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
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).
- 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
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
11. Voluntarily signed and dated written informed consent prior to any study specific
12. Patients with a french social security in compliance with the French law relating to
biomedical research (Huriet Law 88-1138 and related decrees).
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
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
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
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