A Study Evaluating the Safety, Pharmacokinetics, and Preliminary Efficacy of Orally Administered SM08502 Combined With Hormonal Therapy or Chemotherapy in Subjects With Advanced Solid Tumors

Sponsor

Biosplice Therapeutics, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT05084859

Collaborator

(none)

150

Enrollment

Locations

Arms

55.9

Anticipated Duration (Months)

5.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study is an open-label, multi-center, dose-escalation, dose expansion study in adult subjects with advanced solid tumors. The study will evaluate the safety, tolerability, PK, and preliminary anti-tumor efficacy of SM08502 administered orally (PO), once daily (QD), following a 5 days on 2 days off treatment schedule in combination with chemotherapy or hormonal therapy. Alternative dosing schedules may be explored in Part 1 if necessary. The recommended Part 2 dose and schedule for each combination will then be further evaluated in the Part 2 expansion.

Dosing will occur in 21- or 28-day cycles (depending on the combination partner) and treatment with SM08502 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
Castration-resistant Prostate Cancer Non-small Cell Lung Cancer Colorectal Cancer	Drug: SM08502 Drug: Abiraterone Drug: Prednisone Drug: Docetaxel Drug: FOLFIRI Protocol Drug: Panitumumab	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

150 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1b, Open-Label, Dose-Escalation, Dose-Expansion Study Evaluating the Safety, Pharmacokinetics, and Efficacy of Orally Administered SM08502 Combined With Hormonal Therapy or Chemotherapy in Subjects With Advanced Solid Tumors

Actual Study Start Date :

Nov 3, 2021

Anticipated Primary Completion Date :

Jul 1, 2026

Anticipated Study Completion Date :

Jul 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CRPC (Castration Resistant Prostate Cancer) - SM08502 + Abiraterone/Prednisone Part 1 (dose escalation cohorts) will evaluate SM08502 in subjects with advanced CRPC. Subjects will recieve increasing doses of SM08502 with fixed doses of Abiraterone/Prednisone to determine the MTD and recommended Part 2 dose and schedule. Escalation will follow a 3+3+3 design within each cohort. Part 2 will further evaluate the recommended dose and schedule of SM08502 in subjects with advanced CRPC. Approximately 20 subjects will be enrolled.	Drug: SM08502 SM08502 to be administered orally. Drug: Abiraterone Abiraterone to be administered orally. Drug: Prednisone Prednisone to be administered orally.
Experimental: NSCLC (Non-Small Cell Lung Cancer) - SM08502 + Docetaxel Part 1 (dose escalation cohorts) will evaluate SM08502 in subjects with advanced NSCLC. Subjects will recieve increasing doses of SM08502 with fixed doses of docetaxel to determine the MTD and recommended Part 2 dose and schedule. Escalation will follow a 3+3+3 design within each cohort. Part 2 will further evaluate the recommended dose and schedule of SM0850 in subjects with advanced NSCLC. Approximately 20 subjects will be enrolled.	Drug: SM08502 SM08502 to be administered orally. Drug: Docetaxel Docetaxel to be administered intravenously.
Experimental: CRC (Colorectal Cancer) - SM08502 + FOLFIRI/Panitumumab Part 1 (dose escalation cohorts) will evaluate SM08502 in subjects with advanced CRC. Subjects will recieve increasing doses of SM08502 with fixed doses of FOLFIRI/Panitumumab to determine the MTD and recommended Part 2 dose and schedule. Escalation will follow a 3+3+3 design within each cohort. Part 2 will further evaluate the recommended dose and schedule of SM08502. Subjects that have RAS wild type tumors will receive FOLFIRI and panitumumab with SM08502 (n=15). Subjects that have RAS mutant tumors will receive FOLFIRI with SM08502 (n=15).	Drug: SM08502 SM08502 to be administered orally. Drug: FOLFIRI Protocol FOLFIRI Protocol to be administered intravenously. Drug: Panitumumab Panitumumab to be administered intravenously.

Arm

Intervention/Treatment

Experimental: CRPC (Castration Resistant Prostate Cancer) - SM08502 + Abiraterone/Prednisone

Part 1 (dose escalation cohorts) will evaluate SM08502 in subjects with advanced CRPC. Subjects will recieve increasing doses of SM08502 with fixed doses of Abiraterone/Prednisone to determine the MTD and recommended Part 2 dose and schedule. Escalation will follow a 3+3+3 design within each cohort. Part 2 will further evaluate the recommended dose and schedule of SM08502 in subjects with advanced CRPC. Approximately 20 subjects will be enrolled.

Drug: SM08502

SM08502 to be administered orally.

Drug: Abiraterone

Abiraterone to be administered orally.

Drug: Prednisone

Prednisone to be administered orally.

Experimental: NSCLC (Non-Small Cell Lung Cancer) - SM08502 + Docetaxel

Part 1 (dose escalation cohorts) will evaluate SM08502 in subjects with advanced NSCLC. Subjects will recieve increasing doses of SM08502 with fixed doses of docetaxel to determine the MTD and recommended Part 2 dose and schedule. Escalation will follow a 3+3+3 design within each cohort. Part 2 will further evaluate the recommended dose and schedule of SM0850 in subjects with advanced NSCLC. Approximately 20 subjects will be enrolled.

Drug: SM08502

SM08502 to be administered orally.

Drug: Docetaxel

Docetaxel to be administered intravenously.

Experimental: CRC (Colorectal Cancer) - SM08502 + FOLFIRI/Panitumumab

Part 1 (dose escalation cohorts) will evaluate SM08502 in subjects with advanced CRC. Subjects will recieve increasing doses of SM08502 with fixed doses of FOLFIRI/Panitumumab to determine the MTD and recommended Part 2 dose and schedule. Escalation will follow a 3+3+3 design within each cohort. Part 2 will further evaluate the recommended dose and schedule of SM08502. Subjects that have RAS wild type tumors will receive FOLFIRI and panitumumab with SM08502 (n=15). Subjects that have RAS mutant tumors will receive FOLFIRI with SM08502 (n=15).

Drug: SM08502

SM08502 to be administered orally.

Drug: FOLFIRI Protocol

FOLFIRI Protocol to be administered intravenously.

Drug: Panitumumab

Panitumumab to be administered intravenously.

Outcome Measures

Primary Outcome Measures

Part 1 - Incidence of Treatment Emergent Adverse Events (TEAEs) [Consent date to approximately 56 days after last patient dose.]
As measured by NCI CTCAE version 5.0.
Part 1 - Maximum tolerated dose (MTD) of SM08502 when combined with standard of care agents. [DLT period of 28 days per dose level]
Based on frequency and severity of dose-limiting toxicities (DLTs).
Part 1 - Blood samples for measurement of the plasma levels of SM08502 and its metabolite [Sample collection timepoints: Cycle1 (Day1 (0,2,4,6, hrs), Day2, Day8, Day15, Day22) Cycle 2 (Day1, Day2) Cycle3-5 (Day1) and EOT. Each cycle is 21 or 28 days depending on tumor type.]
Maximum (Cmax) and minimum (Cmin) Plasma concentration of SM08502 and its metabolite SM08955.
Part 1 - Blood samples for measurement of the plasma levels of SM08502 and its metabolite [Sample collection timepoints: Cycle1 (Day1 (0,2,4,6, hrs), Day2, Day8, Day15, Day22) Cycle 2 (Day1, Day2) Cycle3-5 (Day1) and EOT. Each cycle is 21 or 28 days depending on tumor type.]
Area under the plasma concentration time curve (AUC) from zero to 24 hours: AUC0-24 for SM08502 and its metabolite SM08955
Part 1 - Blood samples for measurement of the plasma levels of SM08502 and its metabolite [Sample collection timepoints: Cycle1 (Day1 (0,2,4,6, hrs), Day2, Day8, Day15, Day22) Cycle 2 (Day1, Day2) Cycle3-5 (Day1) and EOT. Each cycle is 21 or 28 days depending on tumor type.]
Area under the plasma concentration time curve (AUC) from zero to the last measurable concentration: AUClast for SM08502 and its metabolite SM08955.
Part 1 - Plasma drug concentration [Sample collection timepoints: Cycle1 (Day1 (0,2,4,6, hrs), Day2, Day8, Day15, Day22) Cycle 2 (Day1, Day2) Cycle3-5 (Day1) and EOT. Each cycle is 21 or 28 days depending on tumor type.]
Maximum steady-state plasma drug concentration (Cmaxss) during a dosage interval.
Part 2 - Incidence of Safety and tolerability of SM08502 [Consent date to approximately 56 days after last patient dosed]
As measured by treatment emergent adverse events (TEAEs) as measured by NCI CTCAE version from subjects treated at the recommended Part 2 dose and schedule.
Part 2 - Objective response rate [Approximately 5 years]
Using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or Prostate Cancer Working Group 3 Criteria (PCWG3) where appropriate.

Secondary Outcome Measures

Part 1 - Objective Response rate [Approximately 5 years]
Tumor response using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or Prostate Cancer Working Group 3 Criteria (PCWG3) where appropriate.
Part 2 - Blood samples for measurement of the plasma levels of SM08502 and its metabolite [Sample collection timepoints: Cycle1 (Day1 (0,2,4,6, hrs), Day2, Day8, Day15,) Cycle 2-5 (Day1). Each cycle is 21 or 28 days depending on tumor type.]
Maximum (Cmax) and minimum (Cmin) Plasma concentration of SM08502 and its metabolite SM08955.
Part 2 - Blood samples for measurement of the plasma levels of SM08502 and its metabolite [Sample collection timepoints: Cycle1 (Day1 (0,2,4,6, hrs), Day2, Day8, Day15,) Cycle 2-5 (Day1). Each cycle is 21 or 28 days depending on tumor type.]
Area under the plasma concentration time curve (AUC) from zero to 24 hours: AUC0-24 for SM08502 and its metabolite SM08955
Part 2 - Blood samples for measurement of the plasma levels of SM08502 and its metabolite [Sample collection timepoints: Cycle1 (Day1 (0,2,4,6, hrs), Day2, Day8, Day15,) Cycle 2-5 (Day1). Each cycle is 21 or 28 days depending on tumor type.]
Area under the plasma concentration time curve (AUC) from zero to the last measurable concentration: AUClast for SM08502 and its metabolite SM08955.
Part 2 - Blood samples for measurement of the plasma levels of SM08502 and its metabolite [Sample collection timepoints: Cycle1 (Day1 (0,2,4,6, hrs), Day2, Day8, Day15,) Cycle 2-5 (Day1). Each cycle is 21 or 28 days depending on tumor type.]
Maximum steady-state plasma drug concentration (Cmaxss) during a dosage interval.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Key Inclusion Criteria:

1.0. Part 1 - Subjects with advanced and/or metastatic solid tumors. Histologic or cytologic confirmation of malignancy must have been obtained at diagnosis. The tumor types include:

CRPC - Subjects with progressive disease in the setting of medical or surgical castration (i.e., castration-resistant prostate cancer).
NSCLC (adenocarcinoma subtype) - Subjects with no targetable mutations must have received a platinum-containing doublet chemotherapy regimen and a checkpoint inhibitor (either in combination or monotherapy, if indicated) and have progressed. Subjects with targetable mutations/alterations such as EGFR, ALK, or NTRK must have received prior targeted therapy and have progressed.
CRC - Subjects must have received one prior line of standard chemotherapy such as FOLFOX +/- a VEGF-inhibitor and have progressed or are intolerant of oxaliplatin based regimens.

1.1. Part 2 - Subjects with advanced and/or metastatic solid tumors. Histologic or cytologic confirmation of malignancy must have been obtained at diagnosis. The tumor types include:

CRPC - Subjects with progressive disease in the setting of medical or surgical castration (i.e., castration- resistant prostate cancer).
NSCLC (adenocarcinoma subtype) - Subjects with no targetable mutations must have received a platinum-containing doublet chemotherapy regimen and a checkpoint inhibitor (either in combination or monotherapy, if indicated) and have progressed. Subjects with targetable mutations/alterations such as EGFR, ALK, NTRK must have received prior targeted therapy and have progressed.
CRC - Subjects must have received one prior line of standard chemotherapy such as FOLFOX +/- either a VEGF-inhibitor or EGFR inhibitor (if indicated) and have progressed or are intolerant of oxaliplatin based regimens.

2.0. Male or female subjects ≥ 18 years of age.

3.0 Measurable or evaluable disease per RECIST 1.1 (Part 1). For Part 2, at least one measurable lesion per RECIST 1.1 that has not been previously irradiated. In CRPC subjects (Parts 1 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 for those without measurable disease.

4.0. Subjects must have archived tumor specimens available for analysis Otherwise, a fresh tumor biopsy will be required at study entry.

5.0.. 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.

The following intervals must elapse between end of last treatment and receiving the first dose of SM08502:

Chemotherapy: 3 weeks.
Mitomycin C or a nitrosourea: 6 weeks.
Radiotherapy: 3 weeks.
Major surgery: 6 weeks.
Targeted therapy, including monoclonal antibodies and immuno-oncology therapies: 4 weeks or 5 half-lives, whichever is shortest.

