A Study of Tasisulam-sodium Versus Paclitaxel as Treatment for Metastatic Melanoma

Study Overview
=================
Brief Summary
-----------------
The primary purpose of this study was to see how tasisulam-sodium affected metastatic melanoma when compared against paclitaxel as measured by overall survival.

Official Title
-----------------
A Randomized Phase 3 Study of Tasisulam-sodium Administered as an Intravenous Infusion on Day 1 of a 28-Day Cycle Versus Paclitaxel as Second-line Treatment in Patients With Metastatic Melanoma

Conditions
-----------------
Melanoma

Intervention / Treatment
-----------------
* Drug: Tasisulam-sodium
* Drug: Paclitaxel


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Have a histologic and/or cytologic diagnosis of metastatic melanoma (Stage IV). Have the presence of evaluable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.0). Have a performance status of 0-1 on the Eastern Cooperative Oncology Group (ECOG) Scale. Have progressed after 1 previous systemic treatment containing dacarbazine or temozolomide for metastatic melanoma. Have discontinued all previous therapies for cancer, including chemotherapy, radiotherapy, immunotherapy, or other investigational therapy for at least 30 days (6 weeks for mitomycin-C or nitrosoureas) before study enrollment and recovered from the acute effects of therapy (except alopecia). Have a serum albumin level greater than or equal to 3.0 grams per deciliter (g/dL) or greater than or equal to 30 grams per liter (g/L). Exclusion Criteria: Have received greater than or equal to 2 previous chemotherapy-containing systemic treatment regimens for metastatic melanoma. An immunotherapy or antibody-based regimen (including biologic agents and vaccination-based treatments), or treatment with a targeted agent (for example, BRAF or c-Kit inhibitor is not counted as a prior treatment regimen for determining study eligibility, unless either was combined with a cytotoxic drug). Have active central nervous system (CNS) or leptomeningeal metastasis (brain metastasis) at the time of study entry. Participants with signs or symptoms of neurological compromise should have appropriate radiographic imaging performed before study entry to rule out occult brain metastasis. Participants with a history of a solitary CNS metastasis previously treated with curative intent (for example, stereotactic radiation or surgery) and not requiring steroids are eligible. Are receiving warfarin. Have primary ocular or mucosal melanoma. Any previous treatment with paclitaxel or a paclitaxel-containing regimen for metastatic melanoma. Have serious concomitant disorders, including active bacterial, fungal, or viral infection, incompatible with the study (at the discretion of the investigator). Have previously completed or withdrawn from this study or any other study investigating tasisulam-sodium. Have a known hypersensitivity to paclitaxel or Cremophor EL (polyoxyethylated castor oil). Are pregnant or lactating. Have received a recent (within 30 days before enrollment) or are receiving concurrent yellow fever vaccination. Have known positive test results in human immunodeficiency virus (HIV), hepatitis B surface antigen (HBSAg), or hepatitis C antibodies (HCAb). Are unable to withhold dosing of non-steroidal anti-inflammatory drugs (NSAIDs) or proton-pump inhibitors (PPIs) for at least 72 hours before and after treatment with tasisulam-sodium.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tasisulam-sodium<br>Individualized tasisulam-sodium dose was dependent on participant's height, weight, and gender. Dose was adjusted based on laboratory parameters. Treatment was administered intravenously on Day 1 of a 28-day cycle, until disease progression. | Drug: Tasisulam-sodium<br>* Administered intravenously on Day 1 of a 28-day cycle, until disease progression.<br>* Other names: LY573636;|
| Active Comparator: Paclitaxel<br>Paclitaxel 80 milligrams per square meter (mg/m^2) administered intravenously on Days 1, 8, and 15 of a 28-day cycle, until disease progression | Drug: Paclitaxel<br>* 80 mg/m^2 administered intravenously on Days 1, 8, and 15 of a 28-day cycle, until disease progression<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is duration from enrollment to death; OS censored for participants who were alive at last contact. | Randomization to date of death from any cause (assessed at every cycle and every 60 days following treatment discontinuation) up to 14.32 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS is time from date of first dose to first observation of disease progression (PD); PD=20% increase in sum of the longest diameter of target lesions, or death from any cause. | Randomization to date of objectively determined PD, or death from any cause (assessed at every cycle and every 60 days following treatment discontinuation) up to 13.70 months | 
| Percentage of Randomized Participants Having a Confirmed Best Response of Partial Response (PR) or Complete Response (CR) | Response Evaluation Criteria In Solid Tumors (RECIST) criteria: CR=disappearance of all target lesions; PR=30% decrease in sum of longest diameter of target lesions; Progressive disease (PD)=20% increase in sum of the longest diameter of target lesions. | First date RECIST criteria met for CR or PR (whichever occurred first) until first date of documented PD, or death from any cause (assessed every other cycle) up to 13.70 months | 
| Duration of Response (DoR) for Participants Having an Objective Response of Partial Response (PR) or Complete Response (CR) | Response using Response Evaluation Criteria In Solid Tumors (RECIST) criteria: CR=disappearance of all target lesions; PR=30% decrease in sum of longest diameter of target lesions; Progressive disease (PD)=20% increase in sum of the longest diameter of target lesions. Analysis was adjusted for Baseline Lactate Dehydrogenase (LDH); Disease Stage; Sex; Previous Single Agent Immunotherapy Treatment; Age Group. Due to limited number of responses for either treatment arm, DoR analysis was not performed. | First date RECIST criteria met for CR or PR (whichever occurred first) until first date of documented PD, or death from any cause (assessed every other cycle) up to 13.70 months | 
