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Tisotumab vedotin

Antineoplastic Agents, Immunological

Tisotumab vedotin (HuMax-TF-ADC)

Johann de Bono, Professor

The purpose of the trial is to establish the tolerability of tisotumab vedotin (HuMax-TF-ADC) dosed three times every four weeks (3q4wk) in a mixed population of patients with specified solid tumors.

The study is conducted in two parts. In the Dose Escalation portion of the trial, subjects are enrolled into cohorts at increasing dose levels of tisotumab vedotin (HuMax-TF-ADC) in 28 day treatment cycles.

The Cohort Expansion portion of the trial will further explore the recommended phase 2 dose of tisotumab vedotin (HuMax-TF-ADC) as determined in Part 1.

Tisotumab Vedotin (HuMax®-TF-ADC) Safety Study in Patients With Solid Tumors

Dose-escalating and Cohort Expansion Safety Trial of Tissue Factor Specific Antibody Drug Conjugate Tisotumab Vedotin (HuMax®-TF-ADC) in Patients With Locally Advanced and/or Metastatic Solid Tumors Known to Express Tissue Factor

An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.

A SAE is defined as an AE that met one or more of the following criteria/outcomes which were classified as serious:

Required inpatient hospitalization or prolongation of existing hospitalization. Resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions.

Was a congenital anomaly/birth defect. Medically important determined by the investigator. Resulted in death. Was life-threatening.

An infusion-related adverse event (AE) was defined as an AE occurring during infusion where the onset date and time of the event occurred within infusion time (+24 hours), and the event was judged as related to tisotumab vedotin by the investigator.

A CTCAE AE was determined using the CTCAE grading systems based on NCI-CTCAE version 4.03 assessed by the investigator.

A treatment-related AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; which has a causal relationship with the treatment.

The number of participants with any markedly abnormal standard safety laboratory values collected throughout study. Markedly abnormal laboratory values are defined as any grade \>=3 laboratory abnormality events.

Due to severe ocular toxicity, participants switched to receive Tisotumab vedotin at 2.0 mg/kg administered as an intravenous infusion, over a minimum of 30 minutes, once every 3 weeks (1q3wk). Data has only been provided for participants who received the original dosing schedule of 3 times every 4 weeks (3q4wk).

Data is only available for Part 1, for Part 2 inadequate samples were collected after the third dose to define a terminal phase.

Data is only available for Part 1, for Part 2 inadequate samples were collected to fully evaluate separate PK parameters after doses 1, 2, and 3.

Data is only available for Part 1, for Part 2 inadequate samples were collected after the third dose to define a terminal phase, and therefore t1/2 could not be determined.

Data is only available for Part 1, for Part 2 inadequate pharmacokinetic samples were collected after the third dose to define a terminal phase, and therefore CL could not be determined.

Data is only available for Part 1, for Part 2 inadequate samples were collected after the third dose to define a terminal phase, and therefore Vz could not be determined.

CL could not be estimated for Part 1 or Part 2 participants due to insufficient number of samples taken.

Vz could not be estimated for Part 1 or Part 2 participants due to insufficient number of samples taken.

Data is only available for Part 1, for Part 2, inadequate samples were collected to fully evaluate separate PK parameters after doses 1, 2, and 3.

Best OR (by investigators assessment) was the best response recorded from the start of the treatment until disease progression or death. Complete response: the disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \< 10 mm. Based on non-target lesions, complete response was defined as disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (\< 10 mm short axis).

Partial response (PR): ≥ 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum of LDs.

Stable disease: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum of LDs while in trial. Based on non-target lesions, stable disease was defined as persistence of 1 or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits.

Best OR (by investigators assessment) was the best response recorded from the start of the treatment until disease progression or death. Complete response: the disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \< 10 mm. Based on non-target lesions, complete response was defined as disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (\< 10 mm short axis).

Partial response (PR): ≥ 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum of LDs.

Stable Disease: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum of LDs while in trial. Based on non-target lesions, stable disease was defined as persistence of 1 or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits.

