Non-hematologic Malignancy
Conditions
Keywords
Drug therapy
Brief summary
The purposes of this study are to evaluate the safety and tolerability of sapanisertib (MLN0128) milled active pharmaceutical ingredient (API) capsules administered both as a single agent and in combination with paclitaxel, to characterize the effect of a high-fat meal on the pharmacokinetics (PK) of sapanisertib milled API capsules, and to characterize the PK of sapanisertib milled API capsules when administered on an empty stomach approximately 24 hours after paclitaxel infusion.
Detailed description
The drug being tested in this study is called sapanisertib (MLN0128). Sapanisertib is being tested to assess its safety and tolerability when administered alone or in combination with paclitaxel in people who have nonhematologic malignancies. Sapanisertib is also being tested to characterize its PK properties (how is processed by the body) when administered with a high-fat meal compared to on an empty stomach. This study will look at side effects and lab results in people who take sapanisertib with or without paclitaxel. This open label study enrolled 61 patients. Participants receiving only sapanisertib will participate in a 6-day PK Run-In Period where sapanisertib 4 mg capsules are administered under fasted conditions on Days 1 and 4, and with a high-fat breakfast on Day 3. The main treatment period will begin within 14 days from Day 6 of the PK Run-In Period. In the main treatment period participants will receive sapanisertib 4 mg daily in a 28-day Cycle for up to 12 cycles. Participants in the treatment arm receiving sapanisertib and paclitaxel will not have a PK Run-In Period and will receive sapanisertib 6 mg daily on Days 2-4, 9-11, 16-18, and 23-25 in a 28-day Cycle for up to 12 cycles and paclitaxel 80 mg/m\^2 intravenously (IV) on Days 1, 8, and 15 in 28-day Cycle, for up to 12 cycles. The dose of sapanisertib may be modified based on safety and tolerability during each 28-day cycle in either treatment arm. This multi-centre trial will be conducted in the United States. The overall time to participate in this study is up to 15 months. Participants in the sapanisertib only arm will make up to 32 visits to the clinic and participants in the sapanisertib and paclitaxel arm will make up to 26 visits to the clinic. All participants will make a final visit to the clinic 30 days after the last dose of study drug for a follow-up assessment.
Interventions
DRUGSapanisertib
Sapanisertib capsules
DRUGPaclitaxel
Paclitaxel injection
Sponsors
Millennium Pharmaceuticals, Inc.
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. Age is ≥ 18 years, including males and females. 2. Has Advanced nonhematologic malignancies, with the exception of primary brain tumor, and have failed or are not eligible for standard of care therapy. History of brain metastasis may be allowed if all the following criteria are met: brain metastases have been treated, there is no evidence of progression or hemorrhage after treatment, dexamethasone discontinued for ≥ 4 weeks before first study drug administration, and there is no ongoing requirement for dexamethasone or anti-epileptic drugs. 3. Has received not more than 4 prior lines of systemic cytotoxic chemotherapy for advanced or metastatic disease. 4. Has Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1. 5. Has adequate organ function, including the following: * Bone marrow reserve consistent with absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L; platelet count ≥ 100 x 10\^9/L; and hemoglobin ≥ 9 g/dL without transfusion in the last 2 weeks * Hepatic: total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN), transaminases (aspartate aminotransferase \[AST\]/serum glutamic oxaloacetic transaminase \[SGOT\] and alanine aminotransferase \[ALT\]/serum glutamic pyruvic transaminase \[SGPT\]) ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases are present) * Renal: normal serum creatinine or calculated creatinine clearance ≥ 60 mL/min based either on Cockcroft-Gault estimate or based on urine collection (12- or 24-hour) * Metabolic: fasting serum glucose (≤ 130 mg/dL) and fasting triglycerides ≤ 300 mg/dL 6. Has left ventricular ejection fraction (LVEF) within 5 absolute percentage points of institutional standard of normal as measured by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) within 4 weeks before first study drug administration (ie, if the institutional normal is 50%, participant's LVEF may be as low as 45% to be eligible for the study). 7. Is a 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 form through 90 days 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 (eg, calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable methods of contraception.) Male participants, even if surgically sterilized (ie, status postvasectomy), who: * Agree to practice effective barrier contraception during the entire study treatment period and through 90 days 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 \[eg, calendar, ovulation, symptothermal, postovulation methods for the female partner\] and withdrawal are not acceptable methods of contraception.) 8. Has ability to swallow oral medications. 9. Has voluntary written consent obtained 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.
Exclusion criteria
1. Has a diagnosis of primary brain tumor. 2. Has untreated brain metastasis or history of leptomeningeal disease or spinal cord compression. 3. Has failed 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. 4. Has received prior cancer therapy or other investigational therapy within 2 weeks before the first administration of study drug. For prior therapies with a half-life longer than 3 days, the interval must be at least 28 days before the first administration of study drug, and the participant must have documented disease progression. 5. Has initiation of hematopoietic growth factors within 1 week before the first administration of any study drug; participants already receiving hematopoietic growth factors on a chronic basis for ≥ 4 weeks are eligible. 6. Has chronic systemic corticosteroid (except inhalers) use within 1 week before the first administration of study drug. Premedication with dexamethasone before paclitaxel administration in this study is allowed. 7. Has manifestations of malabsorption due to prior gastrointestinal surgery, gastrointestinal disease, or for an unknown reason that may alter the absorption of MLN0128. 8. Has poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) \> 7%; participants with a history of transient glucose intolerance due to corticosteroid administration are allowed if all other eligibility criteria are met. 9. Has other clinically significant comorbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise the participant's participation in the study. 10. Has a known human immunodeficiency virus infection. 11. Is pregnant (positive serum or urine pregnancy test) or breastfeeding. 12. Has any history of unstable angina, myocardial infarction, New York Heart Association Class III or IV heart failure, and/or pulmonary hypertension. 13. Has significant active cardiovascular disease including: * Uncontrolled high blood pressure (ie, systolic blood pressure \> 180 mmHg, diastolic blood pressure \> 95 mmHg) * Grade 3 or higher valvular disease * Grade 3 or higher atrial fibrillation * Grade 3 or higher bradycardia * Endocarditis * Pulmonary embolism * Recent cerebrovascular accident/transient ischemic attack ≤ 6 months before enrollment 14. Diagnosed or treated for another malignancy within 2 years before the first dose or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection. 15. Single-Agent QD Arm participants participating in the pharmacokinetic (PK) Run-In (only): participants who use proton pump inhibitors (PPIs) less than 5 days before the first MLN0128 PK Run-In dose OR use H2 receptor antagonists within 24 hours of the first PK Run-In dose.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC(0-8): Area Under the Plasma Concentration Curve From Time Zero to 8 Hours Post-dose for Sapanisertib Milled API Capsules Under Fasted Conditions Approximately 24 Hours After Paclitaxel Infusion | Cycle 1, Day 2 pre-dose and at multiple time points (up to 8 hours) post-dose | — |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From Day 1, Cycle 1 through 30 days after the last dose of study drug (up to 15 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 (example, 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. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. An SAE is defined as an untoward medical occurrence, significant hazard, contraindication, side effect or precaution that at any dose: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. |
| Geometric Mean Ratio of Cmax: Maximum Observed Plasma Concentration of Sapanisertib Milled Active Pharmaceutical Ingredient (API) Capsules Under Fasted and Fed Conditions | Days 3 and 5 predose and at multiple time points (up to 24 hours) post-dose | — |
| Geometric Mean Ratio of AUC(0-last): Area Under the Plasma Concentration Curve From Time Zero to the Time of the Last Quantifiable Concentration of Sapanisertib Milled API Capsules Under Fasted and Fed Conditions | Days 3 and 5 predose and at multiple time points (up to 24 hours) post-dose | — |
| Geometric Mean Ratio of AUC(0-inf): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for Sapanisertib Milled API Capsules Under Fasted and Fed Conditions | Days 3 and 5 predose and at multiple time points (up to 24 hours) post-dose | — |
| Cmax: Maximum Observed Plasma Concentration of Sapanisertib Milled API Capsules Under Fasted Conditions Approximately 24 Hours After Paclitaxel Infusion | Cycle 1, Day 2 pre-dose and at multiple time points (up to 8 hours) post-dose | — |
| Tmax: Time to Reach the Maximum Plasma Concentration of Sapanisertib Milled API Capsules Under Fasted Conditions Approximately 24 Hours After Paclitaxel Infusion | Cycle 1, Day 2 pre-dose and at multiple time points (up to 8 hours) post-dose | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Geometric Mean Ratio of Cmax: Maximum Observed Plasma Concentration of Sapanisertib Milled Versus Unmilled API Capsules Under Fasted Conditions | Days 1 and 3 pre-dose and at multiple time points (up to 24 hours) post-dose | — |
| Geometric Mean Ratio of AUC(0-last): Area Under the Plasma Concentration Curve From Time Zero to the Time of the Last Quantifiable Concentration for Sapanisertib Milled Versus Unmilled API Capsules Under Fasted Conditions | Days 1 and 3 pre-dose and at multiple time points (up to 24 hours) post-dose | — |
| AUC(0-inf): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for Sapanisertib Milled Versus Unmilled API Capsules Under Fasted Conditions | Days 1 and 3 pre-dose and at multiple time points (up to 24 hours) post-dose | — |
| Overall Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Baseline then every 2 cycles beginning at Cycle 3, Day 1, until disease progression, death or end of study (Up to 14 months) | ORR is defined as the percentage of participants with complete response (CR) or partial response (PR) using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions. |
| Progression Free Survival (PFS) | Baseline then every 2 cycles beginning at Cycle 3, Day 1, until disease progression, death or end of study (Up to 14 months) | PFS is defined as the time from the date of first study drug administration to the date of first documented PD or death due to any cause. PD was based on response evaluation criteria in solid tumors (RECIST V1.1), defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. |
| Clinical Benefit Response (CBR) | Baseline then every 2 cycles beginning at Cycle 3, Day 1, until disease progression, death or end of study (Up to 14 months) | CBR is defined as the percentage of participants with complete response (CR) or partial response (PR) or stable disease (SD) using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions. SD is neither shrinkage by greater than or equal to 30% of the sum of the longest diameter of target lesions or the increase of lesions by greater than or equal to 20% of the sum of the longest diameter of target lesions. |
| Change From Baseline in Tumor Volume/Size | From Cycle 1 Day -14 to 14 months | Changes in tumor size and volume will be determined by measurements from computed tomography (CT) and magnetic resonance imaging (MRI) scans. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 4 investigative sites in United States from 26 March 2015 to 31 May 2018.
Pre-assignment details
Participants were enrolled in 3 cohorts in the study: 1)Single-Agent QD Arm, 2)Combination Arm and 3)Single-Agent QW Arm. Participants in Single-Agent QD Arm first completed pharmacokinetic (PK) run-in period, to assess the effect of dosing condition (ie, fed vs fasted) and manufacturing process (ie, milled vs unmilled API) on PK of sapanisertib.
Participants by arm
| Arm | Count |
|---|---|
| Single-Agent QD Arm: Sapanisertib 3 mg Following Pharmacokinetic (PK) - Run in Period, sapanisertib 3 mg milled capsules, orally, once, daily in a 28-day Cycle, under fasted conditions, starting from Cycle 2 for up to 9 cycles. | 11 |
| Single-Agent QD Arm: Sapanisertib 4 mg Following PK Run-In Period, sapanisertib 4 mg milled capsules, orally, once, daily in a 28-day Cycle, under fasted conditions, starting from Cycle 2 for up to 13 cycles. | 8 |
| Combination Arm: Sapanisertib 4 mg + Paclitaxel 80 mg/m^2 Sapanisertib 4 mg milled capsules, orally, once, for 3 consecutive days following each paclitaxel administration (Days 2-4, 9-11, 16-18, and 23-25) in a 28-day Cycle, under fasted conditions, for up to 12 cycles, and paclitaxel 80 mg/m\^2, intravenously (IV), on Days 1, 8, and 15 in 28-day Cycle, for up to 6 cycles. | 7 |
| Combination Arm: Sapanisertib 6 mg + Paclitaxel 80 mg/m^2 Sapanisertib 6 mg milled capsules, orally, once, for 3 consecutive days following each paclitaxel administration (Days 2-4, 9-11, 16-18, and 23-25) in a 28-day Cycle, under fasted conditions, for up to 9 cycles, and paclitaxel 80 mg/m\^2, IV, on Days 1, 8, and 15 in 28-day Cycle, for up to 9 cycles. | 15 |
| Single-Agent QW Arm: Sapanisertib 20 mg Sapanisertib 20 mg, capsules milled API, QW in a 28-day Cycle, for up to 6 cycles. | 7 |
| Single-Agent QW Arm: Sapanisertib 30 mg Sapanisertib 30 mg, capsules, milled API, QW in a 28-day Cycle, for up to 10 cycles. | 13 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 0 | 3 | 0 | 3 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Progressive Disease | 6 | 4 | 4 | 9 | 3 | 3 |
| Overall Study | Reason not Specified | 3 | 0 | 2 | 1 | 2 | 6 |
| Overall Study | Received drug in run-in and discontinued | 0 | 2 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 1 | 2 | 1 | 1 |
Baseline characteristics
| Characteristic | Single-Agent QD Arm: Sapanisertib 4 mg | Combination Arm: Sapanisertib 4 mg + Paclitaxel 80 mg/m^2 | Combination Arm: Sapanisertib 6 mg + Paclitaxel 80 mg/m^2 | Single-Agent QW Arm: Sapanisertib 20 mg | Single-Agent QW Arm: Sapanisertib 30 mg | Total | Single-Agent QD Arm: Sapanisertib 3 mg |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 60.5 years STANDARD_DEVIATION 8.17 | 56.2 years STANDARD_DEVIATION 7.75 | 63.4 years STANDARD_DEVIATION 12.74 | 57.0 years STANDARD_DEVIATION 16.45 | 60.5 years STANDARD_DEVIATION 12.02 | 60.7 years STANDARD_DEVIATION 12.47 | 62.5 years STANDARD_DEVIATION 15.76 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 7 Participants | 14 Participants | 6 Participants | 12 Participants | 58 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants |
| Height | 168.0 cm STANDARD_DEVIATION 8.52 | 170.2 cm STANDARD_DEVIATION 6.68 | 166.0 cm STANDARD_DEVIATION 11.43 | 165.3 cm STANDARD_DEVIATION 11.92 | 164.4 cm STANDARD_DEVIATION 5.05 | 165.9 cm STANDARD_DEVIATION 8.76 | 163.9 cm STANDARD_DEVIATION 7.78 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 7 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 6 Participants | 11 Participants | 5 Participants | 11 Participants | 49 Participants | 9 Participants |
| Region of Enrollment United States | 8 Participants | 7 Participants | 15 Participants | 7 Participants | 13 Participants | 61 Participants | 11 Participants |
| Sex: Female, Male Female | 6 Participants | 5 Participants | 11 Participants | 3 Participants | 10 Participants | 44 Participants | 9 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 4 Participants | 4 Participants | 3 Participants | 17 Participants | 2 Participants |
| Weight | 74.4 kg STANDARD_DEVIATION 14.11 | 87.2 kg STANDARD_DEVIATION 35.23 | 75.3 kg STANDARD_DEVIATION 27.45 | 63.3 kg STANDARD_DEVIATION 15.55 | 61.8 kg STANDARD_DEVIATION 11.1 | 71.6 kg STANDARD_DEVIATION 21.96 | 71.2 kg STANDARD_DEVIATION 17.02 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 19 | 0 / 17 | 0 / 11 | 1 / 6 | 0 / 7 | 1 / 15 | 0 / 7 | 1 / 13 |
| other Total, other adverse events | 7 / 19 | 6 / 19 | 9 / 17 | 11 / 11 | 6 / 6 | 7 / 7 | 14 / 15 | 6 / 7 | 12 / 13 |
| serious Total, serious adverse events | 1 / 19 | 0 / 19 | 2 / 17 | 3 / 11 | 2 / 6 | 2 / 7 | 7 / 15 | 4 / 7 | 7 / 13 |
Outcome results
Primary
AUC(0-8): Area Under the Plasma Concentration Curve From Time Zero to 8 Hours Post-dose for Sapanisertib Milled API Capsules Under Fasted Conditions Approximately 24 Hours After Paclitaxel Infusion
Time frame: Cycle 1, Day 2 pre-dose and at multiple time points (up to 8 hours) post-dose
Population: PK population included participants with protocol specified dosing and conditions and PK data to reliably estimate PK parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PK-Run In Period Fasted (Unmilled) | AUC(0-8): Area Under the Plasma Concentration Curve From Time Zero to 8 Hours Post-dose for Sapanisertib Milled API Capsules Under Fasted Conditions Approximately 24 Hours After Paclitaxel Infusion | 144.8 ng*hr/mL | Standard Deviation 84.15 |
| PK-Run In Period Fed (Milled) | AUC(0-8): Area Under the Plasma Concentration Curve From Time Zero to 8 Hours Post-dose for Sapanisertib Milled API Capsules Under Fasted Conditions Approximately 24 Hours After Paclitaxel Infusion | 260.6 ng*hr/mL | Standard Deviation 89.59 |
Primary
Cmax: Maximum Observed Plasma Concentration of Sapanisertib Milled API Capsules Under Fasted Conditions Approximately 24 Hours After Paclitaxel Infusion
Time frame: Cycle 1, Day 2 pre-dose and at multiple time points (up to 8 hours) post-dose
Population: PK population included participants with protocol specified dosing and conditions and PK data to reliably estimate PK parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PK-Run In Period Fasted (Unmilled) | Cmax: Maximum Observed Plasma Concentration of Sapanisertib Milled API Capsules Under Fasted Conditions Approximately 24 Hours After Paclitaxel Infusion | 35.2 ng/mL | Standard Deviation 22.33 |
| PK-Run In Period Fed (Milled) | Cmax: Maximum Observed Plasma Concentration of Sapanisertib Milled API Capsules Under Fasted Conditions Approximately 24 Hours After Paclitaxel Infusion | 71.4 ng/mL | Standard Deviation 29.16 |
Primary
Geometric Mean Ratio of AUC(0-inf): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for Sapanisertib Milled API Capsules Under Fasted and Fed Conditions
Time frame: Days 3 and 5 predose and at multiple time points (up to 24 hours) post-dose
Population: PK population included participants with protocol specified dosing and conditions and PK data to reliably estimate PK parameters. Overall number of participants analyzed is the number of participants with the data available for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PK-Run In Period Fasted (Unmilled) | Geometric Mean Ratio of AUC(0-inf): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for Sapanisertib Milled API Capsules Under Fasted and Fed Conditions | 382.8 ng*hr/mL | Geometric Coefficient of Variation 64.7 |
| PK-Run In Period Fed (Milled) | Geometric Mean Ratio of AUC(0-inf): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for Sapanisertib Milled API Capsules Under Fasted and Fed Conditions | 369.2 ng*hr/mL | Geometric Coefficient of Variation 50 |
90% CI: [0.72, 1.49]
Primary
Geometric Mean Ratio of AUC(0-last): Area Under the Plasma Concentration Curve From Time Zero to the Time of the Last Quantifiable Concentration of Sapanisertib Milled API Capsules Under Fasted and Fed Conditions
Time frame: Days 3 and 5 predose and at multiple time points (up to 24 hours) post-dose
Population: PK population included participants with protocol specified dosing and conditions and PK data to reliably estimate PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PK-Run In Period Fasted (Unmilled) | Geometric Mean Ratio of AUC(0-last): Area Under the Plasma Concentration Curve From Time Zero to the Time of the Last Quantifiable Concentration of Sapanisertib Milled API Capsules Under Fasted and Fed Conditions | 205.9 ng*hr/mL | Geometric Coefficient of Variation 59.8 |
| PK-Run In Period Fed (Milled) | Geometric Mean Ratio of AUC(0-last): Area Under the Plasma Concentration Curve From Time Zero to the Time of the Last Quantifiable Concentration of Sapanisertib Milled API Capsules Under Fasted and Fed Conditions | 229.2 ng*hr/mL | Geometric Coefficient of Variation 58.2 |
90% CI: [0.59, 1.36]
Primary
Geometric Mean Ratio of Cmax: Maximum Observed Plasma Concentration of Sapanisertib Milled Active Pharmaceutical Ingredient (API) Capsules Under Fasted and Fed Conditions
Time frame: Days 3 and 5 predose and at multiple time points (up to 24 hours) post-dose
Population: PK population included participants with protocol specified dosing and conditions and PK data to reliably estimate PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PK-Run In Period Fasted (Unmilled) | Geometric Mean Ratio of Cmax: Maximum Observed Plasma Concentration of Sapanisertib Milled Active Pharmaceutical Ingredient (API) Capsules Under Fasted and Fed Conditions | 21.6 ng/mL | Geometric Coefficient of Variation 37.4 |
| PK-Run In Period Fed (Milled) | Geometric Mean Ratio of Cmax: Maximum Observed Plasma Concentration of Sapanisertib Milled Active Pharmaceutical Ingredient (API) Capsules Under Fasted and Fed Conditions | 36.4 ng/mL | Geometric Coefficient of Variation 50.6 |
90% CI: [0.46, 0.76]
Primary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
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 (example, 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. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. An SAE is defined as an untoward medical occurrence, significant hazard, contraindication, side effect or precaution that at any dose: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.
Time frame: From Day 1, Cycle 1 through 30 days after the last dose of study drug (up to 15 months)
Population: Safety population included participants who received at least 1 dose of study drug. PK-Run In population included participants who received more than one dose of study drug in PK Run-In period.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PK-Run In Period Fasted (Unmilled) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | At least one AE | 7 Participants |
| PK-Run In Period Fasted (Unmilled) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious AE | 1 Participants |
| PK-Run In Period Fed (Milled) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | At least one AE | 6 Participants |
| PK-Run In Period Fed (Milled) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious AE | 0 Participants |
| PK-Run In Period Fasted (Milled) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | At least one AE | 9 Participants |
| PK-Run In Period Fasted (Milled) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious AE | 2 Participants |
| Single-Agent QD Arm: Sapanisertib 3 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | At least one AE | 11 Participants |
| Single-Agent QD Arm: Sapanisertib 3 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious AE | 3 Participants |
| Single-Agent QD Arm: Sapanisertib 4 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | At least one AE | 6 Participants |
| Single-Agent QD Arm: Sapanisertib 4 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious AE | 2 Participants |
| Combination Arm: Sapanisertib 4 mg + Paclitaxel 80 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious AE | 2 Participants |
| Combination Arm: Sapanisertib 4 mg + Paclitaxel 80 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | At least one AE | 7 Participants |
| Combination Arm: Sapanisertib 6 mg + Paclitaxel 80 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious AE | 7 Participants |
| Combination Arm: Sapanisertib 6 mg + Paclitaxel 80 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | At least one AE | 14 Participants |
| Single-Agent QW Arm: Sapanisertib 20 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | At least one AE | 6 Participants |
| Single-Agent QW Arm: Sapanisertib 20 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious AE | 4 Participants |
| Single-Agent QW Arm: Sapanisertib 30 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | At least one AE | 13 Participants |
| Single-Agent QW Arm: Sapanisertib 30 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious AE | 7 Participants |
Primary
Tmax: Time to Reach the Maximum Plasma Concentration of Sapanisertib Milled API Capsules Under Fasted Conditions Approximately 24 Hours After Paclitaxel Infusion
Time frame: Cycle 1, Day 2 pre-dose and at multiple time points (up to 8 hours) post-dose
Population: PK population included participants with protocol specified dosing and conditions and PK data to reliably estimate PK parameters.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PK-Run In Period Fasted (Unmilled) | Tmax: Time to Reach the Maximum Plasma Concentration of Sapanisertib Milled API Capsules Under Fasted Conditions Approximately 24 Hours After Paclitaxel Infusion | 2.2 hours |
| PK-Run In Period Fed (Milled) | Tmax: Time to Reach the Maximum Plasma Concentration of Sapanisertib Milled API Capsules Under Fasted Conditions Approximately 24 Hours After Paclitaxel Infusion | 1.1 hours |
Secondary
AUC(0-inf): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for Sapanisertib Milled Versus Unmilled API Capsules Under Fasted Conditions
Time frame: Days 1 and 3 pre-dose and at multiple time points (up to 24 hours) post-dose
Population: PK population included participants with protocol specified dosing and conditions and PK data to reliably estimate PK parameters. Overall number of participants analyzed is the number of participants with the data available for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PK-Run In Period Fasted (Unmilled) | AUC(0-inf): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for Sapanisertib Milled Versus Unmilled API Capsules Under Fasted Conditions | 369.2 hr*ng/mL | Geometric Coefficient of Variation 50 |
| PK-Run In Period Fed (Milled) | AUC(0-inf): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for Sapanisertib Milled Versus Unmilled API Capsules Under Fasted Conditions | 400.8 hr*ng/mL | Geometric Coefficient of Variation 48.2 |
| PK-Run In Period Fasted (Milled) | AUC(0-inf): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for Sapanisertib Milled Versus Unmilled API Capsules Under Fasted Conditions | 1326.2 hr*ng/mL | Geometric Coefficient of Variation 61.5 |
| Single-Agent QD Arm: Sapanisertib 3 mg | AUC(0-inf): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for Sapanisertib Milled Versus Unmilled API Capsules Under Fasted Conditions | 1636.6 hr*ng/mL | Geometric Coefficient of Variation 45.2 |
90% CI: [0.67, 1.26]
Secondary
Change From Baseline in Tumor Volume/Size
Changes in tumor size and volume will be determined by measurements from computed tomography (CT) and magnetic resonance imaging (MRI) scans.
Time frame: From Cycle 1 Day -14 to 14 months
Population: Data was not collected for this outcome measure.
Secondary
Clinical Benefit Response (CBR)
CBR is defined as the percentage of participants with complete response (CR) or partial response (PR) or stable disease (SD) using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions. SD is neither shrinkage by greater than or equal to 30% of the sum of the longest diameter of target lesions or the increase of lesions by greater than or equal to 20% of the sum of the longest diameter of target lesions.
Time frame: Baseline then every 2 cycles beginning at Cycle 3, Day 1, until disease progression, death or end of study (Up to 14 months)
Population: Safety population included participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PK-Run In Period Fasted (Unmilled) | Clinical Benefit Response (CBR) | CR + PR + SD (>= 6 Months) | 36.4 percentage of participants |
| PK-Run In Period Fasted (Unmilled) | Clinical Benefit Response (CBR) | CR+PR+SD | 63.6 percentage of participants |
| PK-Run In Period Fed (Milled) | Clinical Benefit Response (CBR) | CR+PR+SD | 33.3 percentage of participants |
| PK-Run In Period Fed (Milled) | Clinical Benefit Response (CBR) | CR + PR + SD (>= 6 Months) | 33.3 percentage of participants |
| PK-Run In Period Fasted (Milled) | Clinical Benefit Response (CBR) | CR+PR+SD | 42.9 percentage of participants |
| PK-Run In Period Fasted (Milled) | Clinical Benefit Response (CBR) | CR + PR + SD (>= 6 Months) | 14.3 percentage of participants |
| Single-Agent QD Arm: Sapanisertib 3 mg | Clinical Benefit Response (CBR) | CR+PR+SD | 53.3 percentage of participants |
| Single-Agent QD Arm: Sapanisertib 3 mg | Clinical Benefit Response (CBR) | CR + PR + SD (>= 6 Months) | 26.7 percentage of participants |
| Single-Agent QD Arm: Sapanisertib 4 mg | Clinical Benefit Response (CBR) | CR+PR+SD | 42.9 percentage of participants |
| Single-Agent QD Arm: Sapanisertib 4 mg | Clinical Benefit Response (CBR) | CR + PR + SD (>= 6 Months) | 0.0 percentage of participants |
| Combination Arm: Sapanisertib 4 mg + Paclitaxel 80 mg/m^2 | Clinical Benefit Response (CBR) | CR + PR + SD (>= 6 Months) | 7.7 percentage of participants |
| Combination Arm: Sapanisertib 4 mg + Paclitaxel 80 mg/m^2 | Clinical Benefit Response (CBR) | CR+PR+SD | 46.2 percentage of participants |
Secondary
Geometric Mean Ratio of AUC(0-last): Area Under the Plasma Concentration Curve From Time Zero to the Time of the Last Quantifiable Concentration for Sapanisertib Milled Versus Unmilled API Capsules Under Fasted Conditions
Time frame: Days 1 and 3 pre-dose and at multiple time points (up to 24 hours) post-dose
Population: PK population included participants with protocol specified dosing and conditions and PK data to reliably estimate PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PK-Run In Period Fasted (Unmilled) | Geometric Mean Ratio of AUC(0-last): Area Under the Plasma Concentration Curve From Time Zero to the Time of the Last Quantifiable Concentration for Sapanisertib Milled Versus Unmilled API Capsules Under Fasted Conditions | 229.2 hr*ng/mL | Geometric Coefficient of Variation 58.2 |
| PK-Run In Period Fed (Milled) | Geometric Mean Ratio of AUC(0-last): Area Under the Plasma Concentration Curve From Time Zero to the Time of the Last Quantifiable Concentration for Sapanisertib Milled Versus Unmilled API Capsules Under Fasted Conditions | 204.6 hr*ng/mL | Geometric Coefficient of Variation 57.3 |
| PK-Run In Period Fasted (Milled) | Geometric Mean Ratio of AUC(0-last): Area Under the Plasma Concentration Curve From Time Zero to the Time of the Last Quantifiable Concentration for Sapanisertib Milled Versus Unmilled API Capsules Under Fasted Conditions | 1238.1 hr*ng/mL | Geometric Coefficient of Variation 53.3 |
| Single-Agent QD Arm: Sapanisertib 3 mg | Geometric Mean Ratio of AUC(0-last): Area Under the Plasma Concentration Curve From Time Zero to the Time of the Last Quantifiable Concentration for Sapanisertib Milled Versus Unmilled API Capsules Under Fasted Conditions | 1528.8 hr*ng/mL | Geometric Coefficient of Variation 43.5 |
90% CI: [0.75, 1.68]
Secondary
Geometric Mean Ratio of Cmax: Maximum Observed Plasma Concentration of Sapanisertib Milled Versus Unmilled API Capsules Under Fasted Conditions
Time frame: Days 1 and 3 pre-dose and at multiple time points (up to 24 hours) post-dose
Population: PK population included participants with protocol specified dosing and conditions and PK data to reliably estimate PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PK-Run In Period Fasted (Unmilled) | Geometric Mean Ratio of Cmax: Maximum Observed Plasma Concentration of Sapanisertib Milled Versus Unmilled API Capsules Under Fasted Conditions | 36.4 ng/mL | Geometric Coefficient of Variation 50.6 |
| PK-Run In Period Fed (Milled) | Geometric Mean Ratio of Cmax: Maximum Observed Plasma Concentration of Sapanisertib Milled Versus Unmilled API Capsules Under Fasted Conditions | 34.0 ng/mL | Geometric Coefficient of Variation 48.1 |
| PK-Run In Period Fasted (Milled) | Geometric Mean Ratio of Cmax: Maximum Observed Plasma Concentration of Sapanisertib Milled Versus Unmilled API Capsules Under Fasted Conditions | 208.6 ng/mL | Geometric Coefficient of Variation 17.3 |
| Single-Agent QD Arm: Sapanisertib 3 mg | Geometric Mean Ratio of Cmax: Maximum Observed Plasma Concentration of Sapanisertib Milled Versus Unmilled API Capsules Under Fasted Conditions | 235.2 ng/mL | Geometric Coefficient of Variation 43.4 |
90% CI: [0.78, 1.47]
Secondary
Overall Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST)
ORR is defined as the percentage of participants with complete response (CR) or partial response (PR) using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions.
Time frame: Baseline then every 2 cycles beginning at Cycle 3, Day 1, until disease progression, death or end of study (Up to 14 months)
Population: Safety population included participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PK-Run In Period Fasted (Unmilled) | Overall Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 9.1 percentage of participants |
| PK-Run In Period Fed (Milled) | Overall Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 16.7 percentage of participants |
| PK-Run In Period Fasted (Milled) | Overall Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 14.3 percentage of participants |
| Single-Agent QD Arm: Sapanisertib 3 mg | Overall Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 20.0 percentage of participants |
| Single-Agent QD Arm: Sapanisertib 4 mg | Overall Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 0.0 percentage of participants |
| Combination Arm: Sapanisertib 4 mg + Paclitaxel 80 mg/m^2 | Overall Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 0.0 percentage of participants |
Secondary
Progression Free Survival (PFS)
PFS is defined as the time from the date of first study drug administration to the date of first documented PD or death due to any cause. PD was based on response evaluation criteria in solid tumors (RECIST V1.1), defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: Baseline then every 2 cycles beginning at Cycle 3, Day 1, until disease progression, death or end of study (Up to 14 months)
Population: Data was not collected for this outcome measure.