A Trial of Tisotumab Vedotin in Cervical Cancer

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.

• tisotumab vedotin (Drug), also known as TIVDAK: All patients will be treated with tisotumab vedotin once every three weeks until progression or toxicity

Primary outcomes

• Percentage of Participants With Confirmed Objective Response (OR) as Assessed by the Independent Review Committee (IRC) [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.

Secondary outcomes

• Duration of Response (DOR) as Assessed by the IRC [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 [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 [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 [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 [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 [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 [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) [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) [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 [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) [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 [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.

Sex: Female, ages: 18 Years to any

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

Participant flow

Outcome results

• Percentage of Participants With Confirmed Objective Response (OR) as Assessed by the Independent Review Committee (IRC) (Primary), Number, Percentage of Participants: Tisotumab Vedotin 23.8 (15.9 to 33.3) (p 0.0002)
• Duration of Response (DOR) as Assessed by the IRC (Secondary), Median, Months: Tisotumab Vedotin 8.3 (4.2 to 13.5)
• Percentage of Participants With Confirmed OR as Assessed by the Investigator (Secondary), Number, Percentage of Participants: Tisotumab Vedotin 20.8 (13.4 to 30.0)
• DOR as Assessed by the Investigator (Secondary), Median, Months: Tisotumab Vedotin 8.2 (3.7 to 18.4)
• Time to Response (TTR) as Assessed by the IRC (Secondary), Median, Months: Tisotumab Vedotin 1.4 (1.1 to 5.1)
• TTR as Assessed by the Investigator (Secondary), Median, Months: Tisotumab Vedotin 1.4 (1.1 to 4.5)
• Progression Free Survival (PFS) as Assessed by the IRC (Secondary), Median, Months: Tisotumab Vedotin 4.2 (3.0 to 4.4)
• PFS as Assessed by the Investigator (Secondary), Median, Months: Tisotumab Vedotin 4.1 (3.3 to 4.6)
• Overall Survival (OS) (Secondary), Median, Months: Tisotumab Vedotin 12.3 (9.6 to 14.1)
• Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) (Secondary), Count of participants, Participants: Tisotumab Vedotin 101
• Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs (Secondary), Count of participants, Participants: Tisotumab Vedotin 34
• Plasma Concentrations of Tisotumab Vedotin (HuMax-TF), Tisotumab Vedotin Antibody-drug Conjugate (HuMax-TF-ADC), and Free Monomethyl Auristatin E (MMAE) (Secondary), Geometric mean, ng/mL: Tisotumab Vedotin 163.48 +/- 60.70
• Number of Participants With Positive Anti-drug Antibodies (ADA) to Tisotumab Vedotin (Secondary), Count of participants, Participants: Tisotumab Vedotin 2

Adverse events

Time frame: From Day 1 through 30 days after the last dose of study drug (approximately 49 months)

Serious adverse events by term

Other adverse events by term

218 more terms not shown.

• Results publication: Feng S, Gunawan R, Passey C, Voellinger J, Polhamus D, Gerritsen A, O'Day C, Carret AS, Soumaoro I, Gupta M, Hanley WD. Exposure-safety Markov modeling of ocular adverse events in patient populations treated with tisotumab vedotin. J Pharmacokinet Pharmacodyn. 2025 Oct 3;52(5):55. doi: 10.1007/s10928-025-10003-w. PMID 41044356
• Results publication: Passey C, Voellinger J, Gibiansky L, Gunawan R, Nicacio L, Soumaoro I, Hanley WD, Winter H, Gupta M. Exposure-safety and exposure-efficacy analyses for tisotumab vedotin for patients with locally advanced or metastatic solid tumors. CPT Pharmacometrics Syst Pharmacol. 2023 Sep;12(9):1262-1273. doi: 10.1002/psp4.13007. Epub 2023 Jul 26. PMID 37496366
• Results publication: 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. PMID 33845034

• Study Protocol (PDF, 2019-06-17)
• Statistical Analysis Plan (PDF, 2019-10-31)