A Japanese Trial of TH-302 in Subjects With Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma

Study Overview
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Brief Summary
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This is a Phase 2, single-arm, Japanese multicenter trial to evaluate the safety, tolerability, and efficacy of TH-302 in combination with doxorubicin in subjects with locally advanced unresectable or metastatic soft tissue sarcoma (STS).

Official Title
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A Phase II, Single-arm, Japanese Multicenter Trial of TH-302 in Combination With Doxorubicin in Subjects With Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma

Conditions
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Soft Tissue Sarcoma

Intervention / Treatment
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* Drug: TH-302
* Drug: Doxorubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female Japanese subjects greater than or equal to (>=) 15 years of age Able to understand the purposes and risks of the trial and has signed or, if appropriate, the subject's parent or legal guardian has signed a written informed consent form approved by the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) Pathologically confirmed diagnosis of STS of the histopathologic types as specified in the protocol Locally advanced unresectable or metastatic disease with no standard curative therapy available and for whom treatment with single agent doxorubicin is considered appropriate Recovered from reversible toxicities of prior therapy Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (at least one target lesion outside of previous radiation fields or progressed within a previous radiation field) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Life expectancy of at least 3 months Acceptable liver function, renal function, hematologic status (without growth factor support for neutropenia or transfusion dependency), and cardiac function as specified in the protocol All women of childbearing potential must have a negative serum pregnancy test and all subjects must agree to use effective means of contraception (surgical sterilization or the use of barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel or an intrauterine device, intrauterine device [IUD]) with their partner from entry into the trial through 6 months after the last dose. Post-menopausal women must meet the criteria of 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone (FSH) levels greater than (>) 35 international units per liter (IU/L) Exclusion Criteria: Low grade tumors according to standard grading systems (for example, American Joint Committee on Cancer [AJCC] Grade 1 and 2 or Fédération Nationale des Centres de Lutte Contre le Cancer [FNCLCC] Grade 1) Prior systemic therapy for advanced or metastatic STS (neoadjuvant therapy followed by surgical resection and adjuvant therapy permitted) Prior STS therapy with ifosfamide or cyclophosphamide or other nitrogen mustards; prior systemic therapy with an anthracycline or anthracenedione; or prior mediastinal/cardiac radiotherapy Current use of drugs with known cardiotoxicity or known interactions with doxorubicin Anti-cancer treatment with radiation therapy, neoadjuvant or adjuvant chemotherapy, targeted therapies, immunotherapy, hormones or other antitumor therapies within 4 weeks prior to trial entry (6 weeks for nitrosoureas or mitomycin C). Significant cardiac dysfunction precluding treatment with doxorubicin as specified in the protocol Seizure disorders requiring anticonvulsant therapy unless seizure-free for the last year Known brain metastases (unless previously treated and well controlled for a period of >=3 months before screening) Previously diagnosed malignancies, except for adequately treated non-melanoma skin cancer, in situ cancer, or other cancer from which the subject has been disease-free for at least 5 years before screening Severe chronic obstructive or other pulmonary disease with hypoxemia (requires supplementary oxygen, symptoms due to hypoxemia or oxygen saturation <90% by pulse oximetry after a 2 minute walk) or in the opinion of the investigator any physiological state likely to cause normal tissue hypoxia Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1, without complete recovery Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy Prior therapy with a hypoxic cytotoxin Subjects who participated in an investigational drug or device trial within 28 days prior to trial entry Known infection with human immunodeficiency virus (HIV) or active infection with hepatitis B or hepatitis C Subjects who have exhibited allergic reactions to a structural compound similar to TH-302 or the drug product excipients Subjects who are taking medications that prolong QT interval and have a risk of Torsades de Pointes Subjects with a corrected QT (QTc) interval calculated according to Bazett's formula of >450 milliseconds (msec) based on a screening electrocardiogram (ECG) Subjects with a history of long QT syndrome Subjects taking a medication that is a moderate or strong inhibitor or inducer of cytochrome P450 3A4 (CYP3A4) Females who are pregnant or breast-feeding Concomitant disease or condition that could interfere with the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study Unwillingness or inability to comply with the study protocol for any reason Legal incapacity or limited legal capacity

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TH-302 and doxorubicin<br> | Drug: TH-302<br>* TH-302 will be administered at a dose of 300 milligram per square meter (mg/m^2) by intravenous infusion over 30 minutes on Days 1 and 8 of every 21-day cycle until the evidence of significant treatment-related toxicity or progressive disease.<br>Drug: Doxorubicin<br>* Doxorubicin will be administered at a dose of 75 mg/m^2 by intravenous injection (over at least 5 minutes) or by intravenous infusion over 6-96 hours on Day 1 of every 21-day cycle starting 2 to 4 hours after completion of TH-302 administration until the evidence of significant treatment-related toxicity or progressive disease.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) by Independent Central Review (Phase II Treatment Period) | PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | From first dose of study drug administration until PD or death, evaluated at 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) by Investigator Review (Phase II Treatment Period) | PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease (PD) is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | From first dose of study drug administration until PD or death, evaluated at 6 months | 
| Progression-free Survival (PFS) by Investigator and Independent Central Review (Phase II Treatment Period) | PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease (PD) is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | From first dose of study drug administration until PD or death, evaluated at 3 months and 9 months | 
| Progression-free Survival (PFS) (Phase II Treatment Period) | PFS was planned to assess as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive Disease (PD) is defined as at least a 20 percent (%) increase in the Sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | From first dose of study drug administration until PD or death, assessed up to 12 months | 
| Best Overall Response (BOR) by Independent Central Review (Phase II Treatment Period) | BOR was planned to be determine according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as adjudicated by an Independent Central Review. BOR is defined as the best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of randomization until disease progression or recurrence (taking the smallest measurement recorded since start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 millimeter (mm). PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or appearance of 1 or more new lesions. | From first dose of study drug administration until PD or death, assessed up to 12 months | 
| Best Overall Response (BOR) by Investigator (Phase II Treatment Period) | BOR was planned to be determine according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as adjudicated by an Independent Central Review. BOR is defined as the best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of randomization until disease progression or recurrence (taking the smallest measurement recorded since start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 millimeter (mm). PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or appearance of 1 or more new lesions. | From first dose of study drug administration until PD or death, assessed up to 12 months | 
| Duration of Response (Phase II Treatment Period) | Duration of response according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) is defined as the time from the first assessment of complete response (CR) or partial response (PR) until the date of the first occurrence of progressive disease (PD), or until the date of death. CR: Disappearance of all evidence of target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to less than (<) 10 millimeter (mm). PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | From first dose of study drug administration until PD or death, assessed up to 12 months | 
| Overall Survival (OS) (Phase II Treatment Period) | OS is defined as the time from first dose to death due to any cause. | From first dose of study drug administration until the last subject completes the survival follow-up, assessed up to 12 months | 
| Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) (Safety Run-In Phase) | An adverse event (AE) was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. The term TEAE is defined as AEs starting or worsening after the first intake of the stud drug. | From baseline until end of trial, assessed up to Day 210 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Evofosfamide, Doxorubicin, Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma, TH-302