BACKGROUND: Few effective second-line treatments exist for women with recurrent or metastatic cervical cancer. Accordingly, we aimed to evaluate the efficacy and safety of tisotumab vedotin, a tissue factor-directed antibody-drug conjugate, in this patient population. METHODS: This multicentre, open-label, single-arm, phase 2 study was done across 35 academic centres, hospitals, and community practices in Europe and the USA. The study included patients aged 18 years or older who had recurrent or metastatic squamous cell, adenocarcinoma, or adenosquamous cervical cancer; disease progression on or after doublet chemotherapy with bevacizumab (if eligible by local standards); who had received two or fewer previous systemic regimens for recurrent or metastatic disease; had measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1); and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 2·0 mg/kg (up to a maximum of 200 mg) tisotumab vedotin intravenously once every 3 weeks until disease progression (determined by the independent review committee) or unacceptable toxicity. The primary endpoint was confirmed objective response rate based on RECIST (version 1.1), as assessed by the independent review committee. Activity and safety analyses were done in patients who received at least one dose of the drug. This study is ongoing with recruitment completed and is registered with ClinicalTrials.gov, NCT03438396. FINDINGS: 102 patients were enrolled between June 12, 2018, and April 11, 2019; 101 patients received at least one dose of tisotumab vedotin. Median follow-up at the time of analysis was 10·0 months (IQR 6·1-13·0). The confirmed objective response rate was 24% (95% CI 16-33), with seven (7%) complete responses and 17 (17%) partial responses. The most common treatment-related adverse events included alopecia (38 [38%] of 101 patients), epistaxis (30 [30%]), nausea (27 [27%]), conjunctivitis (26 [26%]), fatigue (26 [26%]), and dry eye (23 [23%]). Grade 3 or worse treatment-related adverse events were reported in 28 (28%) patients and included neutropenia (three [3%] patients), fatigue (two [2%]), ulcerative keratitis (two [2%]), and peripheral neuropathies (two [2%] each with sensory, motor, sensorimotor, and neuropathy peripheral). Serious treatment-related adverse events occurred in 13 (13%) patients, the most common of which included peripheral sensorimotor neuropathy (two [2%] patients) and pyrexia (two [2%]). One death due to septic shock was considered by the investigator to be related to therapy. Three deaths unrelated to treatment were reported, including one case of ileus and two unknown causes. INTERPRETATION: Tisotumab vedotin showed clinically meaningful and durable antitumour activity with a manageable and tolerable safety profile in women with previously treated recurrent or metastatic cervical cancer. Given the poor prognosis for this patient population and the low activity of current therapies in this setting, tisotumab vedotin, if approved, would represent a new treatment for women with recurrent or metastatic cervical cancer. FUNDING: Genmab, Seagen, Gynaecologic Oncology Group, and European Network of Gynaecological Oncological Trial Groups.

• MeSH
• dospělí MeSH
• humanizované monoklonální protilátky škodlivé účinky   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   mortalita   MeSH
• metastázy nádorů MeSH
• nádory děložního čípku farmakoterapie   mortalita   patologie   MeSH
• oligopeptidy škodlivé účinky   terapeutické užití   MeSH
• tkáňový faktor analýza   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• humanizované monoklonální protilátky MeSH
• oligopeptidy MeSH
• tisotumab vedotin MeSH Prohlížeč
• tkáňový faktor MeSH

UNLABELLED: Relationships between patient characteristics, ofatumumab pharmacokinetics, and treatment outcomes were investigated in this phase 2 trial of ofatumumab plus fludarabine and cyclophosphamide (FC) in untreated chronic lymphocytic leukemia. Patients were randomized 1:1 to receive 500 or 1000 mg ofatumumab (Cycle 1; 300 mg) plus FC every 4 weeks for six cycles. Median Cmax and Ctrough values were similar at Cycle 1 regardless of the ultimate clinical outcome. At later doses, these values were higher for patients with complete response (CR) than for other patients. Higher Cmax and Ctrough values at Cycles 3 and 6 were significantly associated with an increased likelihood of CR, whereas ofatumumab pharmacokinetics were not associated with an objective response (OR) on the basis of univariate analyses. Multivariate analyses indicated that baseline patient/disease factors were predominantly associated with CR (17p status) or OR (bulky lymphadenopathy, gender, and serum thymidine kinase), rather than ofatumumab pharmacokinetics. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT00410163).

