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

NCT02406781 | Completed Phase 2 Results DMC

• 2 other identifiers: IB 2014-042014-004568-39
• Study Type: interventional
• Target: 129
• Locations: 1 country
• Sites: 8

Brief Summary

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

Conditions

Sarcoma

Keywords

Efficacy of MK 3475 with Metronomic Cyclophosphamide; Advanced Sarcomas; Leiomyosarcoma; Undifferentiated Sarcoma; Other Sarcoma; GIST; Osteosarcoma

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (3)

• Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1.

  6 months from treatment initiation

• Median Progression-free Survival

  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

  From start of treatment, and during treatment until death for any cause for up to 30 months

Study Arms (7)

Stratum 1: Advanced Leiomyosarcoma

EXPERIMENTAL

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

Stratum 2: Advanced undifferentiated sarcoma

EXPERIMENTAL

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

Stratum 3: Advanced other sarcoma

EXPERIMENTAL

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

Stratum 4: Advanced osteosarcoma

EXPERIMENTAL

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

Stratum 5: Advanced GIST

EXPERIMENTAL

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

Stratum 6: Advanced soft-tissue sarcomas with immune signature

EXPERIMENTAL

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

Stratum 7: Metastatic soft-tissue sarcoma.

EXPERIMENTAL

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

Interventions

Combination of MK3475 with Metronomic CP DRUG

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.

Also known as: Pembrolizumab, Endoxan

Stratum 1: Advanced Leiomyosarcoma; Stratum 2: Advanced undifferentiated sarcoma; Stratum 3: Advanced other sarcoma; Stratum 4: Advanced osteosarcoma; Stratum 5: Advanced GIST; Stratum 6: Advanced soft-tissue sarcomas with immune signature

Combination of MK3475 with Metronomic CP and G100 DRUG

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.

Also known as: Pembrolizumab, Endoxan, GLA-SE (glucopyranosyl lipid adjuvant-stable emulsion).

Stratum 7: Metastatic soft-tissue sarcoma.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Advanced non resectable / metastatic disease for strata 1 to 6. For stratum 7: locally advanced or metastatic disease with at least one injectable lesion.
• For stratum 5, documented disease progression according to RECIST criteria after the first line imatinib and second line sunitinib.
• 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.
• 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.
• Age ≥ 18 years.
• ECOG performance status ≤ 1.
• Measurable disease according to RECIST v1.1 outside any previously irradiated field. At least one site of disease must be uni-dimensionally ≥ 10 mm.
• Life expectancy \> 3 months (except for stratum 7 \> 6 months).
• ≥ 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.
• No symptomatic central nervous system disease.
• No chronic use of glucocorticoids.
• Adequate hematological, renal, metabolic and hepatic function:
• 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
• ALT and AST ≤ 2.5 x upper limit of normality (ULN) (≤ 5 in case of liver metastasis)

You may not qualify if:

• Previous treatment with MK3475 or CP or G100.
• 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).
• Evidence of progressive or symptomatic central nervous system (CNS) or leptomeningeal metastases.
• 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.
• Participation to a study involving a medical or therapeutic intervention in the last 30 days.
• Previous enrolment in the present study.
• Patient unable to follow and comply with the study procedures because of any geographical, familial, social or psychological reasons.
• Known hypersensitivity to any involved study drug or of its formulation components.
• 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.
• 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.
• 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.
• Has known active hepatitis B or hepatitis C.
• Has a known history of HIV (HIV1/2 antibodies).
• Has received a live vaccine within 30 days prior to the first dose of trial treatment.
• For strata 6 to 7:

Sponsors & Collaborators

• Institut Bergonié: lead
• Merck Sharp & Dohme LLC: collaborator
• Ministry of Health, France: collaborator
• Immune Design, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA): collaborator

Study Sites (8)

Institut Bergonié

Bordeaux, 33076, France

Location

Centre Oscar Lambret

Lille, 59020, France

Location

Centre Léon Bérard

Lyon, 69373, France

Location

Institut Paoli Calmettes

Marseille, 13273, France

Location

Institut Curie

Paris, 75005, France

Location

Institut de Cancérologie de l'Ouest

Saint-Herblain, 44805, France

Location

Institut Claudius Regaud

Toulouse, 31052, France

Location

Institut Gustave Roussy

Villejuif, 94800, France

Location

Related Publications (6)

• 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.

  PMID: 28662235 RESULT

• 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.

  PMID: 35618839 RESULT

• 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.

  PMID: 36303228 RESULT

• 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.

  PMID: 38374062 DERIVED

• 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.

  PMID: 31442817 DERIVED

• 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.

  PMID: 31401903 DERIVED

MeSH Terms

Conditions

Sarcoma; Leiomyosarcoma; Osteosarcoma

Interventions

pembrolizumab; Cyclophosphamide; TLR4 agonist G100

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Muscle Tissue; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Results Point of Contact

• Title: Pr Antoine Italiano
• Organization: Institut Bergonie

a.italiano@bordeaux.unicancer.fr

0524071947

Study Officials

• Antoine ITALIANO, MD, PhD

  Institut Bergonié

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 12, 2015
• First Posted: April 2, 2015
• Study Start: June 1, 2015
• Primary Completion: November 24, 2020
• Study Completion: January 15, 2023
• Last Updated: December 10, 2025
• Results First Posted: December 10, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

FR (8)