Clinical trial NCT02552121: Tisotumab Vedotin (HuMax®-TF-ADC) Safety Study in Patients With Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Ovary Cancer
Cervix Cancer
Endometrium Cancer
Bladder Cancer
Prostate Cancer (CRPC)
Esophagus Cancer
Lung Cancer (NSCLC)
Keywords: ovary cancer
cervix cancer
endometrium cancer
bladder cancer
prostate cancer (CRPC)
esophagus cancer
lung cancer (NSCLC)
Lead sponsor: Seagen Inc.
Sponsor class: INDUSTRY
Collaborators: name: Genmab
First posted: 2015-09-16
Enrollment: 33
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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 according to RECIST v1.1

* Age ≥ 18 years.
* Acceptable renal function.
* Acceptable liver function.
* Acceptable hematological status (hematologic support allowed under certain circumstances).
* 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.
* Diffuse alveolar hemorrhage from vasculitis.
* Known bleeding diathesis.
* Ongoing major bleeding.
* Trauma with increased risk of life-threatening 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.
* Therapeutic anti-coagulative or long term anti-platelet treatment except use of low dose acetylsalicylic acid (ASA) up to 81 mg/day and non-ASA nonsteroidal anti-inflammatory drugs (NSAIDs).
* 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 ≥ 150 mg (prednisone or equivalent doses of corticosteroids) within two weeks before the first infusion.
* No dietary supplements allowed during the study period, except multivitamins, vitamin D and calcium.
* Major surgery within six weeks or open biopsy within 14 days before drug infusion.
* Plan for any major surgery during treatment period.
* Patients not willing or able to have a pre-trial tumor biopsy taken (the screening biopsy can be omitted if archived material is available).
* Presence or anticipated requirement of epidural catheter in relation to infusions (within 48 hours before and after dose of trial drug).
* 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.
* Prior therapy with a conjugated or unconjugated auristatin derivative.
* 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.
* Breast cancer in BRCA1 or BRACA2 positive ovarian cancer patients.
* Any curable cancer with a complete response (CR) of \> 5 years duration.
* Radiographic evidence of cavitating pulmonary lesions and tumor adjacent to or invading any large blood vessel unless approved by sponsor.
* Ongoing, significant , uncontrolled medical condition.
* Presence of peripheral neuropathy.
* Active viral, bacterial or fungal infection requiring intravenous treatment with antimicrobial therapy starting less than four weeks prior to first dose.
* Oral treatment with antimicrobial therapy starting less than two weeks prior to first dose.
* 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.
* Active ocular surface disease at baseline (based on ophthalmological evaluation).
* History of cicatricial conjunctivitis (as evaluated by an ophthalmologist).

Primary outcomes:
measure: Part 1: Number of Participants Who Experience at Least One Adverse Event (AE)
timeFrame: Baseline to end of follow-up; maximum time of follow-up was 24 weeks
measure: Part 2: Number of Participants Who Experience at Least One Adverse Event (AE)
timeFrame: Baseline to end of trial (Part 2), up to 36 weeks
measure: Part 1: Number of Participants Who Experienced at Least One or More Serious Adverse Event (SAE)
timeFrame: Baseline to end of follow-up; maximum time of follow-up was 24 weeks
measure: Part 2: Number of Participants Reporting One or More Serious Adverse Events (SAE)
