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

Seagen Inc.33 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Ovary Cancer Cervix Cancer Endometrium Cancer Bladder Cancer Prostate Cancer (CRPC)Esophagus Cancer Lung Cancer (NSCLC)

Interventions

Tisotumab vedotin (HuMax-TF-ADC)DRUG

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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).

Locations (16)

MD Anderson Cancer Center

Houston, Texas, United States

Institut Jules Bordet

Brussels, Brussels Capital, Belgium

Outcomes

Primary Outcomes

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

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.

Time frame: Baseline to end of follow-up; maximum time of follow-up was 24 weeks

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

Time frame: Baseline to end of trial (Part 2), up to 36 weeks

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

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.

Time frame: Baseline to end of follow-up; maximum time of follow-up was 24 weeks

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

Data from ClinicalTrials.gov

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Secondary Outcomes

Part 1: Number of Participants With Markedly Abnormal Laboratory Values

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.

Time frame: Baseline to end of follow-up; maximum time of follow-up was 24 weeks

Part 2: Number of Participants With Markedly Abnormal Laboratory Values

Time frame: Baseline to end of trial (Part 2), up to 36 weeks

Part 1: Number of Participants Who Experienced a Skin Rash

Time frame: Baseline to end of follow-up; maximum time of follow-up was 24 weeks

Part 2: Number of Participants Who Experienced a Skin Rash

Time frame: Baseline to end of trial (Part 2), up to 36 weeks

Part 1: Number of Participants Who Experienced a Bleeding Event

Time frame: Baseline to end of trial (Part 1), up to 72 weeks

Part 2: Number of Participants Who Experienced a Bleeding Event

Time frame: Baseline to end of trial (Part 2), up to 36 weeks

Part 1: Number of Participants Who Experienced a Neuropathy Event

Time frame: Baseline to end of follow-up; maximum time of follow-up was 24 weeks

Part 2: Number of Participants Who Experienced a Neuropathy Event

Time frame: Baseline to end of trial (Part 2), up to 36 weeks

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)

Time frame: 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

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)

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).

Time frame: 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

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

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

Time frame: 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

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

Time frame: 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

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

Time frame: 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

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)

Time frame: 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

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

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.

Time frame: Before infusion of Day 1, 8 and 15 of Cycle 1

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

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.

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

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.

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

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.

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)

Time frame: 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

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

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

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)

Time frame: 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

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)

Time frame: 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

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

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.

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

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

Time frame: 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

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

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

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

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.

Time frame: Before infusion on Day 1, 8 and 15 of Cycle 1

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)

Time frame: 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

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

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

Time frame: 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

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)

Time frame: 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

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

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.

Time frame: Before infusion on Day 1, 8 and 15 of Cycle 1

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

Time frame: Baseline to end of follow-up; maximum follow-up was 24 weeks

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

Time frame: Baseline to end of trial (Part 2), up to 36 weeks

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

Time frame: Baseline to end of trial (Part 1), up to 72 weeks

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

Time frame: Baseline to end of trial (Part 2), up to 36 weeks

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

Time frame: Baseline to end of follow-up; maximum follow-up was 24 weeks

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

Time frame: Baseline to end of follow-up; maximum follow-up was 24 weeks

Part 2: Response Evaluation Based on CA125 (Cancer Antigen 125 [Ovarian and Endometrial Cancer]): Percentage of Change From Baseline to End of Study

Time frame: Baseline to end of trial (Part 2), up to 36 week

Part 1: Best Overall Response (OR)

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.

Time frame: Baseline to end of trial (Part 1), up to 72 weeks

Part 2: Best Overall Response (OR)

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.

Time frame: Baseline to end of trial (Part 2), up to 36 weeks

Part 1: Number of Participants Who Experienced Disease Control

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.

Time frame: 6, 12, 24 and 36 weeks post first infusion (Part 1)

Part 2: Number of Participants Who Experienced Disease Control

Time frame: 6, 12, 24 and 36 weeks post first infusion (Part 2)

Part 1: Progression Free Survival (PFS)

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.

Time frame: Baseline to end of follow-up; maximum time of follow-up was 24 weeks

Part 2: Progression Free Survival (PFS)

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.

Time frame: Baseline to end of trial (Part 2), up to 36 weeks

Part 1: Duration of Response

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.

Time frame: Baseline to end of trial (Part 1), up to 72 weeks

Part 2: Duration of Response

Time frame: Baseline to end of trial (Part 2), up to 36 weeks