Advanced Solid Tumor, Bladder Cancer, Gastric Cancer, Non Small Cell Lung Cancer, NSCLC, Urothelial Carcinoma
Conditions
Keywords
Pembrolizumab, APR-246, Aprea, eprenetapopt
Brief summary
A phase 1/2, open-label, study to determine the safety and preliminary efficacy of APR-246 in combination with pembrolizumab in subjects with solid tumor malignancies. The study will include a safety lead-in portion followed by a phase 2 expansion portion in specific disease groups.
Detailed description
This is a phase 1/2, open-label, study to determine the safety and preliminary efficacy of APR-246 (eprenetapopt) in combination with pembrolizumab in subjects with solid tumor malignancies. In the safety lead-in part of study (phase 1), the safety and the recommended phase 2 dose (RP2D) of APR-246 will be investigated. In the expansion part of the study (phase 2), both safety and efficacy for the combination therapy will be investigated in the 3 cohorts.
Interventions
DRUGAPR-246 (eprenetapopt) + Pembrolizumab
APR-246 D1-4 + Pembrolizumab D3
Sponsors
Aprea Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent form (ICF) and ability to comply with protocol requirements. 2. Known tumor TP53 mutation status from recent or archival sample. 3. Histologically and/or cytologically confirmed solid tumor malignancy 1. Safety lead in- Advanced non-central nervous system (CNS) primary tumors that have progressed after first line treatment, who are intolerant to first line treatment, or who are unable to receive first line treatment, and for whom pembrolizumab, or pembrolizumab-based therapy is considered appropriate 2. Expansion 1- Patients with a confirmed diagnosis of advanced gastric or gastroesophageal junction (GEJ) tumors that have progressed after first line treatment, who are intolerant to first line treatment, or who are unable to receive first line treatment 3. Expansion 2- Patients with a confirmed diagnosis of advanced bladder/urothelial tumors that have progressed after first line treatment, or who are intolerant to first line treatment, or who are unable to receive first line treatment with cisplatin-based chemotherapy. 4. Expansion 3- Confirmed diagnosis of advanced non-small cell lung cancer (NSCLC) previously treated with anti-PD-1 or anti-PD-L1 therapy. 4. Adequate organ function 1. Creatinine clearance \> 30 mL/min 2. Total serum bilirubin \< 1.5 × upper limit of normal (ULN) unless due to Gilbert's syndrome, tumor involvement, hemolysis or considered an effect of regular blood transfusions 3. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 3 × ULN, unless due to involvement by the underlying malignancy. 5. Projected life expectancy of ≥ 12 weeks. 6. Age ≥ 18 years at the time of signing the ICF. 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 8. In the expansion portion, measurable disease meeting the following criteria: 1. At least 1 lesion of ≥10 mm in the longest diameter (LD) for a non-lymph node or ≥15 mm in the short-axis diameter for a lymph node that is serially measurable according to RECIST 1.1. 2. Lesions that have had external beam radiotherapy or loco-regional therapies such as radiofrequency ablation must show subsequent evidence of substantial size increase (ex. 20% increase in LD) to be deemed a target lesion. 9. Negative serum or urine pregnancy test prior to study treatment initiation in female subjects of childbearing potential. 10. Women of childbearing potential and men with female partners of childbearing potential must be willing to use an effective form of contraception
Exclusion criteria
1. Known history of untreated human immunodeficiency virus (HIV)/HIV with a detectable viral load or active hepatitis B or active hepatitis C infection. 2. Cardiac abnormalities 3. Concomitant malignancies or previous malignancies with less than a 1-year disease-free interval at the time of signing consent. 4. Pregnancy or lactation. 5. Active uncontrolled systemic infection. 6. An autoimmune condition requiring ≥ 10 mg (or equivalent corticosteroid) prednisone daily, or any other systemic immunosuppressive treatment within 28 days of first dose of study therapy. 7. Known history of active tuberculosis. 8. Current (non-infectious) pneumonitis, or a history of pneumonitis that required steroids. 9. A live vaccine administered within 30 days of the first dose of study treatment. 10. Receipt of any investigational product within 14 days or 5 half-lives prior to study treatment initiation, whichever is shortest. 11. Prior intolerance to pembrolizumab or other anti-PD-1/PD-L1 agents.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Evaluate the Safety of APR-246 in Combination With Pembrolizumab in Subjects With Solid Tumors. | Through study completion, approximately 1 year | To determine the Frequency of treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs) related to APR-246 in combination with pembrolizumab. |
