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A Study of Metronomic CP and JX-594 in Patients With Advanced Breast Cancer and Advanced Soft-tissue Sarcoma (METROmaJX) (METROmaJX)

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ClinicalTrials.gov Identifier: NCT02630368
Recruitment Status : Recruiting
First Posted : December 15, 2015
Last Update Posted : October 2, 2017
Sponsor:
Collaborators:
National Cancer Institute, France
Fondation ARC
Information provided by (Responsible Party):
Institut Bergonié

Tracking Information
First Submitted Date  ICMJE November 19, 2015
First Posted Date  ICMJE December 15, 2015
Last Update Posted Date October 2, 2017
Study Start Date  ICMJE September 2015
Estimated Primary Completion Date September 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 10, 2015)
  • Phase Ib : Maximum Tolerated Dose evaluated on the first cycle (D1 to D28) of the combination of JX-594 And metronomic cyclophosphamide [ Time Frame: during the first cycle (28 days) ]
  • Phase II : Advanced soft-tissue sarcoma: Assessment of the antitumor activity of the association of JX-594 and metronomic cyclophosphamide based on 6 month non-progression (CR, PR or SD more than 24 weeks) following RECIST v1.1 criteria [ Time Frame: Phase II : 6 months after the beginning of treatment ]
  • Phase II : Advanced Breast cancer: Assessment of the antitumor activity of the association of JX-594 and metronomic cyclophosphamide Efficacy will be defined based on objective response under treatment (CR or PR) following RECIST v1.1 criteria [ Time Frame: Phase II : 6 months after the beginning of treatment ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02630368 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 10, 2015)
  • Phase Ib : Recommended Phase II dose (RP2D) of the association of JX-594 and metronomic cyclophosphamide [ Time Frame: Phase Ib : Throughout the 6 months of treatment period ]
  • Phase Ib: Objective response under treatment as per RECIST V1.1 [ Time Frame: an average of 6 months ]
  • Phase Ib: Best overall response as per RECIST V1.1 [ Time Frame: an average of 6 months ]
  • Phase Ib: 6-months non-progression as per RECIST V1.1 [ Time Frame: 6-months after the beginning of treatment ]
  • Phase Ib: 1-year progression-free survival as per RECIST V1.1 [ Time Frame: 1-year after the beginning of treatment ]
  • Phase Ib: 2-year progression-free survival as per RECIST V1.1 [ Time Frame: 2-year after the beginning of treatment ]
  • Phase Ib : Pharmacokinetics (PK): PK measurements expressed as Area Under the curve forJX-594 [ Time Frame: Day 8 of cycle 1, Day 15 of cycle 1, Day 22 of cycle 1, Day 1 of cycle 2, Day 8 of cycle 2, Day 22 of cycle 2, Day 8 of cycle 3, Day 8 of cycle 4, Day 8 of cycle 6 (Each cycle = 28 days) ]
  • Phase Ib : Pharmacokinetics (PK): PK measurements expressed as half-life forJX-594 [ Time Frame: Day 8 of cycle 1, Day 15 of cycle 1, Day 22 of cycle 1, Day 1 of cycle 2, Day 8 of cycle 2, Day 22 of cycle 2, Day 8 of cycle 3, Day 8 of cycle 4, Day 8 of cycle 6 (Each cycle = 28 days) ]
  • Phase Ib : Pharmacokinetics (PK): PK measurements expressed as Concentration peak forJX-594 [ Time Frame: Day 8 of cycle 1, Day 15 of cycle 1, Day 22 of cycle 1, Day 1 of cycle 2, Day 8 of cycle 2, Day 22 of cycle 2, Day 8 of cycle 3, Day 8 of cycle 4, Day 8 of cycle 6 (Each cycle = 28 days) ]
  • Phase Ib : Dose-Limiting toxicity of the association of JX-594 and metronomic cyclophosphamide [ Time Frame: during the first cycle (cycle = 28 days) ]
