E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally Advanced or Metastatic Disease in Solid Tumors |
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E.1.1.1 | Medical condition in easily understood language |
Locally Advanced or Metastatic Disease in Solid Tumors |
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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 | PT |
E.1.2 | Classification code | 10029521 |
E.1.2 | Term | Non-small cell lung cancer stage IIIB |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029522 |
E.1.2 | Term | Non-small cell lung cancer stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10059515 |
E.1.2 | Term | Non-small cell lung cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10066490 |
E.1.2 | Term | Progression of non-small cell lung cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10033599 |
E.1.2 | Term | Pancreatic adenocarcinoma metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10033600 |
E.1.2 | Term | Pancreatic adenocarcinoma non-resectable |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10051971 |
E.1.2 | Term | Pancreatic adenocarcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10059326 |
E.1.2 | Term | Pancreatic carcinoma stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 25.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10033610 |
E.1.2 | Term | Pancreatic carcinoma metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10033609 |
E.1.2 | Term | Pancreatic carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10059333 |
E.1.2 | Term | Pancreatic carcinoma stage IVA |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10059335 |
E.1.2 | Term | Pancreatic carcinoma stage IVB |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10033604 |
E.1.2 | Term | Pancreatic cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10033605 |
E.1.2 | Term | Pancreatic cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10033606 |
E.1.2 | Term | Pancreatic cancer non-resectable |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061902 |
E.1.2 | Term | Pancreatic neoplasm |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10071536 |
E.1.2 | Term | Head and neck cancer stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10071537 |
E.1.2 | Term | Head and neck cancer stage III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10071540 |
E.1.2 | Term | Head and neck cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10010035 |
E.1.2 | Term | Colorectal cancer stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052358 |
E.1.2 | Term | Colorectal cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052362 |
E.1.2 | Term | Metastatic colorectal cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10010023 |
E.1.2 | Term | Colorectal neoplasms malignant |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052360 |
E.1.2 | Term | Colorectal adenocarcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061873 |
E.1.2 | Term | Non-small cell lung cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
Parts A, B, and C: This study will evaluate the antitumor activity, safety, and pharmacokinetics (PK) of tisotumab vedotin as monotherapy in patients with locally advanced or metastatic tumors. Part D: Evaluate antitumor activity of tisotumab vedotin in combination with pembrolizumab or with both pembrolizumab and carboplatin.
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E.2.2 | Secondary objectives of the trial |
Parts A, B and C: -Evaluate preliminary antitumor activity of tisotumab vedotin as a single agent -Evaluate the safety and tolerability of tisotumab vedotin as a single agent
Part D: -Evaluate preliminary antitumor activity of tisotumab vedotin in combination with pembrolizumab or with both pembrolizumab and a platinum agent (carboplatin or cisplatin) -Evaluate the safety and tolerability of tisotumab vedotin in combination with pembrolizumab or with both pembrolizumab and carboplatin -Evaluate preliminary safety and tolerability of tisotumab vedotin in combination with pembrolizumab and cisplatin
All Parts of the Study: - Evaluate stability and control of disease - Evaluate durability of response - Evaluate the timing of response - Evaluate progression-free survival (PFS) - Evaluate survival -Assess pharmacokinetics (PK) and immunogenicity of tisotumab vedotin |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Relapsed, locally-advanced or metastatic colorectal or pancreatic cancer, squamous NSCLC, or SCCHN that has failed prior lines of systemic treatment as specified and which are not candidates for standard therapy. ● Colorectal Cancer: Patients with colorectal cancer must have experienced disease progression on or after their most recent systemic therapy for non-operable metastatic disease. Isolated increase in carcinoembryonic antigen (CEA) will not qualify for study entry. Patients must have received prior therapy with each of the following agents, if eligible: a fluoropyrimidine, oxaliplatin, irinotecan, and/or bevacizumab. Patients with known/previously-tested RAS wild-type tumors and/or known/previously-tested MSI-H tumors could have received cetuximab or panitumumab and CPI, if eligible. Patients should have received no more than 3 systemic regimens in the metastatic setting. ● NSCLC: Patients with NSCLC must have histologically or cytologically documented squamous cell NSCLC and must have experienced disease progression on or after their most recent systemic therapy. Patients must have received prior therapy for NSCLC with a platinum-based regimen and a CPI, if eligible. Patients should have received no more than 3 lines of systemic therapy in the metastatic setting. Maintenance therapy should not be counted as a separate line of therapy. - Patients eligible for a tyrosine kinase inhibitor (TKI; ALK, ROS-1 gene rearrangement, or EGFR mutation) should have received such therapy. These patients should have received no more than 4 lines systemic therapy in the metastatic setting. ● Exocrine pancreatic adenocarcinoma: Patients with exocrine pancreatic adenocarcinoma must have biopsy proven, histologically confirmed diagnosis of exocrine pancreatic adenocarcinoma and must have experienced disease progression on or after their most recent systemic therapy for locally advanced or metastatic disease. Isolated increase in CA 19-9 or CEA will not qualify for study entry. Patients must have received prior therapy with a gemcitabine-based or 5FU-based regimen if eligible for such therapy. Patients should have received no more than 1 systemic regimen in the unresectable or metastatic setting. ● SCCHN: Patients with SCCHN must have received a prior platinum-based regimen and/or CPI, if eligible, and must have experienced disease progression following such therapy. Patients should have received no more than 3 systemic lines of therapy in the recurrent/metastatic setting. Maintenance therapy should not be counted as a separate line of therapy. 2. Measurable disease according to RECIST v1.1 as assessed by the investigator. ● A minimum of one non-nodal lesion ≥10 mm in the longest diameter from a non-irradiated area. If target lesion(s) are located within previously irradiated area only, the patient can be enrolled only if there has been demonstrated progression in the “in field” lesion and upon approval of the sponsor’s medical monitor. OR ● Lymph node lesion ≥15 mm in the shortest diameter from a non-irradiated area. 3. Age 18 years or older. 4. An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1. 5. The following baseline laboratory data: ● (ANC) ≥1500/μL assessed at least 2 weeks after growth factor support, if applicable. ● platelet count ≥100 x 109/L assessed at least 2 weeks after transfusion with blood products. ● hemoglobin ≥5.6 mmol/L (9.0 g/dL) assessed at least 2 weeks after transfusion with blood products and/or growth factor support. ● serum bilirubin ≤1.5 x upper limit of normal (ULN) or direct bilirubin ≤2 x ULN in patients diagnosed with Gilbert’s syndrome. ● eGFR ≥50 mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) study equation as applicable. ● alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN. (If liver tumor/metastases are present, then <5 x ULN is allowed). 6. Acceptable coagulation status. 7. Life expectancy of at least 3 months. ●Part D only: · Patients with SCCHN must have received no previous systemic therapy in the recurrent or metastatic disease with the exception of systemic therapy completed >6 months prior, if given as part of multimodal treatment for locally advanced disease. · Patients with NSCLC must have histologically or cytologically documented squamous cell NSCLC and must have received no previous systemic therapy for metastatic disease or radiation therapy to the lung that is > 30 Gy within 6 months of the first dose of study drug. · PD-L1 biomarker expression from IHC analysis should be available - Patients with SCCHN must have a CPS ≥1 to be eligible for the cohorts testing tisotumab vedotin in combination with pembrolizumab. Patients with sqNSCLC must have a TPS ≥1% to be enrolled to cohorts testing tisotumab vedotin in combination with pembrolizumab. - Able to provide fresh or archival tissue for biomarker analysis.
Other inclusion Criteria can be found in the Protocol. |
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E.4 | Principal exclusion criteria |
1. Patients with primary neuroendocrine or sarcomatoid histologies. For SCCHN, patients may not have a primary site of nasopharynx (regardless of histology). 2. Known past or current coagulation defects leading to an increased risk of bleeding; diffuse alveolar hemorrhage from vasculitis; known bleeding diathesis; ongoing major bleeding; trauma with increased risk of life- threatening bleeding or history of severe head trauma or intracranial surgery within 8 weeks of trial entry. 3. Clinically significant cardiac disease; medical history of congestive heart failure (Grade III or IV as classified by the New York Heart Association, see Appendix G); medical history of decreased cardiac ejection fraction of <45%. 4. Ophthalmological: Active ocular surface disease at baseline. Ocular evaluation confirmed by an ophthalmologist at screening. Patients with prior episode of cicatricial conjunctivitis or Steven Johnson syndrome (evaluated by the investigator) are ineligible. Please note that cataract is not considered active ocular surface disease for this protocol. 5. Evidence of malignancy within 3 years of the first dose of study drug, or evidence of residual disease. Exceptions are malignancies with negligible risk of metastasis or death (e.g., 5-year overall survival ≥90%), such as adequately treated metastatic cancers. 