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

Solid Tumor, Adult Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03355066
• Other study ID #: SM08502-ONC-01
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: November 6, 2017
• Est. completion date: December 2025

Study information

• Verified date: October 2022
• Source: Biosplice Therapeutics, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 82
• Est. completion date: December 2025
• Est. primary completion date: December 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Neoplasms
• Solid Tumor, Adult

Intervention

Drug:
• SM08502
SM08502 tablets to be administered orally.

Locations

Country	Name	City	State
United States	Northside Hospital	Atlanta	Georgia
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Gabrail Cancer Center	Canton	Ohio
United States	Sarah Cannon Research Institute at HealthONE	Denver	Colorado
United States	City of Hope Medical Center	Duarte	California
United States	Duke Cancer Institute	Durham	North Carolina
United States	START Midwest	Grand Rapids	Michigan
United States	Vanderbilt University	Nashville	Tennessee
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	University of Oklahoma Medicine Stephenson Cancer Center	Oklahoma City	Oklahoma
United States	UC Davis - Comprehensive Cancer Center	Sacramento	California
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	NEXT Oncology	San Antonio	Texas
United States	UT Health San Antonio - Mays Cancer Center	San Antonio	Texas
United States	Florida Cancer Specialists	Sarasota	Florida
United States	Honor Health Research Institute	Scottsdale	Arizona
United States	University of Arizona Cancer Center	Tucson	Arizona
United States	START Mountain Region	West Valley City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
Biosplice Therapeutics, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1A, Part 1B: Maximum tolerated dose (MTD) of SM08502 based on the frequency and severity of dose-limiting toxicities (DLTs)		DLT period of 28 days per dose level
Primary	Part 1A, Part 1B and Part 2: Number of participants with treatment-emergent adverse events (TEAEs) as assessed by CTCAE v5.0		Approximately 5 years
Primary	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)		Approximately 5 years
Primary	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)		Approximately 5 years
Primary	Part 1A, Part 1B and Part 2: Change from baseline in blood chemistry parameters: albumin (grams per day)		Approximately 5 years
Primary	Part 1A, Part 1B and Part 2: Change from baseline in blood chemistry parameters: chloride, bicarbonate (millimoles per liter)		Approximately 5 years
Primary	Part 1A, Part 1B and Part 2: Change from baseline in blood chemistry parameter: lactic acid dehydrogenase [LDH] (units per liter)		Approximately 5 years
Primary	Part 1A, Part 1B and Part 2: Change from baseline in hematology parameter: hemoglobin [Hb] (grams per liter)		Approximately 5 years
Primary	Part 1A, Part 1B and Part 2: Change from baseline in hematology parameter: hematocrit (proportion of red blood cells in blood)		Approximately 5 years
Primary	Part 1A, Part 1B and Part 2: Change from baseline in hematology parameter: red blood cells [RBC] count (trillion cells per liter)		Approximately 5 years
Primary	Part 1A, Part 1B and Part 2: Change from baseline in hematology parameters: neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count (cells/microliter)		Approximately 5 years
Primary	Part 1A: Change from baseline in prothrombin time [PT] (seconds)		Approximately 5 years
Primary	Part 1A: Change from baseline in partial thromboplastin time [PTT] (seconds)		Approximately 5 years
Primary	Part 1A: Change from baseline in urinalysis parameter: clarity		Approximately 5 years
Primary	Part 1A: Change from baseline in urinalysis parameter: specific gravity (ratio)		Approximately 5 years
Primary	Part 1A: Change from baseline in urinalysis parameter: urine pH		Approximately 5 years
Primary	Part 1A: Change from baseline in urinalysis parameter: protein		Approximately 5 years
Primary	Part 1A: Change from baseline in urinalysis parameter: glucose (millimole per liter)		Approximately 5 years