| To Confirm the Recommended Phase 2 Dose (RP2D) for APR-246 in Combination With Pembrolizumab | Through safety lead in period, during cycle 1 (approximately 21 days) | To determine the dose of APR-246 to be selected for the expansion phase based on the occurence of dose limiting toxicities (DLTs) experienced during the safety assessment period |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Experimental: Safety Lead In Patients with advanced solid tumors. APR 4.5 g/day intravenously (IV) on days 1-4 with pembrolizumab 200 mg IV on day 3 in each 21-day cycle | 6 |
| Experimental: Expansion 1 Patients With Advanced Gastric Cancer. Patients with advanced gastric cancer. APR 4.5 g/day intravenously (IV) on days 1-4 with pembrolizumab 200 mg IV on day 3 in each 21-day cycle | 8 |
| Experimental: Expansion 2 Patients with advanced urothelial/bladder cancer. APR 4.5 g/day intravenously (IV) on days 1-4 with pembrolizumab 200 mg IV on day 3 in each 21-day cycle | 5 |
| Experimental: Expansion 3 Patients With Advanced NSCLC Patients with advanced NSCLC. APR 4.5 g/day intravenously (IV) on days 1-4 with pembrolizumab 200 mg IV on day 3 in each 21-day cycle | 21 |
| Total | 40 |
Baseline characteristics
| Characteristic | Experimental: Safety Lead In | Total | Experimental: Expansion 3 Patients With Advanced NSCLC | Experimental: Expansion 2 | Experimental: Expansion 1 Patients With Advanced Gastric Cancer. |
|---|---|---|---|---|---|
| Age, Continuous | 58 years | 66 years | 67 years | 67 years | 67 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 4 Participants | 4 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 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 | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 5 Participants | 31 Participants | 16 Participants | 3 Participants | 7 Participants |
| Region of Enrollment United States | 6 participants | 40 participants | 21 participants | 5 participants | 8 participants |
| Sex: Female, Male Female | 2 Participants | 17 Participants | 13 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 4 Participants | 23 Participants | 8 Participants | 4 Participants | 7 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 | 5 / 6 | 4 / 6 | 2 / 5 | 10 / 20 |
| other Total, other adverse events | 6 / 6 | 5 / 6 | 5 / 5 | 20 / 20 |
| serious Total, serious adverse events | 1 / 6 | 4 / 6 | 3 / 5 | 7 / 20 |
Outcome results
Primary
To Confirm the Recommended Phase 2 Dose (RP2D) for APR-246 in Combination With Pembrolizumab
To determine the dose of APR-246 to be selected for the expansion phase based on the occurence of dose limiting toxicities (DLTs) experienced during the safety assessment period
Time frame: Through safety lead in period, during cycle 1 (approximately 21 days)
Population: Experimental: Safety Lead In Arm/Group was analyzed for this Outcome Measure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Experimental: Safety Lead In | To Confirm the Recommended Phase 2 Dose (RP2D) for APR-246 in Combination With Pembrolizumab | 4.5 g/d |
Primary
To Evaluate the Safety of APR-246 in Combination With Pembrolizumab in Subjects With Solid Tumors.
To determine the Frequency of treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs) related to APR-246 in combination with pembrolizumab.
Time frame: Through study completion, approximately 1 year
Population: Data is presented by cohort/arm. 3 out of the 40 overall patients did not receive treatment on study. 37 total patients were analyzed
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Experimental: Safety Lead In | To Evaluate the Safety of APR-246 in Combination With Pembrolizumab in Subjects With Solid Tumors. | 6 participants |
| Experimental: Expansion 1 | To Evaluate the Safety of APR-246 in Combination With Pembrolizumab in Subjects With Solid Tumors. | 6 participants |
| Experimental: Expansion 2 | To Evaluate the Safety of APR-246 in Combination With Pembrolizumab in Subjects With Solid Tumors. | 5 participants |
| Experimental: Expansion 3 | To Evaluate the Safety of APR-246 in Combination With Pembrolizumab in Subjects With Solid Tumors. | 20 participants |