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

Study Overview
=================
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).

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

Conditions
-----------------
Cervical Cancer

Intervention / Treatment
-----------------
* Drug: Tisotumab Vedotin
* Drug: Bevacizumab
* Drug: Pembrolizumab
* Drug: Carboplatin


Participation Criteria
=================
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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: Tisotumab Vedotin + bevacizumab<br>Dose escalation: Tisotumab vedotin in combination with bevacizumab once every three weeks in previously treated patients | Drug: Tisotumab Vedotin<br>* Given into the vein (IV)<br>* Other names: TIVDAK;Drug: Bevacizumab<br>* Given via IV<br>* Other names: Avastin;|
| Experimental: B: Tisotumab vedotin + pembrolizumab<br>Dose escalation: Tisotumab vedotin in combination with pembrolizumab once every three weeks in previously treated patients | Drug: Tisotumab Vedotin<br>* Given into the vein (IV)<br>* Other names: TIVDAK;Drug: Pembrolizumab<br>* Given via IV<br>* Other names: Keytruda;|
| Experimental: C: Tisotumab vedotin + carboplatin<br>Dose escalation: Tisotumab vedotin in combination with carboplatin once every three weeks in previously treated patients | Drug: Tisotumab Vedotin<br>* Given into the vein (IV)<br>* Other names: TIVDAK;Drug: Carboplatin<br>* Given via IV<br>* Other names: Paraplatin;|
| Experimental: D: Tisotumab vedotin + carboplatin<br>Dose expansion:Tisotumab vedotin in combination with carboplatin once every three weeks in previously untreated patients | Drug: Tisotumab Vedotin<br>* Given into the vein (IV)<br>* Other names: TIVDAK;Drug: Carboplatin<br>* Given via IV<br>* Other names: Paraplatin;|
| Experimental: E: Tisotumab vedotin + pembrolizumab<br>Dose expansion: Tisotumab vedotin in combination with pembrolizumab once every three weeks in previously untreated patients | Drug: Tisotumab Vedotin<br>* Given into the vein (IV)<br>* Other names: TIVDAK;Drug: Pembrolizumab<br>* Given via IV<br>* Other names: Keytruda;|
| Experimental: F: Tisotumab vedotin + pembrolizumab<br>Dose expansion: Tisotumab vedotin in combination with pembrolizumab once every three weeks in previously treated patients | Drug: Tisotumab Vedotin<br>* Given into the vein (IV)<br>* Other names: TIVDAK;Drug: Pembrolizumab<br>* Given via IV<br>* Other names: Keytruda;|
| Experimental: G: Tisotumab vedotin monotherapy<br>Dose expansion: Tisotumab vedotin monotherapy weekly for three weeks and 1 week off (28 day treatment cycle) in previously treated patients. | Drug: Tisotumab Vedotin<br>* Given into the vein (IV)<br>* Other names: TIVDAK;|
| Experimental: H: Tisotumab vedotin + pembrolizumab + carboplatin +/- bevacizumab<br>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<br>* Given into the vein (IV)<br>* Other names: TIVDAK;Drug: Bevacizumab<br>* Given via IV<br>* Other names: Avastin;Drug: Pembrolizumab<br>* Given via IV<br>* Other names: Keytruda;Drug: Carboplatin<br>* Given via IV<br>* 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
cervical carcinoma