The current design provides a window to analyze the impact of the ACT001+Pembrolizumab combination on the tumor microenvironment and disease outcomes.
Phase 1b: The identified RP2D of combined ACT001 with Pembrolizumab will be determined by standard 3+3 dose escalation methodology among three ACT001 dosages (200mg, 400mg and 800mg, BID) with standard Pembrolizumab dosage. Patients will be dosed approximately 2 weeks prior to surgical resection with a single dose of Pembrolizumab and ACT001. Tumor resection will be performed and a biopsy will be obtained from the resected tumor tissue to evaluate the impact of the study drugs on the TME. After recovery from surgery, patients will resume ACT001 and Pembrolizumab until tumor progression (assessed by iRANO) or an AE requiring discontinuation of study drug. The Safety Monitoring Committee (SMC) will review the data available from all evaluable patients at each dose level prior to recommending escalation to the next dose level. Phase 2a: Using the same dosing schedule and ACT001 dosage as determined in Phase 1b. Patients will be randomized to receive either Pembrolizumab only treatment (Arm A, 10 patients) or ACT001 plus Pembrolizumab treatment (Arm B, 20 patients).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
48
Phase1b - Starting approximately 2 weeks prior to the scheduled surgery, patient will receive an assigned dose of ACT001 by mouth in combination with a single dose of 200 mg pembrolizumab via an intravenous (IV-through a tube in vain) infusion in the clinic. Then patient will self administer ACT001 capsules twice daily by mouth, at the dose to which patient is assigned, until the evening prior to scheduled surgery. Patient will then undergo surgery to remove all or part of tumor. This a standard 3+3 dose escalation.
Phase 2a - Starting approximately 2 weeks prior to the scheduled surgery, patient will receive a single dose of 200 mg pembrolizumab via an intravenous (IV) infusion in the clinic (an IV infusion means the drug will be delivered through a tube in your vein). Patient will then self-administer ACT001 capsules twice daily by mouth, at the dose to which patient is assigned, until the evening prior to scheduled surgery. Patient then will undergo surgery to remove all or part of tumor.
UT MD Anderson Cancer Center, Dept of Neuro-Oncology
Houston, Texas, United States
1b-Incidence, type and severity of treatment-emergent AEs (TEAEs)
Time frame: Approximately 7 months. Each cycle is 21 days; from start of first dose with investigational product until completion of the last study related procedure (including follow-up for safety assessments- 30days after last dose)
1b-Dose limiting toxicities (DLTs)
A DLT is defined as any of the following * Haematological toxicity * Grade 4 neutropenia * Grade ≥ 3 febrile neutropenia or neutropenic infection * Grade 4 thrombocytopenia * Grade 3 thrombocytopenia with clinically significant bleeding * Non-haematological toxicity * Grade ≥ 3 nausea, vomiting or diarrhoea despite optimal supportive therapy * Grade ≥ 3 hypertension despite appropriate intervention * Other grade ≥ 3 non-haematological toxicity, except grade 3 fatigue or transient events (such as allergic reactions or electrolyte disturbances) that are readily controlled with medical therapy and/or are of no clinical concern
Time frame: From first dose of study therapy until the end of the first post-surgery cycle (Cycle 1, Day 21).
1b-Mean changes in vital sign measurements-Heart Rate
Mean change from baseline in vital sign measurements reported in beats/min (inclusive) at each study timepoint.
Time frame: Approximately 8months/ patient. Each cycle is 21 days. Start at screening, Pre-surgical Treatment Period, Cycle 1 and each subsequent Cycle and 30 days after last dose
1b-Mean changes in vital sign measurements- supine blood pressure
Mean change from baseline in vital sign measurements reported in mmHg at each study timepoint
Time frame: Approximately 8months/ patient.Each cycle is 21 days. Start at screening, Pre-surgical Treatment Period, Cycle 1 and each subsequent Cycle and 30 days after last dose
1b-Mean changes in vital sign measurements- body temperature
Mean change from baseline in vital sign measurements reported in degrees Celsius (0C) at each study timepoint.
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Time frame: Approximately 8months/ patient. Each cycle is 21 days. Start at screening, Pre-surgical Treatment Period, Cycle 1 and each subsequent Cycle and 30 days after last dose
1b-Mean changes in vital sign measurements- respiratory rate
Mean change from baseline in vital sign measurements reported in bpm at each study timepoint
Time frame: Approximately 8months/ patient. Each cycle is 21 days. Start at screening, Pre-surgical Treatment Period, Cycle 1 and each subsequent Cycle and 30 days after last dose
1b-Mean changes in electrocardiogram (ECG) parameters
Mean change from baseline in electrocardiogram (ECG) parameters of heart rate, ventricular rate, PR interval, QRS duration, and QTcF.
Time frame: approximately 8months/patient. Each cycle is 21 days. Start at screening, Pre-surgical Treatment Period, Cycle 1 and each subsequent Cycle and 30 days after last dose
1b-Mean changes in Karnofsky Performance Scale score
Mean change from baseline in Karnofsky Performance Scale score
Time frame: Approximately 8 months/patient. Each cycle is 21 days. Start at screening, Pre-surgical Treatment Period, Cycle 1 and each subsequent Cycle and 30 days after last dose
2a-Progression free survival (PFS) at 6 months
Time frame: Six months after initiation of study therapy
1b-Incidence of DLTs according to the MTD/RP2D evaluation process.
Time frame: From first dose of study therapy (per surgery) until the end of the first post-surgery cycle (Cycle 1, Day 21). Each cycle is 21 days.
1b- Pharmacokinetics (PK) of ACT001 in Plasma concentrations in tumor.
Determine ACT001 trough levels in tumor samples.
Time frame: PK analysis will be collected on Day 1 of the pre surgical treatment period.
2a-Overall survival
Overall survival (OS) is defined as time from start of ACT001 dosing at day 1 of cycle 1 until the date of death or date from any cause, assessed up to disease progression.
Time frame: Approximately 7months/patient- screening period is not included. Cycle 1 Day 1 until death, loss to follow-up, withdrawal of consent, date of disease progression or whichever occurs first
2a-Incidence, type and severity of TEAEs
Summary of the treatment-emergent Adverse events experienced during treatment. Adverse events are assessed with Common Terminology Criteria for Adverse Events (CTCAE) 5.0. TEAEs are defined as any medical occurrence reported or observed after the start of dosing with investigational product until completion of the last study related procedure (including follow-up for safety assessments)
Time frame: From start of dosing until 30 days after the last dose of ACT001
2a-Concentration of ACT001 in resected tumor biopsy tissue.
Time frame: Tissue at Surgical Resection only.