A Trial of Tisotumab Vedotin in Cervical Cancer

• ClinicalTrials.gov Identifier: NCT03438396
• Recruitment Status: Completed
• First Posted: February 19, 2018
• Results First Posted: November 4, 2021
• Last Update Posted: July 25, 2023
• Sponsor: Seagen Inc.
• Collaborators: Genmab; European Network of Gynaecological Oncological Trial Groups (ENGOT); Belgian Gynaecological Oncology Group; Gynecologic Oncology Group
• Information provided by (Responsible Party): Seagen Inc.

Tracking Information

• First Submitted Date: February 8, 2018
• First Posted Date: February 19, 2018
• Results First Submitted Date: October 6, 2021
• Results First Posted Date: November 4, 2021
• Last Update Posted Date: July 25, 2023
• Actual Study Start Date: June 12, 2018
• Actual Primary Completion Date: February 6, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 11, 2023)

Percentage of Participants With Confirmed Objective Response (OR) as Assessed by the Independent Review Committee (IRC) [ Time Frame: From Day 1 through IRC verified disease progression, initiation of new anticancer therapy, study withdrawal, or death, whichever occurred first (approximately 20 months) ]

The confirmed OR is defined as best overall response of confirmed complete response (CR) or confirmed partial response (PR) based upon RECIST v1.1, assessed by the IRC. The CR is disappearance of all target and non-target lesions and no new lesions. A confirmed CR is 2 CRs (CR-CR sequence) that were separated by at least 4 weeks with no evidence of progression in-between. The PR is ≥ 30% decrease in the sum of diameters of target lesions (compared to baseline) and no unequivocal progression of existing non-target lesions and no new lesion. A confirmed PR is PR-PR sequence or PR-CR sequence that were separated by at least 4 weeks. The intermediate missing (Not Evaluable [NE]) scan evaluations between response scan and confirmation scan were allowed, eg, PR-NE-PR and PR-NE-NE-PR was considered PR confirmed (a repeat scan not earlier than 4 weeks after initial scan documenting response). 95% CI was calculated using the Clopper-Pearson method.

Original Primary Outcome Measures (submitted: February 16, 2018)

confirmed objective response rate [ Time Frame: up to 2 years ]

Objective response based upon RECIST v1.1, assessed by independent review committee (IRC).

Current Secondary Outcome Measures (submitted: July 11, 2023)

• Duration of Response (DOR) as Assessed by the IRC [ Time Frame: From Day 1 through IRC verified disease progression, initiation of new anticancer therapy, study withdrawal, or death, whichever occurred first (approximately 49 months) ]
  The DOR is defined as the duration from the first documented response of CR or PR (the start date of response, not the date when response was confirmed) to the date of the first documented progression disease (PD) verified by IRC or death. Based upon RECIST v1.1, the CR is defined as disappearance of all target and non-target lesions and no new lesions; the PR is defined as ≥ 30% decrease in the sum of diameters of target lesions (compared to baseline) and no unequivocal progression of existing non-target lesions and no new lesion; and the PD is defined as at least 20% increase in the sum of diameters of target lesions (compared to baseline), unequivocal progression of existing non-target lesions, and/or new lesion. The DOR was estimated using Kaplan-Meier method.
• Percentage of Participants With Confirmed OR as Assessed by the Investigator [ Time Frame: From Day 1 through investigator verified disease progression, initiation of new anticancer therapy, study withdrawal, or death, whichever occurred first (approximately 49 months) ]
  The confirmed OR is defined as best overall response of confirmed CR or confirmed PR based upon RECIST v1.1, assessed by the investigator. The CR is defined as disappearance of all target and non-target lesions and no new lesions. A confirmed CR is defined as 2 CRs (CR-CR sequence) that were separated by at least 4 weeks with no evidence of progression in-between. The PR is defined as ≥ 30% decrease in the sum of diameters of target lesions (compared to baseline) and no unequivocal progression of existing non-target lesions and no new lesion. A confirmed PR is defined as PR-PR sequence or PR-CR sequence that were separated by at least 4 weeks. The intermediate missing (NE) scan evaluations between the response scan and the confirmation scan were allowed, eg, PR-NE-PR and PR-NE-NE-PR was considered PR confirmed (a repeat scan not earlier than 4 weeks after initial scan documenting response). 95% CI was calculated using the Clopper-Pearson method.
• DOR as Assessed by the Investigator [ Time Frame: From Day 1 through investigator verified disease progression, initiation of new anticancer therapy, study withdrawal, or death, whichever occurred first (approximately 49 months) ]
  The DOR is defined as the duration from the first documented response of CR or PR (the start date of response, not the date when response was confirmed) to the date of the first documented PD verified by investigator or death. Based upon RECIST v1.1, the CR is defined as disappearance of all target and non-target lesions and no new lesions; the PR is defined as ≥ 30% decrease in the sum of diameters of target lesions (compared to baseline) and no unequivocal progression of existing non-target lesions and no new lesion; and the PD is defined as at least 20% increase in the sum of diameters of target lesions (compared to baseline), unequivocal progression of existing non-target lesions, and/or new lesion. The DOR was estimated using Kaplan-Meier method.
• Time to Response (TTR) as Assessed by the IRC [ Time Frame: From Day 1 through IRC verified disease progression, initiation of new anticancer therapy, study withdrawal, or death, whichever occurred first (approximately 49 months) ]
  The TTR is defined as the duration from the start of study drug to the first documented response of either CR or PR based on RECIST v1.1, assessed by the IRC. A confirmed CR is defined as 2 CRs (disappearance of all target and non-target lesions and no new lesions) that were separated by at least 4 weeks with no evidence of progression in-between. A confirmed PR is defined as 2 PRs (≥ 30% decrease in the sum of diameters of target lesions compared to baseline and no unequivocal progression of existing non-target lesions and no new lesion) or an un-confirmed PR and an un-confirmed CR or achieved PR-NE-PR or PR-NE-NE-PR that were separated by at least 4 weeks with no evidence of progression in-between.
• TTR as Assessed by the Investigator [ Time Frame: From Day 1 through investigator verified disease progression, initiation of new anticancer therapy, study withdrawal, or death, whichever occurred first (approximately 49 months) ]
  The TTR is defined as the duration from the start of study drug to the first documented response of either CR or PR based on RECIST v1.1, assessed by the investigator. A confirmed CR is defined as 2 CRs (disappearance of all target and non-target lesions and no new lesions) that were separated by at least 4 weeks with no evidence of progression in-between. A confirmed PR is defined as 2 PRs (≥ 30% decrease in the sum of diameters of target lesions compared to baseline and no unequivocal progression of existing non-target lesions and no new lesion) or an un-confirmed PR and an un-confirmed CR or achieved PR-NE-PR or PR-NE-NE-PR that were separated by at least 4 weeks with no evidence of progression in-between.
• Progression Free Survival (PFS) as Assessed by the IRC [ Time Frame: From Day 1 through IRC verified disease progression, initiation of new anticancer therapy, study withdrawal, or death, whichever occurred first (approximately 49 months) ]
  The PFS is defined as the time from the start of study drug until the first documentation of PD based on RECIST v1.1, as assessed by the IRC or death due to any cause, whichever occurred first. The PD based upon RECIST v1.1 is defined as at least 20% increase in the sum of diameters of target lesions (compared to baseline), unequivocal progression of existing non-target lesions, and/or new lesion. The PFS was estimated using Kaplan-Meier method.
• PFS as Assessed by the Investigator [ Time Frame: From Day 1 through investigator verified disease progression, initiation of new anticancer therapy, study withdrawal, or death, whichever occurred first (approximately 49 months) ]
  The PFS is defined as the time from the start of study drug until the first documentation of PD based on RECIST v1.1, as assessed by the investigator or death due to any cause, whichever occurred first. The PD based upon RECIST v1.1 is defined as at least 20% increase in the sum of diameters of target lesions (compared to baseline), unequivocal progression of existing non-target lesions, and/or new lesion. The PFS was estimated using Kaplan-Meier method.
• Overall Survival (OS) [ Time Frame: From Day 1 until death or withdrawal from the study, whichever occurred first (approximately 49 months) ]
  The OS is defined as the time from the start of study treatment until death due to any cause. The OS was estimated using Kaplan-Meier method.
• Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) [ Time Frame: From Day 1 through 30 days after the last dose of study drug (approximately 49 months) ]
  An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A SAE is defined as an AE that meets one of the following criteria: fatal or life-threatening; results in persistent or significant disability/incapacity; constitutes a congenital anomaly/birth defect; medically significant (an event that jeopardizes the participant or may require medical or surgical intervention to prevent one of the outcomes listed above [medical and scientific judgment must be exercised in deciding whether an AE is "medically important"]); required inpatient hospitalization or prolongation of existing hospitalization. A TEAE is defined as an AE occurring or worsening between the first dose of tisotumab vedotin and 30 days after the last dose received.
• Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs [ Time Frame: From Day 1 through 30 days after the last dose of study drug (approximately 49 months) ]
  Laboratory abnormalities that induced clinical signs or symptoms, required concomitant therapy or required changes during treatment emergent period were reported as TEAEs. Number of participants with abnormal clinical laboratory parameters reported as TEAEs are reported.
• Plasma Concentrations of Tisotumab Vedotin (HuMax-TF), Tisotumab Vedotin Antibody-drug Conjugate (HuMax-TF-ADC), and Free Monomethyl Auristatin E (MMAE) [ Time Frame: Predose and end of infusion of Cycle 1 Day 1 (C1D1) and Cycle 6 Day 1 (C6D1) ]
  Plasma concentrations of HuMax-TF, HuMax-TF-ADC, and Free MMAE measures on Cycle 1 Day 1 (predose and end of infusion) and Cycle 6 Day 1 (predose and end of infusion) are reported.
• Number of Participants With Positive Anti-drug Antibodies (ADA) to Tisotumab Vedotin [ Time Frame: Predose of each treatment cycle (Cycle 1 to 21) and end of treatment visit (approximately 49 months) ]
  Number of participants with positive ADA titer to tisotumab vedotin at baseline and post-baseline are reported. Baseline is defined as the latest available measurement made before the first dose of tisotumab vedotin. For post-baseline results, a participant was considered ADA positive if either ADA is negative at baseline and at least one post-baseline result is positive or positive at baseline and at least one positive post-baseline result with a titer higher than baseline.

Original Secondary Outcome Measures (submitted: February 16, 2018)

• Duration of response [ Time Frame: up to 2 years ]
  Duration of response (DOR) based upon RECIST v1.1
• Progression free survival [ Time Frame: up to 2 years ]
  Progression free survival based upon RECIST v1.1
• Overall survival [ Time Frame: up to 2 years ]
  Overall survival

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Trial of Tisotumab Vedotin in Cervical Cancer
• Official Title: A Single Arm, Multicenter, International Trial of Tisotumab Vedotin (HuMax®-TF-ADC) in Previously Treated, Recurrent or Metastatic Cervical Cancer
• Brief Summary: A Single arm, Multicenter, International Trial of Tisotumab Vedotin (HuMax®-TF-ADC) in Previously Treated, Recurrent or Metastatic Cervical Cancer.
• Detailed Description: The purpose of the trial is to evaluate the efficacy and safety/tolerability of tisotumab vedotin in patients with previously treated, recurrent or metastatic cervical cancer. Tisotumab vedotin is an antibody-drug conjugate (ADC) targeting tissue factor (TF), a protein aberrantly expressed in a wide number of tumors including cervical cancer. Preliminary safety and efficacy data observed in a cohort of previously treated cervical cancer patients suggest a positive benefit risk profile for this population of high unmet need.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Cervical Cancer

Intervention

Drug: tisotumab vedotin

All patients will be treated with tisotumab vedotin once every three weeks until progression or toxicity

Other Name: TIVDAK

Study Arms

Experimental: Single arm

tisotumab vedotin (IV), 2.0 mg/kg, every 3 weeks (1Q3W)

Intervention: Drug: tisotumab vedotin

• Publications *: Coleman RL, Lorusso D, Gennigens C, Gonzalez-Martin A, Randall L, Cibula D, Lund B, Woelber L, Pignata S, Forget F, Redondo A, Vindelov SD, Chen M, Harris JR, Smith M, Nicacio LV, Teng MSL, Laenen A, Rangwala R, Manso L, Mirza M, Monk BJ, Vergote I; innovaTV 204/GOG-3023/ENGOT-cx6 Collaborators. Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021 May;22(5):609-619. doi: 10.1016/S1470-2045(21)00056-5. Epub 2021 Apr 9.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 23, 2019): 102
• Original Estimated Enrollment (submitted: February 16, 2018): 100
• Actual Study Completion Date: August 2, 2022
• Actual Primary Completion Date: February 6, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria

• Patients with extra-pelvic metastatic or recurrent cervical cancer including squamous cell, adenocarcinoma or adenosquamous histology who have experienced disease progressed on standard of care chemotherapy in combination with bevacizumab, if eligible.
• Measurable disease according to RECIST v1.1 as assessed by IRC.
• Age ≥ 18 years.
• Acceptable renal function
• Acceptable liver function
• Acceptable hematological status
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• A negative serum pregnancy test for patients of reproductive potential.
• All patients must provide a fresh or archival biopsy during screening.
• Following receipt of verbal and written information about the trial, patients must provide signed informed consent before any trial-related activity is carried out.

Exclusion Criteria

• Have received no more than 2 prior systemic treatment regimens for recurrent or metastatic cervical cancer.
• Known past or current coagulation defects leading to an increased risk of bleeding;
• Ongoing major bleeding
• Active ocular surface disease
• Known past or current malignancy other than the inclusion diagnosis.
• Peripheral neuropathy grade ≥ 2

Sex/Gender

• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Gender Eligibility Description: cervical cancer

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Czechia, Denmark, Germany, Italy, Spain, Sweden, United States

Administrative Information

• NCT Number: NCT03438396
• Other Study ID Numbers: GCT1015-04; innovaTV 204 ( Other Identifier: Genmab )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Seagen Inc.
• Original Responsible Party: Genmab
• Current Study Sponsor: Seagen Inc.
• Original Study Sponsor: Genmab

Collaborators

• Genmab
• European Network of Gynaecological Oncological Trial Groups (ENGOT)
• Belgian Gynaecological Oncology Group
• Gynecologic Oncology Group

• Investigators: Not Provided
• PRS Account: Seagen Inc.
• Verification Date: July 2023