Tisotumab vedotin in patients with advanced or metastatic solid tumours (innovaTV 201): a first-in-human, multicentre, phase 1-2 trial
Authorsde Bono, JS
Thistlethwaite, Fiona C
AffiliationThe Institute of Cancer Research, Royal Marsden NHS Foundation Trust, London, UK.
MetadataShow full item record
AbstractBACKGROUND: Tisotumab vedotin is a first-in-human antibody-drug conjugate directed against tissue factor, which is expressed across multiple solid tumour types and is associated with poor clinical outcomes. We aimed to establish the safety, tolerability, pharmacokinetic profile, and antitumour activity of tisotumab vedotin in a mixed population of patients with locally advanced or metastatic (or both) solid tumours known to express tissue factor. METHODS: InnovaTV 201 is a phase 1-2, open-label, dose-escalation and dose-expansion study done at 21 centres in the USA and Europe. Patients (aged ?18 years) had relapsed, advanced, or metastatic cancer of the ovary, cervix, endometrium, bladder, prostate, oesophagus, squamous cell carcinoma of the head and neck or non-small-cell lung cancer; an Eastern Cooperative Oncology Group performance status of 0-1; and had relapsed after or were not eligible to receive the available standard of care. No specific tissue factor expression level was required for inclusion. In the dose-escalation phase, patients were treated with tisotumab vedotin between 0·3 and 2·2 mg/kg intravenously once every 3 weeks in a traditional 3?+?3 design. In the dose-expansion phase, patients were treated at the recommended phase 2 dose. The primary endpoint was the incidence of adverse events, including serious adverse events, infusion-related, treatment-related and those of grade 3 or worse, and study drug-related adverse events, analysed in all patients who received at least one dose of tisotumab vedotin (full analysis population). This trial is registered with ClinicalTrials.gov, number NCT02001623, and is closed to new participants with follow-up ongoing. FINDINGS: Between Dec 9, 2013, and May 18, 2015, 27 eligible patients were enrolled to the dose-escalation phase. Dose-limiting toxicities, including grade 3 type 2 diabetes mellitus, mucositis, and neutropenic fever, were seen at the 2·2 mg/kg dose; therefore, 2·0 mg/kg of tisotumab vedotin intravenously once every 3 weeks was established as the recommended phase 2 dose. Between Oct 8, 2015, and April 26, 2018, 147 eligible patients were enrolled to the dose-expansion phase. The most common (in ?20% of patients) treatment-emergent adverse events of any grade were epistaxis (102 [69%] of 147 patients), fatigue (82 [56%]), nausea (77 [52%]), alopecia (64 [44%]), conjunctivitis (63 [43%]), decreased appetite (53 [36%]), constipation (52 [35%]), diarrhoea (44 [30%]), vomiting (42 [29%]), peripheral neuropathy (33 [22%]), dry eye (32 [22%]), and abdominal pain (30 [20%]). The most common adverse events of grade 3 or worse were fatigue (14 [10%] of 147 patients), anaemia (eight [5%]), abdominal pain (six [4%]), hypokalaemia (six [4%]), conjunctivitis (five [3%]), hyponatraemia (five [3%]), and vomiting (five [3%]). 67 (46%) of 147 patients had a treatment-emergent serious adverse event. 39 (27%) of 147 patients had a treatment-emergent serious adverse event related to the study drug. Infusion-related reactions occurred in 17 (12%) of 147 patients. Across tumour types, the confirmed proportion of patients who achieved an objective response was 15·6% (95% CI 10·2-22·5; 23 of 147 patients). There were nine deaths across all study phases (three in the dose-escalation phase and six in the dose-expansion phase); only one case of pneumonia in the dose-expansion phase was considered possibly related to study treatment. INTERPRETATIONS: Tisotumab vedotin has a manageable safety profile with encouraging preliminary antitumour activity across multiple tumour types in heavily pretreated patients. Continued evaluation of tisotumab vedotin is warranted in solid tumours. FUNDING: Genmab A/S.
Citationde Bono JS, Concin N, Hong DS, Thistlethwaite FC, Machiels JP, Arkenau HT, et al. Tisotumab vedotin in patients with advanced or metastatic solid tumours (innovaTV 201): a first-in-human, multicentre, phase 1-2 trial. Lancet Oncol. 2019 Mar;20(3):383-93.
- Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study.
- Authors: Coleman RL, Lorusso D, Gennigens C, González-Martín A, Randall L, Cibula D, Lund B, Woelber L, Pignata S, Forget F, Redondo A, Vindeløv SD, Chen M, Harris JR, Smith M, Nicacio LV, Teng MSL, Laenen A, Rangwala R, Manso L, Mirza M, Monk BJ, Vergote I, innovaTV 204/GOG-3023/ENGOT-cx6 Collaborators.
- Issue date: 2021 May
- Pamiparib in combination with tislelizumab in patients with advanced solid tumours: results from the dose-escalation stage of a multicentre, open-label, phase 1a/b trial.
- Authors: Friedlander M, Meniawy T, Markman B, Mileshkin L, Harnett P, Millward M, Lundy J, Freimund A, Norris C, Mu S, Wu J, Paton V, Gao B
- Issue date: 2019 Sep
- Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study.
- Authors: Palanca-Wessels MC, Czuczman M, Salles G, Assouline S, Sehn LH, Flinn I, Patel MR, Sangha R, Hagenbeek A, Advani R, Tilly H, Casasnovas O, Press OW, Yalamanchili S, Kahn R, Dere RC, Lu D, Jones S, Jones C, Chu YW, Morschhauser F
- Issue date: 2015 Jun
- Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study.
- Authors: Banerji U, van Herpen CML, Saura C, Thistlethwaite F, Lord S, Moreno V, Macpherson IR, Boni V, Rolfo C, de Vries EGE, Rottey S, Geenen J, Eskens F, Gil-Martin M, Mommers EC, Koper NP, Aftimos P
- Issue date: 2019 Aug
- Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial.
- Authors: Heery CR, O'Sullivan-Coyne G, Madan RA, Cordes L, Rajan A, Rauckhorst M, Lamping E, Oyelakin I, Marté JL, Lepone LM, Donahue RN, Grenga I, Cuillerot JM, Neuteboom B, Heydebreck AV, Chin K, Schlom J, Gulley JL
- Issue date: 2017 May