| Eligibility |
Inclusion Criteria:
- 1. Written informed consent and any locally-required authorization (EU Data Privacy
Directive in the EU) obtained from the subject prior to performing any
protocol-related procedures, including screening evaluations 2. Age = 18 years at time
of study entry 3. Body weight > 30kg at study inclusion 4. Histologically confirmed
diagnosis of metastatic or advanced soft tissue sarcoma of intermediate or high grade
[according to FNCLCC score; intermediate=grade 2 score of 4-5 points, high grade =
grade 3 score of 6-8 points] with disease progression within 6 months prior to study
inclusion:
• Fibrosarcoma
• Pleomorphic high grade sarcoma ("malignant fibrous histiocytoma")
• Leiomyosarcoma
- Liposarcoma (myxoid liposarcoma, dedifferentiated liposarcoma, pleomorphic
liposarcoma)
- Malignant glomus tumor
- Rhabdomyosarcoma, alveolar or pleomorphic (excluding embryonal)
- Vascular sarcoma (angiosarcoma)
- Synovial sarcoma
- High-grade sarcoma, not otherwise specified (NOS)
- Malignant peripheral nerve sheath tumors
- Other types of sarcoma (not listed as ineligible), if approved by the
coordinating investigator / study coordinator.
Excluding:
Uncertain differentiation (epithelioid, alveolar soft part, clear cell, desmoplastic small
round cell, malignant mesenchymoma, PEComa), chondrosarcoma, Ewing sarcomas/PNET, chordoma,
malignant solitary fibrous tumors, embryonal rhabdomyosarcoma, osteosarcoma,
gastrointestinal stromal tumors, dermatofibrosarcoma protuberans, inflammatory
myofibroblastic sarcoma (low-grade), neuroblastoma, malignant mesothelioma, and mixed
mesodermal tumors of the uterus (Study inclusion is based on local histopathological
diagnosis). 5. Metastatic or locally advanced STS, not amendable to surgery with curative
intention.
6. No prior treatment line for advanced or metastatic disease. 7. ECOG performance status
0-2 8. Patients with measurable disease (at least one uni-dimensionally measurable target
lesion by CT-scan or MRI) according to Response Evaluation Criteria in Solid Tumors (RECIST
1.1) are eligible.
9. If prior palliative radiotherapy has been given to metastatic lesions: either =1
measurable lesion remains outside the radition field or the sole lesion meets RECIST 1.1
criteria for progression at study entry.
10. Patients with bone lesions as the only measurable lesion are eligible, provided that
lesions consist of soft tissue, which is measurable via CT or MRI.
11. Prior radiotherapy and surgery are allowed if completed 4 weeks (for minor surgery and
palliative radiotherapy for bone pain: 2 weeks) prior to start of treatment and patient
recovered from toxic effects.
12. Adequate blood count, liver-enzymes, and renal function:
- Haemoglobin = 9.0 g/dL
- Absolute neutrophil count (ANC) = 1.5 x 109/L (> 1500 per mm3)
- Platelet count = 100 x 109/L (>100,000 per mm3)
- Serum bilirubin = 1.5 x ULN. This will not apply to subjects with confirmed Gilbert's
syndrome (persistent or recurrent hyperbilirubinemia that is predominantly
unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed
only in consultation with their physician.
- AST (SGOT)/ALT (SGPT) = 2.5 x institutional upper limit of normal unless liver
metastases are present, in which case it must be = 5x ULN
- Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault
1976) or by 24-hour urine collection for determination of creatinine clearance 13.
Adequate cardiac function (left ventricular ejection fraction =50% as assessed by
ECHO) 14. Female subjects must either be of non-reproductive potential (ie,
post-menopausal by history: =60 years old and no menses for =1 year without an
alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal
ligation, OR history of bilateral oophorectomy) or must have a negative serum
pregnancy test upon study entry.
15. Subject is willing and able to comply with the protocol for the duration of the
study including undergoing treatment and scheduled visits and examinations including
follow up.
