Efficacy and Safety Study of Tisotumab Vedotin for Patients With Solid Tumors

Study Overview
=================
Brief Summary
-----------------
This trial will study tisotumab vedotin to find out whether it is an effective treatment for certain solid tumors and what side effects (unwanted effects) may occur. There are seven parts to this study. In Part A, the treatment will be given to participants every 3 weeks (3-week cycles). In Part B, participants will receive tisotumab vedotin on Days 1, 8, and 15 every 4-week cycle. In Part C, participants will receive tisotumab vedotin on Days 1 and 15 of every 4-week cycle. In Part D, participants will be given treatment on Day 1 of every 3-week cycle. Participants in Part D will get tisotumab vedotin with either: Pembrolizumab or, Pembrolizumab and carboplatin, or Pembrolizumab and cisplatin In Part E, participants will receive tisotumab vedotin on Days 1 and 15 of every 4-week cycle. In Part F, participants will receive tisotumab vedotin on Days 1, 15, and 29 of every 6-week cycle. Participants in Part F will get tisotumab vedotin with pembrolizumab. In Part G, participants will receive tisotumab vedotin on Days 1, 15, and 29 of every 6-week cycle. Participants in Part G will get tisotumab vedotin with pembrolizumab and carboplatin.

Detailed Description
-----------------
The primary goal of this trial is to assess the activity, safety, and tolerability of tisotumab vedotin for the treatment of selected solid tumors. Patients will be treated with single agent tisotumab vedotin or tisotumab vedotin in combination with other agents. Patients who meet eligibility criteria will be enrolled into cohorts based on tumor type. Tumor types to be evaluated include colorectal cancer, squamous non-small cell lung cancer (sqNSCLC), exocrine pancreatic adenocarcinoma, and squamous cell carcinoma of the head and neck (SCCHN).

Official Title
-----------------
Open Label Phase 2 Study of Tisotumab Vedotin for Locally Advanced or Metastatic Disease in Solid Tumors

Conditions
-----------------
Colorectal Neoplasms, Carcinoma, Non-Small-Cell Lung, Exocrine Pancreatic Cancer, Carcinoma, Squamous Cell of Head and Neck

