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

NCT03355066

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study Evaluating the Safety and Pharmacokinetics of Orally Administered SM08502 in Subjects With Advanced Solid Tumors
  • 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 IDs

  • ORG STUDY ID: SM08502-ONC-01
  • NCT ID: NCT03355066

Conditions

  • Solid Tumor, Adult

Interventions

DrugSynonymsArms
SM08502Part 1A: Dose Escalation

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Part 1A: Dose EscalationExperimentalCohorts 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.
  • SM08502
Part 1B: Dose FindingExperimentalIndications 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.
  • SM08502
Part 2: ExpansionExperimentalPart 2 will evaluate the recommended Part 2 dose and schedule of SM08502, as determined in Part 1B, in 6 cohorts of subjects. The indications to be evaluated include subjects with advanced and/or metastatic CRPC, NSCLC, TNBC, CRC, endometrial cancer, and ovarian cancer for which histologic or cytologic confirmation of malignancy was obtained at diagnosis. Each cohort will enroll approximately 20 subjects.
  • SM08502

Eligibility Criteria

        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). Histologic or cytologic confirmation of
                  malignancy must have been obtained at diagnosis. The indications eligible for
                  Part 1B include: i. NSCLC, ii.TNBC, iii. CRPC, iv. CRC, v. Endometrial cancer,
                  vi. Ovarian cancer

               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 at least two lines of
                  prior therapy. The indications eligible for Part 2 include: i. NSCLC, ii. TNBC,
                  iii. CRPC, iv. CRC, v. Endometrial cancer, vi. Ovarian cancer

          2. Measurable or evaluable disease per RECIST 1.1 (Part 1A). For Parts 1B and 2, at least
             one 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 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. (Exception: Subjects may enter with continuing alopecia
             regardless of any CTCAE grade or with Grade 2 or better neuropathy.) The following
             intervals must elapse between end of last treatment and receiving the first dose of
             SM08502:

               1. Chemotherapy: 3 weeks

               2. Mitomycin C or a nitrosourea: 6 weeks

               3. Radiotherapy: 3 weeks

               4. Major surgery: 6 weeks

               5. Targeted therapy, including monoclonal antibodies and immuno-oncology therapies:
                  4 weeks or 5 half-lives, whichever is shortest

               6. Anti-hormonal therapy: 3 weeks. The exception is ADT for subjects with CRPC who
                  are progressing on therapy, ADT may be continued in this study.

               7. Experimental therapy: 4 weeks or 5 half-lives, whichever is shortest

               8. Other locoregional therapy [e.g., radiofrequency ablation (RFA), TACE
                  (transarterial chemoembolization), TARE (transarterial radioembolization),
                  DEB-TACE (drug eluting bead transarterial chemoembolization)]: 6 weeks

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

               1. 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

               2. Renal function: measured or calculated creatinine clearance via Cockcroft-Gault
                  formula >35 mL/min

               3. Hematology: absolute neutrophil counts ≥ 1500/mm3, platelet counts ≥ 100,000/mm3,
                  hemoglobin ≥ 9.0 g/dL Subjects with values within 10% of these limits deemed not
                  clinically significant by the Investigator may be entered with the approval of
                  the Sponsor's Medical Monitor.

          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 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 requiring antibiotic therapy

          8. Subjects with a second malignancy unless adequately treated with no recurrence for 3
             years. Subjects with a 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.

          9. 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

         10. Subjects with known active human immunodeficiency virus (HIV), hepatitis B virus
             (HBV), or hepatitis C virus (HCV) infection

         11. Subjects with chronic liver disease or dysfunction and a Child-Pugh score of B or C
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part 1A: Maximum tolerated dose (MTD) of SM08502 based on the frequency and severity of dose-limiting toxicities (DLTs)
Time Frame:DLT period of 28 days per dose level
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Part 1A and Part 1B: Tumor response as measured by RECIST 1.1 or PCWG3 criteria where appropriate
Time Frame:Approximately 5 years
Safety Issue:
Description:
Measure:Part 1B and Part 2: Gene expression profile of RNA isolated from whole blood
Time Frame:Approximately 5 years
Safety Issue:
Description:
Measure:Part 2: Cmax of SM08502 and SM08955 following single dose administration of SM08502
Time Frame:Approximately 5 years
Safety Issue:
Description:
Measure:Part 2: tmax of SM08502 and SM08955 following single dose administration of SM08502
Time Frame:Approximately 5 years
Safety Issue:
Description:
Measure:Part 2: AUC0-24 of SM08502 and SM08955 following single dose administration of SM08502
Time Frame:Approximately 5 years
Safety Issue:
Description:
Measure:Part 2: AUClast of SM08502 and SM08955 following single dose administration of SM08502
Time Frame:Approximately 5 years
Safety Issue:
Description:
Measure:Part 2: Cmax,ss of SM08502 and SM08955 following repeat dose administration of SM08502
Time Frame:Approximately 5 years
Safety Issue:
Description:
Measure:Part 2: Cmin,ss of SM08502 and SM08955 following repeat dose administration of SM08502
Time Frame:Approximately 5 years
Safety Issue:
Description:
Measure:Part 2: tmax,ss of SM08502 and SM08955 following repeat dose administration of SM08502
Time Frame:Approximately 5 years
Safety Issue:
Description:
Measure:Part 2: AUC0-24,ss of SM08502 and SM08955 following repeat dose administration of SM08502
Time Frame:Approximately 5 years
Safety Issue:
Description:
Measure:Part 2: Splicing perturbations in post-treatment tumor specimens compared to pre-treatment tumor specimens
Time Frame:Approximately 5 years
Safety Issue:
Description:
Measure:Part 2: Gene mutations in post-treatment tumor specimens compared to pre-treatment tumor specimens
Time Frame:Approximately 5 years
Safety Issue:
Description:
Measure:Part 2: Expression-function of genes in post-treatment tumor specimens compared to pre-treatment tumor specimens
Time Frame:Approximately 5 years
Safety Issue:
Description:
Measure:Part 2: Expression-function of transcripts in post-treatment tumor specimens compared to pre-treatment tumor specimens
Time Frame:Approximately 5 years
Safety Issue:
Description:
Measure:Part 2: Expression-function of proteins in post-treatment tumor specimens compared to pre-treatment tumor specimens
Time Frame:Approximately 5 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Biosplice Therapeutics, Inc.

Trial Keywords

  • SM08502
  • pan Clk/Dyrk inhibitor

Last Updated

August 10, 2021