Clinical trial NCT04274023: Study on TSR-042 in Advanced Clear Cell Sarcoma
Official title: Phase II Study on TSR-042 in Advanced Clear Cell Sarcoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Sarcoma, Clear Cell
Keywords: advanced clear cell sarcoma
anti-PDL1
Lead sponsor: Italian Sarcoma Group
Sponsor class: NETWORK
Collaborators: name: GlaxoSmithKline
First posted: 2020-02-18
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Single arm
Primary purpose: TREATMENT

Brief summary: Phase II,single arm study designed to explore the activity of TSR-042, an immunotherapy agent, in patients with a diagnosis of advanced or metastatic clear cell sarcoma (CCS).

Detailed description: Phase II, single arm, not randomized, European multicentric study designed to explore the activity of TSR-042, a human monoclonal anti-PD-1 inhibitor, in a population of patients with a diagnosis of advanced/metastatic clear cell sarcoma (CCS).

Eligibility criteria: Inclusion Criteria:

1. Written informed consent
2. Histological centrally confirmed diagnosis of clear cell sarcoma
3. Availability of archived tumor tissue block, or 15 slides.
4. Locally advanced disease
5. Measurable disease based on RECIST 1.1
6. Patient can be naive or previously treated with 1 or 2 systemic regimens given for recurrent and/or metastatic disease
7. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
8. Adequate bone marrow function
9. Adequate organ function
10. Cardiac ejection fraction ≥50%
11. At least 18 years of age on day of signing informed consent.
12. Non-pregnant female patients
13. Non-ot breastfeed during the study for 90 days after the last dose of study treatment.
14. Male participant agrees to use an adequate method of contraception
15. No history of arterial and/or venous thromboembolic event within the previous 12 months.
16. Participant receiving corticosteroids may continue as long as their dose is stable for least 4 weeks prior to initiating protocol therapy.
17. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

Exclusion Criteria:

1. Participant must not be simultaneously enrolled in any interventional clinical trial
2. Previous treatment with any non-investigational agents within 14 days of first day of study drug dosing.
3. Must not have received investigational therapy ≤ 4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is shorter, prior initiating protocol therapy
4. Other primary malignancy with \<5 years clinically assessed disease-free interval, except basal cell skin cancer, cervical carcinoma in situ, or other neoplasms judged to entail a low risk of relapse
5. Previous treatment with radiation therapy within 14 days of first day of study drug dosing, or patients who have not recovered from adverse events due to agents administered more than 4 weeks earlier
6. Has known active central nervous system (CNS) metastases, leptomeningeal metastases, and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable, have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
7. Has active, non-infectious pneumonitis
8. Has an active infection requiring systemic therapy
9. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agents
10. Has received a live vaccine within 30 days of planned start of study therapy
11. Major surgery within 3 weeks prior to study entry
12. Any one of the following currently or in the previous 6 months:

Myocardial infarction, congenital long QT syndrome, Torsades de Pointes, arrhythmias right bundle branch block and left anterior hemiblock unstable angina coronary/peripheral artery bypass graft, symptomatic congestive heart failure New York Heart Association Class III or IV, cerebrovascular accident, or transient ischemic attack symptomatic pulmonary embolism. Ongoing cardiac dysrhythmias of Grade \>=3, atrial fibrillation of any grade,or QTcF interval \>470 msec 14. Severe and/or uncontrolled medical disease 15. Patient experienced ≥ Grade 3 immune-related AE with prior immunotherapy 16. Participant has a diagnosis of immunodeficiency or has receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to initiating protocol therapy 17. Any known active hepatitis B or hepatitis C 18. Any known history of human immunodeficiency virus 19. Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment) 20. Expected non-compliance to medical regimens 21. Known history of interstitial lung disease 22. Active autoimmune disease that has required systemic treatment in the past 2 years 23. Known severe hypersensitivity reactions to monoclonal antibodies, any history of anaphylaxis, or uncontrolled asthma

