This study is to determine the safety, pharmacokinetics/pharmacodynamics, and immunologic impact of encapsulated rapamycin in patients with low risk prostate cancer under active surveillance. There will be four groups of patients, each receiving a different dose of rapamycin.
This is a phase Ib trial of encapsulated rapamycin to determine safety, pharmacokinetics/pharmacodynamics, and immunologic impact in patients with low risk prostate cancer under active surveillance. This new formulation, encapsulated rapamycin (sirolimus), provides a more predictable bioavailability of this drug than \[the other formulation\]. The encapsulated and targeted rapamycin (eRapa) can be delivered at a consistent and lower dosage, not only improving the toxicity profile but also capitalizing on the newly appreciated mechanism of partial and/or intermittent mTOR inhibition, making eRapa an ideal immuno-oncologic and chemopreventative agent. Low dose rapamycin has been shown to prevent cancer formation, progression, and/or recurrence in the majority of cancer histologies including the most prevalent: lung, breast, prostate, and colon cancers.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
15
The eRapa (encapsulated rapamycin) drug product consists of sub-micron rapamycin particles incorporated into poly(methyl methacrylate) polymer (Eudragit® L 100 / S 100). This improved formulation and better bioavailability enables eRapa to consistently provide approximately 30% more drug than sirolimus (unpublished data). Improved and predictable delivery allows for consistent and sustained lower dosing, which will result in an improved toxicity profile since the latter is proven to be related to blood concentration levels. This is a phase Ib trial in low risk (Gleason score ≤7 (3+4)) prostate cancer patients under active surveillance to establish dosage safety and treatment levels.
UT Health San Antonio
San Antonio, Texas, United States
Primary Safety and Tolerability (Incidence of Treatment-Emergent Adverse Events)
To analyze the overall safety of eRapa by evaluating the number, frequency, duration, and relation of toxicity events as defined by the Common Terminology Criteria for Adverse Events (CTCAE) v4.03.
Time frame: After 4 weeks of treatment in each dosing cohort.
Primary Safety and Tolerability (Incidence of Treatment-Emergent Adverse Events)
To analyze the overall safety of eRapa by evaluating the number, frequency, duration, and relation of toxicity events as defined by the Common Terminology Criteria for Adverse Events (CTCAE) v4.03.
Time frame: After completion of treatment, approximately 12 weeks, in each dosing cohort.
Primary Safety and Tolerability (Incidence of Treatment-Emergent Adverse Events)
To compare safety between dosing cohorts of eRapa by evaluating the number, frequency, duration, and relation of toxicity events as defined by the Common Terminology Criteria for Adverse Events (CTCAE) v4.03 at the 4 week time point.
Time frame: This will be completed after all dosing cohorts have been enrolled and treated, anticipated to occur at 1 year.
Primary Safety and Tolerability (Incidence of Treatment-Emergent Adverse Events)
To compare safety between dosing cohorts of eRapa by evaluating the number, frequency, duration, and relation of toxicity events as defined by the Common Terminology Criteria for Adverse Events (CTCAE) v4.03 at the 12 week time point.
Time frame: This will be completed after all dosing cohorts have been enrolled and treated, anticipated to occur after 1 year.
Secondary Pharmacokinetics: AUC
Pharmacokinetics of eRapa in blood will be evaluated throughout the trial and compared within and between the dosing cohorts. For cohorts 1 and 2, single dose exposure curves will be generated by assessing the rapamycin levels in whole blood and spot card collection at 0, 0.5, 1, 2, 4, 6, 8, 24, 48, and 72 hrs after the first dose on week 1. Cohorts 3 and 4, exposure curves will be generated during the last week of treatment with blood draws and spot card collection after a dose during the final week at 0, 0.5, 1, 1.5, and 2 hrs.
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Time frame: Cohorts 1 and 2 PK analysis will occur during the first week. Cohorts 3 and 4 PK analysis will occur during week 12 of treatment.
Secondary Pharmacokinetics: Exposure Trough Levels
Pharmacokinetics of eRapa in blood will be evaluated throughout the trial and compared within and between the dosing cohorts. Cohorts 3 and 4, eRapa troughs will be gathered before the first 5 doses of eRapa during the week 1.
Time frame: Cohorts 3 and 4 PK analysis will occur during the first week of treatment.
Secondary Pharmacodynamics: mTOR inhibition in PBMC by assessment of phosphorylation of S6
Pharmacodynamics of eRapa in blood will be evaluated throughout the trial and compared within and between dosing cohorts. For cohorts 1 and 2, mTOR inhibition in PBMC by assessment of phosphorylation of S6 will also be assessed at 0, 0.5, 1, 2, 4, 6, 8, 24, 48, and 72 hrs after the first dose on week 1. Cohorts 3 and 4, mTor inhibitions will be gathered before the first 5 doses of eRapa during the week 1. In addition, during the last week of treatment after a dose during the final week at 0, 0.5, 1, 1.5, and 2 hrs.
