Phase I: Advanced or metastatic solid tumors including Non-Hodgkin Lymphoma (NHL) and preferably Soft Tissue Sarcoma, Merkel Cell Carcinoma, Melanoma, Triple Negative Breast Cancer, Non Smal Cell Lung Cancer Phase IIa: Soft Tissue Sarcoma, Merkel Cell Carcinoma, Melanoma, Triple Negative Breast Cancer, Non Smal Cell Lung Cancer MedDRA version: 21.1 Level: LLT Classification code 10065252 Term: Solid tumor System Organ Class: 100000004864
Conditions
Interventions
Product Code: BT-001
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Not yet defined
Current Sponsor code: BT-001
Other descriptive name: Infectious particle containing sequences codi
Sponsors
TRANSGENE
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: I1. Signed informed consent in accordance to ICH-GCP and national/local regulation before starting any protocol-related procedures I2. Male or female patient aged = 18 years I3. At least 1 injectable measurable cutaneous, subcutaneous or nodal lesion greater or equal to 2 cm in longest diameter; or multiple injectable lesions (maximum 5) that in aggregate have a longest diameter of at least 2 cm, and whenever possible 1 distant non-injected measurable lesion I4. Expected survival of at least 3 months I5. Knowledge of his/her anti-variola vaccine status I6. Provide a fresh tumor sample at baseline and be willing to supply new tumor samples from a biopsy during treatment. I7. ECOG performance status of 0 or 1 I8. Interval of at least 3 weeks between first study drug injection and exposure to prior chemotherapy; 4 weeks for immunotherapy and antibody-based therapy and 2 weeks for palliative radiotherapy I9. Adequate hematological, hepatic and renal functions: Haemoglobin = 9 g/dL Neutrophils = 1 x10E+9/L Lymphocytes = 0.750 x 10E+9/L Platelets = 100 x10E+9/L Alanine aminotransferase (ALT) and aspartate aminotransferase [AST]) = 3 x ULN (up to 5 x ULN if patients exhibits liver metastases); total bilirubin = 1.5 x ULN except for patients with Gilbert’s syndrome who may be included if total bilirubin = 2.5 x ULN Serum creatinine = 1.5 x ULN or creatinine clearance = 60 mL/min according to Cockroft & Gault formula International normalized ratio (INR) = 1.5 I10. Appropriate precaution against pregnancy whilst on study: - Women of childbearing potential (WOCBP) potential must have a negative pregnancy test prior to study entry. - Both men and WOCBP must be using a highly effective contraception method combined with a barrier method (e.g. condom) during BT-001 treatment period and for a minimum of 4 months following the last administration of BT-001 For patients included in Phase I (parts A and B): IA-1 Have histologically confirmed, advanced/metastatic solid tumors including non-Hodgkin lymphoma (NHL) and preferably sarcoma (soft tissue and bone), MCC, melanoma, TNBC or NSCLC, with cutaneous or, palpable subcutaneous lesions or easily injectable lymph nodes For patients included in Phase I, Part A (single agent) only: IB-1 Patients who have failed and/or are intolerant to standard therapeutic options. For patient included in Phase IIa: IC- Soft Tissue Sarcoma (STS) Cohort: IC-1 Have a histologically confirmed metastatic and/or locally advanced inoperable undifferentiated pleomorphic sarcoma/myxofibrosarcoma, cutaneous angiosarcoma, dedifferentiated liposarcoma or leiomyosarcoma. IC-2 Have at least 1 injectable cutaneous or, palpable subcutaneous soft tissue or nodal lesion = 20 mm in longest diameter. IC-3 Have at least one prior line of systemic therapy. A naive patient may be enrolled if they have refused standard systemic treatment. Prior adjuvant therapy will not count if it was completed more than 6 months previously. ID- Merkel Cell Carcinoma (MCC): ID-1 Have histologically confirmed stage IV MCC. ID-2 Have received at least 1 line of treatment for metastatic MCC and have progressed after the most recent line of treatment. IE- Melanoma: IE-1. Have pathologically confirmed metastatic or unresectable stage IIIb/c of IV melanoma with at least one cutaneous or, subcutaneous tumor or palpable lymph node amenable to IT injection. IE-2. Have had prior treatment with anti-PD-1 or anti-PD-L1 agents
Exclusion criteria
Exclusion criteria: E1 Have a tumor adjacent to the trachea or a major blood vessel. E2 Have had major surgery within 4 weeks of first study drug administration. E3 Have received prior treatment with a vaccinia oncolytic virus. E4 Have known significant immunodeficiency due to underlying illness (e.g., HIV/AIDS) and/or immune-suppressive medication including systemic corticosteroids. E5 Have received antiviral therapy active on vaccinia virus (VV), e.g., ribavirin, interferon/pegylated interferon. E6 Have a history of severe exfoliative skin conditions (e.g., eczema or atopic dermatitis) requiring systemic therapy for more than 4 weeks within 2 years prior to BT-001 initiation. E7 Have uncontrolled intercurrent illness including but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social circumstances that could limit compliance with study requirements. E8 Have had a Grade = 3 auto-immune