Advanced Solid Tumors
Conditions
Keywords
Drug therapy
Brief summary
The purpose of this study is to characterize the effect of a single dose of 40 mg sapanisertib (MLN0128) on the electrocardiographic QT/QTc interval in participants with advanced solid tumors.
Detailed description
The drug being tested in this study is called sapanisertib (MLN0128). Sapanisertib is being tested to determine the effect of a single 40 mg dose on the electrocardiographic measure of the time between the start of the Q wave and the end of the T wave in the electrical cycle of the heart (QT)/rate corrected QT (QTc) interval in patients with advanced solid tumors. This study will look at electrocardiogram (ECG) results before and after a single dose of sapanisertib. The study will enroll approximately 30 patients. All participants will receive a single 40 mg dose of sapanisertib capsules on Day 1. Participants may continue to receive sapanisertib for up to 1 year at a dose of up to 30 mg once weekly if a clinical benefit is being derived. This multi-centre trial will be conducted in the United States. The overall time to participate in this study is up to 14 months. Participants will make 6 visits to the clinic and end of study visit 30 to 40 days after last dose of study drug for a follow-up assessment. Participants that continue treatment with sapanisertib will continue to make additional visits to the clinic once or twice every 4 weeks and the end of study visit 30 to 40 days after last dose of study drug for a follow-up assessment.
Interventions
DRUGSapanisertib
Sapanisertib capsules.
Sponsors
Calithera Biosciences, Inc
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men or women participants 18 years or older. * Must have a radiographically or clinically evaluable solid tumor Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Female participants who are postmenopausal for at least 1 year before the screening visit, OR are surgically sterile, OR if they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 3 months after the last dose of study drug, OR agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (periodic abstinence \[e.g., calendar, ovulation, symptothermal, post ovulation methods\] and withdrawal are not acceptable methods of contraception.) * Male participants, even if surgically sterilized (i.e., status post vasectomy), who agree to practice effective barrier contraception during the entire study treatment period and through 3 months after the last dose of study drug, or agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, post ovulation methods for the female partner\] and withdrawal are not acceptable methods of contraception.) * Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care. * Ability to swallow oral medications, willingness to perform mucositis prophylaxis, and suitable venous access for the study-required blood sampling.
Exclusion criteria
* Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the screening period. * Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol. * Treatment with any investigational products within 14 days before the first dose of study drug and systemic anticancer therapy within 28 days before the first dose of study drug. * Untreated brain metastasis or history of leptomeningeal disease or spinal cord compression. * Tumors with involvement of the mediastinum. * Failure to recover from the reversible effects of prior anticancer therapies with the exception of alopecia, and after-effects associated with prior tyrosine kinase inhibitor therapy such as hair depigmentation, hypothyroidism, and/or splinter hemorrhage. * Systemic corticosteroid (inhalers are allowed) within 7 days before the first dose of study drug. * Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown or other reason that may alter the absorption of Sapanisertib. * Diagnosis of diabetes mellitus; participants with a history of transient glucose intolerance due to corticosteroid administration may be enrolled if all other inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Time-Matched Baseline in QTcI, Individual Baseline Corrected Rate-Corrected QT Interval | Baseline; Cycle 1 (28 days cycle): 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24 and 48 hours postdose | The mean changes of QTcI from time-matched baseline was measured by electrocardiogram (ECG) to evaluate the potential effect of drug on QTc interval duration. Holter monitors were used to collect triplicate ECG measurements and were based on a repeated measures mixed effects linear model. A negative change from baseline indicates shortening and a positive change from baseline indicates prolongation of QTcI interval. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUCinf: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for Sapanisertib | Cycle 1 (28 days cycle), Day 1, predose and at multiple timepoints (Up to 48 hours) postdose | — |
