ICECREAM

The ICECREAM study aims to provide important data on the optimal use of currently available therapeutics in patients with metastatic colorectal cancer who have progressed on standard chemotherapy options. The trial is designed to answer two questions in parallel.

The goal of the ICECREAM trial is to investigate and evaluate whether cetuximab should be given alone or in combination with chemotherapy in KRAS wild-type patients. The same treatment option will also be studied in patients with the KRAS G13D mutation. The study design would allow KRAS G13D mutated colorectal cancer patients to have access to treatment that is currently unavailable in Australia.  The ICECREAM study is in follow up and data analysis is currently underway.

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Trial Status

Completed

Cancer Type

Colorectal Cancer

Aim

The ICECREAM study aims to provide important data on the optimal use of currently available therapeutics in patients with metastatic colorectal cancer who have progressed on standard chemotherapy options. The trial is designed to answer two questions in parallel.

Firstly, to determine whether cetuximab is optimally used as monotherapy or in combination with an irinotecan-based regimen in KRAS wild-type patients. Secondly, to determine whether the efficacy of either cetuximab alone or in combination with an irinotecan-based regimen is similar in patients harbouring a KRAS G13D mutation.

Summary

Colorectal cancer is the most common type of gastro-intestinal cancer in Australia, which has some of the highest colorectal cancer rates in the world.

Cetuximab is a type of drug known as a monoclonal antibody, which targets receptors on the surface of the cancer cells called epidermal growth factor receptors (EGFRs). EGFRs stimulate cancer growth. Cetuximab locks on to EGFRs and stops them from stimulating the cancer to grow and spread. Cetuximab is used for the treatment of KRAS wild type (no mutations in the KRAS gene) metastatic colorectal cancer. However, several studies have  suggested that cetuximab can have an effect on tumours with a specific rare KRAS G13D mutation.

The goal of the ICECREAM trial is to investigate and evaluate whether cetuximab should be given alone or in combination with chemotherapy in KRAS wild-type patients. The same treatment option will also be studied in patients with the KRAS G13D mutation. The study design would allow KRAS G13D mutated colorectal cancer patients to have access to treatment that is currently unavailable in Australia.

The ICECREAM study is in follow up and data analysis is currently underway. It has provided evidence that cetuximab alone is not an effective treatment for tumours with the G13D mutation, and therefore cannot be recommended. Although the combination treatment did show a minor benefit, given the side-effects observed and uncertainty about the need for cetuximab, the results do not justify the routine use of this drug combination for patients with this type of mutation.

Another group of patients, who have tumours without mutations, have also been enrolled in the ICECREAM trial. It is already known that cetuximab is an effective treatment for these patients, but it is not clear whether these patients get better results when chemotherapy is combined with cetuximab . This part of the trial will help to answer whether there is a difference in effectiveness between cetuximab when given alone or when combined with chemotherapy for these patients.

To find out more about this trial

Visit ANZTCR for more detailed information.

Trial Status

Completed

Cancer Type

Colorectal Cancer

Protocol Title

Randomised Phase II study of cetuximab alone or in combination with irinotecan in patients with metastatic CRC with either KRAS WT or G13D mutation.

ICECREAM: The Irinotecan Cetuximab Evaluation and the Cetuximab Response Evaluation Among Patients with G13D Mutation.

Publication Reference

  1. Segelov E, Thavaneswaran S, Waring PM, Desai J, Robledo KP, Gebski VJ, Elez E, Nott LM, Karapetis CS, Lunke S, Chantrill LA, Pavlakis N, Khasraw M, Underhill C, Ciardiello F, Jefford M, Wasan H, Haydon A, Price TJ, van Hazel G, Wilson K, Simes J, Shapiro JD. Response to cetuximab with or without irinotecan in patients with refractory metastatic colorectal cancer harboring the KRAS G13D mutation: Australasian Gastro-Intestinal Trials Group ICECREAM Study. Journal of Clinical Oncology 2016; 34(19): 2258–2264.
  2. Segelov E, Waring P, Desai J, Wilson K, Gebski V, Thavaneswaran S, Elez E, Underhill C, Pavlakis N, Chantrill L, Nott L, Jefford M, Khasraw M, Day F, Wasan H, Ciardiello F, Karapetis C, Joubert W, van Hazel G, Haydon A, Price T, Tejpar S, Tebbutt N, Shapiro J. ICECREAM: randomised phase II study of cetuximab alone or in combination with irinotecan in patients with metastatic colorectal cancer with either KRAS, NRAS, BRAF and PI3KCA wild type, or G13D mutated tumours. BMC Cancer 2016; 16: 339.

Conference Presentation Reference

  1. Shapiro JD, Thavaneswaran S, Underhill C, Robledo KP, Karapetis CS, Day FL, Nott LM, M. J, Chantrill LA, Pavlakis N, Tebbutt NC, Price TJ, Khasraw M, Van Hazel G, Waring PM, Tejpar S, Simes J, Gebski V, Desai J, Segelov E. Results of the quad wild type arm of the AGITG ICECREAM study: a randomised phase II study of cetuximab alone or in combination with irinotecan in patients with refractory metastatic colorectal cancer with no mutations in KRAS, NRAS, BRAF or PIK3CA. American Society of Oncology Annual Meeting; 2–6 Jun 2017; Chicago.
  2. Segelov E, Thavaneswaran S, Waring P, Desai J, Mann K, Elez E, Chantrill L, Pavlakis N, Nott L, Underhill C, Khasraw M, Wasan H, Ciardiello F, Jefford M, Joubert W, Haydon A, Karapetis C, Price T, Wilson K, Shapiro J. AGITG ICECREAM study: the Irinotecan Cetuximab Evaluation and Cetuximab Response Evaluation Amongst Patients with a G13D Mutation: analysis of outcomes in patients with refractory metastatic colorectal cancer harbouring the KRAS G13D mutation. European Cancer Congress 2015; 25-29 Sep 2015; Vienna.
  3. Segelov E, Wilson K, Gebski V, Waring P, Tabernero J, Wasan H, Ciardiello F, Desai J, Underhill C, Karapetis C, Khasraw M, Nott L, Joubert W, Pavlakis M, Van Hazel G, Chantrill L, Price T, Jefford M, Haydon A, Shapiro J. ICE CREAM: Irinotecan cetuximab evaluation and the cetuximab response evaluation among patients with G13D mutation. American Society of Clinical Oncology Annual Meeting; 31 May–4 Jun 2013; Chicago. Journal of Clinical Oncology; 31(suppl.): TPS3649.
  4. Segelov E, Wilson K, Gebski V, Waring P, Desai J, Nott L, Karapetis C, Hall M, Wasan H, Shapiro J. ICECREAM: irinotecan cetuximab evaluation and the cetuximab response evaluation among patients with G13D mutation. Clinical Oncological Society of Australia 40th Annual Meeting; 12-14 Nov 2013; Adelaide. Asia-Pacific Journal of Clinical Oncology 2013; S3: 155.

AIM

The ICECREAM study aims to compare the efficacy of cetuximab alone or in combination with irinotecan in patients with KRAS WT or KRAS G13D mutated metastatic colorectal cancer who have progressed on prior oxaliplatin and irinotecan based chemotherapy.

Background

Previous studies by the Australasian Gastro-intestinal Trials Group (AGITG) have demonstrated that cetuximab, an EFGR monoclonal antibody, prolongs survival in patients with metastatic colorectal cancer refractory to all other chemotherapy. Some medical practitioners believe that combining this treatment with irinotecan will achieve better results due to the results of one UK trial that reported modest increases in tumour shrinkage and control of the disease. However, there were greater side effects and survival was not increased on this study.

Soon after the initial cetuximab clinical trials were reported, the AGITG and other groups showed that cetuximab was not effective in people who had the specific abnormality (mutation called a KRAS Gene Mutation) in their colon cancer cells. Up to 40% of patients have this abnormality, which can be easily tested, and only patients without this mutation (KRAS wild-type) are given this treatment. When restricted to this subgroup, the benefits of cetuximab are significantly enhanced.

The picture has become more complicated recently with further research showing patients with a particular type of KRAS mutation (G13D) may actually benefit from cetuximab treatment. Currently, cetuximab is US FDA and Australian TGA approved only for patients without any KRAS mutation (KRAS wild-type).

This ICECREAM study aims to evaluate whether cetuximab should be given alone or in combination with irinotecan chemotherapy in KRAS wild-type patients in whom the disease has progressed despite previous treatment with oxaliplatin and irinotecan chemotherapy. The data on the effect of cetuximab on patients with G13D KRAS mutation was presented and published in 2016.

Clinical Trial Design

ICECREAM is a phase II, open label, randomised multi-centre trial. Eligible patients with either the KRAS wildtype gene or KRAS G13D mutation will be randomised into two groups to receive either cetuximab alone or the combination of cetuximab and irinotecan chemotherapy. One group will receive cetuximab alone and the other group will receive cetuximab in combination with irinotecan. In both groups the treatment will be administered intravenously. Cetuximab is administered weekly to both groups and patients in combination therapy group will receive irinotecan every 14 days.

The study will monitor the patients and evaluate the response to the different treatment plans, by looking at the response on CT scans, survival rates and quality of life. Treatment will continue until disease progression, unacceptable toxicity or either the patient or the physician requests treatment to end.

Study Chairs

Professor Eva Segelov (Monash Health, Monash University, Melbourne VIC)
Associate Professor Jeremy Shapiro (Cabrini Haematology & Oncology Centre, Malvern VIC)

Contact Email

icecream@ctc.usyd.edu.au

Principal Investigator

Professor Eva Segelov

More Information

Available online at the Australian New Zealand Clinical Trial Registry (ANZCTR) here.

Funding

Merck Serono