Study on TSR-042 in Advanced Clear Cell Sarcoma (ACCeSs)

Phase II Study on TSR-042 in Advanced Clear Cell Sarcoma

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).

Study Overview

• Status: Terminated
• Conditions: Sarcoma, Clear Cell
• Intervention / Treatment: Drug: TSR-042

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).

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Silvia Stacchiotti, MD; Phone Number: 2804 39022390; Email: silvia.stacchiotti@istitutotumori.mi.it

Study Locations

• Italy
  • Milan, Italy, 20133
    • Fondazione IRCSS Istituto Nazionale dei Tumori

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TSR-042 arm; TSR-042 at a dose of 500 mg in IV infusion (given over t30-minutes) every 21 days for the first 4 doses, followed by 1.000 mg on day 1 of every 42 day.	Drug: TSR-042; TSR-042 is an IgG4 humanized monoclonal antibody that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L1 and PD-L2.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	Response rate according Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1	At week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Proportion of patients who are still alive at 36 and 60 months after have started the treatment	At 3 and 5 years
Progression Free Survival (PFS)	Survival without disease progression	At 3 and 5 years
Immune-related RECIST (ir-RECIST) response rate	Response rate according ir-RECIST criteria	At weeks 6, 12, 24, 36, 48, 60, 72, 84, 96
Choi criteria response rate	Response rate according Choi criteria	At weeks 6, 12, 24, 36, 48, 60, 72, 84, 96
Clinical Benefit Rate	Proportion of patients who experienced Complete Response, Progression Response or Stable Disease for over 6 months	Month 6
Adverse events related to the treatment	Safety in term of grading of adverse event is evaluate from the firs treatment dose throughout the study according to CTCAE 5.0	Week 3, week 6, week 9, week 12, week 18, week 24, week 36, week 48, week 60, week 72
Growth Modulation Index (GMI)	Correlation between response and prior disease medical treatment: ratio of time to progression with the nth line of therapy to the those with the n-1th line.	At weeks 6, 12, 24, 36, 48, 60, 72, 84, 96
Quality of Life according the 30 questions European Organization for Research and Treatment of Cancer Quality of Life Questionnaire	Evaluation of the quality of life collected with European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30	Day1 Cycle 2, Day 1 Cycle 3, Every 3 cycles (Day1Cyle6, Day1Cycle 9, …) and through study completion, an average of 1 year
Quality of Life according the questionnaire Euro Quality Of Life 5 Domains (EQ-5D)	Evaluation of the quality of life collected with Euro Quality Of Life 5 Domains (EQ-5D)	Day1 Cycle 2, Day 1 Cycle 3, Every 3 cycles (Day1Cyle6, Day1Cycle 9, …) and through study completion, an average of 1 year
Safety according the Patient Reported Outcome according Common Terminology Criteria for Adverse Events (PRO-CTCAE)	Evaluation of the quality of safety reported by the patient with the PRO-CTCAE	Day1 Cycle 2, Day 1 Cycle 3, Every 3 cycles (Day1Cyle6, Day1Cycle 9, …) and through study completion, an average of 1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Expression level of PD1 and PDL1 at pre-treatment evaluated on cancer cells and in tumor infiltrating myeloid cells	Analysis of immune contexture in pretreatment tumor tissue.	Day1 (pre-treatment)
Frequency in the expression of myeloid-derived suppressor cells in peripheral blood mononuclear cell	Immunological monitoring of peripheral blood immune subsets, to evaluate the systemic immunological status of patients,	Day1, day15, day45 of treatment and through study completion, an average of 1 year
Frequency in the expression of anti-tumor immune cells in PBMC collected at baseline and during TSR-042.	Immunological monitoring of peripheral blood immune subsets, to evaluate the systemic immunological status of patients,	Day1, day15, day45 of treatment and through study completion, an average of 1 year

Collaborators and Investigators

• Sponsor: Italian Sarcoma Group
• Collaborators: GlaxoSmithKline
• Investigators: Principal Investigator: Silvia Stacchiotti, MD, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 29, 2024
• Primary Completion (Actual): January 29, 2024
• Study Completion (Actual): January 29, 2024

Study Registration Dates

• First Submitted: February 13, 2020
• First Submitted That Met QC Criteria: February 15, 2020
• First Posted (Actual): February 18, 2020

Study Record Updates

• Last Update Posted (Estimated): February 1, 2024
• Last Update Submitted That Met QC Criteria: January 31, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: anti-PDL1; advanced clear cell sarcoma
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Connective Tissue; Sarcoma; Sarcoma, Clear Cell; Antineoplastic Agents; Dostarlimab
• Other Study ID Numbers: ISG-ACCeSs

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No