| Number of Participants With Atleast One Adverse Event (AE) and Serious Adverse Event (SAE) | From first dose of study drug through 30 days after the last dose of study drug (Up to 13 months) | An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent. |
| Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values Reported as AE | From first dose of study drug through 30 days after the last dose of study drug (Up to 13 months) | The laboratory parameters included clinical chemistry, hematology, and urinalysis. Any abnormal change in the laboratory values were assessed by Investigator and reported as AE. An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. |
| Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Reported as AE | From first dose of study drug through 30 days after the last dose of study drug (Up to 13 months) | Vital sign measurements included blood pressure (diastolic and systolic), heart rate, and temperature. Any abnormal change in the vital sign values were assessed by Investigator and reported as AE. An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. |
| Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval With Bazett Correction (QTcB) | Baseline; Cycle 1 (28 days cycle): 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24 and 48 hours postdose | The mean changes of QTcB from time-matched baseline was measured by ECG to evaluate the potential effect of drug on QTc interval duration. Holter monitors were used to collect triplicate ECG measurements and were based on a repeated measures mixed effects linear model. A negative change from baseline indicates shortening and a positive change from baseline indicates prolongation of QTcB interval. |
| Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval Fridericia Correction (QTcF) | Baseline; Cycle 1 (28 days cycle): 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24 and 48 hours postdose | The mean changes of QTcF from time-matched baseline was measured by ECG to evaluate the potential effect of drug on QTc interval duration. Holter monitors were used to collect triplicate ECG measurements and were based on a repeated measures mixed effects linear model. A negative change from baseline indicates shortening and a positive change from baseline indicates prolongation of QTcF interval. |
| T1/2: Terminal Elimination Half-life for Sapanisertib | Cycle 1 (28 days cycle), Day 1, predose and at multiple timepoints (Up to 48 hours) postdose | — |
| Change From Time-Matched Baseline in PR Interval | Baseline; Cycle 1 (28 days cycle): 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24 and 48 hours postdose | PR interval is defined as the time between the start of the P wave and the beginning of the QRS complex on ECG. Holter monitors were used to collect triplicate ECG measurements and were based on a repeated measures mixed effects linear model. A negative change from baseline indicates shortening and a positive change from baseline indicates prolongation of PR interval. |
| Change From Time-Matched Baseline in Heart Rate | Baseline; Cycle 1 (28 days cycle): 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24 and 48 hours postdose | Heart rate was assessed using the ECG. Holter monitors were used to collect triplicate ECG measurements and were based on a repeated measure mixed effects linear model. A negative change from baseline indicates decrease in heart rate. |
| Cmax: Maximum Observed Plasma Concentration for Sapanisertib | Cycle 1 (28 days cycle), Day 1, predose and at multiple timepoints (Up to 48 hours) postdose | — |
| Tmax: Time to Reach Cmax for Sapanisertib | Cycle 1 (28 days cycle), Day 1, predose and at multiple timepoints (Up to 48 hours) postdose | — |
| AUCt: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Measurable Concentration for Sapanisertib | Cycle 1 (28 days cycle), Day 1, predose and at multiple timepoints (Up to 48 hours) postdose | — |
| Change From Time-Matched Baseline in QRS Interval | Baseline; Cycle 1 (28 days cycle): 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24 and 48 hours postdose | QRS interval is defined as the time between the start of the Q wave and end of the S wave on ECG. Holter monitors were used to collect triplicate ECG measurements and were based on a repeated measures mixed effects linear model. A negative change from baseline indicates shortening and a positive change from baseline indicates prolongation of QRS interval. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 5 investigative sites in the United States from 15 Sep 2014 to 28 Feb 2019.
Pre-assignment details
Participants who had advanced solid tumors were enrolled to receive sapanisertib 40 mg on Day 1. Participants then received sapanisertib 30 mg once weekly (QW) until they experienced disease progression or unacceptable sapanisertib-related toxicity or withdrawal of consent or for up to 12 months (whichever occurred first).
