Advanced Solid Tumor
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGSL-901
Patients took study medication daily, with dosage based on their assigned cohort and regimen.
Sponsors
Stemline Therapeutics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Patients were assigned to the QD or BID regimen based on cohort assignment.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Identify the MTD, Appropriate Dosing Regimen, PK Profile, and Perform Initial Assessment of the Safety Profile of SL-901 | Approximately 2 years | * Safety endpoints include identification of DLTs; rate of TEAEs and SAEs; identification of abnormalities in physical examination, vital signs, clinical laboratory evaluations, and ECG findings. * PK endpoints include assessment of SL-901 plasma concentration over time; assessment of any changes in the PK properties of SL-901 between initial administration and steady-state and between cycles of treatment; explore the correlation between PK parameters and toxicity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assess Preliminary Clinical Activity of SL-901 - Best Overall Response | Approximately 2 years | Clinical activity endpoints include the rate of objective response, rate of CR, DOR, PFS, and OS. |
| Assess Preliminary Clinical Activity of SL-901 - PFS | Approximately 2 years | Progression-free Survival - Investigator's Assessment |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: SL-901 20 mg Subjects received SL-901 20 mg for a 28-day treatment cycle at once daily dosing. | 3 |
| Cohort 2: SL-901 40 mg Subjects received SL-901 40 mg for a 28-day treatment cycle at both once-daily and twice-daily dosing. | 7 |
| Cohort 3: SL-901 60 mg Subjects received SL-901 60 mg for a 28-day treatment cycle at once-daily dosing. | 4 |
| Cohort 4: SL-901 80 mg Subjects received SL-901 80 mg for a 28-day treatment cycle at both once-daily and twice-daily dosing. | 6 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 1 | 0 |
| Overall Study | Deteriorated Performance Status. Unlikely Benefit | 0 | 1 | 0 | 0 |
| Overall Study | Progressive Disease | 3 | 5 | 2 | 5 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Cohort 1: SL-901 20 mg | Cohort 2: SL-901 40 mg | Cohort 3: SL-901 60 mg | Cohort 4: SL-901 80 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 51.7 years STANDARD_DEVIATION 10.69 | 54.3 years STANDARD_DEVIATION 6.58 | 51.0 years STANDARD_DEVIATION 7.75 | 59.5 years STANDARD_DEVIATION 14.35 | 54.8 years STANDARD_DEVIATION 0.05 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 6 Participants | 4 Participants | 5 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 2 Participants | 5 Participants | 3 Participants | 4 Participants | 14 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 3 Participants | 1 Participants | 10 Participants |
| Sex: Female, Male Male | 0 Participants | 4 Participants | 1 Participants | 5 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 1 / 7 | 2 / 4 | 2 / 6 |
| other Total, other adverse events | 3 / 3 | 7 / 7 | 4 / 4 | 5 / 6 |
| serious Total, serious adverse events | 1 / 3 | 3 / 7 | 3 / 4 | 0 / 6 |
Outcome results
Primary
To Identify the MTD, Appropriate Dosing Regimen, PK Profile, and Perform Initial Assessment of the Safety Profile of SL-901
* Safety endpoints include identification of DLTs; rate of TEAEs and SAEs; identification of abnormalities in physical examination, vital signs, clinical laboratory evaluations, and ECG findings. * PK endpoints include assessment of SL-901 plasma concentration over time; assessment of any changes in the PK properties of SL-901 between initial administration and steady-state and between cycles of treatment; explore the correlation between PK parameters and toxicity.
