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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Cervical Cancer
• Intervention / Treatment: Drug: Tisotumab Vedotin; Drug: Bevacizumab; Drug: Pembrolizumab; Drug: Carboplatin

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
• Enrollment (Actual): 214
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Genmab A/S Trial Information; Phone Number: +4570202728; Email: clinicaltrials@genmab.com

Study Locations

• Belgium
  • Brugge, Belgium, 8000
    • AZ Sint-Jan
  • Brussels, Belgium, 1200
    • Cliniques Universitaires Saint-Luc
  • Bruxelles, Belgium, 1200
    • Cliniques Universitaires Saint-Luc
  • Charleroi, Belgium, 6000
    • Grand Hopital de Charleroi
  • Edegem, Belgium, 2650
    • Universitair Ziekenhuis Antwerpen (Uza)
  • Gent, Belgium, 9000
    • Universitair Ziekenhuis Gent
  • Leuven, Belgium, 3000
    • UZ Leuven
  • Leuven, Belgium
    • Universitaire Ziekenhuizen Leuven,
  • Libramont, Belgium, 6800
    • Centre Hospitalier de l'Ardenne
  • Liège, Belgium, 4000
    • Centre Hospitalier Universitaire (Chu) de Liege
  • Loverval, Belgium, 6280
    • Grand Hopital de Charleroi
  • Namur, Belgium, 5000
    • Chu Ucl Namur
  • Namur, Belgium, 5000
    • Sainte-Elisabeth
• Czechia
  • Olomouc, Czechia, 775 20
    • Fakultní nemocnice Olomouc
  • Olomouc, Czechia, 77520
    • Fakultní nemocnice Olomouc
  • Ostrava-Poruba, Czechia, 70852
    • Fakultni nemocnice Ostrava
  • Praha, Czechia, 180 81
    • Fakultni nemocnice Bulovka
  • Praha, Czechia, 18081
    • Nemocnice Na Bulovce
  • Praha 2, Czechia, 128 51
    • Vseobecna fakultni nemocnice v Praze
  • Praha 2, Czechia, 12851
    • Vseobecna fakultni nemocnice v Praze
• Denmark
  • Copenhagen, Denmark, 5072
    • Rigshospitalet
• Ireland
  • Cork, Ireland
    • Cork University Hospital
  • Dublin, Ireland, D07 R2WY
    • Mater Misericordiae University Hospital
  • Waterford, Ireland
    • University Hospital Waterford
  • Waterford, Ireland, X91 ER8E
    • Waterford Regional Hospital
• Italy
  • Catania, Italy, 95100
    • Azienda Ospedaliera Cannizzaro
  • Milano, Italy, 20141
    • Ieo Istituto Europeo Di Oncologia
  • Napoli, Italy, 80131
    • Istituto Nazionale Tumori Fondazione G. Pascale
  • Roma, Italy, 00168
    • Fondazione Policlinico Universitario Agostino Gemelli IRCCS
  • Rome, Italy, 00168
    • Fondazione Policlinico Universitario Agostino Gemelli IRCCS
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Amsterdam UMC, Locatie AMC
  • Amsterdam, Netherlands
    • AMC Medical Research
  • Groningen, Netherlands, 9713 GZ
    • Universitair Medisch Centrum Groningen (Umcg)
  • Nijmegen, Netherlands, 6525 GA
    • Radboudumc
  • Rotterdam, Netherlands, 3015 CC
    • Erasmus Medisch Centrum
  • Rotterdam, Netherlands, 3015
    • Erasmus University Medical Center Rotterdam
  • Utrecht, Netherlands, 3508 GA
    • UMC Utrecht
  • Utrecht, Netherlands, 3584
    • University Medical Center Utrecht (UMC Utrecht)
• Spain
  • Barcelona, Spain, 8035
    • Hospital Universitari Vall d'Hebron
  • Cordoba, Spain, 14004
    • Hospital Universitario Reina Sofia
  • El Palmar, Spain, 30120
    • Hospital Universitario Virgen de la Arrixaca
  • Madrid, Spain, 28041
    • Hospital 12 de Octubre
• Turkey
  • Adana, Turkey, 01220
    • Baskent University Adana Application and Research Center
  • Ankara, Turkey, 06490
    • Baskent University Ankara Hospital
• United Kingdom
  • South Glamorgan
    • Cardiff, South Glamorgan, United Kingdom, CF14 2TL
      • Velindre Cancer Centre
  • Strathclyde
    • Glasgow, Strathclyde, United Kingdom, G12 OYN
      • Beatson West of Scotland Cancer Centre
  • Surrey
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • Royal Marsden Hospital- Sutton
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Arizona Oncology Associates
  • California
    • Orange, California, United States, 92868
      • Univ California, Irvine Medical Center
    • Sylmar, California, United States, 91342
      • Olive View - UCLA Research and Education Institute
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Baptist MD Anderson Cancer Center
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Augusta University
  • Illinois
    • Chicago, Illinois, United States, 60525
      • University Of Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University School of Medicine
  • Kansas
    • Westwood, Kansas, United States, 66205
      • University of Kansas Medical Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Oschner Clinic
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • Montana
    • Billings, Montana, United States, 59101
      • Billings Clinic Cancer Center
    • Billings, Montana, United States, 59102
      • Montana Cancer Consortium
  • New York
    • Brooklyn, New York, United States, 11203
      • SUNY Downstate Medical Center
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • University of North Carolina Chapel Hill
  • Ohio
    • Cincinnati, Ohio, United States, 45206
      • University of Cincinnati Physicians Group
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Cleveland, Ohio, United States, 44106
      • Cleveland Clinic
    • Hilliard, Ohio, United States, 43026
      • Ohio State University Wexner Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
    • Pittsburgh, Pennsylvania, United States, 15213
      • Magee-Womens Hospital of UPMC
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Brown University - Women's and Infant Hospital
  • South Carolina
    • Greenville, South Carolina, United States, 29607
      • St Francis Hospital Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Center
  • Virginia
    • Roanoke, Virginia, United States, 24016
      • Carilion Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A: Tisotumab Vedotin + bevacizumab; Dose escalation: Tisotumab vedotin in combination with bevacizumab once every three weeks in previously treated patients	Drug: Tisotumab Vedotin; Given into the vein (IV); Other Names: TIVDAK; Drug: Bevacizumab; Given via IV; Other Names: Avastin
Experimental: B: Tisotumab vedotin + pembrolizumab; Dose escalation: Tisotumab vedotin in combination with pembrolizumab once every three weeks in previously treated patients	Drug: Tisotumab Vedotin; Given into the vein (IV); Other Names: TIVDAK; Drug: Pembrolizumab; Given via IV; Other Names: KEYTRUDA®
Experimental: C: Tisotumab vedotin + carboplatin; Dose escalation: Tisotumab vedotin in combination with carboplatin once every three weeks in previously treated patients	Drug: Tisotumab Vedotin; Given into the vein (IV); Other Names: TIVDAK; Drug: Carboplatin; Given via IV; Other Names: Paraplatin
Experimental: D: Tisotumab vedotin + carboplatin; Dose expansion:Tisotumab vedotin in combination with carboplatin once every three weeks in previously untreated patients	Drug: Tisotumab Vedotin; Given into the vein (IV); Other Names: TIVDAK; Drug: Carboplatin; Given via IV; Other Names: Paraplatin
Experimental: E: Tisotumab vedotin + pembrolizumab; Dose expansion: Tisotumab vedotin in combination with pembrolizumab once every three weeks in previously untreated patients	Drug: Tisotumab Vedotin; Given into the vein (IV); Other Names: TIVDAK; Drug: Pembrolizumab; Given via IV; Other Names: KEYTRUDA®
Experimental: F: Tisotumab vedotin + pembrolizumab; Dose expansion: Tisotumab vedotin in combination with pembrolizumab once every three weeks in previously treated patients	Drug: Tisotumab Vedotin; Given into the vein (IV); Other Names: TIVDAK; Drug: Pembrolizumab; Given via IV; Other Names: KEYTRUDA®
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.	Drug: Tisotumab Vedotin; Given into the vein (IV); Other Names: TIVDAK
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	Drug: Tisotumab Vedotin; Given into the vein (IV); Other Names: TIVDAK; Drug: Bevacizumab; Given via IV; Other Names: Avastin; Drug: Pembrolizumab; Given via IV; Other Names: KEYTRUDA®; Drug: Carboplatin; Given via IV; Other Names: Paraplatin

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Seagen Inc.
• Collaborators: Merck Sharp & Dohme LLC; GOG Foundation; European Network of Gynaecological Oncological Trial Groups (ENGOT); Genmab; Belgian Gynaecological Oncology Group

Study record dates

Study Major Dates

• Study Start (Actual): February 27, 2019
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: December 13, 2018
• First Submitted That Met QC Criteria: December 20, 2018
• First Posted (Actual): December 24, 2018

Study Record Updates

• Last Update Posted (Actual): February 12, 2024
• Last Update Submitted That Met QC Criteria: February 8, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: cervical carcinoma
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Cervical Diseases; Uterine Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Uterine Cervical Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Immune Checkpoint Inhibitors; Carboplatin; Bevacizumab; Pembrolizumab; Tisotumab vedotin
• Other Study ID Numbers: GCT1015-05; InnovaTV 205 (Other Identifier: Genmab); ENGOT-cx8 (Other Identifier: European Network of Gynaecological Oncological Trial); GOG-3024 (Other Identifier: GOG Foundation); MK-3475-834 (Other Identifier: Merck Sharp & Dohme LLC); KEYNOTE-834 (Other Identifier: Merck Sharp & Dohme LLC); 2017-004758-40 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No