Participants by arm
| Arm | Count |
|---|---|
| Sapanisertib Sapanisertib starting dose of 40 mg, capsules, orally, once, on Day 1, Cycle 1 followed by sapanisertib 30 mg, capsules, orally, once weekly (QW) starting on Cycle 1, Day 8 based on safety and tolerability and as per investigator's discretion up to disease progression, unacceptable sapanisertib-related toxicity, withdrawal of consent, or for up to 12 months (whichever occurred first). | 44 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Progressive Disease | 28 |
| Overall Study | Reason Not Specified | 4 |
| Overall Study | Withdrawal by Subject | 9 |
Baseline characteristics
| Characteristic | Sapanisertib |
|---|---|
| Age, Continuous | 58.6 years STANDARD_DEVIATION 12.24 |
| Body Mass Index (BMI) | 27.141 kg/m^2 STANDARD_DEVIATION 5.8591 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants |
| Height | 166.8 cm STANDARD_DEVIATION 8.61 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) White | 30 Participants |
| Sex: Female, Male Female | 28 Participants |
| Sex: Female, Male Male | 16 Participants |
| Weight | 74.9 kg STANDARD_DEVIATION 16.08 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 44 |
| other Total, other adverse events | 43 / 44 |
| serious Total, serious adverse events | 18 / 44 |
Outcome results
Primary
Mean Change From Time-Matched Baseline in QTcI, Individual Baseline Corrected Rate-Corrected QT Interval
The mean changes of QTcI from time-matched baseline was measured by electrocardiogram (ECG) to evaluate the potential effect of drug on QTc interval duration. Holter monitors were used to collect triplicate ECG measurements and were based on a repeated measures mixed effects linear model. A negative change from baseline indicates shortening and a positive change from baseline indicates prolongation of QTcI interval.
Time frame: Baseline; Cycle 1 (28 days cycle): 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24 and 48 hours postdose
Population: Primary analysis population: participants that have all timepoints collected on Holter ECG monitoring on Day -1 and Day 1 of Cycle 1 including ECG timepoints on Cycle 1 Days 1 to 3 at 24 or 48 hours postdose and baseline comparisons available for these analyses. Number analyzed is number of participants with evaluable data at given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sapanisertib | Mean Change From Time-Matched Baseline in QTcI, Individual Baseline Corrected Rate-Corrected QT Interval | Change from Baseline at 1 Hour Postdose | -1.1 msec | Standard Deviation 11.5 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTcI, Individual Baseline Corrected Rate-Corrected QT Interval | Change from Baseline at 1.5 Hours Postdose | -2.0 msec | Standard Deviation 12.5 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTcI, Individual Baseline Corrected Rate-Corrected QT Interval | Change from Baseline at 3 Hours Postdose | -8.5 msec | Standard Deviation 11.2 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTcI, Individual Baseline Corrected Rate-Corrected QT Interval | Change from Baseline at 0.25 Hours Postdose | -1.3 msec | Standard Deviation 9.5 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTcI, Individual Baseline Corrected Rate-Corrected QT Interval | Change from Baseline at 0.5 Hours Postdose | -7.7 msec | Standard Deviation 9.8 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTcI, Individual Baseline Corrected Rate-Corrected QT Interval | Change from Baseline at 2 Hours Postdose | -4.2 msec | Standard Deviation 11.2 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTcI, Individual Baseline Corrected Rate-Corrected QT Interval | Change from Baseline at 2.5 Hours Postdose | -6.9 msec | Standard Deviation 10.6 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTcI, Individual Baseline Corrected Rate-Corrected QT Interval | Change from Baseline at 4 Hours Postdose | -6.6 msec | Standard Deviation 9.3 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTcI, Individual Baseline Corrected Rate-Corrected QT Interval | Change from Baseline at 6 Hours Postdose | -8.8 msec | Standard Deviation 15.6 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTcI, Individual Baseline Corrected Rate-Corrected QT Interval | Change from Baseline at 8 Hours Postdose | -1.3 msec | Standard Deviation 14.1 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTcI, Individual Baseline Corrected Rate-Corrected QT Interval | Change from Baseline at 10 Hours Postdose | -5.6 msec | Standard Deviation 17.5 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTcI, Individual Baseline Corrected Rate-Corrected QT Interval | Change from Baseline at 24 Hours Postdose | 7.1 msec | Standard Deviation 25.4 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTcI, Individual Baseline Corrected Rate-Corrected QT Interval | Change from Baseline at 48 Hours Postdose | 3.1 msec | Standard Deviation 17.8 |
