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

NCT05084859 | Terminated Phase 1 FDA Drug

• 1 other identifier: SM08502-ONC-03
• Study Type: interventional
• Target: 30
• Locations: 2 countries
• Sites: 20

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.

Conditions

Castration-resistant Prostate Cancer; Non-small Cell Lung Cancer; Colorectal Cancer

Keywords

SM08502; pan Clk/Dyrk inhibitor

Outcome Measures

Primary Outcomes (8)

• Part 1 - Incidence of Treatment Emergent Adverse Events (TEAEs)

  As measured by NCI CTCAE version 5.0.

  Consent date to 28 days after the last dose of study treatment

• Part 1 - Maximum tolerated dose (MTD) of SM08502 when combined with standard of care agents.

  Based on frequency and severity of dose-limiting toxicities (DLTs).

  DLT period of 21 or 28 days per dose level depending on cycle length

• Part 1 - Blood samples for measurement of the plasma levels of SM08502 and its metabolite

  Maximum (Cmax) and minimum (Cmin) Plasma concentration of SM08502 and its metabolite SM08955.

  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.

• Part 1 - Blood samples for measurement of the plasma levels of SM08502 and its metabolite

  Area under the plasma concentration time curve (AUC) from zero to 24 hours: AUC0-24 for SM08502 and its metabolite SM08955

  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.

• Part 1 - Blood samples for measurement of the plasma levels of SM08502 and its metabolite

  Area under the plasma concentration time curve (AUC) from zero to the last measurable concentration: AUClast for SM08502 and its metabolite SM08955.

  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.

• Part 1 - Plasma drug concentration

  Maximum steady-state plasma drug concentration (Cmaxss) during a dosage interval.

  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.

• Part 2 - Incidence of Safety and tolerability of SM08502

  As measured by treatment emergent adverse events (TEAEs) as measured by NCI CTCAE version 5 from subjects treated at the recommended Part 2 dose and schedule.

  Consent date to 28 days after the last dose of study treatment

• Part 2 - Objective response rate

  Using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or Prostate Cancer Working Group 3 Criteria (PCWG3) where appropriate.

  Approximately 5 years

Secondary Outcomes (5)

• Part 1 - Objective Response rate

  Approximately 5 years

• 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.

• 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.

• 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.

• 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.

Study Arms (3)

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

EXPERIMENTAL

Part 1 (dose escalation cohorts) will evaluate SM08502 in subjects with advanced CRPC. Subjects will receive 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; Drug: Abiraterone; Drug: Prednisone

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

EXPERIMENTAL

Part 1 (dose escalation cohorts) will evaluate SM08502 in subjects with advanced NSCLC. Subjects will receive 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; Drug: Docetaxel

CRC (Colorectal Cancer) - SM08502 + FOLFIRI/Panitumumab

EXPERIMENTAL

Part 1 (dose escalation cohorts) will evaluate SM08502 in subjects with advanced CRC. Subjects will receive increasing doses of SM08502 with fixed doses of FOLFIRI plus panitumumab ( RAS wild type tumors) or with fixed doses of FOLFIRI (RAS mutant tumors) 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; Drug: FOLFIRI Protocol; Drug: Panitumumab

Interventions

SM08502 DRUG

SM08502 to be administered orally.

CRC (Colorectal Cancer) - SM08502 + FOLFIRI/Panitumumab; CRPC (Castration Resistant Prostate Cancer) - SM08502 + Abiraterone/Prednisone; NSCLC (Non-Small Cell Lung Cancer) - SM08502 + Docetaxel

Abiraterone DRUG

Abiraterone to be administered orally.

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

Prednisone DRUG

Prednisone to be administered orally.

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

Docetaxel DRUG

Docetaxel to be administered intravenously.

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

FOLFIRI Protocol DRUG

FOLFIRI Protocol to be administered intravenously.

CRC (Colorectal Cancer) - SM08502 + FOLFIRI/Panitumumab

Panitumumab DRUG

Panitumumab to be administered intravenously.

CRC (Colorectal Cancer) - SM08502 + FOLFIRI/Panitumumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• i. CRPC - Subjects with progressive disease in the setting of medical or surgical castration (i.e., castration-resistant prostate cancer).
• ii. 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.
• iii. 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.
• 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:
• i. CRPC - Subjects with progressive disease in the setting of medical or surgical castration (i.e., castration- resistant prostate cancer). Subjects who have not received chemotherapy, are not candidates for chemotherapy, or refuse chemotherapy are eligible (Arm A). Subjects who have received chemotherapy are eligible (Arm B), however, more than 2 prior lines of chemotherapy in any setting are excluded.
• ii. 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.
• iii. 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.
• Male or female subjects ≥ 18 years of age.
• 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.
• Subjects must have archived tumor specimens available for analysis Otherwise, a fresh tumor biopsy will be required at study entry.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Biosplice Therapeutics, Inc.: lead

Study Sites (20)

The University of Arizona Cancer Center (UACC) - North Campus

Tucson, Arizona, 85719-1478, United States

Location

University of Colorado, Anschutz

Aurora, Colorado, 80045-2571, United States

Location

University of Colorado

Aurora, Colorado, 80045, United States

Location

Maine Center for Cancer Medicine

Scarborough, Maine, 04074-7172, United States

Location

START Midwest

Grand Rapids, Michigan, 49546, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10021-0005, United States

Location

Duke Cancer Institute (DCI) - Duke Cancer Center

Durham, North Carolina, 27710-2000, United States

Location

The Carl and Edyth Lindner Center for Research and Education at The Christ Hospital, LLC

Cincinnati, Ohio, 45219, United States

Location

Vanderbilt University

Nashville, Tennessee, 37212, United States

Location

Texas Oncology

Fort Worth, Texas, 76104, United States

Location

Texas Oncology-San Antonio Northeast

San Antonio, Texas, 78217, United States

Location

UT Health San Antonio - Mays Cancer Center - Institute for Drug Development

San Antonio, Texas, 78229, United States

Location

START Mountain Region

West Valley City, Utah, 84119, United States

Location

Virginia Cancer Specialists, PC

Fairfax, Virginia, 20176, United States

Location

Oncology and Hematology Associates of Southwest Virginia, Inc., DBA Blue Ridge Cancer Care

Roanoke, Virginia, 24014, United States

Location

Seattle Cancer Care Alliance (SCCA)

Seattle, Washington, 98109-1023, United States

Location

Chris O'Brien Lifehouse

Camperdown, 2050, Australia

Location

Saint Vincent's Hospital

Darlinghurst, 2010, Australia

Location

Icon Cancer Care-South Brisbane

South Brisbane, 4215, Australia

Location

The Queen Elizabeth Hospital (TQEH)

Woodville South, 5011, Australia

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms

Interventions

abiraterone; Prednisone; Docetaxel; IFL protocol; Panitumumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Darrin Beaupre, MD, PhD, CMO

  Biosplice Therapeutics, Inc.

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 24, 2021
• First Posted: October 20, 2021
• Study Start: November 3, 2021
• Primary Completion: October 20, 2022
• Study Completion: October 20, 2022
• Last Updated: August 9, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (16); AU (4)