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Clinical Trial
. 2020 Dec;159(3):692-698.
doi: 10.1016/j.ygyno.2020.09.048. Epub 2020 Oct 16.

A phase II randomised, placebo-controlled trial of low dose (metronomic) cyclophosphamide and nintedanib (BIBF1120) in advanced ovarian, fallopian tube or primary peritoneal cancer

M R Hall  1 , H-M Dehbi  2 , S Banerjee  3 , R Lord  4 , A Clamp  5 , J A Ledermann  6 , S Nicum  7 , R Lilleywhite  8 , R Bowen  9 , A Michael  10 , A Feeney  11 , R Glasspool  12 , A Hackshaw  13 , G Rustin  14
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Clinical Trial

A phase II randomised, placebo-controlled trial of low dose (metronomic) cyclophosphamide and nintedanib (BIBF1120) in advanced ovarian, fallopian tube or primary peritoneal cancer

M R Hall et al. Gynecol Oncol. 2020 Dec.

Abstract

Background: We investigated the safety and efficacy of a combination of the oral tyrosine kinase inhibitor, nintedanib (BIBF 1120) with oral cyclophosphamide in patients with relapsed ovarian cancer.

Patients and methods: Patients with relapsed ovarian, fallopian tube or primary peritoneal cancer received oral cyclophosphamide (100 mg o.d.) and were randomised (1,1) to also have either oral nintedanib or placebo. The primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS), response rate, toxicity, and quality of life.

Results: 117 patients were randomised, 3 did not start trial treatment, median age 64 years. Forty-five (39%) had received ≥5 lines chemotherapy. 30% had received prior bevacizumab. The median OS was 6.8 (nintedanib) versus 6.4 (placebo) months (hazard ratio 1.08; 95% confidence interval 0.72-1.62; P = 0.72). The 6-month PFS rate was 29.6% versus 22.8% (P = 0.57). Grade 3/4 adverse events occurred in 64% (nintedanib) versus 54% (placebo) of patients (P = 0.28); the most frequent G3/4 toxicities were lymphopenia (18.6% nintedanib versus 16.4% placebo), diarrhoea (13.6% versus 0%), neutropenia (11.9% versus 0%), fatigue (10.2% versus 9.1%), and vomiting (10.2% versus 7.3%). Patients who had received prior bevacizumab treatment had 52 days less time on treatment (P < 0.01). 26 patients (23%) took oral cyclophosphamide for ≥6 months. There were no differences in quality of life between treatment arms.

Conclusions: This is the largest reported cohort of patients with relapsed ovarian cancer treated with oral cyclophosphamide. Nintedanib did not improve outcomes when added to oral cyclophosphamide. Although not significant, more patients than expected remained on treatment for ≥6 months. This may reflect a higher proportion of patients with more indolent disease or the higher dose of cyclophosphamide used.

Clinical trial registration: Clinicaltrials.govNCT01610869.

Keywords: Late stage relapsed ovarian cancer; Nintedanib; Oral cyclophosphamide; Prior bevacizumab.

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Conflict of interest statement

Declaration of Competing Interest Professor Marcia Hall reports grants and personal fees from Clovis Oncology, BMS and Merck and personal fees from Roche, GSK/Tesaro, Astra Zeneca, Boehringer Ingelheim and Amgen outside the submitted work. Dr. Susana Banerjee reports personal fees from Roche, AstraZeneca, GSK/Tesaro, Clovis Oncology, Pharmamar, Seattle Genetics, Merck Serono, Amgen and Genmab; grants from Astra Zeneca and GSK/Tesaro and travel support from Nucana all outside the submitted work. Dr. Rosemary Lord reports personal fees from Tesaro and Astra Zeneca, outside the submitted work. Dr. Andrew Clamp has received research funding and personal fees from Astra Zeneca, and personal fees from Clovis Oncology, Astra Zeneca, GSK/Tesaro, and Roche outside the submitted work. Dr. Shibani Nicum reports grants and personal fees from Astra Zeneca and personal fees from MSD, Roche, Abbvie, Clovis Oncology outside the submitted work. Professor J Ledermann has received fees for Advisory Boards, lectures, symposia from Boehringer Ingelheim, Astra Zeneca, MSD/Merck, Amgen, Artios, GSK/Tesaro, Eisai. He has received research funding from MSD/Merck and AstraZeneca, all outside the submitted work. Dr. Rebecca Bowen reports personal fees from Roche, AstraZeneca, GSK/Tesaro, Clovis Oncology, Amgen, Celgene and Lily Oncology, outside the submitted work. Dr. Agniescka Michael reports personal fees from Roche, outside the submitted work. Dr. Ros Glasspool reports research funding from Boehringer Ingelheim for the NiCCC clinical trial, further research funding from Lilly/Ignyta and personal fees from AstraZeneca, MSD, Clovis, GSK/Tesaro, Immunogen and Sotio outside the submitted work. Professor Gordon Rustin reports personal fees from Abbvie, outside the submitted work.

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