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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

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ClinicalTrials.gov Identifier: NCT05084859
Recruitment Status : Recruiting
First Posted : October 20, 2021
Last Update Posted : November 16, 2021
Sponsor:
Information provided by (Responsible Party):
Biosplice Therapeutics, Inc.

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

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Study Type : Interventional  (Clinical Trial)
Estimated 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 : November 3, 2021
Estimated Primary Completion Date : July 2026
Estimated Study Completion Date : July 2026

Resource links provided by the National Library of Medicine


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.




Primary Outcome Measures :
  1. Part 1 - Incidence of Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Consent date to approximately 56 days after last patient dose. ]
    As measured by NCI CTCAE version 5.0.

  2. Part 1 - Maximum tolerated dose (MTD) of SM08502 when combined with standard of care agents. [ Time Frame: DLT period of 28 days per dose level ]
    Based on frequency and severity of dose-limiting toxicities (DLTs).

  3. Part 1 - Blood samples for measurement of the plasma levels of SM08502 and its metabolite [ Time Frame: 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.

  4. Part 1 - Blood samples for measurement of the plasma levels of SM08502 and its metabolite [ Time Frame: 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

  5. Part 1 - Blood samples for measurement of the plasma levels of SM08502 and its metabolite [ Time Frame: 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.

  6. Part 1 - Plasma drug concentration [ Time Frame: 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.

  7. Part 2 - Incidence of Safety and tolerability of SM08502 [ Time Frame: 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.

  8. Part 2 - Objective response rate [ Time Frame: 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 :
  1. Part 1 - Objective Response rate [ Time Frame: 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.

  2. Part 2 - Blood samples for measurement of the plasma levels of SM08502 and its metabolite [ Time Frame: 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.

  3. Part 2 - Blood samples for measurement of the plasma levels of SM08502 and its metabolite [ Time Frame: 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

  4. Part 2 - Blood samples for measurement of the plasma levels of SM08502 and its metabolite [ Time Frame: 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.

  5. Part 2 - Blood samples for measurement of the plasma levels of SM08502 and its metabolite [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

1.0. 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:

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.

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:

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, 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.

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:

  1. Women who are pregnant or lactating.
  2. Women of childbearing potential (WOCBP) must agree to follow the contraceptive guidelines as outlined in protocol.
  3. Men of reproductive potential must agree to follow the contraceptive guidelines as outlined in protocol.
  4. Subjects with a QTc (Fridericia's) prolongation > CTCAE v5.0 Grade 1 (>480 msec) 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 (e.g., requiring antibiotic therapy).
  8. Organ transplant recipients.
  9. Subjects with untreated, progressing, or known symptomatic brain metastasis.
  10. 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.
  11. Subjects with known hypersensitivity to any excipients in the study drug formulation.
  12. 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.
  13. Subjects with known active human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection.
  14. Subjects considered by the Investigator to be unsuitable for the study for any other reason.
  15. Subjects with chronic liver disease or dysfunction and a Child-Pugh score of B or C.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05084859


Contacts
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Contact: Biosplice Clinical Trials 1-855-222-0515 clinicaltrials@biosplice.com

Locations
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Sponsors and Collaborators
Biosplice Therapeutics, Inc.
Investigators
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Study Chair: Darrin Beaupre, MD, PhD, CMO Biosplice Therapeutics, Inc.
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Responsible Party: Biosplice Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT05084859    
Other Study ID Numbers: SM08502-ONC-03
First Posted: October 20, 2021    Key Record Dates
Last Update Posted: November 16, 2021
Last Verified: November 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Additional relevant MeSH terms:
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Carcinoma, Non-Small-Cell Lung
Colorectal Neoplasms
Neoplasms by Site
Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Lung Diseases
Respiratory Tract Diseases
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Prednisone
Docetaxel
Panitumumab
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Anti-Inflammatory Agents
Glucocorticoids
Hormones