Comparison: Change from Baseline at 0.25 Hours Postdose
Comparison: Change from Baseline at 0.5 Hours Postdose
Comparison: Change from Baseline at 1 Hour Postdose
Comparison: Change from Baseline at 1.5 Hours Postdose
Comparison: Change from Baseline at 2 Hours Postdose
Comparison: Change from Baseline at 2.5 Hours Postdose
Comparison: Change from Baseline at 3 Hours Postdose
Comparison: Change from Baseline at 4 Hours Postdose
Comparison: Change from Baseline at 6 Hours Postdose
Comparison: Change from Baseline at 8 Hours Postdose
Comparison: Change from Baseline at 10 Hours Postdose
Comparison: Change from Baseline at 24 Hours Postdose
Comparison: Change from Baseline at 48 Hours Postdose
Secondary
AUCinf: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for Sapanisertib
Time frame: Cycle 1 (28 days cycle), Day 1, predose and at multiple timepoints (Up to 48 hours) postdose
Population: PK analysis population included all participants who received at least 1 dose of sapanisertib and had sufficient concentration-time data to calculate 1 or more PK parameters. Overall number of participants analyzed were participants with data available for analysis of this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sapanisertib | AUCinf: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for Sapanisertib | 2992.5394 h*ng/mL | Standard Deviation 2405.41705 |
Secondary
AUCt: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Measurable Concentration for Sapanisertib
Time frame: Cycle 1 (28 days cycle), Day 1, predose and at multiple timepoints (Up to 48 hours) postdose
Population: PK analysis population included all participants who received at least 1 dose of sapanisertib and had sufficient concentration-time data to calculate 1 or more PK parameters. Overall number of participants analyzed were participants with data available for analysis of this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sapanisertib | AUCt: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Measurable Concentration for Sapanisertib | 2875.7406 h*ng/mL | Standard Deviation 2110.90918 |
Secondary
Change From Time-Matched Baseline in Heart Rate
Heart rate was assessed using the ECG. Holter monitors were used to collect triplicate ECG measurements and were based on a repeated measure mixed effects linear model. A negative change from baseline indicates decrease in heart rate.
Time frame: Baseline; Cycle 1 (28 days cycle): 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24 and 48 hours postdose
Population: Primary analysis population: participants that have all timepoints collected on Holter ECG monitoring on Day -1 and Day 1 of Cycle 1 including ECG timepoints on Cycle 1 Days 1 to 3 at 24 or 48 hours postdose and baseline comparisons available for these analyses. Number analyzed is number of participants with evaluable data at given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sapanisertib | Change From Time-Matched Baseline in Heart Rate | Change from Baseline at 2.5 Hours Postdose | -0.3 beats per minute (bpm) | Standard Deviation 4.8 |
| Sapanisertib | Change From Time-Matched Baseline in Heart Rate | Change from Baseline at 0.25 Hours Postdose | -0.9 beats per minute (bpm) | Standard Deviation 5.7 |
| Sapanisertib | Change From Time-Matched Baseline in Heart Rate | Change from Baseline at 0.5 Hours Postdose | -4.7 beats per minute (bpm) | Standard Deviation 5.9 |
| Sapanisertib | Change From Time-Matched Baseline in Heart Rate | Change from Baseline at 1 Hour Postdose | -4.2 beats per minute (bpm) | Standard Deviation 6.6 |
| Sapanisertib | Change From Time-Matched Baseline in Heart Rate | Change from Baseline at 1.5 Hours Postdose | -3.7 beats per minute (bpm) | Standard Deviation 6 |
| Sapanisertib | Change From Time-Matched Baseline in Heart Rate | Change from Baseline at 2 Hours Postdose | -1.0 beats per minute (bpm) | Standard Deviation 8.2 |
