| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Angiosarcoma and Undifferentiated Pleomorphic Sarcoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Two types of advanced soft tissue sarcoma (Angiosarcoma and Undifferentiated Pleomorphic Sarcoma ) |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10002476 |
| E.1.2 | Term | Angiosarcoma |
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025552 |
| E.1.2 | Term | Malignant fibrous histiocytoma |
| 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 |
| Determine the progression-free survival rate at 3 months |
|
| E.2.2 | Secondary objectives of the trial |
1.Determine the objective response rate (ORR) and duration of Response (DOR)
2. Determine Progression Free Survival
3. Determine Overall Survival,
4. Determine safety
5. Determine Quality of Life
Exploratory: To explore the association between anti-tumor activity and specific biomarker measures in the tumor tissue and in peripheral blood |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care
• Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study
• Histologically confirmed diagnosis of unresectable locally advanced or metastatic Angiosarcoma or Undifferentiated Pleomorphic Sarcoma, who has progressed/failed to provide clinical benefit on first line standard chemotherapy.
• Age ≥18 years
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of ≤2 at the time of enrollment.
• Evaluable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1).
• Available material from archived formalin-fixed paraffin-embedded tumor tissue obtained within 3 months of study enrollment for biomarkerrelated studies. If not sufficient or available, a newly obtained core or excisional biopsy of a tumor lesion may be performed.
• Patients must have normal organ and marrow function as defined below:
o Absolute neutrophil count (ANC) ≥ 1 x 10⁹/L
o Platelet count ≥ 75 x 10⁹/L
o Serum bilirubin ≤ 1.5 x upper limit of normal (ULN) (patients with Gilbert's Syndrome must have a total bilirubin ≤ 50 mmol/L)
o Aspartate transaminase (AST)/Alanine transaminase (ALT) ≤ 5 x ULN
o Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (using the Cockcroft-Gault formula)
• Women of childbearing potential (WOCBP): Agreement to use contraceptive methods with a failure rate of < 1 % per year during the treatment period and for at least 120 days after the treatment. Safe contraceptive methods for women are birth control pills, intrauterine device, contraceptive injection, contraceptive implant,contraceptive patch or contraceptive vaginal ring.
• Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year during the treatment period and for at least 120 days after the treatment.
• Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile) as well as azoospermic men do not require contraception
|
|
| E.4 | Principal exclusion criteria |
• Have an anticipated life expectancy of <3 months.
• Moderate to severe degree of bronchial asthma or chronic obstructive pulmonary disease.
• Acute or non-stable congestive heart failure
• Have received any previous systemic therapy targeting the PD-1/PDL-1 signaling pathway or other immune checkpoint inhibitors.
• Have received propranolol within 4 weeks prior to treatment.
• Prior to study day one received radiation therapy, chemotherapy or targeted small molecule therapy within 2 weeks and/or monoclonal antibody treatment within 4 weeks.
• Not recovered from the effects of previously administered agents
• Clinically active or unstable CNS metastases as assessed by the treating physician
• Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results
• Participants with active, known or suspected autoimmune disease. Participants with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• Participants with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• Allergies and Adverse Drug Reaction
o History of allergy to study drug components
o History of severe hypersensitivity reaction to any monoclonal antibody
• WOCBP who are pregnant or breastfeeding
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS rate (Percentage of patients alive with CR, PR and SD according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1)) at 3 months |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Due to Simon Two-stage design the primary endpoint will be evaluated at the interim analyse after stage 1 (18 patients ) for each cohort and after conclusion of stage 2 (40 patients in total) for each cohort |
|
| E.5.2 | Secondary end point(s) |
1. ORR (Percentage of patients with CR and PR), including duration hereof using RECIST v 1.1
2. median PFS, using RECIST v 1.1
3. median OS
4. Adverse Events using Common Terminology Criteria for Adverse Events (CTCAE) v5.0
5. The 30 item European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ C30) questionnaire
Exploratory: Characterize tumor cells, immune cell infiltrates, immune markers, vasculature, and markers of angiogenesis and hypoxia in the tumor microenvironment and blood in response to treatment. Measure change in immune cells and markers in TME and blood comparing baseline samples with on treatment samples. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary endpoints are evaluated after conclusion of stage 2 (40 patients in total) for each cohort |
|
| 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 | Yes |
| 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 |
| Biomarkers and Quality of Life |
|
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | 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.8.3 |
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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| 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 trial is defined as LVLS |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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