A Phase I/Randomized Phase II Study of MLN0128 (TAK-228) VS. Pazopanib in Patients With Locally Advanced/Unresectable and/or Metastatic Sarcoma
A Phase I/Randomized Phase II Study of MLN0128 (TAK-228) VS. Pazopanib in Patients With Locally Advanced/Unresectable and/or Metastatic Sarcoma
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.
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
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):
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:
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
Burbank, California 91505, United States
Cameron Park, California 95682, United States
Roseville, California 95661, United States
Vacaville, California 95687, United States
Pekin, Illinois 61554, United States
Baltimore, Maryland 21237, United States
Brighton, Michigan 48114, United States
Brownstown, Michigan 48183, United States
Chelsea, Michigan 48118, United States
East China Township, Michigan 48054, United States
Grosse Pointe Woods, Michigan 48236, United States
Macomb, Michigan 48044, United States
Rochester Hills, Michigan 48309, United States
Warren, Michigan 48093, United States
West Branch, Michigan 48661, United States
Ypsilanti, Michigan 48197, United States
Las Vegas, Nevada 89109, United States
Las Vegas, Nevada 89113, United States
Las Vegas, Nevada 89149, United States
New York, New York 10032, United States
Berlin Corners, Vermont 05602, United States
Spokane, Washington 99204, United States
Spokane, Washington 99218, United States
Spokane Valley, Washington 99216, United States
Stevens Point, Wisconsin 54482, United States