Time frame: Cohorts 1 and 2 PD analysis will occur during the first week. Cohorts 3 and 4 PD analysis will occur during week 12 of treatment.
Secondary Pharmacodynamics: mTOR inhibition upon initial dose
Pharmacodynamics of eRapa in blood will be evaluated throughout the trial and compared within and between dosing cohorts. For cohorts 1 and 2, mTOR inhibition in PBMC by assessment of phosphorylation of S6 will also be assessed at 0, 0.5, 1, 2, 4, 6, 8, 24, 48, and 72 hrs after the first dose on week 1.
Time frame: Cohorts 1 and 2 PD analysis will occur during the first week.
Secondary Pharmacodynamics: mTOR inhibition first week of daily dosing
Pharmacodynamics of eRapa in blood will be evaluated throughout the trial and compared within and between dosing cohorts. For cohorts 3 and 4, mTOR inhibition in PBMC by assessment of phosphorylation of S6 will also be assessed before the first 5 doses of eRapa during the week 1.
Time frame: Cohorts 3 and 4 PD analysis will occur during week 12 of treatment.
Secondary Pharmacodynamics: mTOR inhibition during final week of treatment
Pharmacodynamics of eRapa in blood will be evaluated throughout the trial and compared within and between dosing cohorts. For cohorts 3 and 4, mTOR inhibition in PBMC by assessment of phosphorylation of S6 will also be assessed during the last week of treatment after a dose during the final week at 0, 0.5, 1, 1.5, and 2 hrs.
Time frame: Cohorts 3 and 4 PD analysis will occur during week 12 of treatment.
Secondary Immunologic Response: T cell phenotype individually
Immunologic response will be measured and compared from baseline at specified time points throughout the trial. The specific analysis of T cell naïve/memory/effector phenotype. These results will be assessed individually.
Time frame: Assessments will occur at baseline, during (after 4 weeks), after short-term completion of treatment (after 12 weeks), and long-term completion of treatment (6 months).
Secondary Immunologic Response: T cell function individually
Immunologic response will be measured and compared from baseline at specified time points throughout the trial. The specific analysis of T cell exhaustion markers (PD-1, LAG3, TIM3), and homing markers (CD62L, CCR7). These results will be assessed individually.
Time frame: Assessments will occur at baseline, during (after 4 weeks), after short-term completion of treatment (after 12 weeks), and long-term completion of treatment (6 months).
Secondary Immunologic Response: T cell phenotype within each dosing cohort
Immunologic response will be measured and compared from baseline at specified time points throughout the trial. The specific analysis of T cell naïve/memory/effector phenotype. These results will be assessed within each dosing cohort.
Time frame: Assessments will occur at baseline, during (after 4 weeks), after short-term completion of treatment (after 12 weeks), and long-term completion of treatment (6 months).
Secondary Immunologic Response: T cell function within each dosing cohort
Immunologic response will be measured and compared from baseline at specified time points throughout the trial. The specific analysis of T cell exhaustion markers (PD-1, LAG3, TIM3), and homing markers (CD62L, CCR7). These results will be assessed within each dosing cohort.
Time frame: Assessments will occur at baseline, during (after 4 weeks), after short-term completion of treatment (after 12 weeks), and long-term completion of treatment (6 months).
Secondary Immunologic Response: T cell phenotype overall study-wide
Immunologic response will be measured and compared from baseline at specified time points throughout the trial. The specific analysis of T cell naïve/memory/effector phenotype. These results will be assessed overall study-wide.
Time frame: Assessments will occur at baseline, during (after 4 weeks), after short-term completion of treatment (after 12 weeks), and long-term completion of treatment (6 months).
Secondary Immunologic Response: T cell function overall study-wide
Immunologic response will be measured and compared from baseline at specified time points throughout the trial. The specific analysis of T cell exhaustion markers (PD-1, LAG3, TIM3), and homing markers (CD62L, CCR7). These results will be assessed overall study-wide.
Time frame: Assessments will occur at baseline, during (after 4 weeks), after short-term completion of treatment (after 12 weeks), and long-term completion of treatment (6 months).
Secondary Quality of Life Analysis
Quality of life will be assessed and compared to characterize the impact of eRapa before, during, and after treatment by using the National Institute of Health Patient-Reported Outcomes Measurement Information System (PROMIS-29) and Cognition (long form) assessments.
Time frame: Assessments performed baseline, after completion of therapy (approximately 12 weeks), and after 6 months.