The primary objective of this study is to determine the efficacy of administration of aldoxorubicin compared to investigator*s choice of treatment in subjects with metastatic, locally advanced, or unresectable soft tissue sarcomas who have relapsed…
ID
Source
Brief title
Condition
- Soft tissue neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of this study is to determine the efficacy of
administration of aldoxorubicin compared to investigator*s choice of treatment
in subjects with metastatic, locally advanced, or unresectable soft tissue
sarcomas who have relapsed or were refractory to prior non-adjuvant
chemotherapy, as measured by progression-free survival (PFS).
Secondary outcome
The secondary objectives of this study are to evaluate the efficacy of
aldoxorubicin as measured by OS, 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.
The exploratory objectives are to determine the PK of aldoxorubicin,
doxorubicin, and doxorubicinol following IV administration of aldoxorubicin,
and to evaluate the exposure-response relationships between aldoxorubicin,
doxorubicin, and/or doxorubicinol and PFS, OS, and selected safety parameters,
and quality of life.
Background summary
Aldoxorubicin (INNO-206; DOXO-EMCH) is a novel prodrug that binds covalently to
circulating albumin. The drug is accumulated in tumors and doxorubicin is
released in the tumor by cleaving the acid labile linker (EMCH) in the low pH
tumor environment. This carrier-linked prodrug has demonstrated enhanced
antitumor activity with reduced toxicity in several murine models when compared
with free doxorubicin.
Patients with metastatic, locally advanced, or unresectable soft tissue
sarcomas who have failed prior chemotherapies have a poor prognosis with PFS of
around 2-4.6 months and median OS of approximately 9-12 months. Several
chemotherapy regimens have been explored as palliative therapy for subjects
with these patients and include such agents as ifosfamide, gemcitabine,
docetaxel, vinorelbine, dacarbazine, temozolomide, epirubicin, pazopanib and
liposomal doxorubicin. However, these regimens can be quite toxic and have not
significantly impacted either progression-free or OS in these individuals.
Pazopanib, recently approved in the US and Europe, does appear to extend PFS in
soft tissue sarcoma patients (except liposarcomas) who have relapsed after
receiving prior chemotherapy compared to no treatment, but does not increase
OS. Aldoxorubicin may improve upon the activity of doxorubicin without an
increase in toxicity as has been demonstrated in animal studies.
Study objective
The primary objective of this study is to determine the efficacy of
administration of aldoxorubicin compared to investigator*s choice of treatment
in subjects with metastatic, locally advanced, or unresectable soft tissue
sarcomas who have relapsed or were refractory to prior non-adjuvant
chemotherapy, as measured by progression-free survival (PFS).
and
The secondary objectives of this study are to evaluate the efficacy of
aldoxorubicin as measured by OS, 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.
and
The exploratory objectives are to determine the PK of aldoxorubicin,
doxorubicin, and doxorubicinol following IV administration of aldoxorubicin,
and to evaluate the exposure-response relationships between aldoxorubicin,
doxorubicin, and/or doxorubicinol and PFS, OS, and selected safety parameters,
and quality of life.
Study design
This is a phase 3 open-label study evaluating the efficacy and safety of
aldoxorubicin administered at 350 mg/m2 (260 mg/m2 doxorubicin equivalent)
intravenously on Day 1 every 21 days until tumor progression or unacceptable
toxicity occurs compared to investigator*s choice of treatment among
5 different therapies. These therapies include: 1) 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; 2) pazopanib, 800
mg orally each day until tumor progression or unacceptable toxicity occurs; 3)
gemcitabine, 900 mg/m2 by IVI in less than 60 minutes on Days 1 and 8, plus
docetaxel, 100 mg/m2 by IVI over 1 hour on Day 8 of a 21 day cycle until tumor
progression or unacceptable toxicity occurs; 4) 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 5) 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.
The investigative site must pre-specify their choice of treatments for the
comparator arm to be used at their site, and no more than 3 treatment regimens
may be selected for the comparator arm at each site which must be selected
prior to the study site initiation visit. Subjects will be randomized 1:1 to
receive either aldoxorubicin or investigator*s choice of up to 3 control
regimens pre-selected by the study site. Pretreatment with G-CSF is permitted
according to ASCO Guidelines.
Intervention
site bezoeken, toediening van studie medicatie, het invullen van een
patientendagboekje en tijdens de gehele onderzoeksperiode: lichamelijk
onderzoek, Echo, ECG, CT-scan/MRI, vitale functies meten en bloed- en
urinemonsters verstrekken
study visits, administration of study drugs, completion of patient diaries and
for the entire duration of the study; physical examination, Echo, ECG,
CT-scan/MRI, blood draw and collection of urine samples
Study burden and risks
Possible side effects of Aldoxorubicine, doxorubicine, doxorubicinol,
dacarbazine, pazopanib (Votrient), gemcitabine, docetaxel, ifosfamide.
Risks related to blood draw, ECG, Echo, infusion, CT-scans/MRI
Stationsweg 163
Zuidlaren 9471 GP
NL
Stationsweg 163
Zuidlaren 9471 GP
NL
Listed location countries
Age
Inclusion criteria
1. Has provided written informed consent prior to any study related activities.
2. Age *15 years (US only), and 18-80 (rest of world (ROW)), male or female.
3. 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.
4. 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.
5. 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.
6. 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.
7. Capable of providing informed consent and complying with trial procedures.
8. ECOG PS 0-2.
9. Life expectancy >12 weeks.
10. Measurable tumor lesions according to RECIST 1.1 criteria.[50]
11. 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.)
12. 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.
13. Women of child bearing potential must have a negative serum or urine pregnancy test at the Screening Visit and be non-lactating.
14. Accessibility to the site that optimizes the subject*s ability to keep all study-related appointments.
Exclusion criteria
1. Prior exposure to >375 mg/m2 of doxorubicin or liposomal doxorubicin.
2. Palliative surgery and/or radiation treatment within 30 days prior to date of randomization.
3. Exposure to any investigational agent within 30 days of date of randomization.
4. Exposure to any systemic chemotherapy within 30 days of date of randomization.
5. An inadequate tumor specimen as defined by the central pathologist.
6. 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.
7. Evidence of central nervous system (CNS) metastasis who have not received prior definitive therapy for their lesions.
8. 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.
9. 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
<9 g/dL.
10. Clinically evident congestive heart failure (CHF) > class II of the New York Heart Association (NYHA) (Appendix D) guidelines.
11. Current, serious, clinically significant cardiac arrhythmias, defined as the existence of an absolute arrhythmia or ventricular arrhythmias classified as Lown III, IV or V (Appendix F).
12. Baseline QTc >470 msec and/or previous history of QT prolongation while taking other medications.
13. Concomitant use of medications associated with a high incidence of QT prolongation is not allowed (Appendix G).
14. History or signs of active coronary artery disease with or without angina pectoris within the last 6 months.
15. Serious myocardial dysfunction defined by ECHO as absolute left ventricular ejection fraction (LVEF) below the institution*s lower limit of predicted normal.
16. Known history of HIV infection.
17. Active, clinically significant serious infection requiring treatment with antibiotics, anti-virals or
anti-fungals. The Medical Monitor should be contacted for any uncertainties.
18. Major surgery within 30 days prior to date of randomization.
19. 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.
20. Any condition that is unstable and could jeopardize the subject*s participation in the study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-004103-40-NL |
| ClinicalTrials.gov | NCT02049905 |
| CCMO | NL48870.058.14 |