Time frame: Approximately 2 years
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: SL-901 20 mg | To Identify the MTD, Appropriate Dosing Regimen, PK Profile, and Perform Initial Assessment of the Safety Profile of SL-901 | Any TEAE | 3 adverse event |
| Cohort 1: SL-901 20 mg | To Identify the MTD, Appropriate Dosing Regimen, PK Profile, and Perform Initial Assessment of the Safety Profile of SL-901 | Any SAE | 1 adverse event |
| Cohort 2: SL-901 40 mg | To Identify the MTD, Appropriate Dosing Regimen, PK Profile, and Perform Initial Assessment of the Safety Profile of SL-901 | Any SAE | 3 adverse event |
| Cohort 2: SL-901 40 mg | To Identify the MTD, Appropriate Dosing Regimen, PK Profile, and Perform Initial Assessment of the Safety Profile of SL-901 | Any TEAE | 7 adverse event |
| Cohort 3: SL-901 60 mg | To Identify the MTD, Appropriate Dosing Regimen, PK Profile, and Perform Initial Assessment of the Safety Profile of SL-901 | Any TEAE | 4 adverse event |
| Cohort 3: SL-901 60 mg | To Identify the MTD, Appropriate Dosing Regimen, PK Profile, and Perform Initial Assessment of the Safety Profile of SL-901 | Any SAE | 6 adverse event |
| Cohort 4: SL-901 80 mg | To Identify the MTD, Appropriate Dosing Regimen, PK Profile, and Perform Initial Assessment of the Safety Profile of SL-901 | Any TEAE | 5 adverse event |
| Cohort 4: SL-901 80 mg | To Identify the MTD, Appropriate Dosing Regimen, PK Profile, and Perform Initial Assessment of the Safety Profile of SL-901 | Any SAE | 0 adverse event |
Secondary
Assess Preliminary Clinical Activity of SL-901 - Best Overall Response
Clinical activity endpoints include the rate of objective response, rate of CR, DOR, PFS, and OS.
Time frame: Approximately 2 years
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: SL-901 20 mg | Assess Preliminary Clinical Activity of SL-901 - Best Overall Response | Best Overall Response - Missing | 0 Participants |
| Cohort 1: SL-901 20 mg | Assess Preliminary Clinical Activity of SL-901 - Best Overall Response | Best Overall Response - Stable Disease | 0 Participants |
| Cohort 1: SL-901 20 mg | Assess Preliminary Clinical Activity of SL-901 - Best Overall Response | Best Overall Response - Progressive Disease | 3 Participants |
| Cohort 1: SL-901 20 mg | Assess Preliminary Clinical Activity of SL-901 - Best Overall Response | Best Overall Response - Not Evaluable | 0 Participants |
| Cohort 2: SL-901 40 mg | Assess Preliminary Clinical Activity of SL-901 - Best Overall Response | Best Overall Response - Stable Disease | 2 Participants |
| Cohort 2: SL-901 40 mg | Assess Preliminary Clinical Activity of SL-901 - Best Overall Response | Best Overall Response - Progressive Disease | 4 Participants |
| Cohort 2: SL-901 40 mg | Assess Preliminary Clinical Activity of SL-901 - Best Overall Response | Best Overall Response - Not Evaluable | 0 Participants |
| Cohort 2: SL-901 40 mg | Assess Preliminary Clinical Activity of SL-901 - Best Overall Response | Best Overall Response - Missing | 1 Participants |
| Cohort 3: SL-901 60 mg | Assess Preliminary Clinical Activity of SL-901 - Best Overall Response | Best Overall Response - Progressive Disease | 1 Participants |
| Cohort 3: SL-901 60 mg | Assess Preliminary Clinical Activity of SL-901 - Best Overall Response | Best Overall Response - Stable Disease | 1 Participants |
| Cohort 3: SL-901 60 mg | Assess Preliminary Clinical Activity of SL-901 - Best Overall Response | Best Overall Response - Not Evaluable | 1 Participants |
| Cohort 3: SL-901 60 mg | Assess Preliminary Clinical Activity of SL-901 - Best Overall Response | Best Overall Response - Missing | 1 Participants |
