Clinical Trials /

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

NCT02630368

Description:

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.

Related Conditions:
  • Breast Carcinoma
  • Malignant Solid Tumor
  • Soft Tissue Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: IB 2014-02
  • SECONDARY ID: 2014-001078-33
  • NCT ID: NCT02630368

Conditions

  • Solid Tumors
  • Soft-tissue Sarcoma
  • Breast Cancer

Interventions

DrugSynonymsArms
Cyclophosphamide and JX-594 dose escalationBrand name : ENDOXAN, Brand name: Pexa-VecExperimental phase I dose escalating
Cyclophosphamide and JX-594Brand name : ENDOXAN, Brand name: Pexa-VecExperimental group soft-tissue sarcoma
CyclophosphamideBrand name : ENDOXANControl group soft-tissue sarcoma

Purpose

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).
    

Trial Arms

NameTypeDescriptionInterventions
Experimental phase I dose escalatingExperimentalProspective 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
  • Cyclophosphamide and JX-594 dose escalation
Experimental group soft-tissue sarcomaExperimentalRandomized 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
  • Cyclophosphamide and JX-594
Control group soft-tissue sarcomaExperimentalRandomized 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
  • Cyclophosphamide
Experimental group breast cancerExperimentalSingle-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
  • Cyclophosphamide

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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)
Safety Issue:
Description:

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:
Measure:Phase Ib: Objective response under treatment as per RECIST V1.1
Time Frame:an average of 6 months
Safety Issue:
Description:
Measure:Phase Ib: Best overall response as per RECIST V1.1
Time Frame:an average of 6 months
Safety Issue:
Description:
Measure:Phase Ib: 6-months non-progression as per RECIST V1.1
Time Frame:6-months after the beginning of treatment
Safety Issue:
Description:
Measure:Phase Ib: 1-year progression-free survival as per RECIST V1.1
Time Frame:1-year after the beginning of treatment
Safety Issue:
Description:
Measure:Phase Ib: 2-year progression-free survival as per RECIST V1.1
Time Frame:2-year after the beginning of treatment
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure:Phase Ib : Dose-Limiting toxicity of the association of JX-594 and metronomic cyclophosphamide
Time Frame:during the first cycle (cycle = 28 days)
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:Phase II : Best overall response defined as per RECIST v1.1 criteria
Time Frame:an average of 6 months
Safety Issue:
Description:
Measure:Phase II : For sarcoma only: objective response following CHOI criteria
Time Frame:an average of 6 months
Safety Issue:
Description:
Measure:Phase II : For sarcoma only: best overall response following CHOI criteria
Time Frame:an average of 6 months
Safety Issue:
Description:
Measure:Phase II : For sarcoma only: 6- month non-progression following CHOI criteria
Time Frame:6-months after the beginning of treatment
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:Phase II : Toxicity graded using the common toxicity criteria from the NCI v4.0
Time Frame:an average of 6 months
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Institut Bergonié

Trial Keywords

  • Advanced Soft-tissue Sarcoma
  • Advanced Breast Cancer
  • Maximum Tolerated Dose
  • Efficacy and safety

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