timeFrame: Baseline to end of trial (Part 2), up to 36 weeks
measure: Part 1: Number of Participants Reporting One or More Infusion-related Adverse Events
timeFrame: Day 1, Day 8 & Day 15 (+1 day) until end of treatment (Part 1), approximately 48 weeks
measure: Part 2: Number of Participants Reporting One or More Infusion-related Adverse Events
timeFrame: Day 1, Day 8 & Day 15 (+1 day) until end of trial (Part 2), up to 36 weeks
measure: Part 1: Number of Participants Reporting One or More Common Terminology Criteria for Adverse Events (CTCAE) Grade >=3 Adverse Events
timeFrame: Baseline to end of follow-up; maximum time of follow-up was 24 weeks
measure: Part 2: Number of Participants Reporting One or More Common Terminology Criteria for Adverse Events (CTCAE) Grade >=3 Adverse Events
timeFrame: Baseline to end of trial (Part 2), up to 36 weeks
measure: Part 1: Number of Participants Reporting One or More Treatment-related Adverse Events
timeFrame: Baseline to end of follow-up; maximum time of follow-up was 24 weeks
measure: Part 2: Number of Participants Reporting One or More Treatment-related Adverse Events
timeFrame: Baseline to end of trial (Part 2), up to 36 weeks
Secondary outcomes:
measure: Part 1: Number of Participants With Markedly Abnormal Laboratory Values
timeFrame: Baseline to end of follow-up; maximum time of follow-up was 24 weeks
measure: Part 2: Number of Participants With Markedly Abnormal Laboratory Values
timeFrame: Baseline to end of trial (Part 2), up to 36 weeks
measure: Part 1: Number of Participants Who Experienced a Skin Rash
timeFrame: Baseline to end of follow-up; maximum time of follow-up was 24 weeks
measure: Part 2: Number of Participants Who Experienced a Skin Rash
timeFrame: Baseline to end of trial (Part 2), up to 36 weeks
measure: Part 1: Number of Participants Who Experienced a Bleeding Event
timeFrame: Baseline to end of trial (Part 1), up to 72 weeks
measure: Part 2: Number of Participants Who Experienced a Bleeding Event
timeFrame: Baseline to end of trial (Part 2), up to 36 weeks
measure: Part 1: Number of Participants Who Experienced a Neuropathy Event
timeFrame: Baseline to end of follow-up; maximum time of follow-up was 24 weeks
measure: Part 2: Number of Participants Who Experienced a Neuropathy Event
timeFrame: Baseline to end of trial (Part 2), up to 36 weeks
measure: 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)
timeFrame: Before infusion, end of infusion (+15 minutes), and +2 hours post infusion on days 1, 8 and 15, + 24 hours 1st infusion (Day 2), + 24 hours 3rd infusion (Day 16), + 72 hours 3rd infusion (Day 18), + 168 hours 3rd infusion (Day 22) of Cycle 1
measure: 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)
timeFrame: Before infusion, end of infusion (+15 minutes) and +2 hours post infusion on day 1, and before infusion on days 8 and 15 of Cycle 1
measure: Part 1: AUCinf: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Tisotumab Vedotin (HuMax-TF-ADC)
timeFrame: Before infusion, end of infusion (+15 minutes), and +2 hours post infusion on days 1, 8 and 15, + 24 hours 1st infusion (Day 2), +24 hours 3rd infusion (Day 16), +72 hours 3rd infusion (Day 18), +168 hours 3rd infusion (Day 22) of Cycle 1
measure: Part 1: Cmax: Maximum Observed Plasma Concentration for Tisotumab Vedotin (HuMax-TF-ADC)
timeFrame: Before infusion, end of infusion (+15 minutes), and +2 hours post infusion on days 1, 8, and 15, +24 hours 1st infusion (Day 2), +24 hours 3rd infusion (Day 16), +72 hours 3rd infusion (Day 18), and +168 hours 3rd infusion (Day 22) of Cycle 1
measure: Part 2: Cmax: Maximum Observed Plasma Concentration for Tisotumab Vedotin (HuMax-TF-ADC)
