ICON8: Weekly Chemotherapy in Ovarian Cancer (ICON8)

An International Phase III Randomised Trial of Dose Fractionated Chemotherapy Compared to Standard Three Weekly Chemotherapy, Following Immediate Primary Surgery or as Part of Delayed Primary Surgery, for Women With Newly Diagnosed Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer

The purpose of this study is to determine if weekly chemotherapy (i.e. giving paclitaxel or carboplatin at a lower dose every week) is more effective than standard chemotherapy (paclitaxel and carboplatin given once every three weeks over 18 weeks) in treating ovarian cancer. The investigators also want to see if weekly chemotherapy causes more or fewer side-effects than standard chemotherapy.

Study Overview

• Status: Unknown
• Conditions: Ovarian Cancer
• Intervention / Treatment: Drug: Carboplatin; Drug: Carboplatin; Drug: Paclitaxel; Drug: Paclitaxel

Detailed Description

ICON8 is a three-arm, three stage trial. Patients will be randomised in a 1:1:1 ratio. Patients in arm 1 (control arm) will receive weekly carboplatin and paclitaxel on day 1 of a 21-day cycle for 6 cycles. Patients in arm 2 will receive carboplatin on day 1 and dose-fractionated weekly paclitaxel on day 1, 8 and 15 of a 21-day cycle for 6 cycles. Patients in arm 3 will receive dose-fractionated weekly carboplatin and dose-fractionated weekly paclitaxel on day 1, 8 and 15 of a 21-day cycle for 6 cycles.

The trial will have three planned stages. Stage 1 will be conducted to confirm feasibility and safety of protocol treatment in all patients and separately in the Delayed Primary Surgery (DPS) patients. The outcome measure for stage 2 will be 9-month progression-free survival (PFS) rate. The primary outcome measures for stage 3 will be PFS and overall survival and secondary outcomes will be toxicity, Quality of Life and Health Economics. If pre-defined levels of deliverability, at stage 1, or activity, at stage 2, are not met then the research arms will be reconsidered.

• Study Type: Interventional
• Enrollment (Anticipated): 1485
• Phase: Phase 3

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, WC2B 6NH
    • Recruiting
    • Medical Research Council Clinical Trials Unit
    • Contact: Monique Tomiczek; Phone Number: 02076704767; Email: icon8@ctu.mrc.ac.uk
    • Contact: Laura Farrelly; Phone Number: 02076704789; Email: icon8@ctu.mrc.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Females aged 18 years or more
• Signed informed consent and ability to comply with the protocol

• Histologically confirmed, with core biopsy from a disease site as minimum requirement (cytology alone is insufficient for diagnosis):

  • Epithelial ovarian carcinoma
  • Primary peritoneal carcinoma of Müllerian histological type
  • Fallopian tube carcinoma
• FIGO stage IC or above, which may be based on clinical and radiological assessment in patients who have not undergone immediate primary surgery

• Confirmed high-risk histological subtype for patients with FIGO stage IC/IIA disease, namely:

  • High grade serous carcinoma
  • Clear cell carcinoma
  • Other histological subtype considered poorly differentiated/grade 3
• ECOG Performance Status (PS) 0-2
• Life expectancy > 12 weeks

• Adequate bone marrow function:

  • Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/l
  • Platelets (Plt) ≥ 100 x 109/l
  • Haemoglobin (Hb) ≥ 9g/dl (can be post transfusion)

• Adequate liver function (within 28 days prior to randomisation):

  • Serum bilirubin (BR) ≤ 1.5 x ULN
  • Serum transaminases ≤ 3 x ULN in the absence of parenchymal liver metastases or ≤ 5 x ULN in the presence of parenchymal liver metastases
• Adequate renal function as defined by GFR (Glomerular Filtration Rate) ≥ 30ml/min.

Exclusion Criteria:

• Non-epithelial ovarian cancer, including malignant mixed Müllerian tumours (carcinosarcomas)
• Peritoneal cancer that is not of Müllerian origin, including mucinous histology
• Borderline tumours (tumours of low malignant potential)
• Prior systemic anti-cancer therapy for ovarian cancer (for example chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy or hormonal therapy)
• Previous malignancies within 5 years prior to randomisation apart from: adequately treated carcinoma in-situ of the cervix, breast ductal carcinoma in-situ, non-melanomatous skin cancer; or previous/synchronous early-stage endometrial cancer defined as stage IA (FIGO 2009) grade 1 or 2 endometrioid cancers with no lymphovascular space invasion
• Pre-existing sensory or motor neuropathy grade ≥ 2
• Evidence of any other disease/metabolic dysfunction that in the opinion of the investigator would put the subject at high-risk of treatment-related complications or prevent compliance with the trial protocol
• Planned intraperitoneal cytotoxic chemotherapy
• Any previous radiotherapy to the abdomen or pelvis
• Sexually active women of childbearing potential not willing to use adequate contraception (e.g. oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) for the study duration and at least six months afterwards
• Pregnant or lactating women
• Treatment with any other investigational agent prior to protocol defined progression
• Known hypersensitivity to carboplatin, paclitaxel or their excipients (including cremophor)
• History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI of the brain is mandatory in the case of suspected brain metastases. Spinal MRI is mandatory in the case of suspected spinal cord compression. Patients with brain or meningeal metastases are not eligible

