High Grade Sarcoma, Metastatic Leiomyosarcoma, Metastatic Malignant Peripheral Nerve Sheath Tumor, Metastatic Synovial Sarcoma, Metastatic Undifferentiated Pleomorphic Sarcoma, Metastatic Unresectable Sarcoma, Myxofibrosarcoma, Recurrent Leiomyosarcoma, Recurrent Malignant Peripheral Nerve Sheath Tumor, Recurrent Synovial Sarcoma, Recurrent Undifferentiated Pleomorphic Sarcoma, Stage IIIA Uterine Corpus Leiomyosarcoma AJCC v8, Stage IIIB Uterine Corpus Leiomyosarcoma AJCC v8, Stage IIIC Uterine Corpus Leiomyosarcoma AJCC v8, Stage III Uterine Corpus Leiomyosarcoma AJCC v8, Stage IVA Uterine Corpus Leiomyosarcoma AJCC v8, Stage IVB Uterine Corpus Leiomyosarcoma AJCC v8, Stage IV Uterine Corpus Leiomyosarcoma AJCC v8, Unresectable Leiomyosarcoma
Conditions
Brief summary
This phase I/II trial studies the side effects and best dose of sapanisertib and to see how well it works compared to pazopanib hydrochloride in treating patients with sarcoma that is too large to be removed (locally advanced) or has spread to other areas of the body (metastatic). Sapanisertib and pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed description
PRIMARY OBJECTIVES: I. To determine the safety and maximum tolerable dose of sapanisertib (MLN0128 \[TAK-228\]) within this patient population. (Phase I) II. To determine the differences in progression-free survival (PFS) in patients with sarcoma who receive MLN0128 (TAK-228) as compared to pazopanib (pazopanib hydrochloride). (Phase II) SECONDARY OBJECTIVES: I. To evaluate adverse events. (Phase I/II) II. To evaluate overall response rate (ORR), clinical benefit rate (CBR), and duration of response (DOR). (Phase I/II) III. To evaluate time to progression (TTP) and overall survival (OS). (Phase I/II) EXPLORATORY OBJECTIVES: I. To evaluate PFS and secondary endpoints within patients crossing over to MLN0128 (TAK-228), upon disease progression during treatment with pazopanib. (Phase II) II. To evaluate the 4 month CBR observed within patients treated with MLN0128 (TAK-228) and grouped by histologically defined cohorts. (Phase II) OUTLINE: This is a phase I, dose-escalation study, followed by a randomized phase II study. PHASE I: Patients receive sapanisertib orally (PO) on days 1, 8, 15, and 22 in the absence of disease progression or unacceptable toxicity. PHASE II: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive sapanisertib as in Phase I. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive pazopanib hydrochloride PO once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm I. After completion of study treatment, patients are followed up at 4 weeks and then every 6 months for 2 years.
Interventions
Given PO
Given PO
Given PO
Sponsors
Study design
Eligibility
Inclusion criteria
* Patients must have slides available for submission to central pathology review; this review is mandatory prior to registration to confirm eligibility and proper cohort assignment * HISTOLOGIC COHORT 1: Undifferentiated pleomorphic sarcoma (includes: malignant fibrous histiocytoma, myxofibrosarcoma, high grade sarcoma not otherwise specified \[NOS\]) * HISTOLOGIC COHORT 2: Leiomyosarcoma (either uterine or extra-uterine) * HISTOLOGIC COHORT 3: Other (either malignant peripheral nerve sheath tumor or synovial sarcoma); during the phase II portion of the study, enrollment will be limited to maximum of 25 patients in this cohort * Note that the phase I is limited to the histologic subtypes listed above; since patients will be enrolling onto dose cohorts during the phase I, they will not enroll onto specific histologic cohorts, although the histologic subtype informed will be collected during patient enrollment * Histologic documentation: Eligible patients must have histopathologically confirmed sarcoma of one of the subtypes listed, by central review * Locally advanced or metastatic disease; locally advanced disease is defined as disease not amenable to local therapy such as surgery and/or radiation * Measurable disease * Progression on at least one prior systemic chemotherapy for advanced, unresectable or metastatic disease; prior adjuvant or neoadjuvant therapy is not included as prior systemic chemotherapy unless treatment occurred within the 6 months prior to study enrollment * There is no limit to the number of prior lines of treatment a patient has received * No treatment with biological therapy, immunotherapy, chemotherapy, investigational agent for malignancy, or radiation =\< 28 days before study registration; no treatment with nitrosourea or mitomycin =\< 42 days before study registration * No treatment with radiation therapy =\< 28 days before study registration * Patients should have resolution of any toxic effects of prior therapy (except alopecia) to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, grade 