Phase 3 Study to Treat Patients With Soft Tissue Sarcomas

Study Overview
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Brief Summary
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The purpose of this study is to determine the efficacy and safety of aldoxorubicin in subjects with metastatic, locally advanced, or unresectable soft tissue sarcomas.

Official Title
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A Multicenter, Randomized, Open-Label Phase 3 Study to Investigate the Efficacy and Safety of Aldoxorubicin Compared to Investigator's Choice in Subjects With Metastatic, Locally Advanced, or Unresectable Soft Tissue Sarcomas Who Either Relapsed or Were Refractory to Prior Non-Adjuvant Chemotherapy

Conditions
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Metastatic, Locally Advanced or Unresectable Soft Tissue Sarcoma

Intervention / Treatment
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* Drug: Aldoxorubicin
* Drug: Investigator's Choice Treatment (Darcabazine, Pazopanib, Gemcitabine + Docetaxel, Doxorubicin, Ifosfamide)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has provided written informed consent prior to any study related activities. Age ≥15 years (US only), and 18-80 (rest of world (ROW)), male or female. Histological confirmation of intermediate or high grade soft-tissue sarcoma. Tissue must be sent to a central pathology lab for review but will not preclude entry onto the study. Final assignment of tumor grade and histology will be based on the designation provided by the central pathology review. An adequate tumor specimen obtained by either excisional biopsy, incisional biopsy or core needle biopsy must be sent to the central pathology lab for evaluation. The material must measure at least 0.8 × 0.1 cm in size or contain at least 50 tumor cells. Locally advanced, unresectable, and/or metastatic soft-tissue sarcoma of intermediate or high grade with evidence of disease progression by either computed tomography (CT) or magnetic resonance imaging (MRI) scan, or clinical judgment on or after the last cancer therapy within 6 months prior to randomization. Relapsed or refractory (lack of response) to ≥1 course of systemic therapy regimen(s), excluding adjuvant or neoadjuvant chemotherapy, and is incurable by either surgery or radiation. Capable of providing informed consent and complying with trial procedures. ECOG PS 0-2. Life expectancy >12 weeks. Measurable tumor lesions according to RECIST 1.1 criteria.[50] Women must not be able to become pregnant (e.g., post-menopausal for at least 1 year, surgically sterile, or practicing adequate birth control methods) for the duration of the study. (Adequate contraception includes: oral contraception, implanted contraception, intrauterine device implanted for at least 3 months, or barrier method in conjunction with spermicide.) Males and their female partner(s) of child-bearing potential must use 2 forms of effective contraception (see Inclusion 11 plus condom or vasectomy for males) from the last menstrual period of the female partner during the study treatment and agree to continue use for 6 months after the final dose of study treatment. Women of child bearing potential must have a negative serum or urine pregnancy test at the Screening Visit and be non-lactating. Accessibility to the site that optimizes the subject's ability to keep all study-related appointments. Exclusion Criteria: Prior exposure to >375 mg/m2 of doxorubicin or liposomal doxorubicin. Palliative surgery and/or radiation treatment within 30 days prior to date of randomization. Exposure to any investigational agent within 30 days of date of randomization. Exposure to any systemic chemotherapy within 30 days of date of randomization. An inadequate tumor specimen as defined by the central pathologist. Current evidence/diagnosis of alveolar soft part sarcoma, extraskeletal myxoid chondrosarcoma, rhabdomyosarcoma, osteosarcoma, gastrointestinal stromal tumor (GIST), dermatofibrosarcoma (unless transformed to fibrosarcoma), Ewing's sarcoma, Kaposi's sarcoma, mixed mesodermal tumor, clear cell sarcomas. Evidence of central nervous system (CNS) metastasis who have not received prior definitive therapy for their lesions. History of other malignancies except cured basal cell carcinoma, cutaneous squamous cell carcinoma, melanoma in situ, superficial bladder cancer or carcinoma in situ of the cervix unless documented free of cancer for ≥5 years. Laboratory values: Screening serum creatinine >1.5 x upper limit of normal (ULN), alanine aminotransferase (ALT) >3×ULN or >5×ULN if liver metastases are present, total bilirubin >2×ULN, absolute neutrophil count (ANC) <1,500/mm3, platelet concentration <100,000/mm3, hemoglobin <9g/dL. Clinically evident congestive heart failure (CHF) > class II of the New York Heart Association (NYHA) guidelines. Current, serious, clinically significant cardiac arrhythmias, defined as the existence of an absolute arrhythmia or ventricular arrhythmias classified as Lown III, IV or V. Baseline QTc >470 msec and/or previous history of QT prolongation while taking other medications. Concomitant use of medications associated with a high incidence of QT prolongation is not allowed. History or signs of active coronary artery disease with or without angina pectoris within the last 6 months. Serious myocardial dysfunction defined by ECHO as absolute left ventricular ejection fraction (LVEF) below the institution's lower limit of predicted normal. Known history of HIV infection. Active, clinically significant serious infection requiring treatment with antibiotics, anti-virals or anti-fungals. The Medical Monitor should be contacted for any uncertainties. Major surgery within 30 days prior to date of randomization. Current or past substance abuse or any condition that might interfere with the subject's participation in the study or in the evaluation of the study results. Any condition that is unstable and could jeopardize the subject's participation in the study.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aldoxorubicin<br>Aldoxorubicin is administered at 350 mg/m2 (260 mg/m2 doxorubicin equivalent) intravenously on Day 1 every 21-day cycles until tumor progression or unacceptable toxicity occurs. | Drug: Aldoxorubicin<br> <br> * Other names: INNO-206;|
| Active Comparator: Investigator's Choice of Treatment<br>These treatments include: Dacarbazine administered at 1000 mg/m2 by intravenous infusion (IVI), over 90±15 minutes on Day 1 every 21 days until tumor progression or unacceptable toxicity occurs; Pazopanib, 800 mg orally each day until tumor progression or unacceptable toxicity occurs; Gemcitabine, 900 mg/m2 by IVI over 90 minutes on Days 1 and 8, plus docetaxel, 100 mg/m2 by IVI over 1 hour on Day 8 of a 28 day cycle until tumor progression or unacceptable toxicity occurs; Doxorubicin, 75 mg/m2 by IVI over 5 to 30 minutes every 21 days for a maximum cumulative dose of 550 mg/m2 or unacceptable toxicity occurs; or Ifosfamide 2.0 g/m2 administered over 2 to 4 hours on Days 1-4 of a 21 day cycle + mesna per standard site administration regimen until tumor progression or unacceptable toxicity occurs. | Drug: Investigator's Choice Treatment (Darcabazine, Pazopanib, Gemcitabine + Docetaxel, Doxorubicin, Ifosfamide)<br> <br> * Other names: Ifosfamide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS is defined as the time from the date of randomization to first documentation of objective tumor progression or to death due to any cause in the absence of previous documentation of objective tumor progression. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival is defined as the time from randomization to date of death. In the absence of confirmation of death, survival time will be censored at the last date the subject is known to be alive. | 36 months | 
| Safety Measures | The safety of aldoxorubicin compared to investigator's choice in this population assessed by the frequency and severity of adverse events (AEs), abnormal findings on physical examination, laboratory tests, vital signs, echocardiogram (ECHO) evaluations, electrocardiogram (ECG) results, and weight, as well as disease control rate and tumor response. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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soft tissue sarcoma, unresectable, metastatic, locally advanced, sarcoma