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ICON8 Stage 1A and 1B analysis: safety and feasibility of weekly carboplatin and paclitaxel regimens in first-line ovarian cancer

Date

08 Oct 2016

Session

Poster Display

Presenters

Elizabeth James

Citation

Annals of Oncology (2016) 27 (6): 296-312. 10.1093/annonc/mdw374

Authors

E.C. James1, J. Hook1, S. Stenning1, A. Cook1, C. Coyle1, J. Petrie1, R. Kaplan1, I. McNeish2, T. Perren3, R. Naik4, S. Banerjee5, J.A. Ledermann6, A. Clamp7

Author affiliations

  • 1 Mrc Clinical Trials Unit At Ucl, Institute of Clinical Trials and Methodology-UCL, WC2B6NH - London/GB
  • 2 Institute Of Cancer Sciences, University of Glasgow, G611QH - Glasgow/GB
  • 3 Leeds Institute Of Cancer Medicine And Pathology, Univeristy of Leeds and St. James University Hospital, LS9 7TF - Leeds/GB
  • 4 Northern Gynaecological Oncology Centre, Queen Elizabeth Hospital, Gateshead/GB
  • 5 Gynaecological Unit, The Royal Marsden NHS Foundation Trust, London/GB
  • 6 Cr-uk & Ucl Cancer Trials Centre, UCL Cancer Institute, University College London, W1T 4TJ - London/GB
  • 7 Medical Oncology, The Christie NHS Foundation Trust and Institue of Cancer Sciences, University of Manchester, Manchester/GB
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Background

ICON8 is a randomised GCIG phase III 3-arm trial comparing 6 cycles of standard 3-weekly (q3w) carboplatin/paclitaxel with weekly (q1w) dose-dense treatment. Patients had immediate primary surgery (IPS) or neo-adjuvant chemotherapy and delayed primary surgery (DPS) after 3 cycles. Two interim analyses were planned: 1A, first 50 patients (pts) in each arm; 1B, first 50 DPS pts in each arm, ICON8 being the first trial of dose-dense treatment with DPS.

Methods

1566 women were randomised between Jun 2011 and Nov 2014 to: Arm 1 - q3w carboplatin AUC5/6 + paclitaxel 175mg/m2; Arm 2 - q3w carboplatin AUC5/6 + q1w paclitaxel 80mg/m2; Arm 3 - q1w carboplatin AUC2 + paclitaxel 80 mg/m2. The interim safety analyses included 237 patients. Feasibility was measured by completion of protocol treatment, safety by the rate of any G3+ toxicity experienced per patient.

Results

Stage 1A analysis included 85 IPS and 65 DPS pts, median age 59 years and 64% stage IIIC/IV disease. Stage 1B included 87 further DPS pts (total DPS = 152), median age 62 years, 92% stage IIIC/IV. Protocol treatment completion was lower than expected but >80% 1A and >75% 1B pts received 6 cycles of platinum chemotherapy. Increased paclitaxel dose intensity was achieved (see table). Most common reason for not completing protocol treatment was toxicity. G3+ toxicity was more frequent in arms 2 and 3, mainly due to uncomplicated neutropenia.

Stage 1A Stage 1A Stage 1A Stage 1B Stage 1B Stage 1B
Arm 1 n = 50 Arm 2 n = 50 Arm 3 n = 50 Arm 1 n = 50 Arm 2 n = 52 Arm 3 n = 50
Feasibility
Protocol treatment completion, N(%) P-value (compared to arm 1) 39 (78%) - 29 (58%) 0.03 29 (58%) 0.03 29 (58%) - 34 (65%) 0.47 25 (50%) 0.42
6 cycles platinum chemotherapy, N(%) P-value (compared to arm 1) 44 (88%) - 46 (92%) 0.51 40 (80%) 0.23 40 (80%) - 46 (88%) 0.27 39 (78%) 0.81
Carboplatin dose intensity (AUC/week) median 1.79 1.86 1.83 1.82 1.78 1.77
Paclitaxel dose intensity (mg/m2/weed) median 53.5 64.1 67.8 51.3 65.5 67.9
Toxicity
G3/4+ Toxicity, N(%) 17 (35%) 29 (58%) 24 (48%) 24 (50%) 33 (63%) 23 (46%)
G3/4+ Uncomplicated neutropenia, N(%) 4 (8%) 16 (32%) 11 (22%) 5 (10%) 19 (37%) 13 (26%)
G3/4+ Febrile neutropenia, N(%) 2 (4%) 1 (2%) 1 (2%) 1 (2%) 3 (6%) 0
G3/4+ Thrombocytopenia, N(%) 2 (4%) 2 (4%) 1 (2%) 2 (4%) 3 (6%) 1 (2%)
G2+ Sensory neuropathy, N(%) 12 (25%) 15 (30%) 9 (18%) 16 (33%) 6 (12%) 5 (10%)

Conclusions

Completion of 6 cycles of platinum chemotherapy was high; however, protocol-defined q1w regimens were frequently modified. Protocol treatment completion differed significantly between arms in stage 1A, but not 1B, perhaps reflecting q3w paclitaxel toxicity in DPS patients. Rates of clinically relevant toxicity were acceptable, and despite aggressive dosing thresholds febrile neutropenia was rare. No dose modifications were implemented following stage 1A/1B analyses, but early use of G-CSF was recommended. PFS results are expected in Q2 2017, OS in 2018.

Clinical trial identification

ISCCTN ISRCTN10356387; EudraCT 2010-022209-16

Legal entity responsible for the study

Medical Research Council

Funding

Cancer Research UK

Disclosure

All authors have declared no conflicts of interest.

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