Participants were defined as having disease control at a specific time point if they had an evaluation of complete response (CR) or partial response (PR) at the time point (with a window of +/- 7 days) or had an evaluation of stable disease (SD), PR or CR at any point from the time point minus 7 days or later.

Progression-free survival was defined as the time in weeks from date of first dose until the date of disease progression or death, whichever is earliest.

Duration of response was defined as as the number of days from the first documentation of objective tumor response (complete response \[CR\] or partial response \[PR\]) to the date of first progressive disease (PD) or death.

Genmab

Seagen Inc.

Tisotumab vedotin 0.9 mg/kg was administered as an intravenous infusion, over a minimum of 30 minutes, 3 times every 4 weeks (3q4wk).

Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg

Tisotumab vedotin 1.2 mg/kg was administered as an intravenous infusion, over a minimum of 30 minutes, 3 times every 4 weeks (3q4wk).

Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg

Participants with the indication of ovarian cancer, received Tisotumab vedotin 1.2 mg/kg (the recommended dose for phase II trials \[RP2D\] from the Dose Escalation part), administered as an intravenous infusion, over a minimum of 30 minutes 3 times every 4 weeks (3q4wk).

Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian

Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical

Participants with the indication of ovarian cancer, received Tisotumab vedotin 1.2 mg/kg (RP2D from the Dose Escalation part), administered as an intravenous infusion, over a minimum of 30 minutes 3 times every 4 weeks (3q4wk). Due to severe ocular toxicity, participants switched to receive Tisotumab vedotin at 2.0 mg/kg, administered as an intravenous infusion, once every 3 weeks (1q3w).

Part 2 Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian

Participants with the indication of cervical cancer, received Tisotumab vedotin 1.2 mg/kg (RP2D from the Dose Escalation part), administered as an intravenous infusion, over a minimum of 30 minutes 3 times every 4 weeks (3q4wk). Due to severe ocular toxicity, participants switched to receive Tisotumab vedotin at 2.0 mg/kg, administered as an intravenous infusion, once every 3 weeks (1q3w).

Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical

Participants with the indication of ovarian cancer, received Tisotumab vedotin 2.0 mg/kg, administered as an intravenous infusion, over a minimum of 30 minutes, once every 3 weeks (1q3w); the revised dose and schedule due to severe ocular toxicity observed at 1.2 mg/kg 3q4wk.

Part 2 Cohort Expansion: Cohort 5 1q3w Ovarian

Participants with the indication of cervical cancer, received Tisotumab vedotin 2.0 mg/kg, administered as an intravenous infusion, over a minimum of 30 minutes, once every 3 weeks (1q3w); the revised dose and schedule due to severe ocular toxicity observed at 1.2 mg/kg 3q4wk.

Part 2: Cohort Expansion: Cohort 6 1q3w Cervical

Participants with the indication of ovarian cancer, received Tisotumab vedotin 1.2 mg/kg (RP2D from the Dose Escalation part), administered as an intravenous infusion, over a minimum of 30 minutes 3 times every 4 weeks (3q4wk). Due to severe ocular toxicity, participants switched to receive Tisotumab vedotin at 2.0 mg/kg, administered as an intravenous infusion once every 3 weeks (1q3w).

Participants with the indication of cervical cancer, received Tisotumab vedotin 1.2 mg/kg (RP2D from the Dose Escalation part), administered as an intravenous infusion, over a minimum of 30 minutes 3 times every 4 weeks (3q4wk). Due to severe ocular toxicity, participants switched to receive Tisotumab vedotin at 2.0 mg/kg, administered as an intravenous infusion once every 3 weeks (1q3w).

Total

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Belgium

United States

Denmark

United Kingdom

Region of Enrollment

Part 1: Dose Escalation

Part 2: Cohort Expansion

The study was conducted in two parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Each part was analyzed separately.

