Study of the PI3K Inhibitor SL-901 in Patients With Advanced Solid Tumors

Study STML-901-0119 was a dose-escalation study evaluating multiple doses and schedules of orally administered SL-901 in patients with advanced solid tumors.

Study STML-901-0119 was a multi-center, open-label, dose-escalation, and regimen-finding study aimed to investigate the safety, pharmacokinetics (PK), and pharmacodynamics of SL-901 in patients with advanced solid tumors. This study initially included two parts: Part 1a, which used a 3+3 dose-escalation design to determine the maximum tolerated dose and an appropriate dosing regimen of SL-901 when administered on both once-daily (QD) and twice-daily (BID) schedules; Part 1b, which was intended to evaluate the clinical activity of SL-901 at the selected dose in patients with advanced solid tumors with specific genetic alterations.

The study was stopped after careful consideration of the landscape of similar drugs and evolving standard of care. As a result, Part 1b was not initiated. In Part 1a, eligible patients were enrolled to receive SL-901 orally on a 28-day cycle. Study enrollment was conducted in 2 centers in the United Kingdom, and patients were assigned to either the QD or BID dosing regimen based on their cohort assignment.

Eligibility Criteria:
Inclusion Criteria:

1. 18 years old or older.
2. Population by study stage:

   1. Part 1a: Patients with advanced, metastatic, and/or progressive solid tumors for whom there is no effective standard therapy available.
   2. Part 1b: Patients with histologically confirmed, advanced, metastatic, unresectable, and/or progressive solid tumors for whom there is no effective standard therapy available and their PI3K or DNA-PK pathway is deregulated or their tumor genetic profile has been shown to correlate with sensitivity to PI3K and/or DNA-PK inhibition based on clinical and preclinical experience. Specific criteria will be determined based on ongoing experiments and will be introduced in a future protocol amendment.
3. Evaluable or measurable disease.
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
5. Able to take oral medications.
6. If a woman of childbearing potential (WOCBP), the patient has a negative serum or urine pregnancy test within 1 week before Cycle 1, Day 1 (C1D1). Refer to Section 8.1.3 for further practical information about contraception.
7. The patient (either male or female) agrees to use acceptable contraceptive methods for the duration of time in the study, and to continue to use acceptable contraceptive methods for 1 month after the last dose of SL-901. Refer to Section 8.1.3 for further practical information about contraception.
8. Able to provide written informed consent.
9. Willing to provide consent for biomarker analysis of existing paraffin-embedded tumor samples.

Exclusion Criteria:

1. Received an investigational anticancer drug within 4 weeks of the first planned SL-901 dose.
2. Received major surgery, radiotherapy, or immunotherapy within 4 weeks of C1D1. Localized palliative radiotherapy is permitted for symptom control.
3. Received chemotherapy regimens with delayed toxicity within 4 weeks (6 weeks for prior nitrosourea or mitomycin C) of C1D1.
4. Received chemotherapy regimens given continuously or on a weekly basis which have limited potential for delayed toxicity within 2 weeks of C1D1.
5. Clinically significant, unresolved toxicity from previous anticancer therapy ≥Grade 2 (except alopecia), as determined by the Investigator using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0.
6. Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs.
7. Left ventricular ejection fraction \<50%.
8. Corrected QT interval (based on Fridericia's formula) \>450 msec.
9. Type 1 or 2 diabetes mellitus requiring medication. (In Part 1b, patients with type 2 diabetes mellitus controlled by medication, as indicated by a glycated hemoglobin of ≤7.5% are eligible.)
10. Known active human immunodeficiency virus, hepatitis B, or hepatitis C infection.
11. Ongoing systemic bacterial, fungal, or viral infection.
12. History of interstitial pneumonitis.
13. Absolute neutrophil count (ANC) 1.5×10⁹/L.
14. Hemoglobin \<10 g/dL.
15. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>2.5x the upper limit of normal (ULN).
16. Known hypersensitivity or allergy to the active ingredient or excipients of SL-901.
17. Breast-feeding females.