A Phase 1b/2 Open-Label Trial of Tisotumab Vedotin (HuMax®-TFADC) Monotherapy and in Combination with Other Agents in Subjects with Recurrent or Stage IVB Cervical Cancer

The investigational medicinal product, tisotumab vedotin, is an antibody-drug
conjugate (ADC) composed of a human monoclonal immunoglobulin G1 (subtype *)
targeting tissue factor (TF) conjugated via a protease cleavable valine
citrulline linker to the drug monomethyl auristatin E (MMAE), a dolastatin 10
analog.
Dolastatins and auristatins belong to a class of chemotherapies that act as
microtubule disrupting agents.
Tisotumab vedotin efficiently and specifically binds to TF. TF has a central
physiological role in initiation of the coagulation cascade and is upregulated
during oncological transformation and expressed on the membrane of neoplastic
cells as well as on tumor-associated endothelial cells.
Upon binding to TF, tisotumab vedotin is rapidly internalized into tumor cells
where it
undergoes lysosomal degradation resulting in release of the cytotoxic payload.
Tumor cell death occurs due to MMAE-mediated disruption of microtubules in
TF-positive tumor cell and in neighboring tumor cells through *bystander*
cytotoxicity.
Tisotumab vedotin targets TF-expressing tumors through intracellular delivery
of the potent and clinically validated agent MMAE. TF is expressed in a wide
variety of tumors including the gynecological cancers of the ovary and cervix,
genito-urethral tumors, squamous cell carcinoma of the head and neck, lung
cancers, tumors in the gastrointestinal tract, breast cancer, malignant
melanoma and pancreatic cancer. TF is expressed on the membrane of neoplastic
cells as well as on tumor-associated endothelial cells. Furthermore, expression
of TF on tumor cells has been associated with negative overall survival or
disease-free survival as described in several indications, including ovarian
and bladder cancer.
High differential levels of TF expression have been observed in multiple
cancers including cervical cancer; as such tisotumab vedotin is an attractive
candidate as an anti-cancer therapy in cervical cancer.

This study has been transitioned to CTIS with ID 2023-508832-68-00 check the CTIS register for the current data.

Dose escalation: To establish the MTD and RP2D of tisotumab vedotin in
combination in subjects with cervical cancer
Dose expansion: Evaluate the antitumor activity of tisotumab vedotin
monotherapy and in
combination in subjects with cervical cancer

This is an open label, multi-center trial of tisotumab vedotin monotherapy and
in combination with bevacizumab, pembrolizumab, or carboplatin in subjects with
recurrent or stage IVB cervical cancer.
The trial will be conducted in two parts: dose escalation followed by dose
expansion.

Dose Escalation:
Arm A - Tisotumab vedotin once every 3 weeks (1Q3W) +
Bevacizumab 7.5 mg/kg 1Q3W OR 15 mg/kg 1Q3W (Subjects who
have progressed during or after standard of care therapy or are intolerant or
ineligible to receive standard of care treatments).
Arm B - Tisotumab vedotin 1Q3W + Pembrolizumab 200 mg 1Q3W (Subjects who have
progressed during or after standard of care therapy or are intolerant or
ineligible to receive standard of care treatments).
Arm C - Tisotumab vedotin 1Q3W + Carboplatin AUC 5 1Q3W (Subjects who have
progressed during or after standard of care therapy or are intolerant or
ineligible to receive standard of care treatments).
Dose Expansion:
Arm D - Tisotumab vedotin at the Recommended Phase 2 Dose (RP2D) 1Q3W +
Carboplatin AUC 5 1Q3W (Subjects that have not received prior systemic therapy
for recurrent or stage IVB disease).
Arm E - Tisotumab vedotin at the RP2D 1Q3W + Pembrolizumab 200 mg 1Q3W
(Subjects that have not received prior systemic therapy for recurrent or stage
IVB disease).
Arm F - Tisotumab vedotin at the RP2D 1Q3W + Pembrolizumab 200 mg 1Q3W
(Subjects who have progressed on or after standard of care treatments).
Arm G - Tisotumab vedotin monotherapy (0.9 mg/kg on Days 1, 8 and 15 of
every 28-day cycle [3Q4W]) in cervical cancer subjects who have progressed
on or after at least one but no more than two prior systemic therapies for their
recurrent or stage IVB cervical cancer.
Arm H - Either the 4 drug (quadruplet) regimen (pembrolizumab, bevacizumab,
carboplatin and tisotumab vedotin) or the 3 drug (triplet) regimen
(pembrolizumab, carboplatin and tisotumab vedotin). The dosages will be as
follows:
• Pembrolizumab 200 mg
• Bevacizumab (if assigned) 15mg/kg
• Carboplatin 5AUC
• Tisotumab vedotin 2.0 mg/kg
Up to 30 subjects might be recruited for each expansion arm.

Data from GEN701 cohort expansion demonstrates substantial efficacy of
tisotumab vedotin in subjects with recurrent or metastatic cervical cancer
along with a manageable safety profile. The safety profile of tisotumab vedotin
in the cervical cohort was comparable to the profile observed
for other indications.