| Sapanisertib | Change From Time-Matched Baseline in Heart Rate | Change from Baseline at 3 Hours Postdose | -0.3 beats per minute (bpm) | Standard Deviation 7.2 |
| Sapanisertib | Change From Time-Matched Baseline in Heart Rate | Change from Baseline at 4 Hours Postdose | -0.4 beats per minute (bpm) | Standard Deviation 10.1 |
| Sapanisertib | Change From Time-Matched Baseline in Heart Rate | Change from Baseline at 6 Hours Postdose | 4.8 beats per minute (bpm) | Standard Deviation 6.3 |
| Sapanisertib | Change From Time-Matched Baseline in Heart Rate | Change from Baseline at 8 Hours Postdose | 7.0 beats per minute (bpm) | Standard Deviation 9.7 |
| Sapanisertib | Change From Time-Matched Baseline in Heart Rate | Change from Baseline at 10 Hours Postdose | 7.9 beats per minute (bpm) | Standard Deviation 9.2 |
| Sapanisertib | Change From Time-Matched Baseline in Heart Rate | Change from Baseline at 24 Hours Postdose | 12.4 beats per minute (bpm) | Standard Deviation 11.8 |
| Sapanisertib | Change From Time-Matched Baseline in Heart Rate | Change from Baseline at 48 Hours Postdose | 5.0 beats per minute (bpm) | Standard Deviation 9.8 |
Secondary
Change From Time-Matched Baseline in PR Interval
PR interval is defined as the time between the start of the P wave and the beginning of the QRS complex on ECG. Holter monitors were used to collect triplicate ECG measurements and were based on a repeated measures mixed effects linear model. A negative change from baseline indicates shortening and a positive change from baseline indicates prolongation of PR interval.
Time frame: Baseline; Cycle 1 (28 days cycle): 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24 and 48 hours postdose
Population: Primary analysis population: participants that have all timepoints collected on Holter ECG monitoring on Day -1 and Day 1 of Cycle 1 including ECG timepoints on Cycle 1 Days 1 to 3 at 24 or 48 hours postdose and baseline comparisons available for these analyses. Number analyzed is number of participants with evaluable data at given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sapanisertib | Change From Time-Matched Baseline in PR Interval | Change from Baseline at 0.25 Hours Postdose | -1.8 msec | Standard Deviation 13.9 |
| Sapanisertib | Change From Time-Matched Baseline in PR Interval | Change from Baseline at 0.5 Hours Postdose | -0.8 msec | Standard Deviation 13.6 |
| Sapanisertib | Change From Time-Matched Baseline in PR Interval | Change from Baseline at 1 Hour Postdose | 0.7 msec | Standard Deviation 11.5 |
| Sapanisertib | Change From Time-Matched Baseline in PR Interval | Change from Baseline at 1.5 Hours Postdose | -0.7 msec | Standard Deviation 11.4 |
| Sapanisertib | Change From Time-Matched Baseline in PR Interval | Change from Baseline at 2 Hours Postdose | -1.7 msec | Standard Deviation 9.3 |
| Sapanisertib | Change From Time-Matched Baseline in PR Interval | Change from Baseline at 2.5 Hours Postdose | 0.1 msec | Standard Deviation 11.7 |
| Sapanisertib | Change From Time-Matched Baseline in PR Interval | Change from Baseline at 3 Hours Postdose | -2.7 msec | Standard Deviation 10.8 |
| Sapanisertib | Change From Time-Matched Baseline in PR Interval | Change from Baseline at 4 Hours Postdose | -1.9 msec | Standard Deviation 13.3 |
| Sapanisertib | Change From Time-Matched Baseline in PR Interval | Change from Baseline at 6 Hours Postdose | -8.9 msec | Standard Deviation 13.2 |
| Sapanisertib | Change From Time-Matched Baseline in PR Interval | Change from Baseline at 8 Hours Postdosen | -7.3 msec | Standard Deviation 11.4 |
| Sapanisertib | Change From Time-Matched Baseline in PR Interval | Change from Baseline at 10 Hours Postdose | -12.3 msec | Standard Deviation 11.5 |
| Sapanisertib | Change From Time-Matched Baseline in PR Interval | Change from Baseline at 24 Hours Postdose | -6.8 msec | Standard Deviation 15.7 |
| Sapanisertib | Change From Time-Matched Baseline in PR Interval | Change from Baseline at 48 Hours Postdose | -2.9 msec | Standard Deviation 20.7 |
Secondary
Change From Time-Matched Baseline in QRS Interval
QRS interval is defined as the time between the start of the Q wave and end of the S wave on ECG. Holter monitors were used to collect triplicate ECG measurements and were based on a repeated measures mixed effects linear model. A negative change from baseline indicates shortening and a positive change from baseline indicates prolongation of QRS interval.
Time frame: Baseline; Cycle 1 (28 days cycle): 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24 and 48 hours postdose
Population: Primary analysis population: participants that have all timepoints collected on Holter ECG monitoring on Day -1 and Day 1 of Cycle 1 including ECG timepoints on Cycle 1 Days 1 to 3 at 24 or 48 hours postdose and baseline comparisons available for these analyses. Number analyzed is number of participants with evaluable data at given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sapanisertib | Change From Time-Matched Baseline in QRS Interval | Change from Baseline at 0.25 Hours Postdose | -0.7 msec | Standard Deviation 3.3 |
| Sapanisertib | Change From Time-Matched Baseline in QRS Interval | Change from Baseline at 0.5 Hours Postdose | -1.4 msec | Standard Deviation 3.3 |
| Sapanisertib | Change From Time-Matched Baseline in QRS Interval | Change from Baseline at 1 Hour Postdose | -2.8 msec | Standard Deviation 2.9 |
| Sapanisertib | Change From Time-Matched Baseline in QRS Interval | Change from Baseline at 1.5 Hours Postdose | -1.8 msec | Standard Deviation 4.1 |
| Sapanisertib | Change From Time-Matched Baseline in QRS Interval | Change from Baseline at 2 Hours Postdose | -1.4 msec | Standard Deviation 4 |
| Sapanisertib | Change From Time-Matched Baseline in QRS Interval | Change from Baseline at 2.5 Hours Postdose | -2.3 msec | Standard Deviation 4.7 |
| Sapanisertib | Change From Time-Matched Baseline in QRS Interval | Change from Baseline at 3 Hours Postdose | -2.4 msec | Standard Deviation 3.2 |
| Sapanisertib | Change From Time-Matched Baseline in QRS Interval | Change from Baseline at 4 Hours Postdose | -2.9 msec | Standard Deviation 3.2 |
| Sapanisertib | Change From Time-Matched Baseline in QRS Interval | Change from Baseline at 6 Hours Postdose | -1.3 msec | Standard Deviation 3 |
| Sapanisertib | Change From Time-Matched Baseline in QRS Interval | Change from Baseline at 8 Hours Postdosen | -0.8 msec | Standard Deviation 4.1 |
| Sapanisertib | Change From Time-Matched Baseline in QRS Interval | Change from Baseline at 10 Hours Postdose | -4.0 msec | Standard Deviation 6.5 |
| Sapanisertib | Change From Time-Matched Baseline in QRS Interval | Change from Baseline at 24 Hours Postdose | -1.4 msec | Standard Deviation 4 |
| Sapanisertib | Change From Time-Matched Baseline in QRS Interval | Change from Baseline at 48 Hours Postdose | 0.2 msec | Standard Deviation 5.3 |
Secondary
Cmax: Maximum Observed Plasma Concentration for Sapanisertib
Time frame: Cycle 1 (28 days cycle), Day 1, predose and at multiple timepoints (Up to 48 hours) postdose
Population: Pharmacokinetic (PK) analysis population included all participants who received at least 1 dose of sapanisertib and had sufficient concentration-time data to calculate 1 or more PK parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sapanisertib | Cmax: Maximum Observed Plasma Concentration for Sapanisertib | 337.1 ng/mL | Standard Deviation 178.27 |
Secondary
Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval Fridericia Correction (QTcF)
The mean changes of QTcF from time-matched baseline was measured by ECG to evaluate the potential effect of drug on QTc interval duration. Holter monitors were used to collect triplicate ECG measurements and were based on a repeated measures mixed effects linear model. A negative change from baseline indicates shortening and a positive change from baseline indicates prolongation of QTcF interval.
