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

Sponsor

Seagen Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03786081

Collaborator

Genmab (Industry), European Network of Gynaecological Oncological Trial Groups (ENGOT) (Other), Belgian Gynaecological Oncology Group (Other), Gynecologic Oncology Group (Other), Merck Sharp & Dohme LLC (Industry)

220

Enrollment

Locations

Arms

67.1

Anticipated Duration (Months)

3.3

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Cervical Cancer	Drug: Tisotumab Vedotin Drug: Bevacizumab Drug: Pembrolizumab Drug: Carboplatin	Phase 1/Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

220 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Feb 27, 2019

Anticipated Primary Completion Date :

Sep 30, 2024

Anticipated Study Completion Date :

Sep 30, 2024

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Dose escalation: Dose Limiting Toxicities (DLTs) [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) [approximately 2 years]
Objective response is defined as confirmed partial response (PR) or complete response (CR)

Secondary Outcome Measures

Number of adverse events (AEs) [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 [approximately 2 years]
Objective response is defined as confirmed PR or CR.
Duration of Response (DOR) per RECIST v1.1 by investigator assessment [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 [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 [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) [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) [Up to 42 days]
Pharmacokinetic (PK) parameter
Cmax (Arm G only) [Up to 2 years]
PK parameter
Trough Concentration (Ctrough) (All Arms) [Up to 2 years]
PK parameter
Area under the concentration-time curve (AUC) (All Arms except G) [Through 21 days after first dose]
PK parameter
AUC (Arm G only) [Through 8 days after first dose]
PK parameter
Anti-drug antibodies (ADAs) [Up to 2 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Oncology Associates	Phoenix	Arizona	United States	85016
2	Univ California, Irvine Medical Center	Orange	California	United States	92868
3	Olive View - UCLA Research and Education Institute	Sylmar	California	United States	91342
4	Baptist MD Anderson Cancer Center	Jacksonville	Florida	United States	32207
5	Augusta University	Augusta	Georgia	United States	30912
6	University of Chicago	Chicago	Illinois	United States	60525
7	Indiana University School of Medicine	Indianapolis	Indiana	United States	46202
8	University of Kansas Medical Center	Westwood	Kansas	United States	66205
9	Oschner Clinic	New Orleans	Louisiana	United States	70121
10	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
11	Billings Clinic Cancer Center	Billings	Montana	United States	59101
12	Montana Cancer Consortium	Billings	Montana	United States	59102
13	SUNY Downstate Medical Center	Brooklyn	New York	United States	11203
14	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
15	University of North Carolina Chapel Hill	Chapel Hill	North Carolina	United States	27514
16	University of Cincinnati Physicians Group	Cincinnati	Ohio	United States	45206
17	Cleveland Clinic	Cleveland	Ohio	United States	44106
18	Cleveland Clinic	Cleveland	Ohio	United States	44195
19	Ohio State University Wexner Medical Center	Hilliard	Ohio	United States	43026
20	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
21	Magee-Womens Hospital of UPMC	Pittsburgh	Pennsylvania	United States	15213
22	Brown University - Women's and Infant Hospital	Providence	Rhode Island	United States	02905
23	St Francis Hospital Cancer Center	Greenville	South Carolina	United States	29607
24	Huntsman Cancer Center	Salt Lake City	Utah	United States	84112
25	Carilion Clinic	Roanoke	Virginia	United States	24016
26	AZ Sint-Jan	Brugge		Belgium	8000
27	Cliniques universitaires Saint-Luc	Brussels		Belgium	1200
28	Cliniques Universitaires Saint-Luc	Bruxelles		Belgium	1200
29	Grand Hôpital de Charleroi	Charleroi		Belgium	6000
30	Universitair Ziekenhuis Antwerpen (UZA)	Edegem		Belgium	2650
31	Universitair Ziekenhuis Gent	Gent		Belgium	9000
32	UZ Leuven	Leuven		Belgium	3000
33	Universitaire Ziekenhuizen Leuven,	Leuven		Belgium
34	Centre Hospitalier de l'Ardenne	Libramont		Belgium	6800
35	Centre Hospitalier Universitaire (CHU) de Liège	Liège		Belgium	4000
36	Grand Hôpital de Charleroi	Loverval		Belgium	6280
37	CHU UCL Namur	Namur		Belgium	5000
38	Sainte-Elisabeth	Namur		Belgium	5000
39	Fakultni nemocnice Olomouc	Olomouc		Czechia	775 20
40	Fakultni nemocnice Olomouc	Olomouc		Czechia	77520
41	Fakultni nemocnice Ostrava	Ostrava-Poruba		Czechia	70852
42	Fakultni nemocnice Ostrava	Ostrava-Poruba		Czechia	70852
43	Vseobecna fakultni nemocnice v Praze	Praha 2		Czechia	128 51
44	Vseobecna fakultni nemocnice v Praze	Praha 2		Czechia	12851
45	Fakultni nemocnice Bulovka	Praha		Czechia	180 81
46	Nemocnice Na Bulovce	Praha		Czechia	18081
47	Rigshospitalet	Copenhagen		Denmark	5072
48	Cork University Hospital	Cork		Ireland
49	Mater Misericordiae University Hospital	Dublin		Ireland	D07 R2WY D
50	University Hospital Waterford	Waterford		Ireland
51	Azienda Ospedaliera Cannizzaro	Catania		Italy	95100
52	Istituto Nazionale Tumori Fondazione G. Pascale	Napoli		Italy	80131
53	Fondazione Policlinico Universitario Agostino Gemelli IRCCS	Roma		Italy	00168
54	Fondazione Policlinico Universitario Agostino Gemelli IRCCS	Rome		Italy	00168
55	Amsterdam UMC, Locatie AMC	Amsterdam		Netherlands	1105 AZ
56	AMC Medical Research	Amsterdam		Netherlands
57	Universitair Medisch Centrum Groningen (UMCG)	Groningen		Netherlands	9713 GZ
58	Radboudumc	Nijmegen		Netherlands	6525 GA
59	Erasmus Medisch Centrum	Rotterdam		Netherlands	3015 CC
60	Erasmus University Medical Center Rotterdam	Rotterdam		Netherlands	3015
61	UMC Utrecht	Utrecht		Netherlands	3508 GA
62	University Medical Center Utrecht (UMC Utrecht)	Utrecht		Netherlands	3584
63	Baskent University Adana Application and Research Center	Adana		Turkey	01220
64	Baskent University Ankara Hospital	Ankara		Turkey	06490
65	Velindre Cancer Centre	Cardiff	South Glamorgan	United Kingdom	CF14 2TL
66	Beatson West of Scotland Cancer Centre	Glasgow	Strathclyde	United Kingdom	G12 OYN
67	Royal Marsden Hospital- Sutton	Sutton	Surrey	United Kingdom	SM2 5PT