Safety and Efficacy of Tisotumab Vedotin Monotherapy & in Combination With Other Cancer Agents in Subjects With Cervical Cancer

• ClinicalTrials.gov Identifier: NCT03786081
• Recruitment Status: Active, not recruiting
• First Posted: December 24, 2018
• Last Update Posted: February 12, 2024
• Sponsor: Seagen Inc.
• Collaborators: Genmab; European Network of Gynaecological Oncological Trial Groups (ENGOT); Belgian Gynaecological Oncology Group; GOG Foundation; Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Seagen Inc.

Tracking Information

• First Submitted Date: December 13, 2018
• First Posted Date: December 24, 2018
• Last Update Posted Date: February 12, 2024
• Actual Study Start Date: February 27, 2019
• Estimated Primary Completion Date: December 31, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 15, 2022)

• Dose escalation: Dose Limiting Toxicities (DLTs) [ Time Frame: DLTs will be identified during the first treatment cycle (21 day cycles) ]
  To establish the MTD and RP2D of tisotumab vedotin in combination
• Dose expansion: Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) [ Time Frame: approximately 2 years ]
  Objective response is defined as confirmed partial response (PR) or complete response (CR)

Original Primary Outcome Measures (submitted: December 20, 2018)

• Dose escalation: Dose Limiting Toxicities (DLTs) [ Time Frame: DLTs will be identified during the first treatment cycles (21 days cycles) ]
  To establish the MTD and RP2D of tisotumab vedotin in combination
• Dose expansion: Evaluate the antitumor activity of tisotumab vedotin in combination in subjects with cervical cancer [ Time Frame: approximately 2 years ]
  Objective Response Rate (ORR) based upon RECIST v1.1.

Current Secondary Outcome Measures (submitted: January 15, 2022)

• Number of adverse events (AEs) [ Time Frame: up to 2 years ]
  Any untoward medical occurrence in a clinical trial participant whether or not considered related to the medicinal product.
• Dose escalation: ORR per RECIST v1.1 [ Time Frame: approximately 2 years ]
  Objective response is defined as confirmed PR or CR.
• Duration of Response (DOR) per RECIST v1.1 by investigator assessment [ Time Frame: approximately 2 years ]
  Will be calculated from the date of initial documentation of a response (CR or PR) to the date of first documented evidence of progressive disease (PD) or death.
• Time to Response (TTR) per RECIST v1.1 by investigator assessment [ Time Frame: approximately 2 years ]
  Will be calculated from the date of the first dose to the date of the initial documentation of response (CR or PR).
• Progression free survival (PFS) per RECIST v1.1 by investigator assessment [ Time Frame: approximately 2 years ]
  The time from the date of the first trial drug administration to the date of the first documented disease progression or death due to any cause.
• Overall Survival (OS) [ Time Frame: approximately 2 years ]
  The time from the date of the first trial drug administration to the date of death due to any cause.
• Maximum concentration (Cmax) (All Arms except G) [ Time Frame: Up to 42 days ]
  Pharmacokinetic (PK) parameter
• Cmax (Arm G only) [ Time Frame: Up to 2 years ]
  PK parameter
• Trough Concentration (Ctrough) (All Arms) [ Time Frame: Up to 2 years ]
  PK parameter
• Area under the concentration-time curve (AUC) (All Arms except G) [ Time Frame: Through 21 days after first dose ]
  PK parameter
• AUC (Arm G only) [ Time Frame: Through 8 days after first dose ]
  PK parameter
• Anti-drug antibodies (ADAs) [ Time Frame: Up to 2 years ]

Original Secondary Outcome Measures (submitted: December 20, 2018)

• Adverse events (AEs) [ Time Frame: up to 2 years ]
  Frequency, duration, and severity of adverse events (AEs)
• Objective Response Rate [ Time Frame: approximately 2 years ]
  Objective Response Rate (ORR) based upon RECIST v1.1.
• Duration of Response [ Time Frame: approximately 2 years ]
  Duration of Response (DOR) based upon RECIST v1.1.
• Time to Response [ Time Frame: approximately 2 years ]
  Time to Response (TTR) based upon RECIST v1.1.
• Progression free survival [ Time Frame: approximately 2 years ]
  Progression free survival (PFS) based upon RECIST v1.1.
• Overall Survival [ Time Frame: approximately 2 years ]
  Overall Survival (OS)

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

Descriptive Information

• Brief Title: Safety and Efficacy of Tisotumab Vedotin Monotherapy & in Combination With Other Cancer Agents in Subjects With Cervical Cancer
• Official Title: A Phase 1b/2 Open-Label Trial of Tisotumab Vedotin (HuMax®-TF-ADC) Monotherapy and in Combination With Other Agents in Subjects With Recurrent or Stage IVB Cervical Cancer

Brief Summary

This is an open label, multi-center trial of tisotumab vedotin monotherapy and in combination with bevacizumab, pembrolizumab, or carboplatin in subjects with recurrent or stage IVB cervical cancer.

The trial consists of two-parts a dose escalation part and an expansion part. The expansion part of the trial will be initiated once the Recommended Phase 2 Dose (RP2D) of the combinations have been determined in the dose escalation part.

Detailed Description

The dose escalation part will occur in participants with cervical cancer who have progressed during or after standard of care therapy and who are intolerant or ineligible to receive standard of care treatments. Arm A will be conducted by escalating doses of both tisotumab vedotin and bevacizumab. Dose escalations of the tisotumab vedotin + pembrolizumab and tisotumab vedotin + carboplatin combinations (Arms B and C, respectively) will be conducted by combining fixed doses of either pembrolizumab or carboplatin with increasing doses of tisotumab vedotin.

The dose expansion part of this study (Arms D through H) will be conducted in 2 populations: participants with cervical cancer who have not received prior systemic therapy for recurrent or stage IVB cervical cancer (Arms D, E, and H) and participants with cervical cancer who have progressed on or after at least 1 but no more than 2 prior systemic therapies (Arms F and G).

Participants enrolled to Arms D, E, F and H will receive the RP2D of tisotumab vedotin established in the dose escalation part. Participants enrolled to Arm G will receive tisotumab vedotin weekly (at a dose lower than subjects in all other Arms) for three weeks and 1 week off (28-day treatment cycle).

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Cervical Cancer

Intervention

• Drug: Tisotumab Vedotin
  Given into the vein (IV)
  Other Name: TIVDAK
• Drug: Bevacizumab
  Given via IV
  Other Name: Avastin
• Drug: Pembrolizumab
  Given via IV
  Other Name: KEYTRUDA®
• Drug: Carboplatin
  Given via IV
  Other Name: Paraplatin

Study Arms

• Experimental: A: Tisotumab Vedotin + bevacizumab
  Dose escalation: Tisotumab vedotin in combination with bevacizumab once every three weeks in previously treated patients
  Interventions:

  • Drug: Tisotumab Vedotin
  • Drug: Bevacizumab
• Experimental: B: Tisotumab vedotin + pembrolizumab
  Dose escalation: Tisotumab vedotin in combination with pembrolizumab once every three weeks in previously treated patients
  Interventions:

  • Drug: Tisotumab Vedotin
  • Drug: Pembrolizumab
• Experimental: C: Tisotumab vedotin + carboplatin
  Dose escalation: Tisotumab vedotin in combination with carboplatin once every three weeks in previously treated patients
  Interventions:

  • Drug: Tisotumab Vedotin
  • Drug: Carboplatin
• Experimental: D: Tisotumab vedotin + carboplatin
  Dose expansion:Tisotumab vedotin in combination with carboplatin once every three weeks in previously untreated patients
  Interventions:

  • Drug: Tisotumab Vedotin
  • Drug: Carboplatin
• Experimental: E: Tisotumab vedotin + pembrolizumab
  Dose expansion: Tisotumab vedotin in combination with pembrolizumab once every three weeks in previously untreated patients
  Interventions:

  • Drug: Tisotumab Vedotin
  • Drug: Pembrolizumab
• Experimental: F: Tisotumab vedotin + pembrolizumab
  Dose expansion: Tisotumab vedotin in combination with pembrolizumab once every three weeks in previously treated patients
  Interventions:

  • Drug: Tisotumab Vedotin
  • Drug: Pembrolizumab
• Experimental: G: Tisotumab vedotin monotherapy
  Dose expansion: Tisotumab vedotin monotherapy weekly for three weeks and 1 week off (28 day treatment cycle) in previously treated patients.
  Intervention: Drug: Tisotumab Vedotin
• Experimental: H: Tisotumab vedotin + pembrolizumab + carboplatin +/- bevacizumab
  Dose expansion: Tisotumab vedotin in combination with pembrolizumab and carboplatin with or without bevacizumab once every three weeks in previously untreated patients
  Interventions:

  • Drug: Tisotumab Vedotin
  • Drug: Bevacizumab
  • Drug: Pembrolizumab
  • Drug: Carboplatin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 9, 2023): 214
• Original Estimated Enrollment (submitted: December 20, 2018): 140
• Estimated Study Completion Date: December 31, 2024
• Estimated Primary Completion Date: December 31, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Must have squamous, adenosquamous, or adenocarcinoma of the cervix and progressed on or after standard of care treatments or are ineligible or intolerant to standard of care for recurrent or stage IVB cervical cancer (Arms A, B and C only).
• Must have squamous, adenosquamous, or adenocarcinoma of the cervix and must not have received prior systemic therapy for recurrent or stage IVB cervical cancer (Arms D, E, and H only).
• Must have squamous, adenosquamous, or adenocarcinoma of the cervix and progressed on or after at least one but no more than two prior systemic therapies for recurrent or stage IVB cervical cancer (Arms F and G only).
• Must have baseline measurable disease per RECIST v1.1.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (All Arms).
• Is not pregnant, breastfeeding, or expecting to conceive children within the projected duration of the trial and for at least 6 months after the last trial treatment administration
• Participants of childbearing potential must agree to use adequate contraception during and for 6 months after the last dose of trial treatment administration.
• Must sign an informed consent form (ICF) indicating the trial subject understands the purpose of and procedures required for the trial and are willing to participate in the trial (All Arms).

Exclusion Criteria:

• Has clinically relevant bilateral hydronephrosis which cannot be alleviated by ureteral stents or percutaneous drainage. (All Arms)
• Has clinical signs or symptoms of gastrointestinal obstruction and requires parenteral hydration and/or nutrition. Post-operative obstructions within 4 weeks of abdominal surgery are permitted. (All Arms)

• Has clinically significant bleeding issues or risks

  • Prior history (within 3 months) or current evidence of hemoptysis (1/2 teaspoon or more) (Arm A and bevacizumab-eligible participants in Arm H)
  • Recent (within 4 weeks of first dose of trial treatment) clinically significant gastrointestinal or vaginal bleeding requiring PRBC transfusion (Arms A and H only)
  • Recent (within 4 weeks of first dose of trial treatment) evidence of wound healing complications that require medical intervention (Arms A and H only)
• Has active ocular surface disease at baseline. Subjects with prior history of cicatricial conjunctivitis are ineligible (All Arms).
• Clinically significant cardiac disease
• Requires anti-coagulation therapy (Arms A and H only)

Sex/Gender

• Sexes Eligible for Study: Female

• 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, Ireland, Italy, Netherlands, Spain, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT03786081
• Other Study ID Numbers: GCT1015-05; InnovaTV 205 ( Other Identifier: Genmab ); MK-3475-834 ( Other Identifier: Merck Sharp & Dohme LLC ); ENGOT-cx8 ( Other Identifier: European Network of Gynaecological Oncological Trial ); GOG-3024 ( Other Identifier: GOG Foundation ); KEYNOTE-834 ( Other Identifier: Merck Sharp & Dohme LLC ); 2017-004758-40 ( EudraCT Number )
• 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: Not Provided
• 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
• GOG Foundation
• Merck Sharp & Dohme LLC

• Investigators: Not Provided
• PRS Account: Seagen Inc.
• Verification Date: February 2024