manifestations of previous ICIs (e.g., anti-PD-1, anti-PDL1, anti-CTLA-4, or another immune checkpoint targeting agent under investigation). E9 Have received treatment with another investigational agent within 21 days before the inclusion. E10 Taken an anticoagulant medication that cannot be interrupted prior to IT injections. E11 Have active brain metastasis (stable and treated metastasis are accepted). E12 Have had any organ transplantation, including allogenic stem cell or bone marrow transplantation. E13 Have known hypersensitivity to egg. E14 Have had any positive test for hepatitis C virus (HCV) or hepatitis B virus (HBV) indicating acute or chronic infection. E15 Are pregnant or a breastfeeding woman, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 10 mIU/mL). E16 Have any medical, familial, sociological or psychiatric condition that in the opinion of the investigator would prohibit inclusion in the trial. For patients included in Phase I, Part B and IIa only: EA-1. Patient with an active known or suspected auto-immune disease. Patient with type I diabetes or hypothyroidism only requiring hormone replacement are permitted to enroll. EA-2. Have interstitial lung disease that is symptomatic and may interfere with the detection or management of suspected drug-related pulmonary toxicity. EA-3. Have known hypersensitivity to the active substance or to any of the excipients of pembrolizumab.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: _ Phase I PartA: Assess the local and systemic safety and tolerability of BT-001 as a single agent in repeated IT administrations of 1 to 4 mL at 1x10E+06 to 1x10E+08 PFU/mL, determine the Maximum Tolerated Dose (MTD), if any, within this dose range, and determine the Maximum Feasible Dose (MFD) in patients with metastatic/advanced solid tumors. _ Phase I Part B: Assess the local and systemic safety and tolerability of BT-001 in repeated IT administrations at the Recommended Dose for Part B (RDPB) of 1 to 4 mL in combination with IV infusions of pembrolizumab in patients with metastatic/advanced solid tumors. _ Phase IIa: Evaluate the antitumor activity of BT-001 in repeated IT administrations in combination with IV infusions of pembrolizumab in patients with metastatic/advanced Soft Tissue Sarcoma (STS), Merkel Cell Carcinoma (MCC), Melanoma, Non Small Cell Lung Cancer (NSCLC) or Triple negative Breast Cancer (TNBC) using iRECIST;Secondary Objective: _ Evaluate tumor response of injected and non-injected lesions using RECIST version 1.1 [applicable to Phase I and Phase IIa] and iRECIST [applicable to Phase I only] (including clinical evaluation for superficial lesions); _ Assess the local and systemic safety and tolerability of BT-001 in repeated IT administrations in combination with IV infusions of pembrolizumab [only applicable to Phase IIa] _ Assess BT-001 blood pharmacokinetics; _ Monitor GM-CSF and anti-CTLA-4 mAb (4-E03 mAb) concentrations in the blood and in injected lesions; _ Assess immunogenicity by detecting anti-Vaccinia NAbs and antibodies anti-CTLA-4 mAb (anti-4-E03 mAb) in the blood; _ Assess immune changes in the tumor microenvironment for injected and, whenever possible, non-injected lesions; _ Perform BT-001 viral shedding analyses.;Primary end point(s): Phase I: Safety and tolerability: Overall incidence of AEs (including SAEs), patients discontinuing study due to AEs, DLTs, changes in standard laboratory parameters and vital s | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): _ Tumor response: Overall Response Rate (ORR) injected and non-injected lesions using RECIST 1.1 [applicable to Phase I and Phase IIa] and iRECIST [applicable to Phase I only]; _ Safety and tolerability : Overall incidence of AEs (including SAEs), evaluated according to NCI-CTCAE version 5.0 [only applicable to Phase IIa] _ Pharmacokinetics: Virus, GM-CSF and anti-CTLA-4 mAb concentrations over time in the blood and in injected lesions _ Immunogenicity: Anti-Vaccinia NAbs and antibodies anti-CTLA-4 mAb titers over time in injected lesions _ Viral shedding: Virus concentration in skin swabs, saliva, urine and feces samples;Timepoint(s) of evaluation of this end point: _ Safety and tolerability: Same timepoints as in section E.5.1.1 _ Clinical response assessment for ORR: Same timepoints as in section E.5.1.1 _ PK and PD parameters through serial peripheral blood assays at baseline visit and visits on days 1, 2, 3, 5, 8, 15, 22, 29, 36, 43, 44, 45, 64 and through biopsies analysis collected at baseline visit and visits on days 5, 22 in Phase I, part A or at baseline visit and visits on day 64 / end of study visit in Phase I, Part B and Phase IIa _ Neutralizing antibodies titers assayed at baseline visit and visits on Days 8, 22, 36, 64. _ Tumor microenvironment immune changes: Tumor biopsies collected at baseline visit and visits on days 5, 22 _ Virus concentrations in samples collected (skin swabs, saliva, urine and feces) on days 2, 8, 15. | — |
Countries
Belgium, France, United States
Contacts
Public ContactJulien ROMANETTO
TRANSGENE
Outcome results
None listed