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

Study Overview
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Brief Summary
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The purpose of the trial is to establish the tolerability of HuMax-TF-ADC in a mixed population of patients with specified solid tumors.

Detailed Description
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The study is conducted in two parts. The dose escalation portion of the trial subjects are enrolled into cohorts at increasing dose levels of HuMax-TF-ADC in 21 day treatment cycles. In the Cohort Expansion part of the trial, will further explore the recommended phase 2 dose of HuMax-TF-ADC as determined in Part 1

Official Title
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First-in-human, Dose-escalating Safety Study 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

Conditions
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Ovary Cancer, Cervix Cancer, Endometrium Cancer, Bladder Cancer, Prostate Cancer (CRPC), Esophagus Cancer, Lung Cancer(NSCLC), Squamous Cell Carcinoma of the Head and Neck (SCCHN)

Intervention / Treatment
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* Drug: Tisotumab Vedotin (HuMax-TF-ADC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Patients with relapsed, advanced and/or metastatic cancer who have failed available standard treatments or who are not candidates for standard therapy. Patients must have measurable disease Age ≥ 18 years. Acceptable renal function Acceptable liver function Acceptable hematological status (without hematologic support Acceptable coagulation status Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Life expectancy of at least three months. A negative serum pregnancy test (if female and aged between 18-55 years old). Women who are pregnant or breast feeding are not to be included. Patients, both females and males, of reproductive potential must agree to use adequate contraception during and for six months after the last infusion of HuMax-TF-ADC. Following receipt of verbal and written information about the study, patients must provide signed informed consent before any study-related activity is carried out. Exclusion Criteria: Known past or current coagulation defects. Ongoing major bleeding, Have clinically significant cardiac disease A baseline QT interval as corrected by Fridericia's formula (QTcF) > 450 msec, a complete left bundle branch block (defined as a QRS interval ≥ 120 msec in left bundle branch block form) or an incomplete left bundle branch block. Have received granulocyte colony stimulating factor (G-CSF) or granulocyte/macrophage colony stimulating factor support within one week or pegylated G-CSF within two weeks before the Screening Visit. Have received a cumulative dose of corticosteroid ≥ 100 mg (prednisone or equivalent doses of corticosteroids) within two weeks before the first infusion. Major surgery within six weeks or open biopsy within 14 days before drug infusion. Plan for any major surgery during treatment period. Any history of intracerebral arteriovenous malformation, cerebral aneurysm, brain metastases or stroke. Any anticancer therapy including; small molecules, immunotherapy, chemotherapy monoclonal antibodies or any other experimental drug within four weeks or five half lives, whichever is longest, before first infusion. Prior treatment with bevacizumab within twelve weeks before the first infusion. Radiotherapy within 28 days prior to first dose. Patients who have not recovered from symptomatic side effects of radiotherapy at the time of initiation of screening procedure. Known past or current malignancy other than inclusion diagnosis, except for: Cervical carcinoma of Stage 1B or less. Non-invasive basal cell or squamous cell skin carcinoma. Non-invasive, superficial bladder cancer. Prostate cancer with a current PSA level < 0.1 ng/mL. Any curable cancer with a complete response (CR) of > 5 years duration. Known human immunodeficiency virus seropositivity. Positive serology (unless due to vaccination or passive immunization due to Ig therapy) for hepatitis B Positive serology for hepatitis C based on test at screening. Inflammatory bowel disease including Crohn's disease and colitis ulcerosa. Inflammatory lung disease including moderate and severe asthma and chronic obstructive pulmonary disease (COPD) requiring chronic medical therapy. Ongoing acute or chronic inflammatory skin disease.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Escalation phase for dose finding followed by expansion phase
