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

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.

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).