| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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 |
Phase I: Tumeurs solides avancées ou métastatiques incluant les lymphomes non-hodgkiniens , de préférence 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 |
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| 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 | 100000004864 |
|
| 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 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 |
_ 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 tumeurs solides avancées ou métastatiques.
_ Phase IIa: Evaluer l’activité antitumorale d’administrations IT répétées de BT-001 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 en utilisant iRECIST. |
|
| 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. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 and have documented disease progression on these agents prior to registration; patient who have progressed after adjuvant anti-PD1/L1 agents are eligible.
IE-3. Do not have disease that is suitable for local therapy with curative intent. Previous treatment with talimogene laherparepvec in combination with pembrolizumab is not allowed.
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 at least one systemic treatment for metastatic breast cancer; prior treatment must include an anthracycline and a taxane in the neoadjuvant, adjuvant, or metastatic setting.
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 had prior treatment with anti-PD-1 or anti-PD-L1 agents and have documented disease progression on these agents prior to registration and one prior systemic treatment including chemotherapy for tumors with PD-L1 expression < 50%; patients who have progressed after receiving anti-PD1 / L1 in a previous line are eligible.
IG-3. Must have no EGFR or ALK positive tumor mutations |
|
| E.4 | Principal 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. |
|
| 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. |
|
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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