Combination of MK3475 and Metronomic Cyclophosphamide in Patients With Advanced Sarcomas : Multicentre Phase II Trial (PEMBROSARC)

This is a multicenter study assessing the efficacy of different therapeutic strategy in patients with advanced sarcomas.

Study Overview

• Status: Completed
• Conditions: Sarcoma
• Intervention / Treatment: Drug: Combination of MK3475 with Metronomic CP; Drug: Combination of MK3475 with Metronomic CP and G100

Detailed Description

This is a phase 2 trial with 7 strata :

• 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

• Study Type: Interventional
• Enrollment (Actual): 129
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Bordeaux, France, 33076
    • Institut Bergonie
  • Lille, France, 59020
    • Centre Oscar Lambret
  • Lyon, France, 69373
    • Centre Léon Bérard
  • Marseille, France, 13273
    • Institut Paoli Calmettes
  • Paris, France, 75005
    • Institut Curie
  • Saint-Herblain, France, 44805
    • Institut de cancerologie de l'ouest
  • Toulouse, France, 31052
    • Institut Claudius Regaud
  • Villejuif, France, 94800
    • Institut Gustave Roussy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Histology : Leiomyosarcoma, or UPS, or other sarcoma, or GIST or osteosarcoma, or soft-tissue sarcoma with presence of tertiary lymphoid structures (stratum 6) histologically confirmed by central review.
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:

1. Previous treatment with MK3475 or CP or G100.
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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: 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.; Other Names: Pembrolizumab, Endoxan
Experimental: 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.	Drug: 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.; Other Names: Pembrolizumab, Endoxan
Experimental: 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.	Drug: 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.; Other Names: Pembrolizumab, Endoxan
Experimental: 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.	Drug: 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.; Other Names: Pembrolizumab, Endoxan
Experimental: 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.	Drug: 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.; Other Names: Pembrolizumab, Endoxan
Experimental: 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.	Drug: 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.; Other Names: Pembrolizumab, Endoxan
Experimental: 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.	Drug: 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 Names: Pembrolizumab, Endoxan, GLA-SE (glucopyranosyl lipid adjuvant-stable emulsion).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants in Objective Response at 6 Months	Objective response is defined according to RECIST v1.1 as either complete response (disappearance of all target lesions, with any pathological lymph nodes reduced in short axis to <10 mm) or partial response (≥30% decrease in the sum of diameters of target lesions compared with baseline). This primary endpoint is part of a dual endpoint encompassing both non-progression and objective response at 6 months (non-progression is presented as a separate primary outcome). ORR at 6 months will be evaluated only in the following strata: Stratum 1: Advanced leiomyosarcoma ; Stratum 2: Advanced undifferentiated sarcoma ; Stratum 3: Advanced other sarcoma ; Stratum 4: Advanced osteosarcoma	6 months from treatment initiation
Percentage of Particpants in Non-progression at 6 Months	Non-progression is defined as the absence of progressive disease according to RECIST v1.1. Progressive disease defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). This outcome will be assessed as a stand-alone primary endpoint in the following strata: Stratum 5: Advanced gastrointestinal stromal tumor (GIST) ; Stratum 6: Advanced soft tissue sarcomas with immune signature ; Stratum 7: Metastatic soft tissue sarcoma (STS) In strata 1 to 4, non-progression is considered as part of the dual primary endpoint together with objective response at 6 months.	6 months from treatment initiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1.	Best overall response is defined as the best response across all time points (RECIST v1.1). The best overall response is determined once all the data for the participant is known. Each patient has been assigned one of the following categories (RECIST 1.1): complete response (disappearance of all target lesions); partial response (>=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters); progression (20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) and stable disease (nor CR, PR or progression).	6 months from treatment initiation
Median Progression-free Survival	Progression-free survival (PFS) is defined as the time from study treatment initiation to the first occurrence of disease progression or death (of any cause), whichever occurs first. Progressive disease defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). Patients alive and progression free were censored at the date of last follow-up, death, or last patient contact. Progression is assessed as per RECIST v1.1. Progression-free survival is estimated as a function of time using Kaplan-Meier method.	From start of treatment, and during treatment until progression or death for any cause, whichever occurs first, for up to 12 months.
Median Overall Survival	Overall survival (OS) defined as the time from randomization to death (due to any cause). Patients alive were censored at the date of last follow-up or last patient contact. Overall survival was estimated as a function of time using Kaplan-Meier method.	From start of treatment, and during treatment until death for any cause for up to 30 months

Collaborators and Investigators

• Sponsor: Institut Bergonié
• Collaborators: Merck Sharp & Dohme LLC; Ministry of Health, France; Immune Design, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
• Investigators: Study Chair: Antoine ITALIANO, MD, PhD, Institut Bergonie

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2015
• Primary Completion (Actual): November 24, 2020
• Study Completion (Actual): January 15, 2023

Study Registration Dates

• First Submitted: March 12, 2015
• First Submitted That Met QC Criteria: April 1, 2015
• First Posted (Estimated): April 2, 2015

Study Record Updates

• Last Update Posted (Estimated): December 10, 2025
• Last Update Submitted That Met QC Criteria: November 24, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Osteosarcoma; GIST; Leiomyosarcoma; Efficacy of MK 3475 with Metronomic Cyclophosphamide; Advanced Sarcomas; Undifferentiated Sarcoma; Other Sarcoma
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Connective and Soft Tissue; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Muscle Tissue; Sarcoma; Leiomyosarcoma; Osteosarcoma; Organic Chemicals; Hydrocarbons; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Cyclophosphamide; pembrolizumab; TLR4 agonist G100
• Other Study ID Numbers: IB 2014-04; 2014-004568-39 (EudraCT Number)

Plan for Individual participant data (IPD)

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