Symptoms and General Pathology

All Conditions

Neoplasms

Nervous System Diseases

Skin and Connective Tissue Diseases

Diseases and Abnormalities at or Before Birth

Rare Diseases

Recurrence

Sarcoma

Histiocytoma, Malignant Fibrous

Leiomyosarcoma

Sarcoma, Synovial

Nerve Sheath Neoplasms

Neurofibrosarcoma

Histiocytoma

Disease Attributes

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Neoplasms, Connective Tissue

Neoplasms, Nerve Tissue

Nervous System Neoplasms

Peripheral Nervous System Neoplasms

Peripheral Nervous System Diseases

Neuromuscular Diseases

Fibrosarcoma

Neoplasms, Fibrous Tissue

Neurofibromatoses

Neurofibroma

Soft Tissue Sarcoma

Undifferentiated Pleomorphic Sarcoma

Synovial Sarcoma

Malignant Peripheral Nerve Sheath Tumor

Neurofibromatosis

Patients receive sapanisertib as in Phase I. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients receive pazopanib hydrochloride PO 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.

Pazopanib

Pazopanib Hydrochloride

Sapanisertib

William D Tap

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.

Sapanisertib or Pazopanib Hydrochloride in Treating Patients With Locally Advanced 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

Defined as either disease progression or death (in cases where patients have died without evidence of disease progression) in crossover patients.

Will be analyzed using Kaplan-Meier methodology.

Kaplan-Meier methodology will be used to estimate the distribution of\>\>\> TTP.

Kaplan-Meier methodology will be used to estimate the distribution of\>\>\> OS.

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) 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.

The number of patients who experienced grade 3+ adverse events for Phase II Analysis Group 2 for the initial treatment period is reported below.

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.

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.

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 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). Kaplan-Meier methodology will be used to estimate the distribution of OS.

National Cancer Institute (NCI)

Adverse events from all registered Phase I and randomized Phase II patients who initiated treatment (Initial treatment period) and had adverse events assessed are summarized below.

Protocol therapy will consist of 20 mg MLN0128 (TAK-228) administered weekly on days 1, 8, 15, and 22 over a 28-day cycle.

Phase I - Dose Level 0

Protocol therapy will consist of 25 mg MLN0128 (TAK-228) administered weekly on days 1, 8, 15, and 22 over a 28-day cycle.

Phase I - Dose Level 1

Protocol therapy will consist of 30 mg MLN0128 (TAK-228) administered weekly on days 1, 8, 15, and 22 over a 28-day cycle.

Phase I - Dose Level 2

Protocol therapy will consist of 30 mg MLN0128 (TAK-228) administered weekly over a 4-week cycle.

Phase II - Analysis Group 1 MLN0128

Patients receive 800mg Pazopanib orally once daily over a 4-week cycle in the first intervention period/initial treatment period.

Phase II - Analysis Group 1 Pazopanib

Phase II - Analysis Group 2 MLN0128

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.

Phase II - Analysis Group 2 Pazopanib

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Eastern Cooperative Oncology Group PS Scale: 0)Fully active, able to carry on all pre-disease performance without restriction; 1)Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2)Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours; 3)Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; 4)Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair.

ECOG Performance Status

Registered Phase I patients and Randomized Phase II patients

William D. Tap, MD

Number of Phase I Participants With Dose-Limiting Toxicity Events (Phase I)

Phase II Analysis Group 2 - Initial Treatment Period

Progression-free Survival (PFS) (Phase II Analysis Group 2 - Initial Treatment Period)

Phase II Analysis Group 2 - Initial Treatment Period; This analysis excludes cancel patients (who never received treatment i.e. Withdrew before initiation of regimen )

The Number of Patients Who Experienced Grade 3+ Adverse Events (Phase II Analysis Group 2 - Initial Treatment Period)

Complete Response

Partial Response

Stable Disease

Progressive Disease

Phase II Analysis Group 2 - Initial Treatment Period; Patients with tumor response data available are included in this analysis.

Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD], and Progressive Disease [PD])(Phase II Analysis Group 2 - Initial Treatment Period)

Phase II Analysis Group 2 - Initial Treatment Period; Only patients that had a complete response or partial response are included in this analysis.

Duration of Response (Phase II Analysis Group 2 - Initial Treatment Period)

Number of Patients Having CR, PR, or SD at 6 Months (Phase II Analysis Group 2 - Initial Treatment Period)

Time to Progression (TTP) (Phase II Analysis Group 2 - Initial Treatment Period)

Overall Survival (OS) (Phase II Analysis Group 2 - Initial Treatment Period)

Progression-free Survival (PFS) (Phase II)

Duration of Response in Crossover Patients (Phase II)

Time to Progression (TTP) in Crossover Patients (Phase II)

Overall Survival (OS) in Crossover Patients (Phase II)

Cohort-specific Evaluation of 4-month Clinical Benefit Rate (CBR) (Phase II, Analysis Group II)

Patients receive 800mg Pazopanib orally once daily over a 4-week cycle in the first intervention period/initial treatment period. Patients who chose to crossover (crossover to MLN0128 is optional) receive 30 mg MLN0128 (TAK-228) administered weekly over a 4-week cycle in the second intervention period/optional crossover period.