1 or less * Prior treatment with pazopanib or any phosphoinositide 3-kinase (PI3K), mTOR, protein kinase B (AKT), or dual PI3K/mTOR complex (CREB regulated transcription coactivator \[TORC\]1/TORC2) inhibitors will be prohibited * Not pregnant and not nursing; because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown and an agent that has known genotoxic, mutagenic and teratogenic effects; therefore, for women of childbearing potential only, a negative pregnancy test done =\< 7 days prior to registration is required * Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 * Patient history: patients who have any of the following are NOT eligible: * Central nervous system (CNS): Symptomatic, untreated, or uncontrolled brain metastases present * Heme: Active bleeding or bleeding diathesis * Gastrointestinal (GI): * Abdominal fistula, GI perforation, or intra-abdominal abscess within 28 days prior to registration * Acute GI bleed within 28 days of registration * Diabetes mellitus: Patients with diabetes mellitus with inadequate control, based on either a glycosylated hemoglobin (Hgb A1c) of \> 7.0 or fasting blood glucose above or equal to 130 mg/dL * Cardiac and vascular disorders: * History of congenital long QT syndrome or torsades de pointes * Any arrhythmia that is currently not rate-controlled (rate between 60 and 100) * Prolongation of corrected QT interval via Fridericia's formula (QTcF) \> 480 msec * Ongoing unstable angina * Symptomatic peripheral vascular disease * Arterial thrombosis within 28 days of registration including transient ischemic attack (TIA), cerebrovascular accident (CVA), myocardial infarction (MI) * Patients with deep vein thrombosis (DVT) or pulmonary embolism (PE) must be on a stable dose of anticoagulation for 14 days prior to registration * Uncontrolled hypertension, defined as blood pressure (BP) \> 140/90 * Multi gated acquisition scan (MUGA) with ejection fraction (EF), 50% or echocardiogram (echo) with low EF * Class III or IV congestive heart failure (CHF) within 28 days of registration * Chronic concomitant treatment with proton pump inhibitors must discontinue the drug for 7 days prior to registration on the study * Chronic concomitant treatment with strong inhibitors of CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study * Chronic concomitant treatment with strong CYP3A4 inducers is not allowed; patients must discontinue the drug 14 days prior to the start of study treatment * Absolute neutrophil count (ANC) \>= 1,500/mm\^3 * Platelet count \>= 100,000/mm\^3 * Creatinine =\< 1.5 x upper limit of normal (ULN) * Total bilirubin =\< 1.5 x upper limit of normal (ULN); unless patient has Gilbert disease * Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =\< 3 x upper limit of normal (ULN); if liver metastases, =\< 5 x upper limit of normal (ULN) * Urine protein creatinine (UPC) =\< 1; if UPC \>= 1, then a 24-hour urine protein must be assessed; eligible patients must have a 24-hour urine protein value \< 1 g/L * Thyroid stimulating hormone (TSH) within normal limits (WNL); supplementation is acceptable to achieve a TSH WNL; in patients with abnormal TSH however if the Free T4 is normal and patient is clinically euthyroid, patient is eligible
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Phase I Participants With Dose-Limiting Toxicity Events (Phase I) | 28 days | The Maximum Tolerated Dose (MTD) of sapanisertib (MLN0128) is defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients graded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Dose-limiting toxicities include non-hematologic events graded 3 or higher and deemed at least possibly related to treatment. The number of patients reporting a dose-limiting event is reported. |
| Progression-free Survival (PFS) (Phase II Analysis Group 2 - Initial Treatment Period) | Up to 2 years | Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The median and an upper confidence boundary from a 1-sided, 85% confidence interval are estimated using the Kaplan-Meier methods. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD], and Progressive Disease [PD])(Phase II Analysis Group 2 - Initial Treatment Period) | Up to 2 years | The frequencies (and percentages) of tumor response categories (CR, PR, SD, PD) will be summarized for Phase II Analysis Group 2. Complete Response (CR): All of the following must be true: a. Disappearance of all target lesions. b. Each target lymph node must have reduction in short axis to \< 1.0 cm. Partial Response (PR): At least a 30% decrease in PBSD taking as reference the BSD. Progression (PD): At least one of the following must be true: a. At least one new malignant lesion, b. At least a 20% increase in PBSD. c. PD via FDG-PET imaging. d. unequivocal progression of existing non-target lesions and non-target lymph nodes. e. symptomatic deterioration. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD taking as reference the MSD. |
| The Number of Patients Who Experienced Grade 3+ Adverse Events (Phase II Analysis Group 2 - Initial Treatment Period) | Up to 4 months | The number of patients who experienced grade 3+ adverse events for Phase II Analysis Group 2 for the initial treatment period is reported below. |
| Duration of Response (Phase II Analysis Group 2 - Initial Treatment Period) | Time between each patient's best tumor response and progression(or date of last disease assessment for patients who die without progression or are lost to follow-up), assessed up to 2 years | Duration of response is defined as the time between each patient's best tumor response and progression (or date of last disease assessment for patients who die without progression or are lost to follow-up). Complete Response (CR): All of the following must be true: a. Disappearance of all target lesions. b. Each target lymph node must have reduction in short axis to \< 1.0 cm. Partial Response (PR): At least a 30% decrease in PBSD taking as reference the BSD. |
| Number of Patients Having CR, PR, or SD at 6 Months (Phase II Analysis Group 2 - Initial Treatment Period) | Up to 6 months | Will be defined as the number of patients having either complete response (CR), partial response (PR), or stable disease for at least 6 months after starting treatment. The frequencies and rates of tumor response categories (CR, PR, SD, PD, and too early/not evaluated) will be summarized by dose cohort and treatment arm. Complete Response (CR): All of the following must be true: a. Disappearance of all target lesions. b. Each target lymph node must have reduction in short axis to \< 1.0 cm. Partial Response (PR): At least a 30% decrease in PBSD taking as reference the BSD. Progression (PD): At least one of the following must be true: a. At least one new malignant lesion,b. At least a 20% increase in PBSD. c. PD via FDG-PET imaging. d. unequivocal progression of existing non-target lesions and non-target lymph nodes. e. symptomatic deterioration. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD taking as reference the MSD. |
| Time to Progression (TTP) (Phase II Analysis Group 2 - Initial Treatment Period) | Time between randomization and disease progression, assessed up to 2 years | Time to progression is defined as the time between randomization and disease progression. Kaplan-Meier methodology will be used to estimate the distribution of TTP. Progression (PD): At least one of the following must be true: a. At least one new malignant lesion,b. At least a 20% increase in PBSD. c. PD via FDG-PET imaging. d. unequivocal progression of existing non-target lesions and non-target lymph nodes. e. Symptomatic deterioration. |
| Overall Survival (OS) (Phase II Analysis Group 2 - Initial Treatment Period) | Time between randomization and death due to any cause (or last contact for surviving patients and those lost to follow-up), assessed up to 2 years | Overall survival (OS) (Phase II Analysis Group 2 - Initial Treatment Period). Kaplan-Meier methodology will be used to estimate the distribution of OS. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) in Crossover Patients (Phase II) | Time between date the patient initiated sapanisertib and death due to any cause (or last contact for surviving patients and those lost to follow-up), assessed up to 2 years | Kaplan-Meier methodology will be used to estimate the distribution of\>\>\> OS. |
| Cohort-specific Evaluation of 4-month Clinical Benefit Rate (CBR) (Phase II, Analysis Group II) | 4 months | Analyses will be exploratory in nature. |
| Duration of Response in Crossover Patients (Phase II) | Time between each patient's best tumor response and progression>>> (or date of last disease assessment for patients who die without progression or are lost to follow-up), assessed up to 2 years | Will be analyzed using Kaplan-Meier methodology. |
| Progression-free Survival (PFS) (Phase II) | Up to 2 years | Defined as either disease progression or death (in cases where patients have died without evidence of disease progression) in crossover patients. |
| Time to Progression (TTP) in Crossover Patients (Phase II) | Time between date the patient initiated sapanisertib and disease progression, assessed up to 2 years | Kaplan-Meier methodology will be used to estimate the distribution of\>\>\> TTP. |
Countries
United States
Participant flow
Pre-assignment details
