Combination of MK3475 and Metronomic Cyclophosphamide in Patients With Advanced Sarcomas : Multicentre Phase II Trial
NCT ID: NCT02406781
Last Updated: 2025-12-10
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE2
129 participants
INTERVENTIONAL
2015-06-30
2023-01-15
Brief Summary
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Detailed Description
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* Leiomyosarcoma (strata 1) : 33 patients
* Undifferentiated sarcoma (strata 2): 33 patients
* Sarcomas others (strata 3) : 33 patients
* Osteosarcoma (strata 4) : 33 patients
* GIST (strata 5): 31 patients
* Advanced soft-tissue sarcoma with immune signature (strata 6): 32 patients
* Metastatic soft-tissue sarcoma (strata 7): 32 patients
Conditions
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Study Design
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NON_RANDOMIZED
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Stratum 7: Metastatic soft-tissue sarcoma.
Treatment strategy B: Combination of MK3475 with Metronomic CP and G100 adminitrered to patients with metastatic soft-tissue sarcoma.
MK3475 will be administered intravenously. Metronomic CP (Cyclophosphamide) will be administered orally. G100 will be administered by intra-tumoral injection.
Combination of MK3475 with Metronomic CP and G100
Combination of MK3475 with Metronomic CP and G100. Metronomic CP (cyclophosphamide) will be administered per os bi-daily (50 mg x 2), and given on a week on/ week off schedule.
MK3475 will be administered intravenously (200 mg), and given every 3 weeks on day 8.
G100 will be administered by intra-tumoral injection (20µg), one weekly injection for at least 6 weeks and for a maximum of 12 weeks. G100 will start one week before CP administration (impregnation phase).
A treatment cycle consists of 3 weeks. Treatment may continue until disease progression or study discontinuation.
Stratum 1: Advanced Leiomyosarcoma
Treatment strategy A: Combination of MK3475 with Metronomic CP administered to patients with advanced leiomyosarcoma.
MK3475 will be administered intraveinously. Metronomic CP (Cyclophosphamide) will be adminstered orally.
Combination of MK3475 with Metronomic CP
Combination of MK3475 with Metronomic CP. Metronomic CP (cyclophosphamide) will be administered per os bi-daily (50 mg x 2), and given on a week on/ week off schedule.
MK3475 will be administered intraveinously, and given every 3 weeks on day 8. A treatment cycle consists of 3 weeks. Treatment may continue until disease progression or study discontinuation.
Stratum 2: Advanced undifferentiated sarcoma
Treatment strategy A: Combination of MK3475 with Metronomic CP administered to patients with advanced undifferentiated sarcoma.
MK3475 will be administered intraveinously. Metronomic CP (Cyclophosphamide) will be adminstered orally.
Combination of MK3475 with Metronomic CP
Combination of MK3475 with Metronomic CP. Metronomic CP (cyclophosphamide) will be administered per os bi-daily (50 mg x 2), and given on a week on/ week off schedule.
MK3475 will be administered intraveinously, and given every 3 weeks on day 8. A treatment cycle consists of 3 weeks. Treatment may continue until disease progression or study discontinuation.
Stratum 3: Advanced other sarcoma
Treatment strategy A: Combination of MK3475 with Metronomic CP administered to patients with advanced other sarcoma.
MK3475 will be administered intraveinously. Metronomic CP (Cyclophosphamide) will be adminstered orally.
Combination of MK3475 with Metronomic CP
Combination of MK3475 with Metronomic CP. Metronomic CP (cyclophosphamide) will be administered per os bi-daily (50 mg x 2), and given on a week on/ week off schedule.
MK3475 will be administered intraveinously, and given every 3 weeks on day 8. A treatment cycle consists of 3 weeks. Treatment may continue until disease progression or study discontinuation.
Stratum 4: Advanced osteosarcoma
Treatment strategy A: Combination of MK3475 with Metronomic CP administered to patients with advanced osteosarcoma.
MK3475 will be administered intraveinously. Metronomic CP (Cyclophosphamide) will be adminstered orally.
Combination of MK3475 with Metronomic CP
Combination of MK3475 with Metronomic CP. Metronomic CP (cyclophosphamide) will be administered per os bi-daily (50 mg x 2), and given on a week on/ week off schedule.
MK3475 will be administered intraveinously, and given every 3 weeks on day 8. A treatment cycle consists of 3 weeks. Treatment may continue until disease progression or study discontinuation.
Stratum 5: Advanced GIST
Treatment strategy A: Combination of MK3475 with Metronomic CP administered to patients with advanced GIST.
MK3475 will be administered intraveinously. Metronomic CP (Cyclophosphamide) will be adminstered orally.
Combination of MK3475 with Metronomic CP
Combination of MK3475 with Metronomic CP. Metronomic CP (cyclophosphamide) will be administered per os bi-daily (50 mg x 2), and given on a week on/ week off schedule.