• Klíčová slova
• Chemoimmunotherapy, chronic lymphocytic leukemia, ofatumumab, pharmacokinetics,
• MeSH
• chromozomální aberace MeSH
• chronická lymfatická leukemie diagnóza   farmakoterapie   mortalita   MeSH
• dospělí MeSH
• humanizované monoklonální protilátky MeSH
• indukce remise MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• monoklonální protilátky aplikace a dávkování   škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• protinádorové látky imunologicky aktivní aplikace a dávkování   škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• rozvrh dávkování léků MeSH
• senioři MeSH
• staging nádorů MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• humanizované monoklonální protilátky MeSH
• monoklonální protilátky MeSH
• ofatumumab MeSH Prohlížeč
• protinádorové látky imunologicky aktivní MeSH

BACKGROUND: Ofatumumab is a human anti-CD20 monoclonal antibody that has proven efficacy as monotherapy in refractory chronic lymphocytic leukaemia. We assessed the efficacy and safety of ofatumumab maintenance treatment versus observation for patients in remission after re-induction treatment for relapsed chronic lymphocytic leukaemia. METHODS: This open-label, multicentre, randomised phase 3 study enrolled patients aged 18 years or older from 130 centres in 24 countries who had chronic lymphocytic leukaemia in complete or partial remission after second-line or third-line treatment. Eligible patients had a WHO performance status of 0-2, had a response assessment within the previous 3 months, did not have refractory disease, autoimmune haemolytic anaemia requiring treatment, chronic or active infection requiring treatment, and had not previously received maintenance treatment or autologous or allogeneic stem-cell transplant. Using a randomisation list generated by a central computerised system and an interactive voice recognition system, we randomly assigned (1:1) patients to receive ofatumumab (300 mg followed by 1000 mg 1 week later and every 8 weeks for up to 2 years) or undergo observation. Randomisation was stratified by number and type of previous treatment and remission status after induction treatment (block size of four). Treatment assignment was open label. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. We report the results of a prespecified interim analysis after two-thirds of the planned study events (disease progression or death) had happened. This trial is closed to accrual but follow-up is ongoing. This trial is registered with ClinicalTrials.gov, number NCT00802737. FINDINGS: Between May 6, 2010, and June 19, 2014, we enrolled 474 patients: 238 patients were randomly assigned to receive ofatumumab maintenance treatment and 236 to undergo observation. One (<1%) patient in the ofatumumab group did not receive the allocated intervention (withdrawal of consent). The median follow-up was 19·1 months (IQR 10·3-28·8). Progression-free survival was improved in patients assigned to the ofatumumab group (29·4 months, 95% CI 26·2-34·2) compared with those assigned to observation (15·2 months, 11·8-18·8; hazard ratio 0·50, 95% CI 0·38-0·66; p<0·0001). The most common grade 3 or higher adverse events up to 60 days after last treatment were neutropenia (56 [24%] of 237 patients in the ofatumumab group vs 23 [10%] of 237 in the observation group) and infections (31 [13%] vs 20 [8%]). 20 (8%) of 237 patients in the ofatumumab group and three (1%) of 237 patients in the observation group had adverse events that led to permanent discontinuation of treatment. Up to 60 days after last treatment, two deaths related to adverse events occurred in the ofatumumab treatment group and five deaths related to adverse events occurred in the observation group; no deaths were attributed to the study drug. INTERPRETATION: These data are important for the development of optimum maintenance strategies in patients with relapsed chronic lymphocytic leukaemia, notably in the present era of targeted drugs, many of which are to be used until progression.