Time frame: Baseline; Cycle 1 (28 days cycle): 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24 and 48 hours postdose
Population: Primary analysis population: participants that have all timepoints collected on Holter ECG monitoring on Day -1 and Day 1 of Cycle 1 including ECG timepoints on Cycle 1 Days 1 to 3 at 24 or 48 hours postdose and baseline comparisons available for these analyses. Number analyzed is number of participants with evaluable data at given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval Fridericia Correction (QTcF) | Change from Baseline at 0.25 Hours Postdose | -1.3 msec | Standard Deviation 8.5 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval Fridericia Correction (QTcF) | Change from Baseline at 0.5 Hours Postdose | -5.0 msec | Standard Deviation 10.6 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval Fridericia Correction (QTcF) | Change from Baseline at 1 Hour Postdose | 2.1 msec | Standard Deviation 12 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval Fridericia Correction (QTcF) | Change from Baseline at 1.5 Hours Postdose | 0.6 msec | Standard Deviation 12.7 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval Fridericia Correction (QTcF) | Change from Baseline at 2 Hours Postdose | -3.3 msec | Standard Deviation 12.2 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval Fridericia Correction (QTcF) | Change from Baseline at 2.5 Hours Postdose | -7.0 msec | Standard Deviation 11.1 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval Fridericia Correction (QTcF) | Change from Baseline at 3 Hours Postdose | -7.4 msec | Standard Deviation 13.2 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval Fridericia Correction (QTcF) | Change from Baseline at 4 Hours Postdose | -7.7 msec | Standard Deviation 10.3 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval Fridericia Correction (QTcF) | Change from Baseline at 6 Hours Postdose | -10.1 msec | Standard Deviation 13 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval Fridericia Correction (QTcF) | Change from Baseline at 8 Hours Postdose | -4.0 msec | Standard Deviation 15.1 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval Fridericia Correction (QTcF) | Change from Baseline at 10 Hours Postdose | -11.9 msec | Standard Deviation 16.1 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval Fridericia Correction (QTcF) | Change from Baseline at 24 Hours Postdose | 0.8 msec | Standard Deviation 16 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval Fridericia Correction (QTcF) | Change from Baseline at 48 Hours Postdose | 2.5 msec | Standard Deviation 13.2 |
Secondary
Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval With Bazett Correction (QTcB)
The mean changes of QTcB from time-matched baseline was measured by ECG to evaluate the potential effect of drug on QTc interval duration. Holter monitors were used to collect triplicate ECG measurements and were based on a repeated measures mixed effects linear model. A negative change from baseline indicates shortening and a positive change from baseline indicates prolongation of QTcB interval.
Time frame: Baseline; Cycle 1 (28 days cycle): 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24 and 48 hours postdose
Population: Primary analysis population: participants that have all timepoints collected on Holter ECG monitoring on Day -1 and Day 1 of Cycle 1 including ECG timepoints on Cycle 1 Days 1 to 3 at 24 or 48 hours postdose and baseline comparisons available for these analyses. Number analyzed is number of participants with evaluable data at given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval With Bazett Correction (QTcB) | Change from Baseline at 48 Hours Postdose | 7.6 msec | Standard Deviation 14.9 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval With Bazett Correction (QTcB) | Change from Baseline at 0.25 Hours Postdose | -1.9 msec | Standard Deviation 9.7 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval With Bazett Correction (QTcB) | Change from Baseline at 0.5 Hours Postdose | -9.8 msec | Standard Deviation 12.1 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval With Bazett Correction (QTcB) | Change from Baseline at 1 Hour Postdose | -2.0 msec | Standard Deviation 12.4 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval With Bazett Correction (QTcB) | Change from Baseline at 1.5 Hours Postdose | -3.1 msec | Standard Deviation 13.5 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval With Bazett Correction (QTcB) | Change from Baseline at 2 Hours Postdose | -5.1 msec | Standard Deviation 11.4 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval With Bazett Correction (QTcB) | Change from Baseline at 2.5 Hours Postdose | -7.5 msec | Standard Deviation 10.6 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval With Bazett Correction (QTcB) | Change from Baseline at 3 Hours Postdose | -8.3 msec | Standard Deviation 14.6 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval With Bazett Correction (QTcB) | Change from Baseline at 4 Hours Postdose | -8.5 msec | Standard Deviation 8.7 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval With Bazett Correction (QTcB) | Change from Baseline at 6 Hours Postdose | -5.9 msec | Standard Deviation 12.2 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval With Bazett Correction (QTcB) | Change from Baseline at 8 Hours Postdosen | 1.9 msec | Standard Deviation 13.7 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval With Bazett Correction (QTcB) | Change from Baseline at 10 Hours Postdose | -4.4 msec | Standard Deviation 15.3 |
| Sapanisertib | Mean Change From Time-Matched Baseline in QTc With Rate-Corrected QT Interval With Bazett Correction (QTcB) | Change from Baseline at 24 Hours Postdose | 11.9 msec | Standard Deviation 17 |
Secondary
Number of Participants With Atleast One Adverse Event (AE) and Serious Adverse Event (SAE)
An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent.
Time frame: From first dose of study drug through 30 days after the last dose of study drug (Up to 13 months)
Population: Safety population included all participants who received at least 1 dose of sapanisertib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sapanisertib | Number of Participants With Atleast One Adverse Event (AE) and Serious Adverse Event (SAE) | AE | 43 Participants |
| Sapanisertib | Number of Participants With Atleast One Adverse Event (AE) and Serious Adverse Event (SAE) | SAE | 18 Participants |
Secondary
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values Reported as AE
The laboratory parameters included clinical chemistry, hematology, and urinalysis. Any abnormal change in the laboratory values were assessed by Investigator and reported as AE. An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug.
Time frame: From first dose of study drug through 30 days after the last dose of study drug (Up to 13 months)
Population: Safety population included all participants who received at least 1 dose of sapanisertib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sapanisertib | Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values Reported as AE | Vitamin D Deficiency | 2 Participants |
| Sapanisertib | Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values Reported as AE | Blood Creatinine Increased | 2 Participants |
| Sapanisertib | Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values Reported as AE | Blood Triglycerides Increased | 2 Participants |
| Sapanisertib | Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values Reported as AE | Hyperglycemia | 8 Participants |
| Sapanisertib | Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values Reported as AE | Hypertriglyceridemia | 1 Participants |
| Sapanisertib | Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values Reported as AE | Hypomagnesemia | 1 Participants |
| Sapanisertib | Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values Reported as AE | Hypophosphatemia | 2 Participants |
| Sapanisertib | Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values Reported as AE | Anemia | 3 Participants |
| Sapanisertib | Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values Reported as AE | Thrombocytopenia | 1 Participants |
Secondary
Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Reported as AE
Vital sign measurements included blood pressure (diastolic and systolic), heart rate, and temperature. Any abnormal change in the vital sign values were assessed by Investigator and reported as AE. An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug.
Time frame: From first dose of study drug through 30 days after the last dose of study drug (Up to 13 months)
Population: Safety population included all participants who received at least 1 dose of sapanisertib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sapanisertib | Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Reported as AE | Hypotension | 1 Participants |
| Sapanisertib | Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Reported as AE | Pyrexia | 4 Participants |
| Sapanisertib | Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Reported as AE | Postoperative Fever | 1 Participants |
Secondary
T1/2: Terminal Elimination Half-life for Sapanisertib
Time frame: Cycle 1 (28 days cycle), Day 1, predose and at multiple timepoints (Up to 48 hours) postdose
Population: PK analysis population included all participants who received at least 1 dose of sapanisertib and had sufficient concentration-time data to calculate 1 or more PK parameters. Overall number of participants analyzed were participants with data available for analysis of this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sapanisertib | T1/2: Terminal Elimination Half-life for Sapanisertib | 9.0682 hours |
Secondary
Tmax: Time to Reach Cmax for Sapanisertib
Time frame: Cycle 1 (28 days cycle), Day 1, predose and at multiple timepoints (Up to 48 hours) postdose
Population: PK analysis population included all participants who received at least 1 dose of sapanisertib and had sufficient concentration-time data to calculate 1 or more PK parameters.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sapanisertib | Tmax: Time to Reach Cmax for Sapanisertib | 1.5167 hours |