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Trial record 1 of 1 for:    NCT02406781
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Combination of MK3475 and Metronomic Cyclophosphamide in Patients With Advanced Sarcomas : Multicentre Phase II Trial (PEMBROSARC)

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2016 by Institut Bergonié
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
Ministry of Health, France
Information provided by (Responsible Party):
Institut Bergonié
ClinicalTrials.gov Identifier:
NCT02406781
First received: March 12, 2015
Last updated: November 8, 2016
Last verified: November 2016
  Purpose
This is a multicenter study assessing efficacy of the MK 3475 (Pembrolizumab) in combination with metronomic cyclophosphamide in patients with advanced sarcomas.

Condition Intervention Phase
Sarcoma
Drug: Combination of MK3475 with Metronomic CP
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Combination of MK3475 and Metronomic Cyclophosphamide in Patients With

Resource links provided by NLM:


Further study details as provided by Institut Bergonié:

Primary Outcome Measures:
  • Assessment of the efficacy of MK3476 associated with Metronomic Cyclophosphamide per RECIST v1.1 criteria [ Time Frame: 6 months ]

    This primary objective of this study is to assess the efficacy of MK3475 and Metronomic

    Cyclophosphamide (CP) independently for 5 strata as per RECIST v1.1 criteria :

    In terms of 6-month objective response and 6-months non progression for:

    • Advanced leiomyosarcoma
    • Advanced undifferentiated sarcoma
    • Advanced other sarcoma
    • Advanced osteosarcoma

    In terms of·6-month non progression for:

    Advanced GIST



Secondary Outcome Measures:
  • Efficacy of MK3475 and Metronomic CP in terms of Best overall response [ Time Frame: participants will be followed for the duration of treatment, an expected average of 6-months ]
    Assessment of the efficacy of MK3475 and Metronomic CP in terms of best overall response (as per RECIST v1.1 criteria)

  • Efficacy of MK3475 and Metronomic CP in terms of Progression-free Survival [ Time Frame: Progression-free survival assessed at 12 months ]
    Assessment of the efficacy of MK3475 and Metronomic CP in terms of 1-year progression-free survival (as per RECIST v1.1 criteria)

  • Efficacy of MK3475 and Metronomic CP in terms of Immune_related Response [ Time Frame: Immune-related response assessed at 6 months ]
    Assessment of the efficacy of MK3475 and Metronomic CP in terms of 6-months immune-related response (as per Wolchok 2009)

  • Efficacy of MK3475 and Metronomic CP in terms of Overall Survival. [ Time Frame: Overall survival assessed at 12 months ]
    Assessment of the efficacy of MK3475 and Metronomic CP in terms of 1-year overall survival

  • Exploration of blood cytokines levels (TNFγ, TNFα, TGFβ, IL2, 4, 6, 10) (ELISA) [ Time Frame: Blood samples collected at different time points : Baseline, Day 8 cycle 1, Day 8 cycle 2, Day 8 cycle 3, Day 8 cycle 4, Day 8 Cycle 6 and at progression ]
  • Exploration of blood VEGF, Svegfr2 and TPS-1 levels (ELISA) [ Time Frame: Blood samples collected at different time points : Baseline, Day 8 cycle 1, Day 8 cycle 2, Day 8 cycle 3, Day 8 cycle 4, Day 8 Cycle 6 and at progression ]
  • Exploration of lymphocytes subpopulations monitoring, CD8+/Treg ratio (flow cytometry) [ Time Frame: Blood samples collected at different time points : Baseline, Day 8 cycle 1, Day 8 cycle 2, Day 8 cycle 3, Day 8 cycle 4, Day 8 Cycle 6 and at progression ]
  • Exploration of Plasma levels of Kynurenine and Kynurenine to Tryptophan ratio (ELISA and LC/MS) [ Time Frame: Blood samples collected at different time points : Baseline, Day 8 cycle 1, Day 8 cycle 2, Day 8 cycle 3, Day 8 cycle 4, Day 8 Cycle 6 and at progression ]

Estimated Enrollment: 163
Study Start Date: March 2015
Estimated Study Completion Date: March 2018
Estimated Primary Completion Date: March 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Combination of MK3475 with Metronomic CP
Combination of MK3475 with Metronomic CP. 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 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 Name: Pembrolizumab, Endoxan

Detailed Description:

This is a phase 2 trial with 5 strata :

  • Leiomyosarcoma : 33 patients
  • Undifferentiated sarcoma : 33 patients
  • Sarcomas others : 33 patients
  • Osteosarcoma : 33 patients
  • GIST : 31 patients
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histology : Leiomyosarcoma, or UPS, or other sarcoma, or GIST or osteosarcoma, histologically confirmed by central review
  2. Advanced non resectable / metastatic disease
  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 from an archival tissue sample obtained on metastasis or on locally advanced disease, or newly obtained core or excisional biopsy of a tumor lesion
  6. For strata 1, 2 and 3: no more of four previous lines of systemic therapy for metastatic disease
  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
  11. ≥ 1 previous line (s) of chemotherapy in the palliative setting
  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, lymphocyte count ≥ 1.109 /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
  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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02406781

Contacts
Contact: Antoine ITALIANO, MD, PhD a.italiano@bordeaux.unicancer.fr
Contact: Simone Mathoulin-Pelissier, MD,PhD s.mathoulin-pelissier@bordeaux.unicancer.fr

Locations
France
Institut Bergonié Recruiting
Bordeaux, France, 33076
Contact: Antoine ITALIANO, MD         
Principal Investigator: Antoine ITALIANO         
Centre Oscar Lambret Recruiting
Lille, France, 59020
Contact: Nicolas Penel         
Principal Investigator: Nicolas Penel         
Centre Léon Bérard Recruiting
Lyon, France, 69373
Contact: Jean-Yves BLAY, MD-PHD         
Principal Investigator: Jean-Yves BLAY, MD-PHD         
Institut Paoli Calmettes Recruiting
Marseille, France, 13273
Contact: François BERTUCCI         
Principal Investigator: François BERTUCCI         
Institut Curie Recruiting
Paris, France, 75005
Contact: Sophie Piperno-Neumann         
Principal Investigator: Sophie Piperno-Neumann         
Institut de Cancérologie de l'Ouest Recruiting
Saint-Herblain, France, 44805
Contact: Emmanuelle BOMPAS, MD         
Principal Investigator: Emmanuelle BOMPAS, MD         
Institut Claudius Regaud Recruiting
Toulouse, France, 31052
Contact: Christine CHEVREAU         
Principal Investigator: Christine CHEVREAU         
Institut Gustave Roussy Recruiting
Villejuif, France, 94800
Contact: Axel LE CESNE         
Principal Investigator: Axel Le CESNE         
Sponsors and Collaborators
Institut Bergonié
Merck Sharp & Dohme Corp.
Ministry of Health, France
Investigators
Study Chair: Antoine ITALIANO, MD, PhD Institut Bergonié
  More Information

Responsible Party: Institut Bergonié
ClinicalTrials.gov Identifier: NCT02406781     History of Changes
Other Study ID Numbers: IB 2014-04
Study First Received: March 12, 2015
Last Updated: November 8, 2016

Keywords provided by Institut Bergonié:
Efficacy of MK 3475 with Metronomic Cyclophosphamide
Advanced Sarcomas
Leiomyosarcoma
Undifferentiated Sarcoma
Other Sarcoma
GIST
Osteosarcoma

Additional relevant MeSH terms:
Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Cyclophosphamide
Pembrolizumab
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists

ClinicalTrials.gov processed this record on March 23, 2017