| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| advanced or metastatic soft tissue sarcoma |
| fortgeschrittenes oder metastasiertes Weichteilsarkom |
|
| E.1.1.1 | Medical condition in easily understood language |
| advanced or metastatic soft tissue sarcoma |
| fortgeschrittenes oder metastasiertes Weichteilsarkom |
|
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10075333 |
| E.1.2 | Term | Soft tissue sarcoma |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the efficacy of tremelimumab and durvalumab (MEDI4736) in comparison to doxorubicin in treatment-naïve STS patients |
| Untersuchung der Wirksamkeit von Tremelimumab und Durvalumab (MEDI4736) im Vergleich zu Doxorubicin in nicht-vorbehandelten Patienten mit Weichteilsarkom |
|
| E.2.2 | Secondary objectives of the trial |
| Assessment of safety and tolerability of tremelimumab and durvalumab (MEDI4736) combination therapy |
| Untersuchung der Sicherheit und Verträglichkeit der Kombinationstherapie mit Tremelimumab und Durvalumab (MEDI4736) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 10^9/L (> 1500 per mm³)
• Platelet count ≥ 100 x 10^9/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 or by 24-hour urine collection for determination of creatinine clearance
Males: Creatinine CL (mL/min) = Weight (kg) x (140 – Age)/ (72 x serum creatinine (mg/dL))
Females: Creatinine CL (mL/min) = Weight (kg) x (140 – Age) x 0.85/ (72 x serum creatinine (mg/dL))
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. |
|
| E.4 | Principal 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:
a) are asymptomatic and
b) 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, 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| overall survival |
| Gesamtüberleben |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
End of study (EoS)
(End of Study (EoS) is defined as the time point when the last patient has completed 2 year treatment and follow-up period (approx. 12 month after the last durvalumab dose)) |
| Ende der Studie |
|
| E.5.2 | Secondary end point(s) |
- ORR according to conventional and iRECIST 1.1 criteria
- OS mile stone rate at 24 months
- PFS
- Duration of response
- AEs / SAEs and Treatment Emergent Adverse Events according to CTCAE 4.03
- Health related Quality of Life (HR-QoL - EORTC QLQ-C30)
|
- Tumor-Ansprechrate (ORR) (nach konventionellen und iRECIST 1.1 Kriterien)
- Gesamtüberleben (OS) bei 24 Monaten
- Progressionsfreies Überleben (PFS)
- Dauer des Ansprechens (Duration of response)
- UEs/SUEs und therapiebedingte Nebenwirkungen nach CTCAE 4.03
- Gesundheitsbezogene Lebensqualität (HR-QoL – EORTC QLQ-C30) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
End of study (EoS)
(End of Study (EoS) is defined as the time point when the last patient has completed 2 year treatment and follow-up period (approx. 12 month after the last durvalumab dose)) |
| Ende der Studie |
|
| 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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Quality of Life |
| Lebensqualität |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| 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) | Yes |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 14 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
End of study (EoS)
(End of Study (EoS) is defined as the time point when the last patient has completed 2 year treatment and follow-up period (approx. 12 month after the last durvalumab dose)) |
| Ende der Studie |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
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