Tisotumab Vedotin in Squamous Cell Carcinoma of the Vulva

Phase II Study Tisotumab Vedotin in Metastatic or Recurrent Squamous Cell Carcinoma of the Vulva

This is an open-label, single arm, phase 2 study designed to evaluate the efficacy of tisotumab vedotin in participants with recurrent or metastatic squamous cell carcinoma of the vulva by estimating the objective response rate.

Patients will receive tisotumab vedotin every 3 weeks (21 days plus or minus 3 days). Treatment will continue until either unacceptable toxicity, progression of disease, or investigator/patient request for withdrawal.

Inclusion Criteria:

• Age ≥18 years, or considered an adult by local regulations, at time of consent.

• Must sign an informed consent form (ICF) indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study prior to any other study-related assessments or procedures.

• Has recurrent or metastatic vulva cancer with squamous cell histology, and:

  1. Has not received more than 2 prior systemic therapy regimens for recurrent and/or metastatic vulva cancer. Chemotherapy administered in the adjuvant or neoadjuvant setting, or in combination with radiation therapy, should not be counted as separate systemic therapy regimen.
  2. Is not a candidate for curative therapy, including but not limited to radiotherapy or exenterative surgery.

• Measurable disease according to RECIST v1.1 as assessed by the investigator, defined as:

  1. A minimum of one non-nodal lesion ≥10 mm in the longest diameter from a nonirradiated area. If target lesion(s) are located within previously irradiated area only, the participant can be enrolled only if there has been demonstrated progression in the "in field" lesion and upon approval of the sponsor's medical monitor.

     OR

  2. Lymph node lesion ≥15 mm in the shortest diameter from a non-irradiated area.

• Must demonstrate acceptable screening laboratory values:

  1. Calculated eGFR (MDRD formula): ≥50 mL/min/1.73m^2

  2. Alanine aminotransferase (ALT): ≤3× upper limit of normal (ULN) (if liver tumor/metastases are present, then ≤5×ULN is allowed)

  3. Aspartate aminotransferase (AST): ≤3×ULN (if liver tumor/metastases are present, then ≤5×ULN is allowed)

  4. Bilirubin: ≤1.5×ULN (except in participants diagnosed with Gilbert's syndrome, direct bilirubin ≤2×ULN)

  5. Hemoglobin: ≥5.6 mmol/L (9.0 g/dL)

  6. Absolute Neutrophil Count (ANC): ≥1500/μL (1.5x10^9/L)

  7. Platelet count: ≥100×10^9/L

  8. For participants NOT on anti-coagulation therapy:

     1. Activated partial thromboplastin time (aPTT): ≤1.5×ULN
     2. International normalized ratio (INR): ≤1.2

  9. For participants on anti-coagulation therapy:

     1. aPTT: ≤1.5×ULN
     2. INR: ≤2.5

• Has ECOG performance status of 0 or 1 within 28 days prior to registration.

• Has a negative serum pregnancy test for participants of reproductive potential. Participants that are postmenopausal, permanently sterilized or previously subjected to bilateral oophorectomy, bilateral salpingectomy and/or hysterectomy can be considered as not having reproductive potential.

• Participants of reproductive potential must agree to use adequate contraception during and for 6 months after the last study treatment administration. Adequate contraception is defined as highly effective methods of contraception. Two highly effective methods of contraception must be used in countries where this is required.

• Must agree not to breastfeed or donate ova, starting at the time of informed consent and continuing through 6 months after receiving the last dose of study drug administration.

• If required by local health authorities, has negative serology for hepatitis B surface antigen (HBsAg)/HBV DNA, or hepatitis C antibody (HCVAb) or RNA. Active hepatitis C is defined by a known positive HCVAb result and known quantitative HCV RNA results greater than the lower limits of detection of the assay.

• Must be willing and able to adhere to the prohibitions and restrictions specified in the protocol.

Exclusion Criteria:

• Has primary melanoma, adenocarcinoma, sarcomatoid, or other histologies not mentioned in inclusion criterion 3

• Has clinically significant bleeding issues or risks:

  1. Known past or current coagulation defects leading to an increased risk of bleeding
  2. Diffuse alveolar hemorrhage from vasculitis
  3. Known bleeding diathesis
  4. Ongoing major bleeding (ie, participant requires a transfusion of >2 platelet concentrates within 14 days of the first dose of study treatment)
  5. Trauma with increased risk of life-threatening bleeding
  6. History of severe head trauma or intracranial surgery within 8 weeks of study entry

• Has cardiovascular issues or risks:

  1. Clinically significant cardiac disease, including unstable angina or acute myocardial infarction, 6 months prior to screening
  2. Any medical history of congestive heart failure (grade III or IV as classified by the New York Heart Association)
  3. Any medical history of decreased cardiac ejection fraction of <45%
  4. A marked baseline prolongation of QT/QTc interval (eg, repeated demonstration of a QTc interval >450 msec)
  5. 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

• Central nervous system (CNS): any history of intracerebral arteriovenous malformation, cerebral aneurysm, or stroke (transient ischemic attack >28 days prior to screening is allowed).

• Ophthalmological: Active ocular surface disease or a history of cicatricial conjunctivitis or inflammatory conditions that predispose to cicatrizing conjunctivitis (eg, Wagner syndrome, atopic keratoconjunctivitis, autoimmune disease affecting the eyes), ocular Stevens-Johnson syndrome or toxic epidermal necrolysis, mucus pemphigoid, and participants with penetrating ocular transplants are ineligible. Cataracts alone is not an exclusion criterion.

• Other cancer: known past or current malignancy other than inclusion diagnosis. Exceptions are malignancies with a negligible risk of metastasis or death (e.g., 5-year OS ≥90%) such as non-invasive basal cell carcinoma, non-invasive superficial bladder cancer, and ductal carcinoma in situ.

• Brain metastases are allowed if the following criteria are met: definitive therapy (eg, surgery or stereotactic brain radiotherapy) has been completed >8 weeks before the first dose of study treatment; no evidence of clinical or radiologic progression of the brain metastases; participant has completed perioperative corticosteroid therapy or steroid taper. NOTE: Chronic steroid therapy is acceptable provided that the dose is stable for 28 days prior to study enrollment.

• Surgery/procedures: major surgery within 4 weeks (28 days) or minor surgery within 7 days prior to the first study treatment administration. Participants must have recovered adequately from the toxicity or complications from the intervention prior to starting study treatment. Participants who have planned major surgery during the treatment period must be excluded from the study.

• Peripheral neuropathy ≥grade 2.

• Prior anti-cancer therapy:

  1. Any prior treatment with MMAE-derived drugs (e.g. Brentuximab vedotin, Polatuzumab vedotin, Tisotumab vedotin, Disitamab vedotin).
  2. Radiotherapy for palliative intent within 21 days prior to the first administration of study treatment. Participants must have recovered from all clinically significant radiation-related toxicities. At least 42 days must have elapsed from the last administration of chemo-radiotherapy to first study treatment.
  3. Small molecules, chemotherapy, immunotherapy, or monoclonal antibodies within 28 days prior to the first administration of study treatment.
  4. Currently participating in or has participated in a study of an investigational agent or device and received active treatment within 28 days prior to the first dose of study treatment.

• Other:

  1. Ongoing significant, uncontrolled medical condition.
  2. Clinically significant active viral, bacterial, or fungal infection requiring IV or oral treatment with antimicrobial therapy ending <7 days prior to first study treatment administration.
  3. Clinically relevant bilateral hydronephrosis which cannot be alleviated by ureteral stents or percutaneous drainage.
  4. Participants with clinical symptoms or signs of gastrointestinal obstruction and who require parenteral hydration or nutrition at the time of the first dose of study treatment.

• Has known seropositivity of human immunodeficiency virus (HIV); known medical history of hepatitis B or C infection. Note: No testing for HIV, hepatitis B, or hepatitis C is required, unless mandated by local health authorities. Exceptions include latent or controlled HIV infection.

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (dose exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of tisotumab vedotin.

• Is pregnant or intends to conceive children within 6 months of ending study treatment.

• Is breast feeding and cannot discontinue breast feeding for the duration of the study and ≥6 months after the last study treatment administration.

• Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise well-being) or that could prevent, limit, or confound the protocol-specified assessments.

• Known allergies, hypersensitivity, or intolerance to study treatment or its excipients (refer to the Investigator's Brochure for further information on tisotumab vedotin).

• Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study.