The study is a proof of concept, open label, multicentric, 2-parts, Phase I dose escalation
trial. In dose selection part (any histological types except HCC), patients will be treated
with an IT boost injection with Pexa-Vec (fixed dose of 1x109 pfu / injection ) alone at Week
1 followed by IT injections of Pexa-Vec + ipilimumab (up to 4 dose levels) at Weeks 3, 5 and
9. The dose escalation part will follow a classical 3+3 design. 3 to 6 patients will be
enrolled at each DL (Dose Level) depending of the number of Dose Limiting Toxicity (DLT)
observed. At the end of each DL cohort, a teleconference (Dose escalation meeting) will be
organized with the sponsor, in order to select the dose for the next cohort. In Expansion
cohorts ( up to 3 cohorts) patients will be treated with an IT boost injection with Pexa-Vec
alone (fixed dose of 1x109 pfu / injection) at Week 1 followed by IT injections of Pexa-Vec +
ipilimumab (RP2D) at Weeks 3, 5 and 9. In both parts, the treatment with both IMPs should be
continued as per protocol until Withdrawal of consent, Disease progression as per irRC
(immune related response criteria), General or specific changes in the patient's condition
that render the patient unacceptable for further treatment in the judgment of the
investigator, Pregnancy or Unacceptable adverse events(s) including DLTs.
Inclusion Criteria:
- Male or female patients aged ≥ 18 years at time of inform consent signature
- Histologically confirmed, advanced/metastatic solid tumor refractory or relapsing
to/after standard therapy or the patient has refused or does not tolerate standard
therapy. Any tumor types can be considered in Part A except hepatocellular carcinoma
(HCC). In part B, tumor types may include melanoma, MSI-High colorectal carcinoma
(CRC), head and neck tumors, gastric cancers, triple negative breast cancers and
mesothelioma.
- Tumor status (as determined by radiology evaluation): At least one injectable site
≥2cm and ≤8 cm in diameter and one distant non-injected measurable site (target site).
NotaBene: for the DL5 and DL6, depending of the size of the injectable lesions, patients
should present more than 1 injectable lesion (See Appendix 3). Of note, patients with only
one injectable lesion with a diameter = 2 cm are not eligible for theses 2 DLs.
- PS ECOG 0 or 1
- Minimal wash-out period for prior anti-cancer regimens (i.e. chemotherapy,
immunotherapy, or radiation therapy) > 3 weeks before Week 1 day 1.
- Resolution (i.e. ≤ Grade 1) of all toxicity related to prior anti-cancer treatment
with exceptions of alopecia Grade 2, neuropathy Grade 2 and according to biological
values presented in Criteria I8.
- No major surgery within 4 weeks prior Week 1 day 1
- Laboratory requirements:
1. Absolute neutrophil count (ANC) ≥ 1 x 109/L
2. Lymphocytes ≥1 x 109/L
3. Platelets ≥ 100 x 109/L;
4. Hemoglobin ≥ 90 g/L
5. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 3 x ULN (if
patient exhibits liver metastasis, up to 5 x ULN acceptable) and total bilirubin
≤ 3mg/dL
6. Serum creatinine ≤1.5 x ULN or creatinine clearance is ≥60 mL/min according to
Cockcroft-Gault formula
7. International normalized ratio (INR) ≤1.7
8. Serum chemistries within normal limits (high or low) or Grade 1 (with exception
of sodium, potassium, glucose, calcium, upon Investigator discretion)
- Life expectancy > 3 months
- Negative pregnancy test for women of child-bearing potential within 72 hours before
Week 1 Day 1
- Men and women of reproductive potential must be willing to double barrier methods of
contraception during the treatment period and for up to 6 weeks after last Pexa Vec
administration.
- Patient should understand, sign, and date the written voluntary informed consent form
prior to any protocol-specific procedures performed. Patient should be able and
willing to comply with study visits and procedures as per protocol.
- Patients must be covered by a medical insurance.
Exclusion Criteria:
- Known significant immunodeficiency due to underlying illness (e.g., HIV/AIDS) and/or
immune-suppressive medication including systemic corticosteroids and/or blood CD4+
T-cells < 200/µL.
- History of auto-immunity or untreated wounds from infection or inflammatory skin
conditions. Ancient auto-immunity with stable endocrine oral substitution and vitiligo
could be considered eligible by investigators.
- Experience of a severe systemic reaction or side-effect as a result of a previous
smallpox vaccination
- Ongoing severe inflammatory skin condition (as determined by the investigator)
requiring medical treatment
- History of severe eczema (as determined by the investigator) requiring medical
treatment
- Severe or unstable cardiac disease, including significant coronary artery disease
requiring angioplasty or stenting within the preceding 12 months, unless
well-controlled and on stable medical therapy for at least 3 months
- Medical conditions, per the investigator's judgment, that predispose the patient to
untoward medical risk of tachycardia, or hypotension during or following treatment
with Pexa-Vec
- Previous treatment with Pexa-Vec or other vaccinia vector based treatment
- Tumor tissue sample not available for biological studies (from the initial diagnosis
and/or relapse) at time of inclusion
- History of allergic reactions attributed to one of the compound of ipilimumab or
compound of similar composition (as per Yervoy SPC® - see Appendix 5)
- Hepatitis C virus therapy including interferon/pegylated interferon or ribavirin or by
extension any other hepatitis C virus therapy that cannot be discontinued within 14
days prior to any Pexa Vec injection. Sponsor should be consulted if the patient is
taking any other antiviral medications to determine eligibility and/or to determine
wash-out duration.
- Significant bleeding event within the last 12 months that places the patient at risk
for IT injection procedure based on Investigator assessment
- Anticoagulant or anti-platelet medication that cannot be interrupted prior to IT
injections (as listed in the protocol).
- 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 each Pexa Vec
injection.
- Prior malignancy except for the following: basal or squamous cell skin cancer, in situ
cervical cancer, or other cancer adequately treated from which the patient has been
disease-free for at least 3 years
- Active brain metastasis (treated and stable brain metastasis accepted).
- Any prior or planned organ transplant (e.g., liver transplant) or allogeneic
hematopoietic stem cell transplantation.
- Pregnant or breastfeeding women
- Household contact exclusions for patients enrolled: Women who are pregnant or nursing
an infant, 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).