• MeSH
• analýza podle původního léčebného záměru MeSH
• časové faktory MeSH
• chronická lymfatická leukemie diagnóza   mortalita   terapie   MeSH
• dospělí MeSH
• humanizované monoklonální protilátky MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• monoklonální protilátky aplikace a dávkování   škodlivé účinky   MeSH
• pozorné vyčkávání * MeSH
• přežití bez známek nemoci MeSH
• progrese nemoci MeSH
• protinádorové látky aplikace a dávkování   škodlivé účinky   MeSH
• recidiva MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• udržovací chemoterapie škodlivé účinky   metody   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• humanizované monoklonální protilátky MeSH
• monoklonální protilátky MeSH
• ofatumumab MeSH Prohlížeč
• protinádorové látky MeSH

• Klíčová slova
• fludarabine-refractory, ofatumumab, pivotal study,
• MeSH
• chemorezistence * MeSH
• chronická lymfatická leukemie farmakoterapie   mortalita   MeSH
• humanizované monoklonální protilátky MeSH
• lidé MeSH
• monoklonální protilátky farmakologie   terapeutické užití   MeSH
• následné studie MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• vidarabin aplikace a dávkování   analogy a deriváty   terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fludarabine MeSH Prohlížeč
• humanizované monoklonální protilátky MeSH
• monoklonální protilátky MeSH
• ofatumumab MeSH Prohlížeč
• protinádorové látky MeSH
• vidarabin MeSH

BACKGROUND: Treatment for patients with chronic lymphocytic leukaemia who are elderly or who have comorbidities is challenging because fludarabine-based chemoimmunotherapies are mostly not suitable. Chlorambucil remains the standard of care in many countries. We aimed to investigate whether the addition of ofatumumab to chlorambucil could lead to better clinical outcomes than does treatment with chlorambucil alone, while also being tolerable for patients who have few treatment options. METHODS: We carried out a randomised, open-label, phase 3 trial for treatment-naive patients with chronic lymphocytic leukaemia in 109 centres in 16 countries. We included patients who had active disease needing treatment, but in whom fludarabine-based treatment was not possible. We randomly assigned patients (1:1) to receive oral chlorambucil (10 mg/m(2)) on days 1-7 of a 28 day treatment course or to receive chlorambucil by this schedule plus intravenous ofatumumab (cycle 1: 300 mg on day 1 and 1000 mg on day 8; subsequent cycles: 1000 mg on day 1) for three to 12 cycles. Assignment was done with a randomisation list that was computer generated at GlaxoSmithKline, and was stratified, in a block size of two, by age, disease stage, and performance status. The primary endpoint was progression-free survival in the intention-to-treat population and assessment was done by an independent review committee that was masked to group assignment. The study is registered with ClinicalTrials.gov, number NCT00748189. FINDINGS: We enrolled 447 patients, median age 69 years (range 35-92). Between Dec 22, 2008, and May 26, 2011, we randomly assigned 221 patients to chlorambucil plus ofatumumab and 226 patients to chlorambucil alone. Median progression-free survival was 22·4 months (95% CI 19·0-25·2) in the group assigned to chlorambucil plus ofatumumab compared with 13·1 months (10·6-13·8) in the group assigned to chlorambucil only (hazard ratio 0·57, 95% CI 0·45-0·72; p<0·0001). Grade 3 or greater adverse events were more common in the chlorambucil plus ofatumumab group (109 [50%] patients; vs 98 [43%] given chlorambucil alone), with neutropenia being the most common event (56 [26%] vs 32 [14%]). Grade 3 or greater infections had similar frequency in both groups. Grade 3 or greater infusion-related adverse events were reported in 22 (10%) patients given chlorambucil plus ofatumumab. Five (2%) patients died during treatment in each group. INTERPRETATION: Addition of ofatumumab to chlorambucil led to clinically important improvements with a manageable side-effect profile in treatment-naive patients with chronic lymphocytic leukaemia who were elderly or had comorbidities. Chlorambucil plus ofatumumab is therefore an important treatment option for these patients who cannot tolerate more intensive therapy. FUNDING: GlaxoSmithKline, Genmab A/S.

• MeSH
• alkylační protinádorové látky aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• chlorambucil aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• chronická lymfatická leukemie farmakoterapie   MeSH
• dospělí MeSH
• humanizované monoklonální protilátky MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• monoklonální protilátky aplikace a dávkování   škodlivé účinky   MeSH
• prospektivní studie MeSH
• protokoly protinádorové kombinované chemoterapie aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• rozložení podle pohlaví MeSH
• rozvrh dávkování léků MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• věkové rozložení MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• alkylační protinádorové látky MeSH
• chlorambucil MeSH
• humanizované monoklonální protilátky MeSH
• monoklonální protilátky MeSH
• ofatumumab MeSH Prohlížeč