Phase II - Analysis Group 1 Pazopanib Crossover

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. Patients who chose to crossover (crossover to MLN0128 is optional) receive 30 mg MLN0128 (TAK-228) administered weekly over a 4-week cycle in the second intervention period/optional crossover period.

Phase II - Analysis Group 2 Pazopanib Crossover

Initial Treatment (Up to 4 Months)

Optional Crossover (Up to 2 Months)

Antineoplastic Agents

All Drugs and Chemicals

Temozolomide

Antineoplastic Agents, Alkylating

Alkylating Agents

Patients receive cabozantinib PO QD on days 1-28 and temozolomide PO QD on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cabozantinib

Quality-of-Life Assessment

Questionnaire Administration

Mark Agulnik, MD

This phase II trial studies how well cabozantinib and temozolomide work in treating patients with leiomyosarcoma or other soft tissue sarcoma that cannot be removed by surgery (unresectable) or has spread to other places in the body (metastatic). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving cabozantinib and temozolomide may work better than either one alone in treating patients with leiomyosarcoma or other soft tissue sarcoma. Cabozantinib is an investigational drug, which means that it has not been approved by the United States (US) Food and Drug Administration (FDA) or any other regulatory agencies for sale or use by the public for the indication under investigation in this study.

PRIMARY OBJECTIVE:

I. To determine the progression-free survival (defined as complete response \[CR\]+partial response \[PR\]+stable disease \[SD\]) assessed at 12 weeks for subjects in Cohort 1 (Leiomyosarcoma Arm) treated with cabozantinib and temozolomide as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

SECONDARY OBJECTIVES:

I. To determine the overall response rate (defined as CR+PR) for subjects in Cohort 1 treated with a combination of cabozantinib and temozolomide.

II. To determine the clinical benefit rate (CR+PR+SD) for subjects in Cohort 1 treated with a combination of cabozantinib and temozolomide.

III. To evaluate the median progression free rate for subjects with combination of cabozantinib and temozolomide.

IV. To evaluate overall survival for subjects in Cohort 1 treated with a combination of cabozantinib and temozolomide.

V. To assess safety and tolerability for subjects treated with a combination of cabozantinib and temozolomide.

VI. To determine the overall response rate (defined as CR+PR) in Cohort 2 (other soft tissue sarcomas).

VII. To assess Quality of Life (QoL) and subject-reported outcomes as measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and the EuroQoL-Group Health Questionnaire (EQ-5D-5L).

EXPLORATORY OBJECTIVE:

I. To estimate the correlation of progression free rate (PFR) and overall survival (OS) to levels of sVEGFR2, PIGF, VEGF, HGF, sMET, VEGF-C, VEGF-D, and soluble AXL.

OUTLINE:

Patients receive cabozantinib orally (PO) once daily (QD) on days 1-28 and temozolomide PO QD on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients with progressive disease (PD) are followed up every 6 months for up to 2 years and patients without PD are followed up every 6 months for up to 5 years.

Cabozantinib and Temozolomide for the Treatment of Unresectable or Metastatic Leiomyosarcoma or Other Soft Tissue Sarcoma

A Phase II Study of Cabozantinib and Temozolomide in Patients With Unresectable or Metastatic Leiomyosarcoma and Other Soft Tissue Sarcomas

PFS will be the time from the start of treatment to the time of progression, with progression defined as changes in Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 defined imaging, progression in non-target lesions as defined by RECIST 1.1, unequivocal clinical deterioration, or death from any cause.

Will be defined as complete response (CR) + partial response (PR).

Will be defined as CR + PR + stable disease (SD).

Will assess the time from the first dose of study treatment until progression based upon changes in RECIST 1.1, unequivocal clinical deterioration, or death from any cause.

Will assess the time from the first dose of the study treatment until death from any cause, up to a maximum follow-up of two years.

Will assess the presence of all toxicities outlined in National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Will be assessed by the EuroQoL-Group Health Questionnaire (EQ-5D-5L).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Sapanisertib or Pazopanib Hydrochloride in Treating Patients With Locally Advanced or Metastatic Sarcoma	NCT02601209	High Grade Sarc... Metastatic Leio... Metastatic Mali... Metastatic Syno... Metastatic Undi... Metastatic Unre... Myxofibrosarcom... Recurrent Leiom... Recurrent Malig... Recurrent Synov... Recurrent Undif... Stage III Uteri... Stage IIIA Uter... Stage IIIB Uter... Stage IIIC Uter... Stage IV Uterin... Stage IVA Uteri... Stage IVB Uteri... Unresectable Le...	Pazopanib Pazopanib Hydro... Sapanisertib	18 Years -	National Cancer Institute (NCI)
Cabozantinib and Temozolomide for the Treatment of Unresectable or Metastatic Leiomyosarcoma or Other Soft Tissue Sarcoma	NCT04200443	Metastatic Leio... Metastatic Soft... Stage III Uteri... Stage IIIA Uter... Stage IIIB Uter... Stage IIIC Uter... Stage IV Uterin... Stage IVA Uteri... Stage IVB Uteri... Unresectable Le... Unresectable So...	Cabozantinib Quality-of-Life... Questionnaire A... Temozolomide	18 Years -	City of Hope Medical Center

Spots Global Cancer Trial Database for stage ivb uterine corpus leiomyosarcoma ajcc v8