A Study of Weekly Tisotumab Vedotin for Patients With Platinum-Resistant Ovarian Cancer With Safety Run-in (innovaTV 208)

Study Overview
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Brief Summary
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This trial will study tisotumab vedotin to find out what its side effects are and to see if it works for platinum-resistant ovarian cancer (PROC). It will test different doses of tisotumab vedotin that are given at different times. It will also compare the side effects and ability to treat tumors of these different doses and schedules. In this study, there will be a safety run-in group of approximately 12 patients that will look at a dose-dense treatment schedule. In a dose-dense schedule, smaller doses are given more frequently. In addition to the safety run-in patients, there will be three groups in the study. One group will get tisotumab vedotin once every 3 weeks (21-day cycles). The two other groups will get tisotumab vedotin once a week for 3 weeks followed by 1 week off (28-day cycles).

Detailed Description
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The study objectives are to evaluate the safety, antitumor activity, and pharmacokinetics of tisotumab vedotin (TV) administered every 3 weeks or on Days 1, 8, and 15 of every 4-week cycle (3Q4W) for patients with epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer that has relapsed within 6 months of the completion of platinum-based treatment and determined to be platinum resistant. All patients must have PROC and be eligible for single agent chemotherapy. The safety run-in period will evaluate the safety of a weekly schedule. The highest dose level that is considered safe will be the recommended phase 2 dose (RP2D) and will be used in Part A. In Part A, participants will be randomized in a 1:1 ratio to receive tisotumab vedotin intravenously (IV) every 3 weeks (Q3W regimen) or the safety run-in RP2D on Days 1, 8, and 15 of every 4-week cycle (weekly regimen; 3Q4W) if a RP2D has been identified. Participants who enroll in Part B will receive tisotumab vedotin on Days 1, 8, and 15 of every 4-week cycle (weekly regimen) at a pre-specified dose level, if the dose level is considered safe and tolerable in the safety run-in period.

Official Title
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Open Label Phase 2 Study of Tisotumab Vedotin for Patients With Platinum-Resistant Ovarian Cancer With a Safety Run-in of a Dose-Dense Regimen

Conditions
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Ovarian Cancer, Fallopian Tube Cancer, Peritoneal Cancer

Intervention / Treatment
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* Drug: tisotumab vedotin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic documentation of epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer Safety run-in only: PROC. Patients may have received more than 1 prior systemic treatment regimen in the PROC setting. Part A and Part B only: Patients with PROC who have received 1 to 3 anticancer lines of therapy overall, including at least 1 line of therapy containing bevacizumab or biosimilar. Adjuvant ± neoadjuvant are considered 1 line of therapy. Patients may have received a PARP inhibitor or an immuno-oncology (IO) agent; any of these regimens are to be considered a line of therapy for the purposes of this study if not used as maintenance therapy. Maintenance therapy (including bevacizumab, PARP inhibitors and IOs) will be considered part of the preceding line of therapy and not to be counted as a new line of therapy. Any chemotherapy regimen change due to toxicity in the absence of disease progression is considered as part of the same line of therapy. Hormonal therapy will be not be counted towards the lines of therapy. Measurable disease according to RECIST v1.1 as assessed by the investigator An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 Life expectancy of at least 3 months Able to provide fresh or archival tissue for biomarker analysis Exclusion Criteria: Primary platinum-refractory disease, defined as disease progression within 2 months of completion of first line platinum-based therapy Patients with clinical symptoms or signs of gastrointestinal obstruction with the past 6 months or who currently require parenteral nutrition Hematological: Known past or current coagulation defects leading to an increased risk of bleeding, diffuse alveolar hemorrhage from vasculitis, known bleeding diathesis, ongoing major bleeding, or trauma with increased risk of life-threatening bleeding within 8 weeks of trial entry Cardiovascular: Clinically significant cardiac disease including uncontrolled hypertension, unstable angina, acute myocardial infarction with 6 months of screening, serious cardiac arrhythmia requiring medication, medical history of congestive heart failure, or medical history of decreased cardiac ejection fraction of <45% Ophthalmological: Active ocular surface disease at baseline or prior episode of cicatricial conjunctivitis or Stevens Johnson syndrome Prior treatment with MMAE-derived drugs Inflammatory bowel disease including Crohn's disease and ulcerative colitis Ongoing, acute, or chronic inflammatory skin disease Uncontrolled tumor-related pain Inflammatory lung disease requiring chronic medical therapy Grade 3 or higher pulmonary disease unrelated to underlying malignancy Uncontrolled pleural or pericardial effusions Grade >1 peripheral neuropathy Patients who are pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety Run-In (3Q4W Schedule)<br>28-day, 3 dose cycle | Drug: tisotumab vedotin<br>* Intravenous (IV) infusion<br>* Other names: TIVDAK;|
| Experimental: Part A: Tisotumab Vedotin<br>21-day, single dose cycle | Drug: tisotumab vedotin<br>* Intravenous (IV) infusion<br>* Other names: TIVDAK;|
| Experimental: Part A: Tisotumab Vedotin (3Q4W Schedule)<br>28-day, 3 dose cycle | Drug: tisotumab vedotin<br>* Intravenous (IV) infusion<br>* Other names: TIVDAK;|
| Experimental: Part B: Tisotumab Vedotin (3Q4W Schedule)<br>28-day, 3 dose cycle | Drug: tisotumab vedotin<br>* Intravenous (IV) infusion<br>* Other names: TIVDAK;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-Limiting Toxicities (DLTs) (Safety Run-In Only) | Incidence of dose-limiting toxicity (DLT) was evaluated in participants enrolled in the Safety Run-In, who were followed for protocol-defined DLT events up to 28 days after the first dose of tisotumab vedotin. | Up to 28 days | 
| Confirmed Objective Response Rate (ORR) (Part B) | Proportion of participants who achieve a confirmed complete response (CR) or partial response (PR) according to RECIST v1.1 as assessed by the investigator | Up to 9.7 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) (Part B) | An AE is any untoward medical occurrence in a patient or clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Treatment emergent AEs (TEAEs) are defined as events that are new or worsened on or after receiving the first dose of study treatment and up through 30 days after the last dose of study treatment. | Up to 23.0 months | 
| Confirmed and Unconfirmed ORR (Part B) | Proportion of participants who achieve a CR or PR according to RECIST v1.1 as assessed by the investigator | Up to 9.7 months | 
| Cancer Antigen 125 (CA-125) Response Rate According to Gynecologic Cancer Intergroup (GCIG) Criteria (Part B) | Percentage of participants who have at least a 50% reduction in CA-125 value from baseline | Up to 10.1 months | 
| Overall Response According to the Gynecological Cancer Intergroup (GCIG) Combined RECIST and CA-125 Criteria (Part B) | Percentage of participants whose best response is a CR or PR according to the GCIG combined RECIST and CA-125 criteria | Up to 10.1 months | 
| Duration of Response (DOR) (Part B) | Time from the first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of PD or death due to any cause, whichever comes first | Up to 8.3 months | 
| Disease Control Rate (DCR) (Part B) | Percentage of participants who achieved a confirmed Complete Response(CR) or Partial Response (PR) per 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 3.0 months | 
| Time to Response (TTR) (Part B) | Time from the start of study treatment to the first documentation of objective response (CR or PR that is subsequently confirmed) | Up to 23.0 months | 
| Progression-free Survival (PFS) (Part B) | Time from the start of study treatment to the first documentation of PD or death due to any cause, whichever comes first | Up to 9.7 months | 
| Overall Survival (OS) (Part B) | Time from the start of study treatment to date of death due to any cause | Up to 23.0 months | 
| Incidence of Antitherapeutic Antibodies (ATA) (Part B) | The proportion of participants who develop ATA at any time during the study. A positive baseline ATA result is considered positive post-baseline if the post-baseline ATA titer result is at least four times higher than the baseline result. | Up to 6.9 months | 
| Pharmacokinetic (PK) Parameter: Antibody-Drug Conjugate (ADC) Maximum Concentration (Cmax) (Part B) | ADC Cmax was derived from the PK blood samples collected. | Samples for PK measures were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle. | 
| PK Parameter: ADC Time of Cmax (Tmax) (Part B) | ADC Tmax was derived from the PK blood samples collected. | Samples for PK measures were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle. | 
| PK Parameter: ADC Area Under Concentration-Time Curve (AUC) (Part B) | ADC AUC was derived from the PK blood samples collected. | Cycle 1 Dose 1 AUC 7: Assessed from Cycle 1 Days 1 - 8 (predose). Cycle 1 Dose 3 AUC 7: Assessed from Cycle 1 Days 15 - 22. Cycle 1 Dose 3 AUC 14: Assessed from Cycle 1 Days 15 - Cycle 2 Day 1 (predose). | 
| PK Parameter: Free Monomethyl Auristatin E (MMAE) Cmax (Part B) | MMAE Cmax was derived from the PK blood samples collected. | Samples for PK measures were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle. | 
| PK Parameter: MMAE Tmax (Part B) | MMAE Tmax was derived from the PK blood samples collected. | Samples for PK measures were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle. | 
| PK Parameter: MMAE AUC (Part B) | MMAE AUC was derived from the PK blood samples collected. | Samples for PK measures were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle. | 
| PK Parameter: MMAE Trough Concentration (Ctrough) (Part B) | MMAE Ctrough was derived from the PK blood samples collected. | Samples for PK measures were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle. | 
| PK Parameter: Total Antibody (TAb) Cmax (Part B) | TAb Cmax was derived from the PK blood samples collected. | Samples for PK measures were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle. | 
| PK Parameter: TAb Tmax (Part B) | TAb Tmax was derived from the PK blood samples collected. | Samples for PK measures were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle. | 
| PK Parameter: TAb Area Under Concentration-Time Curve (AUC) (Part B) | TAb AUC was derived from the PK blood samples collected. | Cycle 1 Dose 1 AUC 7: Assessed from Cycle 1 Days 1 - 8 (predose). Cycle 1 Dose 3 AUC 7: Assessed from Cycle 1 Days 15 - 22. Cycle 1 Dose 3 AUC 14: Assessed from Cycle 1 Days 15 - Cycle 2 Day 1 (predose). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Platinum-resistant, Antibody drug conjugate, Tisotumab vedotin, PROC, Seattle Genetics