| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Phase I: Advanced or metastatic 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 |
Phase I: Tumeurs solides avancées ou métastatiques incluant les sarcomes des tissus mous, carcinome à cellules de Merkel, mélanome, cancer du sein triple négatif ou cancer du poumon non à petites cellules
Phase IIa: Sarcomes des tissus mous, carcinome à cellules de Merkel, mélanome, cancer du sein triple négatif ou cancer du poumon non à petites cellules |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced or metastatic solid tumors |
| Tumeurs solides avancées ou métastatiques |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
_ 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 Soft Tissue Sarcoma (STS), Merkel Cell Carcinoma (MCC), Melanoma, Non Small Cell Lung Cancer (NSCLC)
or Triple negative Breast Cancer (TNBC).
_ Phase IIa: Evaluate the antitumor activity of BT-001 in repeated IT administrations in combination with IV infusions of pembrolizumab using iRECIST in same patient population than in Phase I Part B |
_ Phase I, Partie A: Evaluer la sécurité d’emploi et la tolérance, locale et systémique, d’administrations IT répétées, de 1 à 4 mL de BT-001, à des doses de 1×10E6 à 1×10E8 UFP/mL, en monothérapie ; déterminer la Dose Maximale Tolérée (DMT), le cas échéant, dans cet intervalle de dose et déterminer la dose maximale atteignable chez des patients porteurs de tumeurs solides avancées ou métastatiques.
_ Phase I, Partie B: Evaluer la sécurité d’emploi et la tolérance, locale et systémique, d’administrations IT répétées, de 1 à 4 mL de BT-001, à la DRPB, en combinaison avec des perfusions IV de pembrolizumab chez des patients porteurs de STM, de CCM, de mélanome, de cancer du sein triple négatif ou de CPNPC avancés ou métastatiques .
_ Phase IIa: Evaluer l’activité antitumorale d’administrations IT répétées de BT-001 en combinaison avec des perfusions IV de pembrolizumab en utilisant iRECIST chez les mêmes population de patient que la Phase I
Partie B.. |
|
| E.2.2 | Secondary objectives of the trial |
_ 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
_ Perform detection of viral DNA concentration in injected lesions, and whenever possible, in a non-injected lesion. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Phase I part B and Phase IIa
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 Histologically confirmed, advanced/metastatic sarcoma (soft tissue and bone), MCC, melanoma, Triple TNBC, or NSCLC, with cutaneous or, palpable subcutaneous lesions or, easily injectable lymph nodes
I4 Failed and/or are intolerant to standard therapeutic options
I5 At least 1 injectable cutaneous, subcutaneous or nodal lesion measurable according to RECIST 1.1 and not exceeding 50mm in the longest diameter and whenever possible another non-injected measurable lesion
I6 Expected survival of at least 3 months.
I7 Knowledge of his/her anti-variola vaccine status
I8 Agree to provide a fresh tumor sample of the lesion
I9 ECOG status of 0 or 1
I10 Highly effective contraception method combined with a barrier method during and after study treatment
I11 Complete COVID-19 primary-vaccination
I12 Interval of at least 3 weeks between first IMP(s) administration and exposure to prior chemotherapy, 4 weeks for immunotherapy and antibody-based therapy, and 2 weeks for palliative radiotherapy
I13 Have adequate hematological, hepatic and renal functions:
Hemoglobin ≥ 9 g/dL (without packed red blood cell transfusion
within the prior 2 weeks)
Neutrophils ≥ 1.5 x10E9/L
Lymphocytes ≥ 0.750 x 10E9/L
Platelets ≥100 x10E9/L
ALT and AST ≤ 2.5 x ULN; total bilirubin is ≤ 1.5 x ULN
Total bilirubin ≤ 1.5 x ULN, except for patients with Gilbert syndrome who must have a total bilirubin level < 3.0 x ULN
Lactate dehydrogenase ≤ 3 x ULN
Creatinine clearance ≥ 60 mL/min according to the Cockroft & Gault formula
International normalized ratio (INR) ≤ 1.5 x ULN
Additional criteria applicable according to patient's condition:
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.
IC-3 Have failed and/or are intolerant to standard therapeutic options.
ID- Merkel Cell Carcinoma (MCC):
ID-1 Have histologically confirmed unresectable stage III or metastatic MCC.