6.0. Subjects must meet the following laboratory criteria at Screening for study entry:

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.
Renal function: measured or calculated creatinine clearance via Cockcroft-Gault formula >35 mL/min.
Hematology: absolute neutrophil counts ≥ 1500/mm3, platelet counts ≥ 100,000/mm3, hemoglobin ≥ 9.0 g/dL.
Coagulation: prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 1.5x ULN.

7.0. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.

8.0. Life expectancy > 3 months.

9.0. Subjects must have no uncontrolled intercurrent illness.

10.0 Subjects must have the ability to swallow and retain oral medication.

11.0 Subjects must be willing to sign and provide informed consent and be capable of giving informed consent in accordance with the Institutional Review Board (IRB) / Ethics Committee (EC) policy.

Key Exclusion Criteria:

Women who are pregnant or lactating.
Women of childbearing potential (WOCBP) must agree to follow the contraceptive guidelines as outlined in protocol.
Men of reproductive potential must agree to follow the contraceptive guidelines as outlined in protocol.
Subjects with a QTc (Fridericia's) prolongation > CTCAE v5.0 Grade 1 (>480 msec) at Screening.
Subjects with clinically significant ventricular tachycardia (VT), atrial fibrillation (AF), ventricular fibrillation (VF), second- or third-degree heart block.
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)..
Subjects with active infection (e.g., requiring antibiotic therapy).
Organ transplant recipients.
Subjects with untreated, progressing, or known symptomatic brain metastasis.
Subjects with a second malignancy unless adequately treated with no recurrence for 3 years. Subjects with a history of previous or recent adequately treated basal cell or squamous cell carcinoma of the skin, or carcinoma in situ of any source are eligible.
Subjects with known hypersensitivity to any excipients in the study drug formulation.
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.
Subjects with known active human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection.
Subjects considered by the Investigator to be unsuitable for the study for any other reason.
Subjects with chronic liver disease or dysfunction and a Child-Pugh score of B or C.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The University of Arizona Cancer Center (UACC) - North Campus	Tucson	Arizona	United States	85719-1478
2	University of California Los Angeles (UCLA) - Cancer Care - Santa Monica	Santa Monica	California	United States	90404-2125
3	University of Colorado, Anschutz	Aurora	Colorado	United States	80045-2571
4	University of Colorado	Aurora	Colorado	United States	80045
5	MedStar Georgetown University Hospital (MGUH)	Washington	District of Columbia	United States	20007-2113
6	Mayo Clinic Hospital - Florida	Jacksonville	Florida	United States	32224-1865
7	Cancer Treatment Centers of America at Southeastern Regional Medical Center	Newnan	Georgia	United States	30265-8001
8	Maine Center for Cancer Medicine	Scarborough	Maine	United States	04074-7172
9	START Midwest	Grand Rapids	Michigan	United States	49546
10	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
11	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10021-0005
12	Duke Cancer Institute (DCI) - Duke Cancer Center	Durham	North Carolina	United States	27710-2000
13	The Carl and Edyth Lindner Center for Research and Education at The Christ Hospital, LLC	Cincinnati	Ohio	United States	45219
14	Vanderbilt University	Nashville	Tennessee	United States	37212
15	Vanderbilt University Medical Center (VUMC) - Vanderbilt-Ingram Cancer Center (VICC) - Nashville	Nashville	Tennessee	United States	37232-6838
16	Texas Oncology	Fort Worth	Texas	United States	76104
17	Texas Oncology-San Antonio Northeast	San Antonio	Texas	United States	78217
18	UT Health San Antonio - Mays Cancer Center - Institute for Drug Development	San Antonio	Texas	United States	78229
19	START Mountain Region	West Valley City	Utah	United States	84119
20	Virginia Cancer Specialists, PC	Fairfax	Virginia	United States	20176
21	Oncology and Hematology Associates of Southwest Virginia, Inc., DBA Blue Ridge Cancer Care	Roanoke	Virginia	United States	24014
22	Seattle Cancer Care Alliance (SCCA)	Seattle	Washington	United States	98109-1023
23	Chris O'Brien Lifehouse	Camperdown		Australia	2050
24	Saint Vincent's Hospital	Darlinghurst		Australia	2010
25	Icon Cancer Care-South Brisbane	South Brisbane		Australia	4215
26	The Queen Elizabeth Hospital (TQEH)	Woodville South		Australia	5011