| Cohort 4: SL-901 80 mg | Assess Preliminary Clinical Activity of SL-901 - Best Overall Response | Best Overall Response - Not Evaluable | 0 Participants |
| Cohort 4: SL-901 80 mg | Assess Preliminary Clinical Activity of SL-901 - Best Overall Response | Best Overall Response - Stable Disease | 2 Participants |
| Cohort 4: SL-901 80 mg | Assess Preliminary Clinical Activity of SL-901 - Best Overall Response | Best Overall Response - Missing | 0 Participants |
| Cohort 4: SL-901 80 mg | Assess Preliminary Clinical Activity of SL-901 - Best Overall Response | Best Overall Response - Progressive Disease | 4 Participants |
Secondary
Assess Preliminary Clinical Activity of SL-901 - PFS
Progression-free Survival - Investigator's Assessment
Time frame: Approximately 2 years
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: SL-901 20 mg | Assess Preliminary Clinical Activity of SL-901 - PFS | Progressive Disease | 3 Participants |
| Cohort 1: SL-901 20 mg | Assess Preliminary Clinical Activity of SL-901 - PFS | No post-baseline and no death | 0 Participants |
| Cohort 1: SL-901 20 mg | Assess Preliminary Clinical Activity of SL-901 - PFS | Subjects with event | 3 Participants |
| Cohort 1: SL-901 20 mg | Assess Preliminary Clinical Activity of SL-901 - PFS | No progressive disease and no death | 0 Participants |
| Cohort 1: SL-901 20 mg | Assess Preliminary Clinical Activity of SL-901 - PFS | Death | 0 Participants |
| Cohort 1: SL-901 20 mg | Assess Preliminary Clinical Activity of SL-901 - PFS | Censored subjects | 0 Participants |
| Cohort 2: SL-901 40 mg | Assess Preliminary Clinical Activity of SL-901 - PFS | No progressive disease and no death | 0 Participants |
| Cohort 2: SL-901 40 mg | Assess Preliminary Clinical Activity of SL-901 - PFS | No post-baseline and no death | 0 Participants |
| Cohort 2: SL-901 40 mg | Assess Preliminary Clinical Activity of SL-901 - PFS | Progressive Disease | 6 Participants |
| Cohort 2: SL-901 40 mg | Assess Preliminary Clinical Activity of SL-901 - PFS | Death | 1 Participants |
| Cohort 2: SL-901 40 mg | Assess Preliminary Clinical Activity of SL-901 - PFS | Censored subjects | 0 Participants |
| Cohort 2: SL-901 40 mg | Assess Preliminary Clinical Activity of SL-901 - PFS | Subjects with event | 7 Participants |
| Cohort 3: SL-901 60 mg | Assess Preliminary Clinical Activity of SL-901 - PFS | Death | 2 Participants |
| Cohort 3: SL-901 60 mg | Assess Preliminary Clinical Activity of SL-901 - PFS | Subjects with event | 2 Participants |
| Cohort 3: SL-901 60 mg | Assess Preliminary Clinical Activity of SL-901 - PFS | Censored subjects | 2 Participants |
| Cohort 3: SL-901 60 mg | Assess Preliminary Clinical Activity of SL-901 - PFS | Progressive Disease | 2 Participants |
| Cohort 3: SL-901 60 mg | Assess Preliminary Clinical Activity of SL-901 - PFS | No post-baseline and no death | 1 Participants |
| Cohort 3: SL-901 60 mg | Assess Preliminary Clinical Activity of SL-901 - PFS | No progressive disease and no death | 1 Participants |
| Cohort 4: SL-901 80 mg | Assess Preliminary Clinical Activity of SL-901 - PFS | No post-baseline and no death | 0 Participants |
| Cohort 4: SL-901 80 mg | Assess Preliminary Clinical Activity of SL-901 - PFS | Subjects with event | 5 Participants |
| Cohort 4: SL-901 80 mg | Assess Preliminary Clinical Activity of SL-901 - PFS | Progressive Disease | 5 Participants |
| Cohort 4: SL-901 80 mg | Assess Preliminary Clinical Activity of SL-901 - PFS | Censored subjects | 1 Participants |
| Cohort 4: SL-901 80 mg | Assess Preliminary Clinical Activity of SL-901 - PFS | No progressive disease and no death | 1 Participants |
| Cohort 4: SL-901 80 mg | Assess Preliminary Clinical Activity of SL-901 - PFS | Death | 2 Participants |