Clinical trial NCT05084859: 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
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Castration-resistant Prostate Cancer
Non-small Cell Lung Cancer
Colorectal Cancer
Keywords: SM08502
pan Clk/Dyrk inhibitor
Lead sponsor: Biosplice Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2021-10-20
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


Eligibility 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). 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.

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.

Primary outcomes:
measure: Part 1 - Incidence of Treatment Emergent Adverse Events (TEAEs)
timeFrame: Consent date to 28 days after the last dose of study treatment
measure: Part 1 - Maximum tolerated dose (MTD) of SM08502 when combined with standard of care agents.
timeFrame: DLT period of 21 or 28 days per dose level depending on cycle length
measure: Part 1 - Blood samples for measurement of the plasma levels of SM08502 and its metabolite
timeFrame: 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.
measure: Part 1 - Blood samples for measurement of the plasma levels of SM08502 and its metabolite
timeFrame: 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.
measure: Part 1 - Blood samples for measurement of the plasma levels of SM08502 and its metabolite
timeFrame: 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.
measure: Part 1 - Plasma drug concentration
timeFrame: 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.
measure: Part 2 - Incidence of Safety and tolerability of SM08502
timeFrame: Consent date to 28 days after the last dose of study treatment
measure: Part 2 - Objective response rate
timeFrame: Approximately 5 years
Secondary outcomes:
measure: Part 1 - Objective Response rate
timeFrame: Approximately 5 years
measure: Part 2 - Blood samples for measurement of the plasma levels of SM08502 and its metabolite
timeFrame: 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.
measure: Part 2 - Blood samples for measurement of the plasma levels of SM08502 and its metabolite
timeFrame: 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.
measure: Part 2 - Blood samples for measurement of the plasma levels of SM08502 and its metabolite
timeFrame: 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.
measure: Part 2 - Blood samples for measurement of the plasma levels of SM08502 and its metabolite
timeFrame: 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.
Other outcomes:
Locations:
city: Tucson
country: United States
facility: The University of Arizona Cancer Center (UACC) - North Campus
state: Arizona
city: Aurora
country: United States
facility: University of Colorado, Anschutz
state: Colorado
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Scarborough
country: United States
facility: Maine Center for Cancer Medicine
state: Maine
city: Grand Rapids
country: United States
facility: START Midwest
state: Michigan
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke Cancer Institute (DCI) - Duke Cancer Center
state: North Carolina
city: Cincinnati
country: United States
facility: The Carl and Edyth Lindner Center for Research and Education at The Christ Hospital, LLC
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Fort Worth
country: United States
facility: Texas Oncology
state: Texas
city: San Antonio
country: United States
facility: Texas Oncology-San Antonio Northeast
state: Texas
city: San Antonio
country: United States
facility: UT Health San Antonio - Mays Cancer Center - Institute for Drug Development
state: Texas
city: West Valley City
country: United States
facility: START Mountain Region
state: Utah
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Roanoke
country: United States
facility: Oncology and Hematology Associates of Southwest Virginia, Inc., DBA Blue Ridge Cancer Care
state: Virginia
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance (SCCA)
state: Washington
city: Camperdown
country: Australia
facility: Chris O'Brien Lifehouse
city: Darlinghurst
country: Australia
facility: Saint Vincent's Hospital
city: South Brisbane
country: Australia
facility: Icon Cancer Care-South Brisbane
city: Woodville South
country: Australia
facility: The Queen Elizabeth Hospital (TQEH)
Study officials:
affiliation: Biosplice Therapeutics, Inc.
name: Darrin Beaupre, MD, PhD, CMO
role: STUDY_CHAIR
References: