ohio, United States, 44718

United States, Oklahoma

University of Oklahoma Medicine Stephenson Cancer Center

Oklahoma City, Oklahoma, United States, 73104

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37232

Vanderbilt University

Nashville, Tennessee, United States, 37232

United States, Texas

NEXT Oncology

San Antonio, Texas, United States, 78229

UT Health San Antonio - Mays Cancer Center

San Antonio, Texas, United States, 78229

United States, Utah

START Mountain Region

West Valley City, Utah, United States, 84119

Sponsors and Collaborators

Biosplice Therapeutics, Inc.

Investigators

• Study Chair: Darrin Beaupre, MD, PhD, CMO; Biosplice Therapeutics, Inc.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Moroney MR, Woodruff E, Qamar L, Bradford AP, Wolsky R, Bitler BG, Corr BR. Inhibiting Wnt/beta-catenin in CTNNB1-mutated endometrial cancer. Mol Carcinog. 2021 Aug;60(8):511-523. doi: 10.1002/mc.23308. Epub 2021 May 26.

Tam BY, Chiu K, Chung H, Bossard C, Nguyen JD, Creger E, Eastman BW, Mak CC, Ibanez M, Ghias A, Cahiwat J, Do L, Cho S, Nguyen J, Deshmukh V, Stewart J, Chen CW, Barroga C, Dellamary L, Kc SK, Phalen TJ, Hood J, Cha S, Yazici Y. The CLK inhibitor SM08502 induces anti-tumor activity and reduces Wnt pathway gene expression in gastrointestinal cancer models. Cancer Lett. 2020 Mar 31;473:186-197. doi: 10.1016/j.canlet.2019.09.009. Epub 2019 Sep 24.

• Responsible Party: Biosplice Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT03355066
• Other Study ID Numbers: SM08502-ONC-01
• First Posted: November 28, 2017
• Last Update Posted: October 19, 2022
• Last Verified: October 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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; HRR; HRD; LOH High; AR-V7

Additional relevant MeSH terms:

Neoplasms