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm 1 (Control Arm); Carboplatin and paclitaxel on day 1 of a 21-day cycle for 6 cycles	Drug: Carboplatin; AUC5 by intravenous infusion over 30-60 minutes; Drug: Carboplatin; AUC2 by intravenous infusion over 30-60 minutes; Drug: Paclitaxel; 175mg/m2 by intravenous infusion over 3 hours; Drug: Paclitaxel; 80mg/m2 by intravenous infusion over 1 hour
Experimental: Arm 2 (Research arm); Carboplatin on day 1 and dose-fractionated weekly paclitaxel on day 1, 8 and 15 of a 21-day cycle for 6 cycles	Drug: Carboplatin; AUC5 by intravenous infusion over 30-60 minutes; Drug: Carboplatin; AUC2 by intravenous infusion over 30-60 minutes; Drug: Paclitaxel; 175mg/m2 by intravenous infusion over 3 hours; Drug: Paclitaxel; 80mg/m2 by intravenous infusion over 1 hour
Experimental: Arm 3 (Research arm); Dose-fractionated weekly carboplatin and weekly paclitaxel on day 1, 8 and 15 of a 21-day cycle for 6 cycles.	Drug: Carboplatin; AUC5 by intravenous infusion over 30-60 minutes; Drug: Carboplatin; AUC2 by intravenous infusion over 30-60 minutes; Drug: Paclitaxel; 175mg/m2 by intravenous infusion over 3 hours; Drug: Paclitaxel; 80mg/m2 by intravenous infusion over 1 hour

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Stage 1: Feasibility assessed as the number of cycles and dose intensity of protocol treatment delivered per patient.	6 months after the 50th patient has been randomised to each arm and 6 months after the 50th patient with a plan to undergo delayed primary surgery has been randomised to each arm
Stage 1: Safety assessed as the rate of any ≥ grade 3 toxicity experienced per patient.	6 months after the 50th patient has been randomised to each arm and 6 months after the 50th patient with a plan to undergo delayed primary surgery has been randomised to each arm
Stage 2: Progression Free Survival rate at 9 months after randomisation	9 months after first 62 patients randomised per arm
Stage 3: Progression Free Survival	PFS expected 1 year after last patient is randomised. OS expected 3 years after last patient is randomised.
Stage 3: Overall Survival	PFS expected 1 year after last patient is randomised. OS expected 3 years after last patient is randomised.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stage 3: Toxicity assessed by number of participants with adverse events	Assessment of toxicity profile of dose-fractionated chemotherapy	Expected 1 year and 3 years after last patient is randomised.
Stage 3: Quality of Life	Assessment of potential impact of dose-fractionated chemotherapy on functionality and well-being in patients undergoing first line treatment for ovarian cancer.	Expected 1 year and 3 years after last patient is randomised.
Stage 3: Health Economics	Cost-effectiveness analysis of dose-fractionated chemotherapy	Expected 1 year and 3 years after last patient is randomised.

Collaborators and Investigators

• Sponsor: Medical Research Council
• Collaborators: Cancer Research UK

Publications and helpful links

General Publications

• Clamp AR, James EC, McNeish IA, Dean A, Kim JW, O'Donnell DM, Gallardo-Rincon D, Blagden S, Brenton J, Perren TJ, Sundar S, Lord R, Dark G, Hall M, Banerjee S, Glasspool RM, Hanna CL, Williams S, Scatchard KM, Nam H, Essapen S, Parkinson C, McAvan L, Swart AM, Popoola B, Schiavone F, Badrock J, Fananapazir F, Cook AD, Parmar M, Kaplan R, Ledermann JA. Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal cancer treatment (ICON8): overall survival results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2022 Jul;23(7):919-930. doi: 10.1016/S1470-2045(22)00283-2. Epub 2022 Jun 9.
• Morgan RD, McNeish IA, Cook AD, James EC, Lord R, Dark G, Glasspool RM, Krell J, Parkinson C, Poole CJ, Hall M, Gallardo-Rincon D, Lockley M, Essapen S, Summers J, Anand A, Zachariah A, Williams S, Jones R, Scatchard K, Walther A, Kim JW, Sundar S, Jayson GC, Ledermann JA, Clamp AR. Objective responses to first-line neoadjuvant carboplatin-paclitaxel regimens for ovarian, fallopian tube, or primary peritoneal carcinoma (ICON8): post-hoc exploratory analysis of a randomised, phase 3 trial. Lancet Oncol. 2021 Feb;22(2):277-288. doi: 10.1016/S1470-2045(20)30591-X. Epub 2020 Dec 22.
• Blagden SP, Cook AD, Poole C, Howells L, McNeish IA, Dean A, Kim JW, O'Donnell DM, Hook J, James EC, White IR, Perren T, Lord R, Dark G, Earl HM, Hall M, Kaplan R, Ledermann JA, Clamp AR. Weekly platinum-based chemotherapy versus 3-weekly platinum-based chemotherapy for newly diagnosed ovarian cancer (ICON8): quality-of-life results of a phase 3, randomised, controlled trial. Lancet Oncol. 2020 Jul;21(7):969-977. doi: 10.1016/S1470-2045(20)30218-7.

Helpful Links

• ICON8 Trial website

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (Anticipated): June 1, 2017

Study Registration Dates

• First Submitted: June 20, 2012
• First Submitted That Met QC Criteria: July 26, 2012
• First Posted (Estimate): July 31, 2012

Study Record Updates

• Last Update Posted (Estimate): July 31, 2012
• Last Update Submitted That Met QC Criteria: July 26, 2012
• Last Verified: July 1, 2012

More Information

Terms related to this study

• Keywords: Randomised controlled trial; Ovarian cancer; Fallopian tube carcinoma; Epithelial ovarian carcinoma; Primary serous peritoneal carcinoma; Gynaecological carcinoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Carboplatin; Paclitaxel; Albumin-Bound Paclitaxel
• Other Study ID Numbers: 2010-022209-16; 10356387 (Other Identifier: ISRCTN)