Intervention / Treatment
-----------------
* Drug: tisotumab vedotin
* Drug: pembrolizumab
* Drug: carboplatin
* Drug: cisplatin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Parts A, B, and C Relapsed, locally-advanced or metastatic colorectal or pancreatic cancer, sqNSCLC, or SCCHN participants who are not candidates for standard therapy. All participants must have experienced disease progression on or after their most recent systemic therapy. Colorectal cancer (closed to enrollment): participants must have received prior therapy with each of following agents, if eligible: a fluoropyrimidine, oxaliplatin, irinotecan, and/or bevacizumab. Participants should have received no more than 3 systemic regimens in the metastatic setting. sqNSCLC (closed to enrollment): Participants with NSCLC must have predominant squamous histology. Participants must have received prior therapy with a platinum-based treatment and a checkpoint inhibitor (CPI), if eligible. Participants should have received no more than 3 lines of systemic therapy in the metastatic setting. Participants eligible for a tyrosine kinase inhibitor should have received such therapy. These participants should have received no more than 4 lines of systemic therapy in the metastatic setting. Exocrine pancreatic adenocarcinoma (closed to enrollment): Participants with exocrine pancreatic adenocarcinoma must have predominant adenocarcinoma histology. Participants must have received prior therapy with a gemcitabine-based or 5FU-based regimen, if eligible, and should have received no more than 1 systemic regimen in the unresectable or metastatic setting. SCCHN (closed to enrollment): Participants with SCCHN in Part C must have received prior therapy with a platinum-based regimen and/or a checkpoint inhibitor (CPI), if eligible, and must have experienced disease progression following such therapy. Participants should have received no more than 3 systemic lines of therapy in the recurrent or metastatic setting. Part E Participants with SCCHN must have experienced disease progression on or after their most recent systemic therapy. Participants should have received no more than 1 or 2 systemic lines of therapy in the recurrent/metastatic setting as specified below. Participants must have received a platinum-based regimen and a PD-(L)1 inhibitor. Parts D, F, and G Part D is closed to enrollment. Part F and Part G will enroll only participants with SCCHN. Participants with SCCHN must have received no previous systemic therapy in the recurrent or metastatic disease setting. Part D only Participants 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 treatment. PD-L1 biomarker expression as determined by a PD-L1 IHC assay should be available Part F only Participants must have CPS ≥1 by local PD-L1 IHC assay to be eligible for enrollment. Participants must be able to submit a tissue sample for retrospective PD-L1 testing. Tissue may be fresh biopsy or archival, collected within 2 years of Cycle 1 Day 1. Part G only Non-EU eligibility criteria: No CPS requirement for the cohort evaluating tisotumab vedotin in combination with pembrolizumab and carboplatin. EU-specific eligibility criteria: Participants must have a CPS ≥1 by local PD-L1 IHC assay. Participants must be able to submit a tissue sample for retrospective PD-L1 testing. Tissue may be fresh biopsy or archival, collected within 2 years of Cycle 1 Day 1. Baseline measurable disease as measured by RECIST v1. 1. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1. Exclusion Criteria: Participants with primary neuroendocrine or sarcomatoid histologies. For SCCHN, participants may not have a primary site of nasopharynx or salivary gland. Active bleeding conditions Ocular surface disease at the time of enrollment (Note: cataract is not considered active ocular surface disease for this protocol) Other cancer: known past or current malignancy other than inclusion diagnosis. Uncontrolled tumor-related pain Inflammatory lung disease. Participants with pulmonary disease are allowed if systemic steroids and long-term oxygen are not required Peripheral neuropathy greater than or equal to Grade 2 Active brain metastasis Part D, F, and G Only: 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Tisotumab Vedotin - Q3W Schedule<br>Tisotumab Vedotin every 3 weeks | Drug: tisotumab vedotin<br>* Given into the vein (IV; intravenously)<br>* Other names: TIVDAK;|
| Experimental: Part B: Tisotumab Vedotin - 3Q4W Schedule<br>Tisotumab Vedotin on Days 1, 8, and 15 of 28-day cycle | Drug: tisotumab vedotin<br>* Given into the vein (IV; intravenously)<br>* Other names: TIVDAK;|
| Experimental: Part C: Tisotumab Vedotin - 2Q4W Schedule<br>Tisotumab Vedotin on Days 1 and 15 of every 28-day cycle in participants with SCCHN or sqNSCLC | Drug: tisotumab vedotin<br>* Given into the vein (IV; intravenously)<br>* Other names: TIVDAK;|
