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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
151
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
Anchorage Associates in Radiation Medicine
Anchorage, Alaska, United States
Anchorage Radiation Therapy Center
Anchorage, Alaska, United States
Alaska Breast Care and Surgery LLC
Anchorage, Alaska, United States
Alaska Oncology and Hematology LLC
Anchorage, Alaska, United States
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
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
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
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
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
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
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
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
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