Weight

Height

Body Mass Index (BMI)

Part 1: Number of Participants Who Experience at Least One Adverse Event (AE)

Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian

Part 2: Number of Participants Who Experience at Least One Adverse Event (AE)

Part 1: Number of Participants Who Experienced at Least One or More Serious Adverse Event (SAE)

Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian

Part 2: Number of Participants Reporting One or More Serious Adverse Events (SAE)

Part 1: Number of Participants Reporting One or More Infusion-related Adverse Events

Part 2: Number of Participants Reporting One or More Infusion-related Adverse Events

Part 1: Number of Participants Reporting One or More Common Terminology Criteria for Adverse Events (CTCAE) Grade >=3 Adverse Events

Part 2: Number of Participants Reporting One or More Common Terminology Criteria for Adverse Events (CTCAE) Grade >=3 Adverse Events

Part 1: Number of Participants Reporting One or More Treatment-related Adverse Events

Part 2: Number of Participants Reporting One or More Treatment-related Adverse Events

Part 1: Number of Participants With Markedly Abnormal Laboratory Values

Part 2: Number of Participants With Markedly Abnormal Laboratory Values

Part 1: Number of Participants Who Experienced a Skin Rash

Part 2: Number of Participants Who Experienced a Skin Rash

Part 1: Number of Participants Who Experienced a Bleeding Event

Part 2: Number of Participants Who Experienced a Bleeding Event

Part 1: Number of Participants Who Experienced a Neuropathy Event

Part 2: Number of Participants Who Experienced a Neuropathy Event

Cycle 1

Cycle 1 Day 1

Cycle 1 Day 8

Cycle 1 Day 15

Insufficient samples were taken in Cycle 2 and beyond to calculate PK parameters, therefore only Cycle 1 is reported. Cycle 1 is an overall value, calculated over the entire cycle.

Part 1: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for Tisotumab Vedotin (HuMax-TF-ADC)

Cycle 1 Dose 1

Cycle 1 Dose 2

Cycle 1 Dose 3

Participants with the indication of ovarian cancer, received Tisotumab vedotin 2.0 mg/kg, administered as an intravenous infusion, over a minimum of 30 minutes, once every 3 weeks (1q3w); the revised dose and schedule due to severe ocular toxicity observed at 1.2 mg/kg 3q4wk

Insufficient samples were collected for cohorts 3-6 to calculate PK parameters. Insufficient samples were taken in Cycle 2 and beyond to calculate PK parameters, only Cycle 1 is reported. Cycle 1 is an overall value, calculated over the cycle. Includes data for all randomized participants for whom data were available.

Part 2: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for Tisotumab Vedotin (HuMax-TF-ADC)

Insufficient samples were taken in Cycle 2 and beyond to calculate PK parameters, therefore only Cycle 1 is reported. Includes data for all randomized participants for whom data were available.

Part 1: AUCinf: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Tisotumab Vedotin (HuMax-TF-ADC)

Part 1: Cmax: Maximum Observed Plasma Concentration for Tisotumab Vedotin (HuMax-TF-ADC)

Part 2: Cmax: Maximum Observed Plasma Concentration for Tisotumab Vedotin (HuMax-TF-ADC)

Part 1: Tmax: Time to Reach the Maximum Plasma Concentration for Tisotumab Vedotin (HuMax-TF-ADC)

Part 2: Tmax: Time to Reach the Maximum Plasma Concentration for Tisotumab Vedotin (HuMax-TF-ADC)

Insufficient samples were taken in Cycle 2 and beyond to calculate PK parameters, therefore only Cycle 1 is reported.

Part 1: Trough Concentration (Ctrough) Steady State Plasma Pharmacokinetic for Tisotumab Vedotin (HuMax-TF-ADC)

Part 1: Dose Escalation: Cohort 1 3q4wk 0.9mg/kg

Part 1: Terminal Phase Elimination Half-life (T1/2) for Tisotumab Vedotin (HuMax-TF-ADC)

Part 1: Total Clearance (CL) of Tisotumab Vedotin (HuMax-TF-ADC)

Part 1: Apparent Volume of Distribution (Vz) for Tisotumab Vedotin (HuMax-TF-ADC)

Part 1: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for Total HuMax-TF (Conjugated and Non-conjugated)

Part 2: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for Total HuMax-TF (Conjugated and Non-conjugated)

Part 1: AUCinf: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Total HuMax-TF (Conjugated and Non-conjugated)

Part 1: Cmax: Maximum Observed Plasma Concentration for Total HuMax-TF (Conjugated and Non-conjugated)

Part 2: Cmax: Maximum Observed Plasma Concentration for Total HuMax-TF (Conjugated and Non-conjugated)

Part 1: Tmax: Time to Reach the Maximum Plasma Concentration for Total HuMax-TF (Conjugated and Non-conjugated)

Part 2: Tmax: Time to Reach the Maximum Plasma Concentration for Total HuMax-TF (Conjugated and Non-conjugated)

Part 1: Terminal Phase Elimination Half-life (T1/2) for Total HuMax-TF (Conjugated and Non-conjugated)

CL could not be estimated for Part 1 or Part 2 participants.

Part 1 and Part 2: Total Clearance (CL) of Total HuMax-TF (Conjugated and Non-conjugated)

Vz could not be estimated for Part 1 or Part 2 participants.

Part 1 & Part 2: Apparent Volume of Distribution (Vz) for Total HuMax-TF (Conjugated and Non-conjugated)

Insufficient samples were taken in Cycle 2 and beyond to calculate PK parameters, therefore only Cycle 1 is reported. Data includes all randomized participants for whom data were available.

Part 1: Trough Concentration (Ctrough) Steady State Plasma Pharmacokinetic for Total HuMax-TF (Conjugated and Non-conjugated)

Part 1: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for Free Toxin (MMAE)

Part 2: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for Free Toxin (MMAE)

Part 1: Cmax: Maximum Observed Plasma Concentration for Free Toxin (MMAE)

Participants with the indication of cervical cancer, received Tisotumab vedotin 2.0 mg/kg, administered as an intravenous infusion, over a minimum of 30 minutes, once every 3 weeks (1q3w); the revised dose and schedule due to severe ocular toxicity observed at 1.2 mg/kg 3q4wk

Part 2: Cmax: Maximum Observed Plasma Concentration for Free Toxin (MMAE)

Part 1: Tmax: Time to Reach the Maximum Plasma Concentration for Free Toxin (MMAE)

Part 2: Tmax: Time to Reach the Maximum Plasma Concentration for Free Toxin (MMAE)

Part 1: Trough Concentration (Ctrough) Steady State Plasma Pharmacokinetic for Free Toxin (MMAE)

Part 1: Number of Participants With a Positive Anti-drug Antibody (ADA) Immunogenicity Result

Participants with the indication of ovarian cancer, received Tisotumab vedotin 2.0 mg/kg, administered as an intravenous infusion, over a minimum of 30 minutes, once every 3 weeks (1q3w); the revised dose and schedule due to severe ocular toxicity.

Participants with the indication of cervical cancer, received Tisotumab vedotin 2.0 mg/kg, administered as an intravenous infusion, over a minimum of 30 minutes, once every 3 weeks (1q3w); the revised dose and schedule due to severe ocular toxicity.

Part 2: Number of Participants With a Positive Anti-drug Antibody (ADA) Immunogenicity Result

Part 1: Number of Patients Who Experienced Anti-tumor Activity Measured by Tumor Shrinkage

Part 2: Anti-tumor Activity Measured by Percentage of Change in Sum of Lesion Measurements

PSA is only assessed for participants with prostate cancer. 2 participants in Part 1 Cohort 1 and 1 participant in Part 1 Cohort 2 had the indication of prostate cancer.

Part 1: Response Evaluation Based on PSA (Prostate Specific Antigen [Prostate Cancer]): Percentage Change From Baseline to End of Study

CA 125 is only assessed for participants with ovarian and endometrial cancer, 1 participant in Cohort 1 and 1 participant in Cohort 2 had the indication of ovarian or endometrial cancer. No participants from Cohort 1 with the indication of ovarian and endometrial Cancer had results at the End of Study visit.

Part 1: Response Evaluation Based on CA125 (Cancer Antigen 125 [Ovarian and Endometrial Cancer]): Percentage of Change From Baseline to End of Study

CA 125 was only assessed for participants with Ovarian cancer. No participants from Cohort 5 participated in the End of Trial visit.

Spots Global Cancer Trial Database for Tisotumab Vedotin (HuMax®-TF-ADC) Safety Study in Patients With Solid Tumors

Trial Identification

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Study Description

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