Primary	Part 1A: Change from baseline in urinalysis parameter: ketones (millimoles per liter)		Approximately 5 years
Primary	Part 1A: Change from baseline in urinalysis parameter: occult blood (10^9 cells per liter)		Approximately 5 years
Primary	Part 1A: Change from baseline in urinalysis parameter: nitrite		Approximately 5 years
Primary	Part 1A: Change from baseline in urinalysis parameter: leukocytes (counts per high power field)		Approximately 5 years
Primary	Part 1A, Part 1B and Part 2: Change from baseline in body temperature (degrees celsius)		Approximately 5 years
Primary	Part 1A, Part 1B and Part 2: Change from baseline in pulse rate (beats per minute)		Approximately 5 years
Primary	Part 1A, Part 1B and Part 2: Change from baseline in respiratory rate (breaths per minute)		Approximately 5 years
Primary	Part 1A, Part 1B and Part 2: Change from baseline in blood pressure (systolic and diastolic) (millimeters of mercury)		Approximately 5 years
Primary	Part 1A, Part 1B and Part 2: Change from baseline in electrocardiogram (ECG) parameters: PR interval, QRS interval, QT interval, QTcF (milliseconds)		Approximately 5 years
Primary	Part 1A and Part 1B: Cmax of SM08502 and its metabolite (SM08955) following single dose administration of SM08502		Approximately 5 years
Primary	Part 1A and Part 1B: tmax of SM08502 and SM08955 following single dose administration of SM08502		Approximately 5 years
Primary	Part 1A and Part 1B: AUC0-24 of SM08502 and SM08955 following single dose administration of SM08502		Approximately 5 years
Primary	Part 1A and Part 1B: AUClast of SM08502 and SM08955 following single dose administration of SM08502		Approximately 5 years
Primary	Part 1A and Part 1B: Cmax,ss of SM08502 and SM08955 following repeat dose administration of SM08502		Approximately 5 years
Primary	Part 1A and Part 1B: Cmin,ss of SM08502 and SM08955 following repeat dose administration of SM08502		Approximately 5 years
Primary	Part 1A and Part 1B: tmax,ss of SM08502 and SM08955 following repeat dose administration of SM08502		Approximately 5 years
Primary	Part 1A and Part 1B: AUC0-24,ss of SM08502 and SM08955 following repeat dose administration of SM08502		Approximately 5 years
Primary	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		Approximately 5 years
Secondary	Part 1A and Part 1B: Tumor response as measured by RECIST 1.1 or PCWG3 criteria where appropriate		Approximately 5 years
Secondary	Part 1A, Part 1B and Part 2: Gene expression profile of RNA isolated from whole blood		Approximately 5 years
Secondary	Part 2: Cmax of SM08502 and SM08955 following single dose administration of SM08502		Approximately 5 years
Secondary	Part 2: tmax of SM08502 and SM08955 following single dose administration of SM08502		Approximately 5 years
Secondary	Part 2: AUC0-24 of SM08502 and SM08955 following single dose administration of SM08502		Approximately 5 years
Secondary	Part 2: AUClast of SM08502 and SM08955 following single dose administration of SM08502		Approximately 5 years
Secondary	Part 2: Cmax,ss of SM08502 and SM08955 following repeat dose administration of SM08502		Approximately 5 years
Secondary	Part 2: Cmin,ss of SM08502 and SM08955 following repeat dose administration of SM08502		Approximately 5 years
Secondary	Part 2: tmax,ss of SM08502 and SM08955 following repeat dose administration of SM08502		Approximately 5 years
Secondary	Part 2: AUC0-24,ss of SM08502 and SM08955 following repeat dose administration of SM08502		Approximately 5 years
Secondary	Part 2: Gene expression and splicing alterations in post-treatment compared to pre-treatment tumor specimens		Approximately 5 years
Secondary	Part 2 Food Effect substudy: Cmax of SM08502 and SM08955 following single dose administration of SM08502 in fed and fasted states.		Approximately 5 years
Secondary	Part 2 Food effect substudy: tmax of SM08502 and SM08955 following single dose administration of SM08502 in fed and fasted states.		Approximately 5 years
Secondary	Part 2: AUC0-24 of SM08502 and SM08955 following single dose administration of SM08502 in fed and fasted states.		Approximately 5 years