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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Seagen Inc.
- 入组人数
- 33
- 试验地点
- 16
- 主要终点
- Part 1: Number of Participants Who Experience at Least One Adverse Event (AE)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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.
排除标准
- •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).
研究组 & 干预措施
Tisotumab vedotin (HuMax-TF-ADC)
干预措施: Tisotumab vedotin (HuMax-TF-ADC) (Drug)
结局指标
主要结局
Part 1: Number of Participants Who Experience at Least One Adverse Event (AE)
时间窗: Baseline to end of follow-up; maximum time of follow-up was 24 weeks
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.
Part 1: Number of Participants Reporting One or More Infusion-related Adverse Events
时间窗: Day 1, Day 8 & Day 15 (+1 day) until end of treatment (Part 1), approximately 48 weeks
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.
Part 2: Number of Participants Who Experience at Least One Adverse Event (AE)
时间窗: Baseline to end of trial (Part 2), up to 36 weeks
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.
Part 1: Number of Participants Reporting One or More Common Terminology Criteria for Adverse Events (CTCAE) Grade >=3 Adverse Events
时间窗: Baseline to end of follow-up; maximum time of follow-up was 24 weeks
A CTCAE AE was determined using the CTCAE grading systems based on NCI-CTCAE version 4.03 assessed by the investigator.
Part 1: Number of Participants Who Experienced at Least One or More Serious Adverse Event (SAE)
时间窗: Baseline to end of follow-up; maximum time of follow-up was 24 weeks
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.
Part 2: Number of Participants Reporting One or More Serious Adverse Events (SAE)
时间窗: Baseline to end of trial (Part 2), up to 36 weeks
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.
Part 2: Number of Participants Reporting One or More Infusion-related Adverse Events
时间窗: Day 1, Day 8 & Day 15 (+1 day) until end of trial (Part 2), up to 36 weeks
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.
Part 2: Number of Participants Reporting One or More Common Terminology Criteria for Adverse Events (CTCAE) Grade >=3 Adverse Events
时间窗: Baseline to end of trial (Part 2), up to 36 weeks
A CTCAE AE was determined using the CTCAE grading systems based on NCI-CTCAE version 4.03 assessed by the investigator.
Part 1: Number of Participants Reporting One or More Treatment-related Adverse Events
时间窗: Baseline to end of follow-up; maximum time of follow-up was 24 weeks
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.
Part 2: Number of Participants Reporting One or More Treatment-related Adverse Events
时间窗: Baseline to end of trial (Part 2), up to 36 weeks
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.
次要结局
- Part 2: Number of Participants Who Experienced a Neuropathy Event(Baseline to end of trial (Part 2), up to 36 weeks)
- Part 2: Number of Participants With Markedly Abnormal Laboratory Values(Baseline to end of trial (Part 2), up to 36 weeks)
- Part 1: Number of Participants Who Experienced a Bleeding Event(Baseline to end of trial (Part 1), up to 72 weeks)
- Part 2: Number of Participants Who Experienced a Bleeding Event(Baseline to end of trial (Part 2), up to 36 weeks)
- Part 1: Number of Participants Who Experienced a Skin Rash(Baseline to end of follow-up; maximum time of follow-up was 24 weeks)
- Part 1: Number of Participants Who Experienced a Neuropathy Event(Baseline to end of follow-up; maximum time of follow-up was 24 weeks)
- Part 2: Tmax: Time to Reach the Maximum Plasma Concentration for Tisotumab Vedotin (HuMax-TF-ADC)(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: Total Clearance (CL) of Tisotumab Vedotin (HuMax-TF-ADC)(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 Total HuMax-TF (Conjugated and Non-conjugated)(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)(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 1: Cmax: Maximum Observed Plasma Concentration for Free Toxin (MMAE)(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: Anti-tumor Activity Measured by Percentage of Change in Sum of Lesion Measurements(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(Baseline to end of follow-up; maximum follow-up was 24 weeks)
- Part 1: Number of Participants With Markedly Abnormal Laboratory Values(Baseline to end of follow-up; maximum time of follow-up was 24 weeks)
- Part 2: Number of Participants Who Experienced a Skin Rash(Baseline to end of trial (Part 2), up to 36 weeks)
- 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)(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: 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)(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)(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)(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: Apparent Volume of Distribution (Vz) for Tisotumab Vedotin (HuMax-TF-ADC)(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 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)(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: 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)(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 & Part 2: Apparent Volume of Distribution (Vz) for Total HuMax-TF (Conjugated and Non-conjugated)(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: Trough Concentration (Ctrough) Steady State Plasma Pharmacokinetic for Total HuMax-TF (Conjugated and Non-conjugated)(Before infusion on Day 1, 8 and 15 of Cycle 1)
- Part 1: Response Evaluation Based on CA125 (Cancer Antigen 125 [Ovarian and Endometrial Cancer]): Percentage of Change From Baseline to End of Study(Baseline to end of follow-up; maximum follow-up was 24 weeks)
- Part 1: AUCinf: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Tisotumab Vedotin (HuMax-TF-ADC)(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: Tmax: Time to Reach the Maximum Plasma Concentration for Tisotumab Vedotin (HuMax-TF-ADC)(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 1: Tmax: Time to Reach the Maximum Plasma Concentration for Total HuMax-TF (Conjugated and Non-conjugated)(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: Tmax: Time to Reach the Maximum Plasma Concentration for Total HuMax-TF (Conjugated and Non-conjugated)(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 and Part 2: Total Clearance (CL) of Total HuMax-TF (Conjugated and Non-conjugated)(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: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for Free Toxin (MMAE)(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 Free Toxin (MMAE)(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)(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: Tmax: Time to Reach the Maximum Plasma Concentration for Free Toxin (MMAE)(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 2: Number of Participants With a Positive Anti-drug Antibody (ADA) Immunogenicity Result(Baseline to end of trial (Part 2), up to 36 weeks)
- Part 2: Best Overall Response (OR)(Baseline to end of trial (Part 2), up to 36 weeks)
- Part 1: Trough Concentration (Ctrough) Steady State Plasma Pharmacokinetic for Tisotumab Vedotin (HuMax-TF-ADC)(Before infusion of Day 1, 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)(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 1: Cmax: Maximum Observed Plasma Concentration for Total HuMax-TF (Conjugated and Non-conjugated)(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: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for Free Toxin (MMAE)(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)(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(Baseline to end of follow-up; maximum follow-up was 24 weeks)
- Part 1: Best Overall Response (OR)(Baseline to end of trial (Part 1), up to 72 weeks)
- Part 1: Number of Participants Who Experienced Disease Control(6, 12, 24 and 36 weeks post first infusion (Part 1))
- Part 1: Terminal Phase Elimination Half-life (T1/2) for Tisotumab Vedotin (HuMax-TF-ADC)(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 1: Number of Patients Who Experienced Anti-tumor Activity Measured by Tumor Shrinkage(Baseline to end of trial (Part 1), up to 72 weeks)
- Part 1: Progression Free Survival (PFS)(Baseline to end of follow-up; maximum time of follow-up was 24 weeks)
- Part 2: Duration of Response(Baseline to end of trial (Part 2), up to 36 weeks)
- Part 2: Response Evaluation Based on CA125 (Cancer Antigen 125 [Ovarian and Endometrial Cancer]): Percentage of Change From Baseline to End of Study(Baseline to end of trial (Part 2), up to 36 week)
- Part 1: Duration of Response(Baseline to end of trial (Part 1), up to 72 weeks)
- Part 2: Number of Participants Who Experienced Disease Control(6, 12, 24 and 36 weeks post first infusion (Part 2))
- Part 2: Progression Free Survival (PFS)(Baseline to end of trial (Part 2), up to 36 weeks)