timeFrame: Before infusion, end of infusion (+15 minutes) and +2 hours post infusion on day 1, and before infusion on days 8 and 15 of Cycle 1
measure: Part 1: Tmax: Time to Reach the Maximum Plasma Concentration for Tisotumab Vedotin (HuMax-TF-ADC)
timeFrame: Before infusion, end of infusion (+15 minutes), and +2 hours post infusion on days 1, 8, and 15, +24 hours 1st infusion (Day 2), +24 hours 3rd infusion (Day 16), +72 hours 3rd infusion (Day 18), and +168 hours 3rd infusion (Day 22) of Cycle 1
measure: Part 2: Tmax: Time to Reach the Maximum Plasma Concentration for Tisotumab Vedotin (HuMax-TF-ADC)
timeFrame: Before infusion, end of infusion (+15 minutes) and +2 hours post infusion on day 1, and before infusion on days 8 and 15 of Cycle 1
measure: Part 1: Trough Concentration (Ctrough) Steady State Plasma Pharmacokinetic for Tisotumab Vedotin (HuMax-TF-ADC)
timeFrame: Before infusion of Day 1, 8 and 15 of Cycle 1
measure: Part 1: Terminal Phase Elimination Half-life (T1/2) for Tisotumab Vedotin (HuMax-TF-ADC)
timeFrame: Before infusion, end of infusion (+15 minutes), and +2 hours post infusion on days 1, 8, and 15, +24 hours 1st infusion (Day 2), +24 hours 3rd infusion (Day 16), +72 hours 3rd infusion (Day 18), and +168 hours 3rd infusion (Day 22) of Cycle 1
measure: Part 1: Total Clearance (CL) of Tisotumab Vedotin (HuMax-TF-ADC)
timeFrame: Before infusion, end of infusion (+15 minutes), and +2 hours post infusion on days 1, 8, and 15, +24 hours 1st infusion (Day 2), +24 hours 3rd infusion (Day 16), +72 hours 3rd infusion (Day 18), and +168 hours 3rd infusion (Day 22) of Cycle 1
measure: Part 1: Apparent Volume of Distribution (Vz) for Tisotumab Vedotin (HuMax-TF-ADC)
timeFrame: Before infusion, end of infusion (+15 minutes), and +2 hours post infusion on days 1, 8, and 15, +24 hours 1st infusion (Day 2), +24 hours 3rd infusion (Day 16), +72 hours 3rd infusion (Day 18), and +168 hours 3rd infusion (Day 22) of Cycle 1
measure: 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)
timeFrame: Before infusion, end of infusion (+15 minutes), and +2 hours post infusion on days 1, 8, and 15, +24 hours 1st infusion (Day 2), +24 hours 3rd infusion (Day 16), +72 hours 3rd infusion (Day 18), and +168 hours 3rd infusion (Day 22) of Cycle 1
measure: 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)
timeFrame: Before infusion, end of infusion (+15 minutes) and +2 hours post infusion on day 1, and before infusion on days 8 and 15 of Cycle 1
measure: Part 1: AUCinf: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Total HuMax-TF (Conjugated and Non-conjugated)
timeFrame: Before infusion, end of infusion (+15 minutes), and +2 hours post infusion on days 1, 8, and 15, +24 hours 1st infusion (Day 2), +24 hours 3rd infusion (Day 16), +72 hours 3rd infusion (Day 18), and +168 hours 3rd infusion (Day 22) of Cycle 1
measure: Part 1: Cmax: Maximum Observed Plasma Concentration for Total HuMax-TF (Conjugated and Non-conjugated)
timeFrame: Before infusion, end of infusion (+15 minutes), and +2 hours post infusion on days 1, 8, and 15, +24 hours 1st infusion (Day 2), +24 hours 3rd infusion (Day 16), +72 hours 3rd infusion (Day 18), and +168 hours 3rd infusion (Day 22) of Cycle 1
measure: Part 2: Cmax: Maximum Observed Plasma Concentration for Total HuMax-TF (Conjugated and Non-conjugated)
timeFrame: Before infusion, end of infusion (+15 minutes) and +2 hours post infusion on day 1, and before infusion on days 8 and 15 of Cycle 1
measure: Part 1: Tmax: Time to Reach the Maximum Plasma Concentration for Total HuMax-TF (Conjugated and Non-conjugated)
timeFrame: Before infusion, end of infusion (+15 minutes), and +2 hours post infusion on days 1, 8, and 15, +24 hours 1st infusion (Day 2), +24 hours 3rd infusion (Day 16), +72 hours 3rd infusion (Day 18), and +168 hours 3rd infusion (Day 22) of Cycle 1
measure: Part 2: Tmax: Time to Reach the Maximum Plasma Concentration for Total HuMax-TF (Conjugated and Non-conjugated)
timeFrame: Before infusion, end of infusion (+15 minutes) and +2 hours post infusion on day 1, and before infusion on days 8 and 15 of Cycle 1
measure: Part 1: Terminal Phase Elimination Half-life (T1/2) for Total HuMax-TF (Conjugated and Non-conjugated)
timeFrame: Before infusion, end of infusion (+15 minutes), and +2 hours post infusion on days 1, 8, and 15, +24 hours 1st infusion (Day 2), +24 hours 3rd infusion (Day 16), +72 hours 3rd infusion (Day 18), and +168 hours 3rd infusion (Day 22) of Cycle 1
measure: Part 1 and Part 2: Total Clearance (CL) of Total HuMax-TF (Conjugated and Non-conjugated)
timeFrame: 0 to 2 hours post-dose on days 1, 8, 15, +24 hrs 1st infusion, +24 hrs 3rd infusion, +72 hrs 3rd infusion, +168 hrs 3rd infusion (Part 1) and 0 to 2 hours post-dose on day 1, and pre-dose days 8 and 15 (Part 2) of Cycle 1
measure: Part 1 & Part 2: Apparent Volume of Distribution (Vz) for Total HuMax-TF (Conjugated and Non-conjugated)
timeFrame: 0 to 2 hours post-dose on days 1, 8, 15, +24 hrs 1st infusion, +24 hrs 3rd infusion, +72 hrs 3rd infusion, +168 hrs 3rd infusion (Part 1) and 0 to 2 hours post-dose on day 1, and pre-dose days 8 and 15 (Part 2) of Cycle 1
measure: Part 1: Trough Concentration (Ctrough) Steady State Plasma Pharmacokinetic for Total HuMax-TF (Conjugated and Non-conjugated)
timeFrame: Before infusion on Day 1, 8 and 15 of Cycle 1
measure: 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)
timeFrame: Before infusion, end of infusion (+15 minutes), and +2 hours post infusion on days 1, 8, and 15, +24 hours 1st infusion (Day 2), +24 hours 3rd infusion (Day 16), +72 hours 3rd infusion (Day 18), and +168 hours 3rd infusion (Day 22) of Cycle 1
measure: 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)
timeFrame: Before infusion, end of infusion (+15 minutes) and +2 hours post infusion on day 1, and before infusion on days 8 and 15 of Cycle 1
measure: Part 1: Cmax: Maximum Observed Plasma Concentration for Free Toxin (MMAE)
timeFrame: Before infusion, end of infusion (+15 minutes), and +2 hours post infusion on days 1, 8, and 15, +24 hours 1st infusion (Day 2), +24 hours 3rd infusion (Day 16), +72 hours 3rd infusion (Day 18), and +168 hours 3rd infusion (Day 22) of Cycle 1
measure: Part 2: Cmax: Maximum Observed Plasma Concentration for Free Toxin (MMAE)
timeFrame: Before infusion, end of infusion (+15 minutes) and +2 hours post infusion on day 1, and before infusion on days 8 and 15 of Cycle 1
measure: Part 1: Tmax: Time to Reach the Maximum Plasma Concentration for Free Toxin (MMAE)
timeFrame: Before infusion, end of infusion (+15 minutes), and +2 hours post infusion on days 1, 8, and 15, +24 hours 1st infusion (Day 2), +24 hours 3rd infusion (Day 16), +72 hours 3rd infusion (Day 18), and +168 hours 3rd infusion (Day 22) of Cycle 1
measure: Part 2: Tmax: Time to Reach the Maximum Plasma Concentration for Free Toxin (MMAE)
timeFrame: Before infusion, end of infusion (+15 minutes) and +2 hours post infusion on day 1, and before infusion on days 8 and 15 of Cycle 1
measure: Part 1: Trough Concentration (Ctrough) Steady State Plasma Pharmacokinetic for Free Toxin (MMAE)
timeFrame: Before infusion on Day 1, 8 and 15 of Cycle 1
measure: Part 1: Number of Participants With a Positive Anti-drug Antibody (ADA) Immunogenicity Result
timeFrame: Baseline to end of follow-up; maximum follow-up was 24 weeks
measure: Part 2: Number of Participants With a Positive Anti-drug Antibody (ADA) Immunogenicity Result
timeFrame: Baseline to end of trial (Part 2), up to 36 weeks
measure: Part 1: Number of Patients Who Experienced Anti-tumor Activity Measured by Tumor Shrinkage
timeFrame: Baseline to end of trial (Part 1), up to 72 weeks
measure: Part 2: Anti-tumor Activity Measured by Percentage of Change in Sum of Lesion Measurements
timeFrame: Baseline to end of trial (Part 2), up to 36 weeks
measure: Part 1: Response Evaluation Based on PSA (Prostate Specific Antigen [Prostate Cancer]): Percentage Change From Baseline to End of Study
timeFrame: Baseline to end of follow-up; maximum follow-up was 24 weeks
measure: Part 1: Response Evaluation Based on CA125 (Cancer Antigen 125 [Ovarian and Endometrial Cancer]): Percentage of Change From Baseline to End of Study
timeFrame: Baseline to end of follow-up; maximum follow-up was 24 weeks
measure: Part 2: Response Evaluation Based on CA125 (Cancer Antigen 125 [Ovarian and Endometrial Cancer]): Percentage of Change From Baseline to End of Study
timeFrame: Baseline to end of trial (Part 2), up to 36 week
measure: Part 1: Best Overall Response (OR)
timeFrame: Baseline to end of trial (Part 1), up to 72 weeks
measure: Part 2: Best Overall Response (OR)
timeFrame: Baseline to end of trial (Part 2), up to 36 weeks
measure: Part 1: Number of Participants Who Experienced Disease Control
timeFrame: 6, 12, 24 and 36 weeks post first infusion (Part 1)
measure: Part 2: Number of Participants Who Experienced Disease Control
timeFrame: 6, 12, 24 and 36 weeks post first infusion (Part 2)
measure: Part 1: Progression Free Survival (PFS)
timeFrame: Baseline to end of follow-up; maximum time of follow-up was 24 weeks
measure: Part 2: Progression Free Survival (PFS)
timeFrame: Baseline to end of trial (Part 2), up to 36 weeks
measure: Part 1: Duration of Response
timeFrame: Baseline to end of trial (Part 1), up to 72 weeks
measure: Part 2: Duration of Response
timeFrame: Baseline to end of trial (Part 2), up to 36 weeks
Other outcomes:
Locations:
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Bruxelles
country: Belgium
facility: Institut Jules Bordet
state: Brussels
city: Leuven
country: Belgium
facility: Universitaire Ziekenhuizen Leuven
state: Flemish Brabant
city: Charleroi
country: Belgium
facility: Grand Hôpital de Charleroi
state: Hainaut
city: Liege
country: Belgium
facility: CHU de Liège
state: Liège
city: Yvoir
country: Belgium
facility: CHU UCL Namur - site Godinne
state: Namur
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Namur
country: Belgium
facility: CHU UCL Namur - Sainte Elisabeth
city: Copenhagen
country: Denmark
facility: Rigshospitalet, Copenhagen University Hospital
city: Gyor
country: Hungary
facility: Petz Aladár Megyei Oktató Kórház
state: Gyor-Moson-Sopron
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Központ
state: Hajdu-Bihar
city: Budapest
country: Hungary
facility: Semmelweis Egyetem Onkológiai Központ
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
state: England
city: London
country: United Kingdom
facility: Sarah Cannon Cancer Center
state: England
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
state: England
city: Sutton
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
Study officials:
affiliation: The Institute of Cancer Research & The Royal Marsden NHS Foundation Trust
name: Johann de Bono, Professor
role: PRINCIPAL_INVESTIGATOR
References: