Symptoms and General Pathology

All Conditions

Neoplasms

Rare Diseases

Recurrence

Leiomyosarcoma

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Sarcoma

Soft Tissue Sarcoma

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Doxorubicin

Liposomal doxorubicin

Trabectedin

Olaratumab

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Antineoplastic Agents, Alkylating

Alkylating Agents

Trabectedin \[T\], Doxorubicin \[D\], and Olaratumab \[O\]

Administered intravenously per protocol on Day 1 for 21-day cycles.

Marilyn Huang, MD, MS

This study seeks to determine if addition of trabectedin (T) to combination doxorubicin (D) and olaratumab (O), is feasible and tolerable with antitumor activity in metastatic or recurrent Leiomyosarcomas (LMS) patients who have limited therapeutic options.

This is a traditional 3+3 phase I trial design to identify the recommended phase II dose (RP2D) of Trabectedin \[T\] that can be used in combination with Doxorubicin \[D\] and Olaratumab \[O\] for the treatment of patients with advanced stage or recurrent LMS.

Patients will be treated at an assigned dose level of combination therapy per dose escalation design.

Trabectedin, Doxorubicin and Olaratumab in Patients With Metastatic or Recurrent Leiomyosarcoma

A Phase I Study of Trabectedin in Combination With Fixed Doses of Doxorubicin and Olaratumab in Patients With Metastatic or Recurrent Leiomyosarcoma

Determination of the recommended phase 2 dose (RP2D) of Trabectedin \[T\] to be used in combination with Doxorubicin \[D\] and Olaratumab \[O\] for the treatment of patients with metastatic or recurrent LMS. Patients will be treated at one of 4-6 dose levels according to the standard dose escalation/de-escalation scheme. In accordance with this scheme, the RP2D of TDO will be established as the highest dose level tested for which no more than 2 out of 12 patients experiences dose-limiting toxicity (DLT).

Determination of the safety, tolerability, and toxicity profile of administering TDO in metastatic or recurrent LMS patients, including assessment of dose-limiting toxicities (DLTs).

Clinical benefit rate (CBR), as defined by best response, (Complete Response (CR), Partial Response (PR) or Stable Disease (SD)) will be assessed using Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1.

Janssen Scientific Affairs, LLC

University of Miami

Associate Professor

Nervous System Diseases

Skin and Connective Tissue Diseases

Diseases and Abnormalities at or Before Birth

Histiocytoma, Malignant Fibrous

Sarcoma, Synovial

Nerve Sheath Neoplasms

Neurofibrosarcoma

Histiocytoma

Disease Attributes

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

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)

Liposarcoma

Neoplasms, Adipose Tissue

Patients receive alisertib PO BID on days 1-7. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Alisertib

Laboratory Biomarker Analysis

Mark Dickson

This phase II trial studies how well alisertib works in treating patients with sarcoma that has spread to other places in the body and usually cannot be cured or controlled with treatment (advanced) or has spread to other places in the body (metastatic). Alisertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To determine the response rate (complete response \[CR\] + partial response \[PR\]) assessed for patients within each cohort: liposarcoma (cohort 1); leiomyosarcoma (non-uterine) (cohort 2); undifferentiated sarcoma (including pleomorphic undifferentiated sarcoma, formerly known as malignant fibrous histiocytoma, and myxofibrosarcoma) (cohort 3); malignant peripheral nerve sheath tumor (cohort 4); and other sarcomas (cohort 5).

SECONDARY OBJECTIVES:

I. To estimate the progression-free survival (PFS) and overall survival (OS) for patients treated with MLN8237 (alisertib) in each cohort.

II. To assess the adverse events associated with patients treated with MLN8237 in each cohort.

TERTIARY OBJECTIVES:

I. To correlate potential clinical benefit with markers of aurora kinase inhibition in pre- and post-treatment tumor biopsies.

II. To correlate clinical outcome with change in fluorine F 18 fluorothymidine (FLT)-positron emission tomography (PET) uptake at baseline versus after one week of treatment (ie, week 2 of cycle 1).

OUTLINE:

Patients receive alisertib orally (PO) twice daily (BID) on days 1-7. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 18 months.

Alisertib in Treating Patients With Advanced or Metastatic Sarcoma

Phase II Study of MLN8237 in Advanced/Metastatic Sarcoma

The primary endpoint was estimated by the number of confirmed responses divided by the total number of evaluable patients per cohort. The study used a two stage Simon design to assess the primary endpoint. A confirmed tumor response rate of 5% was considered not promising; an observed confirmed response rate of 25% was considered promising. One confirmed response within the initial 9 patients enrolled within each cohort, expanded enrollment to 24 patients in that cohort. 3 out of 24 patients with confirmed tumor responses was considered evidence that this treatment could be recommended for further testing. This study design yielded 90% power to detect a true confirmed response rate of at least 25% at .10 level of significance if the true rate is at most 5%. There was a 63% chance of stopping early if the true confirmed response rate was 5%.

The distribution will be estimated by the methods of Kaplan and Meier. The estimates of survival at specific time points will be calculated (eg, median, 6 month survival).

The distribution will be estimated by the methods of Kaplan and Meier. The estimates of PFS at specific time points will be calculated (eg, median, 1 year PFS).

Adverse Events: Incidence of adverse events, assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Adverse events were collected every cycle during treatment and up to one month after treatment. Adverse events were summarized using summary statistics and frequency tables for each separate cohort. Per protocol, analysis was descriptive in nature. In this section, the number of patients that reported a grade 4 or higher event are summarized. A complete listing of Adverse Events is provided in the Adverse Events section below.

Liposarcoma patients receive alisertib PO BID on days 1-7. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cohort 1

Leiomyosarcoma patients receive alisertib PO BID on days 1-7. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cohort 2

Undifferentiated Sarcoma patients receive alisertib PO BID on days 1-7. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cohort 3

Malignant Peripheral Nerve Sheath Tumor patients receive alisertib PO BID on days 1-7. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cohort4

Other Sarcoma patients receive alisertib PO BID on days 1-7. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cohort 5

United States

Region of Enrollment

Mark Andrew Dickson M.D.

Cohort 4

The Primary Endpoint for This Trial Was the Percent of Confirmed Tumor Responses. Confirmed Tumor Response to Treatment Was Defined as a Complete or Partial Response(Per RECIST 1.1) on Two Consecutive Evaluations at Least 6 Weeks Apart.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Trabectedin, Doxorubicin and Olaratumab in Patients With Metastatic or Recurrent Leiomyosarcoma	NCT03437070	Leiomyosarcoma	Trabectedin Doxorubicin Olaratumab	18 Years -	University of Miami
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)
Alisertib in Treating Patients With Advanced or Metastatic Sarcoma	NCT01653028	Myxofibrosarcom... Recurrent Adult... Recurrent Leiom... Recurrent Lipos... Recurrent Malig... Recurrent Undif... Stage III Soft ... Stage IV Soft T...	Alisertib Laboratory Biom...	18 Years -	National Cancer Institute (NCI)
Trabectedin, Doxorubicin and Olaratumab in Patients With Metastatic or Recurrent Leiomyosarcoma	NCT03437070	Leiomyosarcoma	Trabectedin Doxorubicin Olaratumab	18 Years -	University of Miami
Trabectedin, Doxorubicin and Olaratumab in Patients With Metastatic or Recurrent Leiomyosarcoma	NCT03437070	Leiomyosarcoma	Trabectedin Doxorubicin Olaratumab	18 Years -	University of Miami

Spots Global Cancer Trial Database for recurrent leiomyosarcoma