  • Phase Ib : Predictive biomarkers analysis (cytokines levels) [ Time Frame: baseline, day 8 of cycle 1, day 22 of cycle 1, day 8 of cycle 2, day 8 of cycle 4, day 8 of cycle 6. Each cycle = 28 days ]
  • Phase Ib : Predictive biomarkers analysis (lymphocytes levels) [ Time Frame: baseline, day 8 of cycle 1, day 22 of cycle 1, day 8 of cycle 2, day 8 of cycle 4, day 8 of cycle 6. Each cycle = 28 days ]
  • Phase II : Best overall response defined as per RECIST v1.1 criteria [ Time Frame: an average of 6 months ]
  • Phase II : For sarcoma only: objective response following CHOI criteria [ Time Frame: an average of 6 months ]
  • Phase II : For sarcoma only: best overall response following CHOI criteria [ Time Frame: an average of 6 months ]
  • Phase II : For sarcoma only: 6- month non-progression following CHOI criteria [ Time Frame: 6-months after the beginning of treatment ]
  • Phase II : 1-year Progression-Free Survival (PFS) defined as the time from study treatment initiation to the first occurrence of disease progression or death (of any cause), whichever occurs first [ Time Frame: one year after the beginning of treatment ]
  • Phase II : 2-year Progression-Free Survival (PFS) defined as the time from study treatment initiation to the first occurrence of disease progression or death (of any cause), whichever occurs first [ Time Frame: two years the beginning of treatment ]
  • Phase II : 1-year Overall Survial (OS) defined as the time from study treatment initiation to death (of any cause) [ Time Frame: one year after the beginning of treatment ]
  • Phase II : 2-year Overall Survial (OS) defined as the time from study treatment initiation to death (of any cause) [ Time Frame: two year after the beginning of treatment ]
  • Phase II : Toxicity graded using the common toxicity criteria from the NCI v4.0 [ Time Frame: an average of 6 months ]
  • Predictive biomarkers (cytokines level) [ Time Frame: baseline, day 8 of cycle 1, day 22 of cycle 1, day 8 of cycle 2, day 8 of cycle 4, day 8 of cycle 6. Each cycle = 28 days ]
  • Predictive biomarkers (lymphocytes level) [ Time Frame: baseline, day 8 of cycle 1, day 22 of cycle 1, day 8 of cycle 2, day 8 of cycle 4, day 8 of cycle 6. Each cycle = 28 days ]
  • Phase II : Relationship between levels of anti-JX-594 antibodies and efficacy of CP + JX-594 in terms of 6-month non progression for sarcoma (as per RECIST V1.1) [ Time Frame: Six months after the beginning of treatment ]
  • Phase II : Relationship between levels of anti-JX-594 antibodies and efficacy of CP + JX-594 in terms of objective response for breast cancer (as per RECIST V1.1) [ Time Frame: an average of 6 months ]
  • Phase II : Relationship between activation of the pRB/E2F/TK pathway and efficacy of CP + JX-594 on available archived tumor tissue in terms of 6- month non progression for sarcoma (as per RECIST V1.1) [ Time Frame: Phase II : Six months after the beginning of treatment ]
  • Phase II : Relationship between activation of the pRB/E2F/TK pathway and efficacy of CP + JX-594 on available archived tumor tissue in terms objective response for breast cancer (as per RECIST V1.1) [ Time Frame: an average of 6 months ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Metronomic CP and JX-594 in Patients With Advanced Breast Cancer and Advanced Soft-tissue Sarcoma (METROmaJX)
Official Title  ICMJE A Phase I/II Study of Metronomic Cyclophosphamide and Oncolytic Poxvirus JX-594 in Patients With Advanced Breast Cancer and Advanced Soft Tissue Sarcoma (METROmaJX)
Brief Summary

