E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma |
|
E.1.1.1 | Medical condition in easily understood language |
Locally advanced soft tissue sarcoma (type of cancer that develops from certain tissues, like bone or muscle) that is not resectable or is diseminated into the body |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.1 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10041299 |
E.1.2 | Term | Soft tissue sarcomas |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
1. To evaluate the efficacy of TH-302 in combination with doxorubicin as determined by overall survival in subjects with locally advanced unresectable or metastatic soft tissue sarcoma previously untreated with chemotherapy (neoadjuvant and adjuvant chemotherapy permitted) compared with doxorubicin
alone
2. To assess the safety of TH-302 in combination with doxorubicin in subjects with locally advanced unresectable or metastatic soft tissue sarcoma compared with doxorubicin alone |
|
E.2.2 | Secondary objectives of the trial |
1. To evaluate the efficacy of TH-302 in combination with doxorubicin as determined by progression-free survival and response rate in subjects with locally advanced unresectable or metastatic soft tissue sarcoma compared with doxorubicin alone
2. To investigate the pharmacokinetics of TH-302, Br-IPM, doxorubicin and doxorubicinol in plasma |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Serum and Plasma Hypoxia Biomarker Measures
For subjects who consent to this sub-study, quantitative measurements
of serum and plasma hypoxia biomarkers will be obtained from collected
blood samples. Results of this analysis will be associated with efficacy
and safety endpoints and pharmacokinetic data.
Archival Tumor Tissue Biomarker Measures
For subjects who consent to the tumor tissue analysis, quantitative
measurements of archival tumor tissue biomarkers will be obtained from
specimen collected prior to study entry. Results of this analysis will be
associated with efficacy and safety endpoints and pharmacokinetic data. |
|
E.3 | Principal inclusion criteria |
1. Male or female ≥ 15 years of age
2. Ability to understand the purposes and risks of the study and has signed or, if appropriate, the subject’s parent or legal guardian has signed a written informed consent form approved by the investigator’s IRB/Ethics Committee
3. Pathologically confirmed diagnosis of soft tissue sarcoma of the following histopathologic types:
Other soft tissue sarcomas for which doxorubicin is appropriate first line therapy
Synovial sarcoma
High grade fibrosarcoma
Undifferentiated sarcoma; sarcoma not otherwise specified (NOS)
Liposarcoma
Leiomyosarcoma (excluding GIST)
Angiosarcoma (excluding Kaposi’s sarcoma)
Malignant peripheral nerve sheath tumor
Pleomorphic Rhabdomyosarcoma
Myxofibrosarcoma
Epithelioid sarcoma
Undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma (MFH) (including pleomorphic, giant cell, myxoid and inflammatory forms)
4. Locally advanced unresectable or metastatic disease with no standard curative therapy available and for whom treatment with single agent doxorubicin is considered appropriate
5. Recovered from reversible toxicities of prior therapy
6. Measurable disease by RECIST 1.1 criteria (at least one target lesion outside of previous radiation fields or progressed within a previous radiation field)
7. ECOG performance status of 0 or 1
8. Life expectancy of at least 3 months
9. Acceptable liver function:
Bilirubin ≤ 1.5 x upper limit of normal (ULN); does not apply to subjects with Gilbert’s syndrome
AST (SGOT) and ALT (SGPT) ≤ 3.0 x ULN); if liver metastases are present, then ≤ 5 x ULN is allowed
10. Acceptable renal function:
Serum creatinine ≤ 1.5 times ULN or calculated creatinine clearance ≥ 60 mL/min (by the Cockcroft Gault formula)
11. Acceptable hematologic status (without growth factor
support or transfusion dependency):
ANC ≥ 1500 cells/μL
Platelet count ≥ 100,000/μL
Hemoglobin ≥ 9.0 g/dL
12. Acceptable cardiac function:
Normal 12-lead ECG (clinically insignificant abnormalities permitted)
LVEF normal by MUGA or echocardiogram (>50% per CTCAE v4.0)
13. 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 IUD) with their partner from entry into
the study 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 FSH levels >35 mIU/ml (IU/L). |
|
E.4 | Principal exclusion criteria |
1. Low grade tumors according to standard grading systems (eg AJCC Grade 1 and 2 or FNCLCC Grade 1)
2. Prior systemic therapy for advanced or metastatic soft tissue sarcoma (neoadjuvant therapy followed by surgical resection and adjuvant therapy permitted). Palliative radiotherapy to non-target lesions is allowed if completed at least two weeks prior to study entry.
3. Prior soft tissue sarcoma therapy with ifosfamide or cyclophosphamide or other nitrogen mustards
4. Prior systemic therapy with an anthracycline or anthracenedione
5. Prior mediastinal/cardiac radiotherapy
6. Current use of drugs with known cardiotoxicity or known interactions with doxorubicin
7. Anti-cancer treatment with radiation therapy, neoadjuvant or adjuvant chemotherapy, targeted therapies, immunotherapy, hormones or other antitumor therapies within 4 weeks prior to study entry (6 weeks for nitrosoureas or mitomycin C)
8. Significant cardiac dysfunction precluding treatment with doxorubicin:
History of congestive heart failure
Myocardial infarction within the past 6 months or severe myocardial insufficiency
Uncontrolled arrhythmias within the past 6 months
Angina pectoris requiring antianginal medication within the past 6 months
Clinically significant valvular heart disease
Poorly controlled hypertension
9. Seizure disorders requiring anticonvulsant therapy unless seizure-free for the last year
10. Known brain metastases (unless previously treated and well controlled for a period of ≥ 3 months)
11. 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
12. 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
13. Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1, without complete recovery
14. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy
15. Prior therapy with a hypoxic cytotoxin
16. Subjects who participated in an investigational drug or device study within 28 days prior to study entry
17. Known infection with HIV, or active infection with hepatitis B, or hepatitis C
18. Subjects who have exhibited allergic reactions to a structural compoundsimilar to TH-302 or the drug product excipients
19. Females who are pregnant or breast-feeding
20. 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
21. Unwillingness or inability to comply with the study protocol for any reason |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Overall survival which is defined as the duration from
date of randomization to date of death. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
An interim analysis will be conducted after enrollment of 620 patients is
nearing completion. This interim will be conducted based on OS and is
expected to occur after 235 deaths. |
|
E.5.2 | Secondary end point(s) |
Progression-free survival
Response rate
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Canada |
Denmark |
France |
Italy |
Austria |
Australia |
Germany |
Hungary |
Spain |
Israel |
Poland |
Russian Federation |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
last survival follow-up of last patient |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 3 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 12 |
E.8.9.2 | In all countries concerned by the trial days | 3 |