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tisotumab Vedotin (HuMax-TF-ADC)<br>All arms of the trial (borh in escalation and expansion phase) will be administered tisotumab vedotin (HuMax-TF-ADC) | Drug: Tisotumab Vedotin (HuMax-TF-ADC)<br> <br> * Other names: TIVDAK;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation Part: Evaluation of Treatment-Emergent Adverse Events | Evaluation of treatment-emergent adverse events (TEAEs) includes number of participants with at least one: TEAE Serious TEAE Infusion-related TEAE Common Terminology Criteria for Adverse Events (CTCAE) grade >=3 Treatment-related TEAE A CTCAE TEAE was determined using the CTCAE grading systems based on National Cancer Institute (NCI)-CTCAE version 4.03 assessed by the investigator per the below definitions. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE. | Treatment emergent adverse events are reported from Day 1 to 30 days after dosing. The treatment duration ranged from 1 to 249 days in the dose escalation part. | 
| Dose Expansion Part: Evaluation of Treatment-Emergent Adverse Events | Evaluation of treatment-emergent adverse events (TEAEs) includes number of participants with at least one: TEAE Serious TEAE Infusion-related TEAE Common Terminology Criteria for Adverse Events (CTCAE) grade >=3 Treatment-related TEAE A CTCAE TEAE was determined using the CTCAE grading systems based on NCI-CTCAE version 4.03 assessed by the investigator per the below definitions. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE. | Treatment emergent adverse events are reported from Day 1 to 30 days after dosing. The treatment duration ranged from 1 to 325 days in the dose expansion part. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation and Expansion Part: Number of Participants With Markedly Abnormal Hematology Values | Number of participants with markedly abnormal hematology values was defined as all participants who experienced at least 1 CTCAE grade >= 3 hematology value. A markedly abnormal hematology value was determined using the CTCAE grading systems based on National Cancer Institute (NCI)-CTCAE version 4.03 assessed by the investigator per the below definitions. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE. | Day 1 to end of follow-up, up to a maximum of 60 weeks | 
| Dose Escalation and Expansion Parts: Number of Participants With Markedly Abnormal Coagulation Values | Number of participants with markedly abnormal coagulation values was defined as all participants who experienced at least 1 CTCAE grade >= 3 coagulation value. A markedly abnormal coagulation value was determined using the CTCAE grading systems based on National Cancer Institute (NCI)-CTCAE version 4.03 assessed by the investigator per the below definitions. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE. | Day 1 to end of follow-up, up to a maximum of 60 weeks | 
| Dose Escalation and Expansion Part: Number of Participants With Markedly Abnormal Biochemistry Values | Number of participants with markedly abnormal biochemistry results were defined as all participants who experienced at least 1 CTCAE grade >= 3 biochemistry value. A markedly abnormal biochemistry value was determined using the CTCAE grading systems based on National Cancer Institute (NCI)-CTCAE version 4.03 assessed by the investigator per the below definitions. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE. | Day 1 to end of follow-up, up to a maximum of 60 weeks | 
| Dose Escalation and Expansion Parts: Number of Participants Who Experienced a Skin Rash |  | Day 1 to end of follow-up, up to a maximum of 60 weeks | 
| Dose Escalation and Expansion Parts: Number of Participants Who Experienced a Bleeding Event of Special Interest | Bleeding adverse events of special interest included treatment emergent adverse events with preferred terms within the following standardised MedDRA queries (SMQs): Haemorrhage terms, excluding laboratory terms SMQ [20000039] (Broad) and Haemorrhage, laboratory terms SMQ [20000040] (Narrow). Bleeding adverse events of special interest were evaluated according to the NCI-CTCAE version 4.03. Bleeding events of all grades are included. Grade 1:Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE. | Day 1 to end of follow-up, up to a maximum of 60 weeks | 
| Dose Escalation and Expansion Part: Number of Participants Who Experienced a Peripheral Neuropathy Event | Peripheral neuropathy events of special interest were evaluated according to the NCI-CTCAE version 4.03. Peripheral neuropathy events of all grades are included in the numbers below. Grade 1:Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE. | Day 1 to end of follow-up, up to a maximum of 60 weeks | 
| Dose Escalation Part: Clearance of Tisotumab Vedotin and Total HuMax-TF | Pharmacokinetic (PK) parameters in plasma were determined based on non compartmental methods and calculated separately for Cycle 1 and Cycle 2 in each part of the study. Data was not collected to report or calculate clearance for the expansion phase. | Before infusion, Day 1 (pre-dose) and 0.25 to 336 hours post-dose of Cycle 1 and Cycle 2 (each cycle was 21 days) | 
| Dose Escalation Part: Volume of Distribution of Tisotumab Vedotin and Total HuMax-TF | PK parameters in plasma were determined based on non compartmental methods and calculated separately for Cycle 1 and Cycle 2 in each part of the study. Data was not planned to be collected for the volume of distribution of tisotumab vedotin and total HuMax-TF for the dose expansion part. | Before infusion, Day 1 (pre-dose) and 0.25 to 336 hours post-dose of Cycle 1 and Cycle 2 (each cycle was 21 days) | 
| Dose Escalation and Expansion Part: Area Under the Curve From Time Zero to the Last Measurable Concentration (AUC0-t) of Tisotumab Vedotin and Total HuMax-TF | PK parameters in plasma were determined based on non-compartmental methods and calculated separately for Cycle 1 and Cycle 2 in each part of the study. | Before infusion, Day 1 (pre-dose) and 0.25 to 336 hours post-dose of Cycle 1 and Cycle 2 (each cycle was 21 days) | 
| Dose Escalation Part: Area Under the Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Tisotumab Vedotin and Total HuMax-TF | PK parameters in plasma were determined based on non compartmental methods and calculated separately for Cycle 1 and Cycle 2. AUC0-inf was only analyzed in the dose escalation part of the study. Data was not planned to be collected for the AUC0-inf of tisotumab vedotin and total HuMax-TF for the dose expansion part. | Before infusion, Day 1 (pre-dose) and 0.25 to 336 hours post-dose of Cycle 1 and Cycle 2 (each cycle was 21 days) | 
| Dose Escalation and Expansion Part: Maximum Observed Plasma Concentration (Cmax) of Tisotumab Vedotin and Total HuMax-TF | PK parameters in plasma were determined based on non-compartmental methods and calculated separately for Cycle 1 and Cycle 2 in each part of the study. | Before infusion, Day 1 (pre-dose) and 0.25 to 336 hours post-dose of Cycle 1 and Cycle 2 (each cycle was 21 days) | 
| Dose Escalation and Expansion Part: Time of Cmax (Tmax) of Tisotumab Vedotin and Total HuMax-TF | PK parameters in plasma were determined based on non-compartmental methods and calculated separately for Cycle 1 and Cycle 2 in each part of the study. | Before infusion, Day 1 (pre-dose) and 0.25 to 336 hours post-dose of Cycle 1 and Cycle 2 (each cycle was 21 days) | 
| Dose Escalation Part: Half-life (t1/2) of Tisotumab Vedotin and Total HuMax-TF | PK parameters in plasma were determined based on non-compartmental methods and calculated separately for Cycle 1 and Cycle 2. t1/2 was only analyzed for the dose escalation part of the study. Data was not planned to be collected for t1/2 of tisotumab vedotin and total HuMax-TF for the dose expansion part. | Before infusion, Day 1 (pre-dose) and 0.25 to 336 hours post-dose of Cycle 1 and Cycle 2 (each cycle was 21 days) | 
| Dose Escalation and Expansion Part: AUC0-t of Free Monomethyl Auristatin E (MMAE) | PK parameters in plasma were determined based on non compartmental methods and calculated separately for Cycle 1 and Cycle 2 in each part of the study. | Before infusion, Day 1 (pre-dose) and 0.25 to 336 hours post-dose of Cycle 1 and Cycle 2 (each cycle was 21 days) | 
| Dose Escalation Part: AUC0-inf of Free MMAE | PK parameters in plasma were determined based on non-compartmental methods and calculated separately for Cycle 1 and Cycle 2. AUC0-inf was not planned to be collected for the dose expansion part. AUC0-inf was not calculated where the percentage of the AUC that was due to the extrapolation was more than 20%. | Before infusion, Day 1 (pre-dose) and 0.25 to 336 hours post-dose of Cycle 1 and Cycle 2 (each cycle was 21 days) | 
| Dose Escalation and Expansion Part: Cmax of Free MMAE | PK parameters in plasma were determined based on non-compartmental methods and calculated separately for Cycle 1 and Cycle 2 in each part of the study. | Before infusion, Day 1 (pre-dose) and 0.25 to 336 hours post-dose of Cycle 1 and Cycle 2 (each cycle was 21 days) | 
| Dose Escalation and Expansion Part: Tmax of Free MMAE | PK parameters in plasma were determined based on non-compartmental methods and calculated separately for Cycle 1 and Cycle 2 in each part of the study. | Before infusion, Day 1 (pre-dose) and 0.25 to 336 hours post-dose of Cycle 1 and Cycle 2 (each cycle was 21 days) | 
| Dose Escalation Part: PK Parameters, T 1/2 of Free MMAE | PK parameters in plasma were determined based on non compartmental methods and calculated separately for Cycle 1 and Cycle 2. T1/2 was determined only for the dose escalation part of the study. | Before infusion, Day 1 (pre-dose) and 0.25 to 336 hours post-dose of Cycle 1 and Cycle 2 (each cycle was 21 days) | 
| Dose Escalation and Expansion Part: Number of Participants With Positive Anti-Drug Antibodies (ADAs) to Tisotumab Vedotin | Participants who met the criterion for positive ADAs on treatment were defined as participants who were negative at baseline and had at least one positive post-baseline result, or participants who were positive at baseline and had at least one post baseline result with a titer higher than baseline. | Day 1 to end of follow-up, up to a maximum of 60 weeks | 
| Dose Escalation Part: Anti-Tumor Activity Measured by Number of Participants Who Experienced Tumor Shrinkage | Anti-tumor activity measured by the number of participants who experienced tumor shrinkage was not planned to be collected for the dose expansion part. | Day 1 to end of follow-up, up to a maximum of 60 weeks | 
| Dose Expansion Part: Anti-Tumor Activity Measured by Maximum Reduction Among Available Post-Baseline Sum of Lesion Measurements | Anti-tumor activity measured by maximum reduction among available post-baseline sum of lesion measurements was not planned to be collected for the dose escalation part. | Day 1 to end of follow-up, up to a maximum of 60 weeks | 
| Dose Escalation and Expansion Part: Percentage Change From Baseline in Prostate Specific Antigen (PSA) | PSA was only assessed in participants with castrate-resistant prostate cancer. | Day 1 to end of follow-up, up to a maximum of 60 weeks | 
| Dose Escalation and Expansion Part: Percentage Change From Baseline in CA-125 | In the dose escalation part, CA-125 was only assessed for participants with ovarian cancer. In the dose expansion part, CA-125 was intended to be assessed only for participants with ovarian and endometrium cancer, but was additionally assessed for some participants with NSCLC and cervical cancer. | Day 1 to end of follow-up, up to a maximum of 60 weeks | 
| Dose Escalation and Expansion Part: Objective Response Rate | Objective Response Rate per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Response assessment was investigator based for the escalation part and Independent Review Committee (IRC) based for the expansion part. | Day 1 to end of follow-up, up to a maximum of 60 weeks | 
| Dose Escalation and Expansion Part: Disease Control Rate | Disease control rate was defined as the percentage of participants with CR, PR or stable disease (SD) as per investigator assessment per RECIST version 1.1 after 6, 12, 24 and 36 weeks. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease. | At 6, 12, 24 and 36 weeks | 
| Dose Escalation and Expansion Part: Progression Free Survival (PFS) | PFS was defined as the time in weeks from Day 1 in Cycle 1 to first disease progression or death, whichever occurred earliest, as assessed by the investigator. Only deaths that occurred within 60 days of the last visit were considered in the analysis and result are presented based on Kaplan-Meier estimates. Progression as defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase from nadir in the sum of diameters of target lesions, unequivocal progression in non-target lesions, or the appearance of new lesions | Day 1 to end of follow-up, up to a maximum of 60 weeks | 
| Dose Expansion Part: Duration of Response (DOR) | DOR was defined as the median time in weeks from when confirmed response was first documented until the first documented disease progression, or death from any cause, whichever was earliest as assessed by the investigator. A responder was defined as any participant with a best overall response of confirmed CR or PR. | Day 1 to end of follow-up, up to a maximum of 60 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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prostate cancer (CRPC), esophagus cancer, lung cancer(NSCLC), Squamous cell carcinoma of the head and neck (SCCHN), ovary cancer, cervix cancer, endometrium cancer, bladder cancer