1578P - A phase I trial to assess the safety, PK and PD of CXD101 in advanced cancer expressing the biomarker HR23B

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Drug Development
Translational Research
Presenter Toby Eyre
Citation Annals of Oncology (2016) 27 (6): 526-544. 10.1093/annonc/mdw392
Authors T.A. Eyre1, G.P. Collins1, A. Gupta1, S. Sheikh1, V. Woodcock2, J. Whittaker3, L.M. Wang4, E. Soilleux4, F. Tysoe5, R. Cousins5, N. La Thangue3, D. Kerr3, M.R. Middleton2
  • 1Haematology, The Oxford Cancer Centre, Churchill Hospital, Oxford Radcliffe Hospitals NHS Trust, OX3 7LE - Oxford/GB
  • 2Medical Oncology, The Oxford Cancer Centre, Churchill Hospital, Oxford Radcliffe Hospitals NHS Trust, OX3 7LJ - Oxford/GB
  • 3Celleron Therapeutics Ltd, Celleron Therapeutics Ltd, OX14 4SH - Oxford/GB
  • 4Histopathology, John Radcliffe Hospital University of Oxford, OX3 7LE - Oxford/GB
  • 5Early Phase Clinical Trial Unit, The Oxford Cancer Centre, Churchill Hospital, Oxford Radcliffe Hospitals NHS Trust, OX3 7LJ - Oxford/GB

Abstract

Background

We sought to determine the maximal tolerated dose (MTD) of the novel Class I-selective HDAC inhibitor (HDACi) CXD101 in a dose escalation study in advanced solid cancer and lymphoma. A genome-wide loss-of-function screen identified HR23B, a protein that shuttles ubiquitinated cargo proteins to the proteasome, as a sensitivity determinant for HDACi-induced cell apoptosis.

Methods

We escalated CXD101 from 1mg bd for 5 days in a 21 day cycle, following a 3 + 3 design. Eligible patients had advanced solid tumours or lymphoma. A preliminary assessment of efficacy was performed in a dose expansion cohort after the MTD was found. 39 patients were enrolled, of whom 36 were exposed to CXD101. HR23B status was assessed on all available tissue. Responses were assessed by Cheson 2007 and RESIST 1.1.

Results

30 patients were enrolled in the dose escalation cohort of whom 29 were evaluable for DLT assessment. The baseline characteristics are tabulated. The 1st DLT was noted at 16mg bd. Subsequent DLTs were seen at 20mg b.d. (1 of 6), and at the non-tolerated dose of 24/25mg b.d. (2 of 5; both neutropenic infection). The MTD and recommended phase II dose was established at 20mg bd. 6 patients have been treated within the expansion cohort to date. The most frequent adverse events observed were fatigue, nausea and cytopenias. All AEs were manageable. In 22 patients dosed at 16mg b.d. or above, 3 partial responses (2 Hodgkin lymphoma,1 angioimmunoblastic T cell lymphoma) and 1 complete response (follicular lymphoma) were noted (overall response rate 18%) alongside 9 patients with stable disease.

Characteristic Solid Tumour Haematological Tumour Combined
Histology CRCa 3 Lung Ca 2 Cervical Ca 2 Breast Ca 1 Pancreatic Ca 1 Ovarian Ca 1 ENT 1 Other 3 cHL 10 AITL 4 DLBCL 3 PTCL-NOS 2 LPL 1 FL 1 Gray Zone NHL 1 N/A
Gender Male Female 5 9 13 9 18 18
Age (median, range) 58.5 (42-70) 53.5 (21-79) 58 (21-79)
ECOG 0 1 3 11 7 15 10 26
Prior lines of therapy (median, range) 4 (1-17) 4 (1-10) 4 (1-17)
Staging Stage III 1 IV 13 Ann Arbor* II 3 III 2 IIIS 4 IV 12 N/A
International prognostic index (IPI) Low 0-1 Low/Intermediate 2 High/Intermediate 3 High 4-5 Data not available N/A 1 LPL N/A 3 8 9 1 N/A
HR23B status Positive (score 6-7) Negative (score 0-5) Data not available 11 2 1 14 7 1 25 9 2

Conclusions

The MTD for CXD101 observed was 20 mg bd for 5 days in a 3-weekly cycle. Disease activity was seen in T cell lymphoma, Follicular lymphoma and Hodgkin lymphoma. Further analysis of HR23B correlated tumour response and durability is ongoing and will be presented alongside PK and PD data.

Clinical trial identification

NCT01977638

Legal entity responsible for the study

Legal Sponsor: Oxford University Hospitals NHS Trust

Funding

Celleron Therapeutics Ltd.

Disclosure

J. Whittaker, N. La Thangue, D. Kerr: Member of Celleron Therapeutics Management team. All other authors have declared no conflicts of interest.