MK3475 will be administered intraveinously, and given every 3 weeks on day 8. A treatment cycle consists of 3 weeks. Treatment may continue until disease progression or study discontinuation.
Stratum 6: Advanced soft-tissue sarcomas with immune signature
Treatment strategy A: Combination of MK3475 with Metronomic CP administered to patients with advanced soft-tissue sarcomas with immune signature.
MK3475 will be administered intraveinously. Metronomic CP (Cyclophosphamide) will be adminstered orally.
Combination of MK3475 with Metronomic CP
Combination of MK3475 with Metronomic CP. Metronomic CP (cyclophosphamide) will be administered per os bi-daily (50 mg x 2), and given on a week on/ week off schedule.
MK3475 will be administered intraveinously, and given every 3 weeks on day 8. A treatment cycle consists of 3 weeks. Treatment may continue until disease progression or study discontinuation.
Interventions
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Combination of MK3475 with Metronomic CP
Combination of MK3475 with Metronomic CP. Metronomic CP (cyclophosphamide) will be administered per os bi-daily (50 mg x 2), and given on a week on/ week off schedule.
MK3475 will be administered intraveinously, and given every 3 weeks on day 8. A treatment cycle consists of 3 weeks. Treatment may continue until disease progression or study discontinuation.
Combination of MK3475 with Metronomic CP and G100
Combination of MK3475 with Metronomic CP and G100. Metronomic CP (cyclophosphamide) will be administered per os bi-daily (50 mg x 2), and given on a week on/ week off schedule.
MK3475 will be administered intravenously (200 mg), and given every 3 weeks on day 8.
G100 will be administered by intra-tumoral injection (20µg), one weekly injection for at least 6 weeks and for a maximum of 12 weeks. G100 will start one week before CP administration (impregnation phase).
A treatment cycle consists of 3 weeks. Treatment may continue until disease progression or study discontinuation.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Advanced non resectable / metastatic disease for strata 1 to 6. For stratum 7: locally advanced or metastatic disease with at least one injectable lesion.
3. Documented progression according to RECIST criteria. Progression on the last line of treatment should be confirmed by central review with two radiological assessments identical obtained at less than 6 months interval within the 12 months before inclusion.
4. For stratum 5, documented disease progression according to RECIST criteria after the first line imatinib and second line sunitinib.
5. Have provided tissue of a tumor lesion from an archival tissue sample obtained on metastasis or on locally advanced disease, or newly obtained core or excisional biopsy. For strata 6 and 7, tissue \< 3 months old and with no subsequent treatment since or from a newly obtained biopsy.
6. For strata 1, 2, 3 and 6: no more of four previous lines of systemic therapy for metastatic disease and no more than 2 previous line for stratum 7.
7. Age ≥ 18 years.
8. ECOG performance status ≤ 1.
9. Measurable disease according to RECIST v1.1 outside any previously irradiated field. At least one site of disease must be uni-dimensionally ≥ 10 mm.
10. Life expectancy \> 3 months (except for stratum 7 \> 6 months).
11. ≥ 1 previous line (s) of chemotherapy in the palliative setting for strata 1 to 5. For other strata, participant must have advanced disease and must not be a candidate for other approved therapeutic regimen known to provide significant clinical benefit based on investigator judgement.
12. No symptomatic central nervous system disease.
13. No chronic use of glucocorticoids.
14. Adequate hematological, renal, metabolic and hepatic function:
1. Hemoglobin ≥ 9 g/dl (patients may have received prior red blood cell transfusion); ANC ≥ 1.5 x 109/l and platelet count ≥ 100 x 109/l. For stratum 7: lymphocyte count ≥ 0.5.109 /l
2. ALT and AST ≤ 2.5 x upper limit of normality (ULN) (≤ 5 in case of liver metastasis)
3. Total bilirubin ≤ 1.5 x ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels ≥ 1.5 x ULN
4. Albumin ≥ 25g/l
5. Serum creatinine ≤ 1.5 x ULN OR CrCl ≥ 60 ml/min for subject with creatinine levels ≥ 1.5 x ULN,
6. Creatine phosphokinase ≤ 2.5 x ULN
7. INR ≤ 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
8. aPTT ≤ 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
15. No prior or concurrent malignant disease diagnosed or treated in the last 2 years except for adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma.
16. At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy.
17. Recovery to grade ≤ 1 from any adverse event from previous treatment (excluding alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2 (NCI-CTCAE, v 4.0).
18. Women of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for four months after discontinuation of treatment. Acceptable methods for contraception include intrauterine device, oral contraceptive, subdermal implant and double barrier. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for ≥ 1 year.
19. Voluntary signed and dated written informed consents prior to any specific study procedure.
20. Patients with a French social security in compliance with the Law relating to biomedical research (Article 1121-11 of French Public Health Code).
Exclusion Criteria
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
3. Evidence of progressive or symptomatic central nervous system (CNS) or leptomeningeal metastases.
4. Men or women of childbearing potential who are not using an effective method of contraception as previously described; women who are pregnant or breast feeding.
5. Participation to a study involving a medical or therapeutic intervention in the last 30 days.
6. Previous enrolment in the present study.
7. Patient unable to follow and comply with the study procedures because of any geographical, familial, social or psychological reasons.
8. Known hypersensitivity to any involved study drug or of its formulation components.
9. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study.
10. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
11. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
12. Has known active hepatitis B or hepatitis C.
13. Has a known history of HIV (HIV1/2 antibodies).
14. Has received a live vaccine within 30 days prior to the first dose of trial treatment.
15. For strata 6 to 7:
* patients with oral anticoagulation therapy
* known urinary tract obstruction
* previous allogenic bone marrow transplant
* has an active infection requiring systemic treatment within 14 days prior to study
18 Years
ALL
No
Sponsors
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Merck Sharp & Dohme LLC
INDUSTRY
Ministry of Health, France
OTHER_GOV
Immune Design, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
INDUSTRY
Institut Bergonié
OTHER
Responsible Party
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Principal Investigators
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Antoine ITALIANO, MD, PhD
Role: STUDY_CHAIR
Institut Bergonié
Locations
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Institut Bergonié
Bordeaux, , France
Centre Oscar Lambret
Lille, , France
Centre Léon Bérard
Lyon, , France
Institut Paoli Calmettes
Marseille, , France
Institut Curie
Paris, , France
Institut de Cancérologie de l'Ouest
Saint-Herblain, , France
Institut Claudius Regaud
Toulouse, , France
Institut Gustave Roussy
Villejuif, , France
Countries
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References
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Toulmonde M, Penel N, Adam J, Chevreau C, Blay JY, Le Cesne A, Bompas E, Piperno-Neumann S, Cousin S, Grellety T, Ryckewaert T, Bessede A, Ghiringhelli F, Pulido M, Italiano A. Use of PD-1 Targeting, Macrophage Infiltration, and IDO Pathway Activation in Sarcomas: A Phase 2 Clinical Trial. JAMA Oncol. 2018 Jan 1;4(1):93-97. doi: 10.1001/jamaoncol.2017.1617.
Italiano A, Bessede A, Pulido M, Bompas E, Piperno-Neumann S, Chevreau C, Penel N, Bertucci F, Toulmonde M, Bellera C, Guegan JP, Rey C, Sautes-Fridman C, Bougouin A, Cantarel C, Kind M, Spalato M, Dadone-Montaudie B, Le Loarer F, Blay JY, Fridman WH. Pembrolizumab in soft-tissue sarcomas with tertiary lymphoid structures: a phase 2 PEMBROSARC trial cohort. Nat Med. 2022 Jun;28(6):1199-1206. doi: 10.1038/s41591-022-01821-3. Epub 2022 May 26.
Spalato-Ceruso M, Bouteiller F, Guegan JP, Toulmonde M, Bessede A, Kind M, Cousin S, Buy X, Palussiere J, Le Loarer F, Dadone-Montaudie B, Pulido M, Italiano A. Pembrolizumab combined with low-dose cyclophosphamide and intra-tumoral injection of the toll-like receptor 4 agonist G100 in patients with advanced pretreated soft tissue sarcoma: results from the PEMBROSARC basket study. J Hematol Oncol. 2022 Oct 27;15(1):157. doi: 10.1186/s13045-022-01377-2.
Sun CM, Toulmonde M, Spalato-Ceruso M, Peyraud F, Bessede A, Kind M, Cousin S, Buy X, Palussiere J, Bougouin A, Sautes-Fridman C, Fridman HW, Pulido M, Italiano A. Impact of metronomic trabectedin combined with low-dose cyclophosphamide on sarcoma microenvironment and correlation with clinical outcome: results from the TARMIC study. Mol Cancer. 2024 Feb 19;23(1):37. doi: 10.1186/s12943-024-01942-y.
Le Cesne A, Marec-Berard P, Blay JY, Gaspar N, Bertucci F, Penel N, Bompas E, Cousin S, Toulmonde M, Bessede A, Fridman WH, Sautes-Fridman C, Kind M, Le Loarer F, Pulido M, Italiano A. Programmed cell death 1 (PD-1) targeting in patients with advanced osteosarcomas: results from the PEMBROSARC study. Eur J Cancer. 2019 Sep;119:151-157. doi: 10.1016/j.ejca.2019.07.018. Epub 2019 Aug 21.
Hattinger CM, Patrizio MP, Magagnoli F, Luppi S, Serra M. An update on emerging drugs in osteosarcoma: towards tailored therapies? Expert Opin Emerg Drugs. 2019 Sep;24(3):153-171. doi: 10.1080/14728214.2019.1654455. Epub 2019 Aug 14.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Other Identifiers
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2014-004568-39
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
IB 2014-04
Identifier Type: -
Identifier Source: org_study_id
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