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

Institut Bergonié

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Breast Cancer; Soft-tissue Sarcoma; Solid Tumors

Treatments: Drug: Cyclophosphamide and JX-594; Drug: Avelumab and JX-594 and Cyclophosphamide; Drug: Cyclophosphamide; Drug: Cyclophosphamide and JX-594 dose escalation

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT02630368

2014-001078-33 (EudraCT Number)

IB 2014-02

Details and patient eligibility

About

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 trials with two treatments strategies:

Metronomic CP + JX-594: 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.

Metronomic CP + JX-594: 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.

Metronomic CP + JX-594 + Avelumab: phase II study sarcoma: this is a monocentric, single arm phase II study assessing efficacy and safety of avelumab in combination with IT JX-594 and metronomic cyclophosphamide in patients with advanced soft-tissue sarcoma.

Metronomic CP + JX-594 + Avelumab:: phase II study breast cancer: this is a monocentric, single-arm phase II study, assessing efficacy and safety of avelumab in combination with IT JX-594 and metronomic cyclophosphamide in patients with advanced breast cancer.

Full 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, two distincts treatment strategies will be evaluated.

First, treatment by JX-594 and metronomic cyclophosphamide:

• 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).
• 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).

Second, treatment by Avelumab, intratumoral JX-594 and metronomic cyclophosphamide:

• stratum soft-tissue sarcoma, this is a monocenter, single arm phase II clinical trial based on an optimal 2-stage Simon's design.
• stratum breast cancer, this is a monocenter, one-arm phase II clinical trial, based on two-stage optimal Simon's design).

Enrollment: 197 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Main Inclusion Criteria:

1. Histology:

   • Phase Ib : Patient with histologically confirmed solid tumor

   • Phase II :

     • Patients with histologically confirmed HER2 negative breast cancer (treatment by CP+JX-594), or triple negative (treatment by avelumab + CP+JX-594)
     • Patients with histologically confirmed soft tissue sarcoma confirmed by the RRePS Network, b)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. ECOG ≤ 1 (Phase Ib), ≤ 2 (Phase II JX+CP) and ≤ 1 (Phase II avelumab+JX+CP).

5. Life expectancy > 3 months,

6. Measurable disease according to RECIST v1.1 outside any previously irradiated field. For patients treated by avelumab+JX+CP, at least one injectable site ≥ 2 cm and ≤ 8 cm in diameter and one distant non-injected measurable site (target site)

7. At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy.

8. Adequate hematological, renal, metabolic and hepatic functions.

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.

10. Patients informed of risks regarding drug interactions: patients receiving any substances that are inhibitors or inducers of CYP450 2B6 are ineligible

11. Voluntarily signed and dated written informed consent prior to any study specific procedure.

12. Patients with a social security in compliance with the French law.

Main Exclusion Criteria:

1. Previous treatment with JX-594 or other vaccina vector based treatment .

2. Concomitant diseases/conditions (non exhaustive list):

   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.
   4. active autoimmune disease for patients treated by avelumab

3. Active central nervous system metastasis (CNS)

4. Participation to a study involving a medical or therapeutic intervention in the last 30 days.

5. Previous enrolment in the present study.

6. Patient unable to follow and comply with the study procedures because of any geographical, social or psychological reasons.

7. Known hypersensitivity to any involved study drug or any of its formulation components.

8. Use of steroids (any route of administration), interferon/pegylated interferon or ribavirin that cannot be discontinued within 14 days prior to any JX-594 dose.

9. 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.

10. 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. (treatment by CP+JX)

11. Inability to suspend treatment with anti-hypertensive medication for 48 hours prior to and 48 hours after all JX-594 treatments.

12. Pulse oximetry O2 saturation < 90% at rest on room air.

13. Experienced a severe systemic reaction or side-effect as result of previous smallpox vaccination.

14. Cardiac disease: LVEF out of normal limits ; cumulative dose of anthracyclines in excess of 450 mg/m²

15. Known urinary tract obstruction

16. Household contact exclusions for patients enrolled: children< 1 year old ; People with skin disease (e.g., eczema, atopic dermatitis and related diseases...), Immunocompromised hosts (severe deficiencies in cell-mediated immunity, including AIDS, organ transplant recipients, hematologic malignancies)

17. Vaccination within 4 weeks of the first dose of study treatment and while on trial is prohibited except for administration of inactivated vaccines.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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197 participants in 6 patient groups

Experimental phase I dose escalating

Experimental group

Description:

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

Treatment:

Drug: Cyclophosphamide and JX-594 dose escalation

Experimental group soft-tissue sarcoma, treatment by JX-594 + Metronomic cyclophosphamide

Experimental group

Description:

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

Treatment:

Drug: Cyclophosphamide and JX-594

Control group soft-tissue sarcoma, treatment by JX-594 + Metronomic cyclophosphamide

Experimental group

Description:

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

Treatment:

Drug: Cyclophosphamide

Experimental group breast cancer, treatment by JX-594 + Metronomic cyclophosphamide

Experimental group

Description:

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

Treatment:

Drug: Cyclophosphamide and JX-594

Experimental group soft-tissue sarcoma, treatment by Avelumab + ITJX-594 + Metronomic CP

Experimental group

Description:

Experimental phase II soft-tissue sarcoma : Combination of avelumab in combination with intratumoral JX-594 and metronomic cyclophosphamide. Avelumab will be administered by intravenous infusion every 2 weeks, starting at Day 15 of cycle 1. Cyclophosphamide wil be administered orally, 50 mg twice daily, one Week on/one Week off, starting 7 days prior to cycle 1 day 1 ("impregnation phase"). JX-594 will be administered by intratumoral injection on day 1 of cycle 1, every 2 weeks, for a maximum of 4 injections. Number of subjects : 47

Treatment:

Drug: Avelumab and JX-594 and Cyclophosphamide

Experimental group breast cancer, treatment by Avelumab + IT JX-594 + Metronomic CP

Experimental group

Description:

Experimental phase II breast cancer : Combination of avelumab in combination with intratumoral JX-594 and metronomic cyclophosphamide. Avelumab will be administered by intravenous infusion every 2 weeks, starting at Day 15 of cycle 1. Cyclophosphamide wil be administered orally, 50 mg twice daily, one Week on/one Week off, starting 7 days prior to cycle 1 day 1 ("impregnation phase"). JX-594 will be administered by intratumoral injection on day 1 of cycle 1, every 2 weeks, for a maximum of 4 injections. Number of subjects : 32

Treatment:

Drug: Avelumab and JX-594 and Cyclophosphamide