Assessment of the efficacy and safety of JX-594 and metronomic cyclophosphamide in patients with advanced soft-tissue sarcoma and advanced breast cancer, once the Maximum Tolerated Dose have been determined (phase I trial).

Phase I study: this is a prospective open-labeled phase I trial based on a dose escalating study design assessing two dose levels of JX594 when prescribed in combination with metronomic cyclophosphamide.

Phase II study sarcoma: this is a monocentric, randomized two-arm non comparative phase 2 study assessing efficacy and safety of JX-594 in association with metronomic cyclophosphamide in patients with advanced soft-tissue sarcoma.

Phase II study breast cancer: this is a monocentric, single-arm phase II study, assessing efficacy and safety of JX-594 in association with metronomic cyclophosphamide in patients with advanced breast cancer.

Detailed Description

For the phase I study, this is a prospective open-label phase I trial based on a dose escalating study design assessing two dose level of JX-594 when associated to metronomic cyclophosphamide.

For the phase II study, stratum soft-tissue sarcoma, this is a monocenter, randomized non comparative phase II clinical trial. This phase II trial was based on an optimal 2-stage Simon's design. Randomization 2:1 with 2 patients randomized in experimental arm n°1 (association of metronomic cyclophosphamide and JX-594) and 1 patient randomized in control arm n°2 (treatment by metronomic cyclophosphamide alone).

For the phase II study, stratum breast cancer, this is a monocenter, one-arm phase II clinical trial, based on two-stage optimal Simon's design (association of metronomic cyclophosphamide and JX-594).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Solid Tumors
  • Soft-tissue Sarcoma
  • Breast Cancer
Intervention  ICMJE
  • Drug: Cyclophosphamide and JX-594 dose escalation
    Metronomic cyclophosphamide will be administered orally, 50 mg twice daily, one week on/one week off. JX-594 will be administered, as designated by assigned dose-level, intraveinously, on Days 8 and 22 of cycle 1, and on days 8 of each subsequent cycles. One cycle consits of 28 days.
    Other Names:
    • Brand name : ENDOXAN
    • Brand name: Pexa-Vec
  • Drug: Cyclophosphamide and JX-594
    Metronomic cyclophosphamide will be administered orally, 50 mg twice daily, one week on/one week off. JX-594 will be administered, as the dose recommended in the experimental phase I dose escalating study, intraveinously, on Days 8 and 22 of cycle 1, and on days 8 of each subsequent cycles. One cycle consits of 28 days.
    Other Names:
    • Brand name : ENDOXAN
    • Brand name: Pexa-Vec
  • Drug: Cyclophosphamide
    Metronomic cyclophosphamide will be administered orally, 50 mg twice daily, one week on/one week off.
    Other Name: Brand name : ENDOXAN
Study Arms  ICMJE
  • Experimental: Experimental phase I dose escalating

    Prospective open-labeled phase I trial.

    Combination of cyclophosphamide and JX-594 dose escalation. Metronomic cyclophosphamide will be administered orally, 50 mg twice daily, one week on/one week off. JX-594 will be administered, as designated by assigned dose-level, intraveinously, on Days 8 and 22 of cycle 1, and on days 8 of each subsequent cycles. One cycle consits of 28 days.

    Number of subjects : 14

    Intervention: Drug: Cyclophosphamide and JX-594 dose escalation
  • Experimental: Experimental group soft-tissue sarcoma

    Randomized non comparative phase II clinical trial : Arm 1.

    Experimental phase II soft-tissue sarcoma :

    Combination of cyclophosphamide and JX-594. Metronomic cyclophosphamide will be administered orally, 50 mg twice daily, one week on/one week off. JX-594 will be administered, as the dose recommended in the experimental phase I dose escalating study, intraveinously, on Days 8 and 22 of cycle 1, and on days 8 of each subsequent cycles. One cycle consits of 28 days.

    Number of subjects : 48

    Intervention: Drug: Cyclophosphamide and JX-594
  • Experimental: Control group soft-tissue sarcoma

    Randomized non comparative phase II clinical trial : Arm 2.

    Control-arm phase II soft-tissue sarcoma :

    Patients will be treated by metronomic cyclophosphamide. Cyclophosphamide will be administered 50 mg twice daily orally, one week on/one week off. One cycle consits of 28 days.

    Number of subjects : 24

    Intervention: Drug: Cyclophosphamide
  • Experimental: Experimental group breast cancer

    Single-arm phase II clinical trial.

    Experimental phase II Group breast cancer :

    Combination of cyclophosphamide and JX-594. Metronomic cyclophosphamide will be administered orally, 50 mg twice daily, one week on/one week off. JX-594 will be administered, as the dose recommended in the experimental phase I dose escalating study, intraveinously, on Days 8 and 22 of cycle 1, and on days 8 of each subsequent cycles. One cycle consits of 28 days.

    Number of subjects : 32

    Intervention: Drug: Cyclophosphamide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 10, 2015)
118
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2020
Estimated Primary Completion Date September 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Histology:

    • Phase Ib : Patient with histologically confirmed solid tumor
    • Phase II :

      • Patients with histologically confirmed HER2 negative breast cancer
      • Patients with histologically confirmed soft tissue sarcoma (list of accepted histologies in Appendix 1)

        1. Histologically confirmed by central review (Pr. Coindre team), except if the diagnosis was already confirmed by the RRePS Network,
        2. Progressive disease or relapse, after standard therapy according to RECIST v1.1 criteria diagnosed on the basis of two CT scan or MRI obtained at an interval less than 6 months in the period of 12 months prior to inclusion and confirmed by central review
  2. Metastatic or unresectable locally advanced disease
  3. Age ≥ 18 years
  4. Eastern Cooperative Oncology Group (ECOG) performance status (PS)

    ≤ 1 (Phase Ib) and ≤ 2 (Phase II).