6. Tumor lesions invading, encasing, abutting, or involving critical anatomical sites, such as major blood vessels, (such as internal carotid artery, external carotid artery, pulmonary artery, etc) mediastinal blood vessels, and leptomeningeal disease. Mediastinal lymphadenopathy or invasion of mediastinal connective tissue is not an exclusion. 7. Inflammatory bowel disease including Crohn's disease and colitis ulcerosa 8. Ongoing, acute or chronic inflammatory skin disease 9. Uncontrolled tumor-related pain 10. Inflammatory lung disease, including moderate and severe asthma. Patients with chronic obstructive pulmonary disease are allowed if not requiring systemic steroids and long-term oxygen 11. Medications or treatment regimens: ● therapeutic anti-coagulation therapy is permitted IF the patient is no longer being actively titrated for anti-coagulation. For oral anticoagulation therapy, patients must be on steady doses for at least 4 weeks prior to the first dose of study drug. ● Chronic prophylactic treatment with ASA (e.g., aspirin) in combination with other anti-coagulation therapy is prohibited. ● Cumulative dose of corticosteroid ≥150 mg (prednisone or equivalent doses of corticosteroids) within 2 weeks of the first tisotumab vedotin administration is prohibited. 12. Surgery/procedures: Major surgical procedure (defined as a surgery requiring inpatient hospitalization of at least 48 hours) within 4 weeks or excisional biopsy within 7 days prior to the first study drug administration. Patients who have planned major surgery during the treatment period must be excluded from the trial. 13. Received a live vaccine within 30 days prior to first dose of trial treatment. Examples include in page 57 of Protocol. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. 14. Peripheral neuropathy Grade ≥2. 15. Patients with clinical symptoms or signs of gastrointestinal obstruction and who require parental hydration and/or nutrition. 16. Prior therapy: ● Prior treatment with MMAE-derived drugs. ● At least 42 days must have elapsed from the last administration of chemo-radiotherapy or radiotherapy. Patients must have recovered from all radiation-related toxicities. Palliative radiotherapy within the previous 42 days may be allowed upon discussion with the sponsor´s medical team/designee. ● Small molecules, chemotherapy, immunotherapy, biologics, experimental agents, or any other antitumor therapy within 21 days prior to the first administration of study drug. If underlying disease is progressing on treatment, patients may enroll within 21 days upon approval of the sponsor's medical monitor. Patients must have recovered from all related toxicities. 17. Uncontrolled Grade 3 or higher (per the NCI CTCAE v5.0) viral, bacterial, or fungal infection within 2 weeks prior to first dose of tisotumab vedotin. Routine antimicrobial prophylaxis is permitted. 18. Seropositivity of human immunodeficiency virus; medical history of hepatitis B or C infection. 19. known allergies, hypersensitivity, intolerance, contra-indications to pembrolizumab or contra-indications to specific trial treatment regimen or to platinum-containing compound (for part D) selected for subject. 20. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor.
Other exclusion Criteria can be found in the Protocol.
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E.5 End points |
E.5.1 | Primary end point(s) |
Parts A, B and C: -Investigator-determined confirmed ORR as measured by RECIST v.1.1 Part D: -Investigator-determined confirmed ORR as measured by RECIST v.1.1
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Parts A, B and C: -Investigator-determined confirmed and unconfirmed ORR as measured by RECIST v.1.1 -Type, incidence, severity, seriousness, and relatedness of AEs
Part D: - Investigator-determined confirmed and unconfirmed ORR as measured by RECIST v.1.1 -Type, incidence, severity, seriousness, and relatedness of AEs
All parts of the Study: -Investigator-determined disease control rate (DCR) as measured by RECIST v1.1 -Investigator-determined time to response (TTR) as measured by RECIST v1.1 -Investigator-determined PFS as measured by RECIST v1.1 -Overall survival (OS) -Selected PK parameters for tisotumab vedotin, total antibody, MMAE and pembrolizumab -Incidence of anti-therapeutic antibodies (ATAs) to tisotumab vedotin |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Tolerability and immunogenicity.
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
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 | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
The study will be conducted in 4 parts A, B, C and D |
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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 | Yes |
E.8.2.3.1 | Comparator description |
Part A 2.0mg/Kg Part B 0.9mg/Kg Part C 1.2 mg/kg 3Q4W and 1.7 mg/kg 2Q4W Part D 2.0 mg/kg Q3W |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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 |
Canada |
United States |
France |
Germany |
Italy |
Spain |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | No |
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
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The study will be closed 3 years after the last patient is enrolled or when no patients remain in long-term follow-up, whichever occurs first. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 8 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |