Efficacy and Safety Study of Tisotumab Vedotin for Patients With Solid Tumors

The primary goal of this trial is to assess the activity, safety, and tolerability of tisotumab vedotin for the treatment of selected solid tumors. Patients will be treated with single agent tisotumab vedotin or tisotumab vedotin in combination with other anticancer agents. Patients who meet eligibility criteria will be enrolled into cohorts based on tumor type. Tumor types to be evaluated include colorectal cancer, squamous non-small cell lung cancer (sqNSCLC), exocrine pancreatic adenocarcinoma, and head and neck squamous cell carcinoma (HNSCC).

• tisotumab vedotin (Drug), also known as TIVDAK: Given into the vein (IV; intravenously)
• pembrolizumab (Drug), also known as KEYTRUDA®: 200mg or 400mg given by IV
• carboplatin (Drug): AUC 5mg/mL per minute or AUC 3.3mg/mL per minute given by IV
• cisplatin (Drug): 100mg/m\^2 given by IV

Primary outcomes

• Confirmed Objective Response Rate (ORR) (Parts A, B, C, D, E, F, and G) [Up to approximately 3 years]: Proportion of patients who achieve a confirmed complete response (CR) or partial response (PR) according to RECIST v1.1 as assessed by the investigator

Secondary outcomes

• Incidence of Adverse Events (AEs) [Up to approximately 3 years]: Type, severity, and relatedness of adverse events. An AE is any untoward medical occurrence in a subject or clinical investigational subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment.
• Confirmed and Unconfirmed ORR [Up to approximately 3 years]: Proportion of patients who achieve a CR or PR according to RECIST v1.1 as assessed by the investigator
• Disease Control Rate (DCR) [Up to approximately 3 years]: Proportion of patients who achieve a confirmed CR or PR according to RECIST v1.1 as assessed by the investigator, or meet the stable disease (SD) criteria at least once after start of study treatment at a minimum interval of 12 weeks
• Duration of Response (DOR) [Up to approximately 3 years]: Time from the first documentation of objective response to the first documentation of PD or death due to any cause, whichever comes first, as assessed by the investigator
• Time to Response (TTR) [Up to approximately 1 year]: Time from the start of study treatment to the first documentation of objective response, as assessed by investigator
• Progression-free survival (PFS) [Up to approximately 3 years]: Time from the start of study treatment to the first documentation of PD according to RECIST v1.1 or death due to any cause, whichever comes first, as assessed by the investigator
• Overall Survival (OS) [Up to approximately 4 years]: Time from the start of study treatment to date of death due to any cause
• Cmax [Through 30-37 days following the last dose; up to approximately 3 years]: Maximum observed plasma concentration
• Ctrough [Through 30-37 days following the last dose; up to approximately 3 years]: Observed plasma concentration at the end of the dosing interval
• Incidence of anti-therapeutic antibodies (ATAs) [Through 30-37 days following the last dose; up to approximately 3 years]

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Parts A, B, and C

  * Relapsed, locally-advanced or metastatic colorectal or pancreatic cancer, sqNSCLC, or HNSCC participants who are not candidates for standard therapy.
  * All participants must have experienced disease progression on or after their most recent systemic therapy.
  * Colorectal cancer (closed to enrollment): participants must have received prior therapy with each of following agents, if eligible: a fluoropyrimidine, oxaliplatin, irinotecan, and/or bevacizumab. Participants should have received no more than 3 systemic regimens in the metastatic setting.
  * sqNSCLC (closed to enrollment): Participants with NSCLC must have predominant squamous histology. Participants must have received prior therapy with a platinum-based treatment and a checkpoint inhibitor (CPI), if eligible. Participants should have received no more than 3 lines of systemic therapy in the metastatic setting.

    * Participants eligible for a tyrosine kinase inhibitor should have received such therapy. These participants should have received no more than 4 lines of systemic therapy in the metastatic setting.
  * Exocrine pancreatic adenocarcinoma (closed to enrollment): Participants with exocrine pancreatic adenocarcinoma must have predominant adenocarcinoma histology. Participants must have received prior therapy with a gemcitabine-based or 5FU-based regimen, if eligible, and should have received no more than 1 systemic regimen in the unresectable or metastatic setting.
  * HNSCC (closed to enrollment): Participants with HNSCC in Part C must have received prior therapy with a platinum-based regimen and/or a checkpoint inhibitor (CPI), if eligible, and must have experienced disease progression following such therapy. Participants should have received no more than 3 systemic lines of therapy in the recurrent or metastatic setting.
* Part E

  * Part E is closed to enrollment.
  * Participants with HNSCC must have experienced disease progression on or after their most recent systemic therapy. Participants should have received no more than 1 or 2 systemic lines of therapy in the recurrent/metastatic setting as specified below. Participants must have received a platinum-based regimen and a PD-(L)1 inhibitor.
* Parts D, F, and G

  * Part D and F are closed to enrollment. Part G will enroll only participants with HNSCC.
  * Participants with HNSCC must have received no previous systemic therapy in the recurrent or metastatic disease setting.
  * Part D only

    * Participants with NSCLC must have histologically or cytologically documented squamous cell NSCLC and must have received no previous systemic therapy for metastatic disease or radiation therapy to the lung that is > 30 Gy within 6 months of the first dose of study treatment.
    * PD-L1 biomarker expression as determined by a PD-L1 IHC assay should be available
  * Part F only

    * Participants must have CPS ≥1 by local PD-L1 IHC assay to be eligible for enrollment. Participants must be able to submit a tissue sample for retrospective PD-L1 testing. Tissue may be fresh biopsy or archival, collected within 2 years of Cycle 1 Day 1.
  * Part G only

    * Part G cohort was not opened.
    * Non-EU eligibility criteria: No CPS requirement for the cohort evaluating tisotumab vedotin in combination with pembrolizumab and carboplatin.
    * EU-specific eligibility criteria: Participants must have a CPS ≥1 by local PD-L1 IHC assay.
    * Participants must be able to submit a tissue sample for retrospective PD-L1 testing. Tissue may be fresh biopsy or archival, collected within 2 years of Cycle 1 Day 1.
* Baseline measurable disease as measured by RECIST v1. 1.
* Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.

Exclusion Criteria:

* Participants with primary neuroendocrine or sarcomatoid histologies. For HNSCC, participants may not have a primary site of nasopharynx or salivary gland.
* Active bleeding conditions
* Clinically significant cardiac disease including stable angina, acute myocardial infraction 6 months prior to screening
* Ocular surface disease at the time of enrollment (Note: cataract is not considered active ocular surface disease for this protocol)
* Other cancer: known past or current malignancy other than inclusion diagnosis.
* Uncontrolled tumor-related pain
* Inflammatory lung disease. Participants with pulmonary disease are allowed if systemic steroids and long-term oxygen are not required
* Peripheral neuropathy greater than or equal to Grade 2
* Active brain metastasis
* Ongoing clinically significant toxicity associated with prior treatment (including radiotherapy or surgery).
* Part D, F, and G Only: Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor.

75 more sites not listed.

• Results publication: Feng S, Gunawan R, Passey C, Voellinger J, Polhamus D, Gerritsen A, O'Day C, Carret AS, Soumaoro I, Gupta M, Hanley WD. Exposure-safety Markov modeling of ocular adverse events in patient populations treated with tisotumab vedotin. J Pharmacokinet Pharmacodyn. 2025 Oct 3;52(5):55. doi: 10.1007/s10928-025-10003-w. PMID 41044356

• Pfizer CT.gov Call Center, Study director, Pfizer

NIH grants: 2023