Phase II Analysis Group 1: 32 Patients pre-registered; 7 did not pass screening, leaving 25 to proceed to randomization. Phase II Analysis Group 2: 166 Patients pre-registered; 52 did not pass screening, leaving 114 to proceed to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Phase I - Dose Level 0 Protocol therapy will consist of 20 mg MLN0128 (TAK-228) administered weekly on days 1, 8, 15, and 22 over a 28-day cycle. | 3 |
| Phase I - Dose Level 1 Protocol therapy will consist of 25 mg MLN0128 (TAK-228) administered weekly on days 1, 8, 15, and 22 over a 28-day cycle. | 3 |
| Phase I - Dose Level 2 Protocol therapy will consist of 30 mg MLN0128 (TAK-228) administered weekly on days 1, 8, 15, and 22 over a 28-day cycle. | 3 |
| Phase II - Analysis Group 1 MLN0128 Protocol therapy will consist of 30 mg MLN0128 (TAK-228) administered weekly over a 4-week cycle. | 13 |
| Phase II - Analysis Group 1 Pazopanib Patients receive 800mg Pazopanib orally once daily over a 4-week cycle in the first intervention period/initial treatment period. | 12 |
| Phase II - Analysis Group 2 MLN0128 Protocol therapy will consist of 30 mg MLN0128 (TAK-228) administered weekly over a 4-week cycle. | 56 |
| Phase II - Analysis Group 2 Pazopanib Patients receive 400mg Pazopanib orally once daily over a 4-week cycle and titrated to tolerance (maximum 800mg) by the treating physician in the first intervention period/initial treatment period. | 58 |
| Total | 148 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Initial Treatment (Up to 4 Months) | Did not meet eligibility criteria | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Initial Treatment (Up to 4 Months) | Withdrew before initiation of regimen | 0 | 0 | 0 | 0 | 1 | 2 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Phase I - Dose Level 0 | Phase I - Dose Level 1 | Phase I - Dose Level 2 | Phase II - Analysis Group 1 MLN0128 | Phase II - Analysis Group 1 Pazopanib | Phase II - Analysis Group 2 MLN0128 | Phase II - Analysis Group 2 Pazopanib | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 47.3 years STANDARD_DEVIATION 4.7 | 56.3 years STANDARD_DEVIATION 12.3 | 48.7 years STANDARD_DEVIATION 16 | 53.2 years STANDARD_DEVIATION 11.2 | 53.0 years STANDARD_DEVIATION 16 | 59.7 years STANDARD_DEVIATION 13.4 | 55.7 years STANDARD_DEVIATION 13.6 | 56.4 years STANDARD_DEVIATION 13.5 |
| ECOG Performance Status 0 | 1 Participants | 2 Participants | 1 Participants | 8 Participants | 9 Participants | 35 Participants | 28 Participants | 84 Participants |
| ECOG Performance Status 1 | 2 Participants | 1 Participants | 2 Participants | 5 Participants | 3 Participants | 21 Participants | 30 Participants | 64 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 6 Participants | 3 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 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 | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 4 Participants | 6 Participants | 13 Participants |
| Race (NIH/OMB) White | 1 Participants | 3 Participants | 2 Participants | 12 Participants | 10 Participants | 44 Participants | 48 Participants | 120 Participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 2 Participants | 4 Participants | 8 Participants | 40 Participants | 37 Participants | 96 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 1 Participants | 9 Participants | 4 Participants | 16 Participants | 21 Participants | 52 Participants |
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 |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 1 / 3 | 3 / 3 | 9 / 12 | 5 / 12 | 27 / 55 | 24 / 56 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 12 / 12 | 12 / 12 | 54 / 55 | 55 / 56 |
| serious Total, serious adverse events | 1 / 3 | 0 / 3 | 0 / 3 | 5 / 12 | 6 / 12 | 20 / 55 | 24 / 56 |
Outcome results
Number of Phase I Participants With Dose-Limiting Toxicity Events (Phase I)
The Maximum Tolerated Dose (MTD) of sapanisertib (MLN0128) is defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients graded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Dose-limiting toxicities include non-hematologic events graded 3 or higher and deemed at least possibly related to treatment. The number of patients reporting a dose-limiting event is reported.
Time frame: 28 days
Population: Phase I
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I - Dose Level 0 | Number of Phase I Participants With Dose-Limiting Toxicity Events (Phase I) | 0 Participants |
| Phase I - Dose Level 1 | Number of Phase I Participants With Dose-Limiting Toxicity Events (Phase I) | 0 Participants |
| Phase I - Dose Level 2 | Number of Phase I Participants With Dose-Limiting Toxicity Events (Phase I) | 0 Participants |
Progression-free Survival (PFS) (Phase II Analysis Group 2 - Initial Treatment Period)
Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The median and an upper confidence boundary from a 1-sided, 85% confidence interval are estimated using the Kaplan-Meier methods.
Time frame: Up to 2 years
Population: Phase II Analysis Group 2 - Initial Treatment Period
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I - Dose Level 0 | Progression-free Survival (PFS) (Phase II Analysis Group 2 - Initial Treatment Period) | 2.0 months |
| Phase I - Dose Level 1 | Progression-free Survival (PFS) (Phase II Analysis Group 2 - Initial Treatment Period) | 2.1 months |
Duration of Response (Phase II Analysis Group 2 - Initial Treatment Period)
Duration of response is defined as the time between each patient's best tumor response and progression (or date of last disease assessment for patients who die without progression or are lost to follow-up). Complete Response (CR): All of the following must be true: a. Disappearance of all target lesions. b. Each target lymph node must have reduction in short axis to \< 1.0 cm. Partial Response (PR): At least a 30% decrease in PBSD taking as reference the BSD.
Time frame: Time between each patient's best tumor response and progression(or date of last disease assessment for patients who die without progression or are lost to follow-up), assessed up to 2 years
Population: Phase II Analysis Group 2 - Initial Treatment Period; Only patients that had a complete response or partial response are included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I - Dose Level 0 | Duration of Response (Phase II Analysis Group 2 - Initial Treatment Period) | 0.9 months |
| Phase I - Dose Level 1 | Duration of Response (Phase II Analysis Group 2 - Initial Treatment Period) | 1.8 months |
Number of Patients Having CR, PR, or SD at 6 Months (Phase II Analysis Group 2 - Initial Treatment Period)
Will be defined as the number of patients having either complete response (CR), partial response (PR), or stable disease for at least 6 months after starting treatment. The frequencies and rates of tumor response categories (CR, PR, SD, PD, and too early/not evaluated) will be summarized by dose cohort and treatment arm. Complete Response (CR): All of the following must be true: a. Disappearance of all target lesions. b. Each target lymph node must have reduction in short axis to \< 1.0 cm. Partial Response (PR): At least a 30% decrease in PBSD taking as reference the BSD. Progression (PD): At least one of the following must be true: a. At least one new malignant lesion,b. At least a 20% increase in PBSD. c. PD via FDG-PET imaging. d. unequivocal progression of existing non-target lesions and non-target lymph nodes. e. symptomatic deterioration. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD taking as reference the MSD.
Time frame: Up to 6 months
Population: Phase II Analysis Group 2 - Initial Treatment Period
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I - Dose Level 0 | Number of Patients Having CR, PR, or SD at 6 Months (Phase II Analysis Group 2 - Initial Treatment Period) | 1 Participants |
| Phase I - Dose Level 1 | Number of Patients Having CR, PR, or SD at 6 Months (Phase II Analysis Group 2 - Initial Treatment Period) | 5 Participants |
Overall Survival (OS) (Phase II Analysis Group 2 - Initial Treatment Period)
Overall survival (OS) (Phase II Analysis Group 2 - Initial Treatment Period). Kaplan-Meier methodology will be used to estimate the distribution of OS.
Time frame: Time between randomization and death due to any cause (or last contact for surviving patients and those lost to follow-up), assessed up to 2 years
Population: Phase II Analysis Group 2 - Initial Treatment Period
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I - Dose Level 0 | Overall Survival (OS) (Phase II Analysis Group 2 - Initial Treatment Period) | 12.2 months |
| Phase I - Dose Level 1 | Overall Survival (OS) (Phase II Analysis Group 2 - Initial Treatment Period) | 13.7 months |
The Number of Patients Who Experienced Grade 3+ Adverse Events (Phase II Analysis Group 2 - Initial Treatment Period)
The number of patients who experienced grade 3+ adverse events for Phase II Analysis Group 2 for the initial treatment period is reported below.
Time frame: Up to 4 months
Population: Phase II Analysis Group 2 - Initial Treatment Period; This analysis excludes cancel patients (who never received treatment i.e. Withdrew before initiation of regimen )
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I - Dose Level 0 | The Number of Patients Who Experienced Grade 3+ Adverse Events (Phase II Analysis Group 2 - Initial Treatment Period) | 28 Participants |
| Phase I - Dose Level 1 | The Number of Patients Who Experienced Grade 3+ Adverse Events (Phase II Analysis Group 2 - Initial Treatment Period) | 38 Participants |
Time to Progression (TTP) (Phase II Analysis Group 2 - Initial Treatment Period)
Time to progression is defined as the time between randomization and disease progression. Kaplan-Meier methodology will be used to estimate the distribution of TTP. Progression (PD): At least one of the following must be true: a. At least one new malignant lesion,b. At least a 20% increase in PBSD. c. PD via FDG-PET imaging. d. unequivocal progression of existing non-target lesions and non-target lymph nodes. e. Symptomatic deterioration.