| Percentage of Randomized Participants Having a Confirmed Best Overall Response of Partial Response (PR) or Complete Response (CR) Plus Participants With an Overall Response of Stable Disease (SD) | Response using Response Evaluation Criteria In Solid Tumors (RECIST) criteria: CR=disappearance of all target lesions; PR=30% decrease in sum of longest diameter of target lesions; SD=small changes that do not meet above criteria; PD=20% increase in sum of the longest diameter of target lesions. | First date RECIST criteria met for CR, PR, or SD until first date of documented progressive disease (PD), or death from any cause (assessed every other cycle) up to 13.70 months | 
| Time to Deterioration in the Functional Assessment of Cancer Therapy-Melanoma Trial Outcome Index (FACT-M TOI) Score | FACT-M measures domains of health-related quality of life (HR-QoL): physical well-being, social/family well-being, emotional well-being, functional well-being, and additional concerns of melanoma. FACT-M TOI is the sum of FACT-M physical well-being, functional well-being, and melanoma subscales. Scores range from 0 to 120; Higher scores=better quality of life (QoL). FACT-M TOI score deterioration was defined as time from randomization to a minimally important difference in TOI score or death. | Randomization to first date of deterioration in FACT-M TOI, or death from any cause (assessed every cycle and up to 30 days following treatment discontinuation) up to 13.21 months | 
| Change From Baseline at Cycle 2 in Functional Assessment of Cancer Therapy-Melanoma (FACT-M) up to 30 Days Following Treatment Discontinuation | FACT-M measures domains of health-related quality of life (HR-QoL): physical well-being, social/family well-being, emotional well-being, functional well-being, and additional concerns of melanoma. Total scores range from 0 to 172; Higher scores=better HR-QoL. Least Squares (LS) Mean value was adjusted for treatment group, cycle, treatment-by-cycle interaction, age, Eastern Cooperative Oncology Group (ECOG) performance status, stage of disease at study entry, and best response to previous chemotherapy. | Baseline at Cycle 2, up to 30 days following treatment discontinuation | 
| Change From Baseline at Cycle 3 in Functional Assessment of Cancer Therapy-Melanoma (FACT-M) up to 30 Days Following Treatment Discontinuation | FACT-M measures domains of health-related quality of life (HR-QoL): physical well-being, social/family well-being, emotional well-being, functional well-being, and additional concerns of melanoma. Total scores range from 0 to 172; Higher scores=better HR-QoL. Least Squares (LS) Mean value was adjusted for treatment group, cycle, treatment-by-cycle interaction, age, Eastern Cooperative Oncology Group (ECOG) performance status, stage of disease at study entry, and best response to previous chemotherapy. | Baseline at Cycle 3, up to 30 days following treatment discontinuation | 
| Change From Baseline at Cycle 4 in Functional Assessment of Cancer Therapy-Melanoma (FACT-M) up to 30 Days Following Treatment Discontinuation | FACT-M measures domains of health-related quality of life (HR-QoL): physical well-being, social/family well-being, emotional well-being, functional well-being, and additional concerns of melanoma. Total scores range from 0 to 172; Higher scores=better HR-QoL. Least Squares (LS) Mean value was adjusted for treatment group, cycle, treatment-by-cycle interaction, age, Eastern Cooperative Oncology Group (ECOG) performance status, stage of disease at study entry, and best response to previous chemotherapy. | Baseline at Cycle 4, up to 30 days following treatment discontinuation | 
| Change From Baseline at Cycle 2 in EuroQol-5 Dimensions (EQ-5D) up to 30 Days Following Treatment Discontinuation | EQ-5D consists of 5 items that assess participant's overall health. Participants choose 1 of 3 options that best describe the status of each item. EQ-5D United Kingdom (UK)-based index scores range from -0.59 (worst health) to 1.0 (1.0=perfect health; Positive change from baseline=health improvement). Least Squares (LS) Mean value was adjusted for treatment group, cycle, treatment-by-cycle interaction, age, Eastern Cooperative Oncology Group (ECOG) performance status, stage of disease at study entry, and best response to previous chemotherapy. | Baseline at Cycle 2, up to 30 days following treatment discontinuation | 
| Change From Baseline at Cycle 3 in EuroQol-5 Dimensions (EQ-5D) up to 30 Days Following Treatment Discontinuation | EQ-5D consists of 5 items that assess participant's overall health. Participants choose 1 of 3 options that best describe status of each item. EQ-5D United Kingdom (UK)-based index scores range from -0.59 (worst health) to 1.0 (1.0=perfect health; Positive change from baseline=health improvement). Least Squares (LS) Mean value was adjusted for treatment group, cycle, treatment-by-cycle interaction, age, Eastern Cooperative Oncology Group (ECOG) performance status, stage of disease at study entry, and best response to previous chemotherapy. | Baseline at Cycle 3, up to 30 days following treatment discontinuation | 
| Change From Baseline at Cycle 4 Baseline in EuroQol-5 Dimensions (EQ-5D) up to 30 Days Following Treatment Discontinuation | EQ-5D consists of 5 items that assess participant's overall health. Participants choose 1 of 3 options that best describe status of each item. EQ-5D United Kingdom (UK)-based index scores range from -0.59 (worst health) to 1.0 (1.0=perfect health; Positive change from baseline=health improvement). Least Squares (LS) Mean value was adjusted for treatment group, cycle, treatment-by-cycle interaction, age, Eastern Cooperative Oncology Group (ECOG) performance status, stage of disease at study entry, and best response to previous chemotherapy. | Baseline at Cycle 4, up to 30 days after treatment discontinuation | 
| Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) During Cycle 1 |  | After drug infusion in Cycle 1 (5 samples drawn over the 28-day cycle) | 
| Pharmacokinetics: Maximum Plasma Concentration (Cmax) During Cycle 2 |  | After drug infusion in Cycle 2 (2 samples drawn over the 28-day cycle) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
metastatic, second-line