PARC: a phase I/II study evaluating the safety and activity of pegylated recombinant human arginase BCT-100 in relapsed/refractory cancers of children and young adults.

Background: The survival for many children with relapsed/refractory cancers remains poor despite advances in therapies. Arginine metabolism plays a key role in the pathophysiology of a number of pediatric cancers. We report the first in child study of a recombinant human arginase, BCT-100, in children with relapsed/refractory hematological, solid or CNS cancers. Procedure: PARC was a single arm, Phase I/II, international, open label study. BCT-100 was given intravenously over one hour at weekly intervals. The Phase I section utilized a modified 3 + 3 design where escalation/de-escalation was based on both the safety profile and the complete depletion of arginine (defined as adequate arginine depletion; AAD <8µM arginine in the blood after 4 doses of BCT-100). The Phase II section was designed to further evaluate the clinical activity of BCT-100 at the pediatric RP2D determined in the Phase I section, by recruitment of patients with pediatric cancers into 4 individual groups. A primary evaluation of response was conducted at eight weeks with patients continuing to receive treatment until disease progression or unacceptable toxicity. Results: 49 children were recruited globally. The Phase I cohort of the trial established the Recommended Phase II Dose of 1600U/kg iv weekly in children, matching that of adults. BCT-100 was very well tolerated. No responses defined as a CR, CRi or PR were seen in any cohort within the defined 8 week primary evaluation period. However a number of these relapsed/refractory patients experienced prolonged radiological SD. Conclusion: Arginine depletion is a clinically safe and achievable strategy in children with cancer. The RP2D of BCT-100 in children with relapsed/refractory cancers is established at 1600U/kg intravenously weekly and can lead to sustained disease stability in this hard to treat population. Clinical trial registration: EudraCT, 2017-002762-44; ISRCTN, 21727048; and ClinicalTrials.gov, NCT03455140.

Thromboprophylaxis with unmonitored intermediate-dose low molecular weight heparin in pregnancies with a previous arterial or venous thrombotic event.

The comparatively high rate of complications, both to the mother and foetus, of warfarin and unfractionated heparin have led to an increased use of low molecular weight heparins (LMWH) in pregnant women at risk of thrombosis. However, despite reliable pharmacokinetics of LMWH, current practice is that anti-activated factor X levels are monitored in this group of patients. We report the use of unmonitored dalteparin in 27 pregnancies of 25 women who had previous thrombotic events. All women had normal renal function and weighed less than 85 kg prior to conceiving. The regimen consisted of 5000 IU dalteparin once daily started at the time of a positive pregnancy test, and increased to twice daily at 16-20 weeks gestation. In this cohort of patients there was a low complication rate. None of the women developed recurrent venous thromboses during these pregnancies but two women with known cerebral antiphospholipid syndrome developed recurrent cerebral ischaemia, which responded to an increase in dose. In our small group of patients, we have found that the use of intermediate-dose LMWH in pregnant women does not need to be monitored, and that it is safe and probably effective in preventing recurrent venous but not arterial thromboembolic events in high-risk pregnancies.