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

NCT ID: NCT03355066

Last Updated: 2024-08-09

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 82 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-11-06
• Study Completion Date: 2022-11-14

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).

Conditions

Solid Tumor, Adult

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

SM08502

Intervention Type: DRUG

SM08502 tablets to be administered orally.

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.

Group Type: EXPERIMENTAL

SM08502

Intervention Type: DRUG

SM08502 tablets to be administered orally.

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.

Group Type: EXPERIMENTAL

SM08502

Intervention Type: DRUG

SM08502 tablets to be administered orally.

Interventions

SM08502

SM08502 tablets to be administered orally.

Intervention Type: DRUG

Eligibility Criteria

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.

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Biosplice Therapeutics, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Darrin Beaupre, MD, PhD, CMO

Role: STUDY_CHAIR

Biosplice Therapeutics, Inc.

Locations

Honor Health Research Institute

Scottsdale, Arizona, United States

University of Arizona Cancer Center

Tucson, Arizona, United States

City of Hope Medical Center

Duarte, California, United States

UC Davis - Comprehensive Cancer Center

Sacramento, California, United States

Sarah Cannon Research Institute at HealthONE

Denver, Colorado, United States

Florida Cancer Specialists

Sarasota, Florida, United States

Northside Hospital

Atlanta, Georgia, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

START Midwest

Grand Rapids, Michigan, United States

Washington University School of Medicine

St Louis, Missouri, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Duke Cancer Institute

Durham, North Carolina, United States

Gabrail Cancer Center

Canton, Ohio, United States

University of Oklahoma Medicine Stephenson Cancer Center

Oklahoma City, Oklahoma, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Vanderbilt University

Nashville, Tennessee, United States

NEXT Oncology

San Antonio, Texas, United States

UT Health San Antonio - Mays Cancer Center

San Antonio, Texas, United States

START Mountain Region

West Valley City, Utah, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 34038589 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31560935 (View on PubMed)

Other Identifiers

SM08502-ONC-01

Identifier Type: -

Identifier Source: org_study_id