Time frame: Time between randomization and disease progression, assessed up to 2 years
Population: Phase II Analysis Group 2 - Initial Treatment Period
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I - Dose Level 0 | Time to Progression (TTP) (Phase II Analysis Group 2 - Initial Treatment Period) | 2.0 months |
| Phase I - Dose Level 1 | Time to Progression (TTP) (Phase II Analysis Group 2 - Initial Treatment Period) | 2.1 months |
Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD], and Progressive Disease [PD])(Phase II Analysis Group 2 - Initial Treatment Period)
The frequencies (and percentages) of tumor response categories (CR, PR, SD, PD) will be summarized for Phase II Analysis Group 2. Complete Response (CR): All of the following must be true: a. Disappearance of all target lesions. b. Each target lymph node must have reduction in short axis to \< 1.0 cm. Partial Response (PR): At least a 30% decrease in PBSD taking as reference the BSD. Progression (PD): At least one of the following must be true: a. At least one new malignant lesion, b. At least a 20% increase in PBSD. c. PD via FDG-PET imaging. d. unequivocal progression of existing non-target lesions and non-target lymph nodes. e. symptomatic deterioration. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD taking as reference the MSD.
Time frame: Up to 2 years
Population: Phase II Analysis Group 2 - Initial Treatment Period; Patients with tumor response data available are included in this analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I - Dose Level 0 | Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD], and Progressive Disease [PD])(Phase II Analysis Group 2 - Initial Treatment Period) | Complete Response | 0 Participants |
| Phase I - Dose Level 0 | Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD], and Progressive Disease [PD])(Phase II Analysis Group 2 - Initial Treatment Period) | Stable Disease | 14 Participants |
| Phase I - Dose Level 0 | Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD], and Progressive Disease [PD])(Phase II Analysis Group 2 - Initial Treatment Period) | Progressive Disease | 28 Participants |
| Phase I - Dose Level 0 | Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD], and Progressive Disease [PD])(Phase II Analysis Group 2 - Initial Treatment Period) | Partial Response | 2 Participants |
| Phase I - Dose Level 1 | Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD], and Progressive Disease [PD])(Phase II Analysis Group 2 - Initial Treatment Period) | Partial Response | 2 Participants |
| Phase I - Dose Level 1 | Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD], and Progressive Disease [PD])(Phase II Analysis Group 2 - Initial Treatment Period) | Complete Response | 0 Participants |
| Phase I - Dose Level 1 | Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD], and Progressive Disease [PD])(Phase II Analysis Group 2 - Initial Treatment Period) | Progressive Disease | 26 Participants |
| Phase I - Dose Level 1 | Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD], and Progressive Disease [PD])(Phase II Analysis Group 2 - Initial Treatment Period) | Stable Disease | 23 Participants |
Cohort-specific Evaluation of 4-month Clinical Benefit Rate (CBR) (Phase II, Analysis Group II)
Analyses will be exploratory in nature.
Time frame: 4 months
Duration of Response in Crossover Patients (Phase II)
Will be analyzed using Kaplan-Meier methodology.
Time frame: Time between each patient's best tumor response and progression>>> (or date of last disease assessment for patients who die without progression or are lost to follow-up), assessed up to 2 years
Overall Survival (OS) in Crossover Patients (Phase II)
Kaplan-Meier methodology will be used to estimate the distribution of\>\>\> OS.
Time frame: Time between date the patient initiated sapanisertib and death due to any cause (or last contact for surviving patients and those lost to follow-up), assessed up to 2 years
Progression-free Survival (PFS) (Phase II)
Defined as either disease progression or death (in cases where patients have died without evidence of disease progression) in crossover patients.
Time frame: Up to 2 years
Time to Progression (TTP) in Crossover Patients (Phase II)
Kaplan-Meier methodology will be used to estimate the distribution of\>\>\> TTP.
Time frame: Time between date the patient initiated sapanisertib and disease progression, assessed up to 2 years