  5. Life expectancy > 3 months,
  6. Measurable disease according to RECIST v1.1 outside any previously irradiated field.
  7. At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy.
  8. Adequate hematological, renal, metabolic and hepatic function.

    1. Hemoglobin ≥ 10 g/dl (patients may have received prior red blood cell [RBC] transfusion, if clinically indicated); leucocytes ≥ 3 x 10puissance9/l, absolute neutrophil count (ANC) ≥ 1.2 x 10puissance9/l, lymphocytes count ≥ 1.0 x 10puissance9/l and platelet count ≥ 100 x 10puissance9/l.
    2. Alkaline phosphatase (AP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normality (ULN) (≤ 5 in case of extensive skeletal involvement for AP exclusively) and < 5 x ULN for AST and ALT in case of liver metastasis.
    3. Total bilirubin ≤ 1.5 x ULN.
    4. Albumin ≥ lower limit normal value.
    5. Calculated creatinine clearance (CrCl) ≥ 40 ml/min (according to Cockroft and Gault formula).
  9. Women of childbearing potential must have a negative serum pregnancy test before study entry. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for six months after discontinuation of treatment. Acceptable methods of contraception include intrauterine device (IUD), oral contraceptive, subdermal implant and double barrier.
  10. Patients receiving any substances that are inhibitors or inducers of CYP450 2B6 are ineligible (non-exhaustive indicative list on Appendix 7, for further information see http://medicine.iupui.edu/clinpharm/ddis/table.aspx). As part of the enrolment/informed consent procedures, the patient will be counselled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
  11. Voluntarily signed and dated written informed consent prior to any study specific procedure.
  12. Patients with a french social security in compliance with the French law relating to biomedical research (Huriet Law 88-1138 and related decrees).

Exclusion Criteria:

  1. Previous treatment with JX-594 or other vaccina vector based treatment.
  2. Concomitant diseases/conditions:

    1. Clinically significant immunodeficiency, such as HIV or active Hepatite B or C
    2. Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in this study.
    3. History of severe exfoliative skins condition requiring systemic treatment for more than 4 weeks in the last two years.
  3. Active central nervous system metastasis (CNS)
  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, social or psychological reasons.
  8. Known hypersensitivity to any involved study drug or any of its formulation components.
  9. Use of interferon/pegylated interferon or ribavirin that cannot be discontinued within 14 days prior to any Pexa-Vec dose, Medical Monitor should be contacted if patient is taking any other anti-viral medications to determine eligibility.
  10. No prior malignancy except for the following: adequately treated basal or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage 1 or Stage 2 cancer from which the patient is currently in complete remission or any other cancer from which the patient has been disease-free for 3 years.
  11. Active cardiovascular disease, including but not limited to significant coronary artery disease (e.g. requiring angioplasty or stenting) or congestive heart failure within the preceding 12 months. (Note: for patients with a present or past history of cardiovascular disease, cardiology consultation and clearance must be obtained).
  12. Inability to suspend treatment with anti-hypertensive medication (including but not limited to: diuretics, beta-blockers, angiotensin converting enzyme [ACE] inhibitors, aldosterone antagonists, etc.) for 48 hours prior to and 48 hours after all JX-594 treatments.
  13. Pulse oximetry O2 saturation < 90% at rest on room air.
  14. Experienced a severe systemic reaction or side-effect as result of previous smallpox vaccination.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Antoine ITALIANO, MD, PhD +33 524071947 a.italiano@bordeaux.unicancer.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02630368
Other Study ID Numbers  ICMJE IB 2014-02
2014-001078-33 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Institut Bergonié
Study Sponsor  ICMJE Institut Bergonié
Collaborators  ICMJE
  • National Cancer Institute, France
  • Fondation ARC
Investigators  ICMJE
Study Chair: Antoine ITALIANO, MD, PhD Institut Bergonié
PRS Account Institut Bergonié
Verification Date September 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP