Clinical Trial: Sapanisertib or Pazopanib Hydrochloride in Treating Patients With Locally Advanced or Metastatic Sarcoma

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: A Phase I/Randomized Phase II Study of MLN0128 (TAK-228) vs. Pazopanib in Patients With Locally Advanced/Unresectable and/or Metastatic Sarcoma

Brief Summary: This partially randomized 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 Summary:

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)

TERTIARY 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. Courses 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
Sponsor: National Cancer Institute (NCI)

Current Primary Outcome:

• Maximum tolerated dose of sapanisertib defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients) (Phase I) [ Time Frame: 28 days ]
• PFS, defined as either disease progression or death (in cases where patients have died without evidence of disease progression) (Phase II) [ Time Frame: Up to 2 years ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

• CBR, defined as the number of patients having either CR, PR, or stable disease for at least 6 months after starting treatment [ Time Frame: Up to 2 years ]
  The frequencies and rates of tumor response categories (CR, PR, SD, and PD) will be summarized by dose cohort and treatment arm, and Fisher's Exact test will be used to compare the association of objective response rate (a tumor response of either CR or PR) and treatment.
• Duration of response [ 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 ]
  Will be analyzed using Kaplan-Meier methodology.
• Incidence of adverse events graded according to NCI CTCAE version 4.0 [ Time Frame: Up to 30 days after completion of study treatment ]
  Adverse events will be summarized by dose cohorts and treatment arm. Summary statistics (e.g., mean, median, standard deviation) and frequency tables will be used to describe the distributions of adverse events. Rates of adverse events occurring in the sapanisertib arm will be compared to the pazopanib hydrochloride arm with chi-squared tests (or suitable alternative) used for comparisons where applicable. Adverse event analyses will separate events associated with the original treatment assignments from those having occurred after crossing over to receive sapanisertib at disease progression.
• 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 ]
  Kaplan-Meier methodology will be used to estimate the distribution of OS.
• TTP [ Time Frame: Time between randomization and disease progression, assessed up to 2 years ]
  Kaplan-Meier methodology will be used to estimate the distribution of TTP.
• Tumor response (complete response [CR], partial response [PR], stable disease [SD], and progressive disease [PD]) [ Time Frame: Up to 2 years ]
  The frequencies and rates of tumor response categories (CR, PR, SD, and PD) will be summarized by dose cohort and treatment arm, and Fisher's Exact test will be used to compare the association of objective response rate (a tumor response of either CR or PR) and treatment.

Original Secondary Outcome:

• CBR, defined as the number of patients having either CR, PR, or stable disease for at least 6 months after starting treatment [ Time Frame: Up to 2 years ]
• Duration of response [ 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 ]
  Will be analyzed using Kaplan-Meier methodology.
• Incidence of adverse events graded according to NCI CTCAE version 4.0 [ Time Frame: Up to 30 days after completion of study treatment ]
  Adverse events will be summarized by dose cohorts and treatment arm. Summary statistics (e.g., mean, median, standard deviation) and frequency tables will be used to describe the distributions of adverse events. Rates of adverse events occurring in the sapanisertib arm will be compared to the pazopanib hydrochloride arm with chi-squared tests (or suitable alternative) used for comparisons where applicable. Adverse event analyses will separate events associated with the original treatment assignments from those having occurred after crossing over to receive sapanisertib at disease progression.
• 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 ]
  Kaplan-Meier methodology will be used to estimate the distribution of OS.
• TTP [ Time Frame: Time between randomization and disease progression, assessed up to 2 years ]
  Kaplan-Meier methodology will be used to estimate the distribution of TTP.
• Tumor response (complete response [CR], partial response [PR], stable disease [SD], and progressive disease [PD]) [ Time Frame: Up to 2 years ]
  The frequencies and rates of tumor response categories (CR, PR, SD, and PD) will be summarized by dose cohort and treatment arm, and Fisher's Exact test will be used to compare the association of objective response rate (a tumor response of either CR or PR) and treatment.

Dates:
Date Received: November 9, 2015
Date Started: November 2015
Date Completion:
Last Updated: May 18, 2017
Last Verified: May 2017