Primary outcomes:
measure: Overall Response Rate
timeFrame: At week 12
Secondary outcomes:
measure: Immune-related RECIST (ir-RECIST) response rate
timeFrame: At weeks 6, 12, 24, 36, 48, 60, 72, 84, 96
measure: Choi criteria response rate
timeFrame: At weeks 6, 12, 24, 36, 48, 60, 72, 84, 96
measure: Progression Free Survival (PFS)
timeFrame: At 3 and 5 years
measure: Overall Survival
timeFrame: At 3 and 5 years
measure: Clinical Benefit Rate
timeFrame: Month 6
measure: Adverse events related to the treatment
timeFrame: Week 3, week 6, week 9, week 12, week 18, week 24, week 36, week 48, week 60, week 72
measure: Growth Modulation Index (GMI)
timeFrame: At weeks 6, 12, 24, 36, 48, 60, 72, 84, 96
measure: Quality of Life according the 30 questions European Organization for Research and Treatment of Cancer Quality of Life Questionnaire
timeFrame: Day1 Cycle 2, Day 1 Cycle 3, Every 3 cycles (Day1Cyle6, Day1Cycle 9, …) and through study completion, an average of 1 year
measure: Quality of Life according the questionnaire Euro Quality Of Life 5 Domains (EQ-5D)
timeFrame: Day1 Cycle 2, Day 1 Cycle 3, Every 3 cycles (Day1Cyle6, Day1Cycle 9, …) and through study completion, an average of 1 year
measure: Safety according the Patient Reported Outcome according Common Terminology Criteria for Adverse Events (PRO-CTCAE)
timeFrame: Day1 Cycle 2, Day 1 Cycle 3, Every 3 cycles (Day1Cyle6, Day1Cycle 9, …) and through study completion, an average of 1 year
Other outcomes:
measure: Expression level of PD1 and PDL1 at pre-treatment evaluated on cancer cells and in tumor infiltrating myeloid cells
timeFrame: Day1 (pre-treatment)
measure: Frequency in the expression of myeloid-derived suppressor cells in peripheral blood mononuclear cell
timeFrame: Day1, day15, day45 of treatment and through study completion, an average of 1 year
measure: Frequency in the expression of anti-tumor immune cells in PBMC collected at baseline and during TSR-042.
timeFrame: Day1, day15, day45 of treatment and through study completion, an average of 1 year
Locations:
city: Milan
country: Italy
facility: Fondazione IRCSS Istituto Nazionale dei Tumori
Study officials:
affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
name: Silvia Stacchiotti, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Granter SR, Weilbaecher KN, Quigley C, Fletcher CD, Fisher DE. Clear cell sarcoma shows immunoreactivity for microphthalmia transcription factor: further evidence for melanocytic differentiation. Mod Pathol. 2001 Jan;14(1):6-9. doi: 10.1038/modpathol.3880249.
citation: Antonescu CR, Tschernyavsky SJ, Woodruff JM, Jungbluth AA, Brennan MF, Ladanyi M. Molecular diagnosis of clear cell sarcoma: detection of EWS-ATF1 and MITF-M transcripts and histopathological and ultrastructural analysis of 12 cases. J Mol Diagn. 2002 Feb;4(1):44-52. doi: 10.1016/S1525-1578(10)60679-4.
citation: Stacchiotti S, Grosso F, Negri T, Palassini E, Morosi C, Pilotti S, Gronchi A, Casali PG. Tumor response to sunitinib malate observed in clear-cell sarcoma. Ann Oncol. 2010 May;21(5):1130-1. doi: 10.1093/annonc/mdp611. Epub 2010 Jan 21. No abstract available.
citation: Tazzari M, Palassini E, Vergani B, Villa A, Rini F, Negri T, Colombo C, Crippa F, Morosi C, Casali PG, Pilotti S, Stacchiotti S, Rivoltini L, Castelli C. Melan-A/MART-1 immunity in a EWS-ATF1 translocated clear cell sarcoma patient treated with sunitinib: a case report. BMC Cancer. 2015 Feb 14;15:58. doi: 10.1186/s12885-015-1044-0.