Exclusion Criteria:
- 1. Patients who are suitable for anthracycline-based combination therapies 2. Cardiac
events such as arrhythmias, myocardial infarction, CHF, apoplexy, lung embolism within
6 months prior to study treatment 3. Mean QT interval corrected for heart rate (QTc)
=470 ms calculated from 3 electrocardiograms (ECGs) using Fredericia's correction 4.
Uncontrolled severe hypertension (failure of diastolic blood pressure to fall below
100 mmHg and systolic blood pressure >160 mmHg) 5. Previous malignancy (other than
STS) which either progresses or requires active treatment.
Exceptions are: basal cell cancer of the skin, pre-invasive cancer of the cervix, T1a or
T1b prostate carcinoma, or superficial bladder tumor [Ta, Tis and T1].
6. History or clinical evidence of CNS metastases
Exceptions are: Subjects who have completed local therapy and who meet both of the
following criteria:
1. are asymptomatic and
2. have no requirement for steroids 6 weeks prior to start of study treament. Screening
with CNS imaging (CT or MRI) is required only if clinically indicated or if the
subject has a history of CNS metastases 7. Active or prior documented autoimmune
disease within the past 2 years. NOTE: Subjects with vitiligo, Grave's disease, or
psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
8. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
ulcerative colitis) 9. History of primary immunodeficiency 10. History of allogeneic
organ transplant 11. History of hypersensitivity to durvalumab, tremelimumab (alone or
in combination), doxorubicin or any of the constituents of the products 12. Medication
that is known to interfere with any of the agents applied in the trial.
13. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active
bleeding diatheses including any subject known to have evidence of acute or chronic
hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric
illness/social situations that would limit compliance with study requirements or
compromise the ability of the subject to give written informed consent.
14. Major surgical procedure (as defined by the Investigator) within 28 days prior to
the first dose of study medication. Note: Local surgery of isolated lesions for
palliative intent is acceptable.
15. Any unresolved toxicity >CTCAE grade 2 from previous anti-cancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
criteria.
- Patients with Grade =2 neuropathy will be evaluated on a case-by-case basis after
consultation with the Coordinating Investigator.
- Patients with irreversible toxicity not reasonably expected to be exacerbated by
treatment with durvalumab or tremelimumab (if applicable) may be included only
after consultation with the Coordinating Investigator.
16. Any prior Grade =3 immune-related adverse event (irAE) while receiving any
previous immunotherapy agent, or any unresolved irAE >Grade 1 17. Known history
of previous clinical diagnosis of tuberculosis 18. Receipt of live attenuated
vaccination within 30 days prior to study entry or within 30 days of receiving
durvalumab 19. Female subjects who are pregnant, breast-feeding or male or female
patients of reproductive potential who are not employing an effective method of
birth control (failure rate of less than 1% per year) 20. Any condition that, in
the opinion of the investigator, would interfere with evaluation of study
treatment or interpretation of patient safety or study results 21. Participation
in another clinical study with an investigational product during the last 30 days
before inclusion 22. Any previous treatment with a PD-1 or PD-L1 or CTLA-4
inhibitor, including durvalumab and tremelimunab 23. Current or prior use of
immunosuppressive medication within 28 days before the first dose of durvalumab,
with the exceptions of intranasal and inhaled corticosteroids or systemic
corticosteroids at physiological doses, which are not to exceed 10 mg/day of
prednisone, or an equivalent corticosteroid 24. Receipt of the last dose of
anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted
therapy, biologic therapy, tumor embolization, monoclonal antibodies, other
investigational agent) = 21 days prior to the first dose of study drug or =4
half-lifes of the agent administered, which ever comes first.
25. Previous enrollment or randomization in the present study (does not include
screening failure).
26. Patient who has been incarcerated or involuntarily institutionalized by court
order or by the authorities (§ 40 Abs. 1 S. 3 Nr. 4 AMG).
27. Patients who are unable to consent because they do not understand the nature,
significance and implications of the clinical trial and therefore cannot form a
rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].
|