| Experimental: Part D: Tisotumab Vedotin Combination Therapy - Q3W Schedule<br>Tisotumab vedotin + pembrolizumab + (carboplatin or cisplatin). Given on Day 1 of every 21-day cycle. | Drug: tisotumab vedotin<br>* Given into the vein (IV; intravenously)<br>* Other names: TIVDAK;Drug: pembrolizumab<br>* 200mg or 400mg given by IV<br>* Other names: Keytruda;Drug: carboplatin<br>* AUC 5mg/mL per minute or AUC 3.3mg/mL per minute given by IV<br>Drug: cisplatin<br>* 100mg/m^2 given by IV<br>|
| Experimental: Part E: Tisotumab Vedotin - 2Q4W Schedule<br>Tisotumab Vedotin on Days 1 and 15 of every 28-day cycle in participants with SCCHN in the second- or third-line setting | Drug: tisotumab vedotin<br>* Given into the vein (IV; intravenously)<br>* Other names: TIVDAK;|
| Experimental: Part F: Tisotumab Vedotin Combination Therapy - Q2W Schedule<br>Tisotumab Vedotin + pembrolizumab. Tisotumab Vedotin given on Days 1, 15, and 29 of every 6-week cycle. Pembrolizumab given on Day 1 of every 6-week cycle. | Drug: tisotumab vedotin<br>* Given into the vein (IV; intravenously)<br>* Other names: TIVDAK;Drug: pembrolizumab<br>* 200mg or 400mg given by IV<br>* Other names: Keytruda;|
| Experimental: Part G: Tisotumab Vedotin Combination Therapy - Q2W Schedule<br>Tisotumab Vedotin + pembrolizumab + carboplatin. Tisotumab Vedotin and carboplatin given on Days 1, 15, and 29 of every 6-week cycle. Pembrolizumab given on Day 1 of every 6-week cycle. | Drug: tisotumab vedotin<br>* Given into the vein (IV; intravenously)<br>* Other names: TIVDAK;Drug: pembrolizumab<br>* 200mg or 400mg given by IV<br>* Other names: Keytruda;Drug: carboplatin<br>* AUC 5mg/mL per minute or AUC 3.3mg/mL per minute given by IV<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Objective Response Rate (ORR) (Parts A, B, C, D, F, and G) | Proportion of patients who achieve a confirmed complete response (CR) or partial response (PR) according to RECIST v1.1 as assessed by the investigator | Up to approximately 3 years | 
| Confirmed ORR per blinded independent central review (BICR) (Part E) | Proportion of patients who achieve a confirmed CR or PR according to RECIST v1.1 as assessed by BICR | Up to approximately 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events (AEs) | Type, severity, and relatedness of adverse events. An AE is any untoward medical occurrence in a subject or clinical investigational subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. | Up to approximately 3 years | 
| Confirmed and Unconfirmed ORR | Proportion of patients who achieve a CR or PR according to RECIST v1.1 as assessed by the investigator | Up to approximately 3 years | 
| Confirmed and Unconfirmed ORR per BICR (Part E) | Proportion of patients who achieve a CR or PR according to RECIST v1.1 as assessed by BICR | Up to approximately 1 year | 
| Disease Control Rate (DCR) | Proportion of patients who achieve a confirmed CR or PR according to RECIST v1.1 as assessed by the investigator, or meet the stable disease (SD) criteria at least once after start of study treatment at a minimum interval of 12 weeks | Up to approximately 3 years | 
| DCR per BICR (Part E) | Proportion of patients who achieve a confirmed CR or PR according to RECIST v1.1 as assessed by BICR, or meet the stable disease (SD) criteria at least once after start of study treatment at a minimum interval of 12 weeks | Up to approximately 1 year | 
| Duration of Response (DOR) | Time from the first documentation of objective response to the first documentation of PD or death due to any cause, whichever comes first, as assessed by the investigator | Up to approximately 3 years | 
| DOR per BICR (Part E) | Time from the first documentation of objective response to the first documentation of PD or death due to any cause, whichever comes first, as assessed by BICR | Up to approximately 3 years | 
| Time to Response (TTR) | Time from the start of study treatment to the first documentation of objective response, as assessed by investigator | Up to approximately 1 year | 
| TTR per BICR (Part E) | Time from the start of study treatment to the first documentation of objective response, as assessed by BICR | Up to approximately 1 year | 
| Progression-free survival (PFS) | Time from the start of study treatment to the first documentation of PD according to RECIST v1.1 or death due to any cause, whichever comes first, as assessed by the investigator | Up to approximately 3 years | 
| PFS per BICR (Part E) | Time from the start of study treatment to the first documentation of PD according to RECIST v1.1 or death due to any cause, whichever comes first, as assessed by BICR | Up to approximately 3 years | 
| Overall Survival (OS) | Time from the start of study treatment to date of death due to any cause | Up to approximately 4 years | 
| Cmax | Maximum observed plasma concentration | Through 30-37 days following the last dose; up to approximately 3 years | 
| Ctrough | Observed plasma concentration at the end of the dosing interval | Through 30-37 days following the last dose; up to approximately 3 years | 
| Incidence of anti-therapeutic antibodies (ATAs) |  | Through 30-37 days following the last dose; up to approximately 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Colorectal cancer, NSCLC, SCCHN, CRC, Pancreatic cancer, Head and neck cancer, Seattle Genetics, HNSCC