Patient case: 49-year-old female with lung cancer; genetic feature: ERBB2

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

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).

Eligibility: 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.

Relevance to patient case: not relevant