ID-2 Have failed and/or are intolerant to standard therapeutic options.
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 failed and/or are intolerant to prior treatment with anti-PD-1 or anti-PD-L1 agents alone or in combination with anti-CTLA-4.
IE-3 Have received therapy targeting BRAF or MEK when appropriate and have failed and/or are intolerant to it
IE-4 Do not have disease that is suitable for local therapy with curative intent
IE-5 Have not received previous treatment with Imlygic
IF- Triple Negative Breast Cancer (TNBC):
IF-1 Have metastatic or locally advanced, histologically confirmed TNBC characterized by absence of human epidermal growth factor 2, estrogen receptor, and progesterone receptor expression.
IF-2 Have failed and/or are intolerant to standard therapeutic options.
IF-3 Have documented disease progression on or after the most recent therapy.
IG- Non-Small Cell Lung Cancer (NSCLC):
IG-1. Have histologically confirmed NSCLC, stage IIIb-IV or delayed
relapse of any stage not amenable to surgery or RT with curative intent.
IG-2. Have failed and/or are intolerant to standard therapeutic options.
IG-3. Must have no EGFR, ALK or BRAF positive tumor mutations or ROS1 rearrangement. |
|
| E.4 | Principal exclusion criteria |
Phase I Part B and Phase IIa:
E1 Have a tumor adjacent to the trachea or a major blood vessel for planned injection.
E2 Have had major surgery within 4 weeks of first IMP(s) Phase I Part B and Phase IIa:
E1 Have a tumor adjacent to the trachea or a major blood vessel for planned injection.
E2 Have had major surgery within 4 weeks of first IMP(s) administration.
E3 Have received prior treatment with a vaccinia oncolytic virus.
E4 Have received antiviral therapy active on vaccinia virus (VV), e.g., ribavirin, interferon/pegylated interferon..
E5 Have received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137), and was discontinued from that treatment due to a Grade 3 or higher immunerelated
Adverse Event (irAE).
E6 Have received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to the start of treatment.
E7 Have received prior radiotherapy within 2 weeks of start of study treatment or have had a history of radiation pneumonitis.
E8 Have received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention.
E9 A WOCBP who has a positive serum pregnancy test (within 72 hours) prior to the start of treatment.
E10 Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
E11 Is taking an anticoagulant medication that cannot be interrupted prior to IT injections.
E12 Have had an allogenic tissue/solid organ transplant or allogenic stem cell or bone marrow transplantation.
E13 Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 28 days prior the first dose of study drugs.
E14 Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
E15 Has known active CNS metastases and/or carcinomatous meningitis.
E16 Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
E17 Has an active autoimmune disease that has required systemic treatment in past 2 years.
E18 Has a history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease.
E19 Has an active infection requiring systemic therapy.
E20 Has a known history of HIV infection.
E21 Has a known history of Hepatitis B or known active Hepatitis C virus infection.
E22 Has a history or current evidence of any condition, therapy, or laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant's participation for the full duration of the study
E23 Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
E24 Has received radiation therapy to the lung that is >30Gy within 6 months of the first dose of trial treatment for patients having NSCLC
E25 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
E26 Have known hypersensitivity to egg or to any excipients of BT-001
E27 Have a history of myocarditis or congestive heart failure, unstable
angina pectoris, uncontrolled infection, or myocardial infarction 6 months prior to clinical trial entry
E28 COVID-19 vaccination or infection within 2 weeks prior to start of treatment
E29 History of monkeypox infection or anti-monkeypox vaccination within 30 days prior to the first dose of study intervention |
|
| E.5 End points |
| E.5.1 | 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 signs evaluated according to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 5.0.
Phase IIa:
Overall Response Rate (ORR) for injected and non-injected lesions according to Immune RECIST (iRECIST
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I:
Safety and tolerability assessment at baseline visit and visits on days 1, 2, 3, 8, 15, 22, 29, 36, 43, 64, 71; 85, then every 8 weeks, at end of study visit and at safety follow-up visit.
Phase IIa:
Clinical response assessment for ORR will be evaluated by clinical exam at visits on days 1, 8, 15, 22, 29, 43, 64, 85 and then every 8 weeks and by imaging exams at visits on days 1, 43, 85 and then every 8 weeks
|
|
| E.5.2 | 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 |
|
| E.5.2.1 | 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, 43, 64. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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