An RCT of Concurrent and Maintenance Cediranib in Women With Platinum-sensitive Relapsed Ovarian Cancer (ICON6)

• ClinicalTrials.gov Identifier: NCT00532194
• Recruitment Status: Unknown
• First Posted: September 20, 2007
• Last Update Posted: September 23, 2015
• Sponsor: Medical Research Council
• Collaborators: Cancer Research UK; National Health and Medical Research Council, Australia; Australia New Zealand Gynaecological Oncology Group; NCIC Clinical Trials Group; Grupo Español de Investigación en Cáncer de Ovario; AstraZeneca
• Information provided by (Responsible Party): Andrew Embleton, Medical Research Council

Tracking Information

• First Submitted Date: September 19, 2007
• First Posted Date: September 20, 2007
• Last Update Posted Date: September 23, 2015
• Study Start Date: July 2007
• Actual Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: March 11, 2015): Progression-free survival [ Time Frame: Apr 2013 ]

Original Primary Outcome Measures (submitted: September 19, 2007)

• Stage 1: Safety [ Time Frame: May 2008 ]
• Stage 2: Progression-free survival [ Time Frame: May 2010 ]
• Stage 3: Overall survival [ Time Frame: Oct 2013 ]

Current Secondary Outcome Measures (submitted: March 11, 2015)

• Overall survival [ Time Frame: Q2 2016 ]
• Toxicity [ Time Frame: Q2 2015 ]
• Quality of Life [ Time Frame: Q2 2015 ]

Original Secondary Outcome Measures (submitted: September 19, 2007)

• Stage 1: none [ Time Frame: May 2008 ]
• Stage 2: overall survival and toxicity [ Time Frame: May 2010 ]
• Stage 3: Progression-free survival, toxicity, quality of life [ Time Frame: Oct 2013 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: An RCT of Concurrent and Maintenance Cediranib in Women With Platinum-sensitive Relapsed Ovarian Cancer
• Official Title: A Randomised, Placebo-controlled, Trial of Concurrent Cediranib [AZD2171] (With Platinum-based Chemotherapy) and Concurrent and Maintenance Cediranib in Women With Platinum-sensitive Relapsed Ovarian Cancer
• Brief Summary: The purpose of this study is to assess the safety and efficacy of cediranib in combination with standard chemotherapy, in patients who have relapsed with ovarian, fallopian tube or epithelial cancer, after first line platinum based treatment.

Detailed Description

ICON6 is a randomised three-arm, two stage, double-blind, placebo-controlled multicentre Gynaecologic Cancer InterGroup (GCIG) phase III trial.

All patients will receive 6 cycles of platinum-based chemotherapy. Trial drug will be administered for up to 18 months from randomisation or until progression, whichever is sooner. Patients who have not progressed at 18 months from randomisation can continue Trial Drug until progression, if in the opinion of the clinician and the patient there is continuing clinical benefit.

Patients in Arm A (the reference arm) will receive a platinum-based chemotherapy regimen plus a daily oral placebo tablet for the duration of the chemotherapy and up to 18 months from randomisation or until progression.

Patients in Arm B (concurrent cediranib arm) will also receive a platinum-based chemotherapy regimen plus daily oral cediranib during chemotherapy only, and then an oral daily placebo tablet up to 18 months from randomisation or until progression.

Patients in Arm C (concurrent and maintenance cediranib arm) will also receive a platinum-based chemotherapy regimen plus oral cediranib daily during chemotherapy and then continued up to 18 months from randomisation or until progression.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Ovarian Cancer

Intervention

Drug: cediranib

Once-daily oral tablet starting dose 20mg

Other Names:

• AZD2171
• Recentin

Study Arms

• Placebo Comparator: A (reference)
  Patients in this arm will receive standard platinum based chemotherapy plus a daily oral placebo tablet for the duration of chemotherapy and then until protocol defined disease progression occurs.
• Active Comparator: B (concurrent cediranib)
  Patients in this arm will receive standard platinum based chemotherapy plus a daily oral cediranib tablet during chemotherapy only and then an oral daily placebo tablet until protocol defined disease progression occurs.
  Intervention: Drug: cediranib
• Active Comparator: C (concurrent and maintenance cediranib)
  Patients in this arm will receive standard platinum based chemotherapy plus a daily oral cediranib tablet during chemotherapy until protocol defined disease progression occurs.
  Intervention: Drug: cediranib

Publications *

• Raja FA, Griffin CL, Qian W, Hirte H, Parmar MK, Swart AM, Ledermann JA. Initial toxicity assessment of ICON6: a randomised trial of cediranib plus chemotherapy in platinum-sensitive relapsed ovarian cancer. Br J Cancer. 2011 Sep 27;105(7):884-9. doi: 10.1038/bjc.2011.334. Epub 2011 Aug 30.
• Ledermann J, Perren T, Raja F, Embleton A, Rustin GJS, Jayson G, Kaye SB, Swart AM, Vaughan M, Hirte H. Randomised double-blind phase III trial of cediranib (AZD 2171) in relapsed platinum sensitive ovarian cancer: Results of the ICON6 trial. Eur J Cancer 2013;49(Suppl. 3):S5 (LBA10).
• Ledermann JA, Embleton-Thirsk AC, Perren TJ, Jayson GC, Rustin GJS, Kaye SB, Hirte H, Oza A, Vaughan M, Friedlander M, Gonzalez-Martin A, Deane E, Popoola B, Farrelly L, Swart AM, Kaplan RS, Parmar MKB; ICON6 collaborators. Cediranib in addition to chemotherapy for women with relapsed platinum-sensitive ovarian cancer (ICON6): overall survival results of a phase III randomised trial. ESMO Open. 2021 Apr;6(2):100043. doi: 10.1016/j.esmoop.2020.100043. Epub 2021 Feb 18.
• Ledermann JA, Embleton AC, Raja F, Perren TJ, Jayson GC, Rustin GJS, Kaye SB, Hirte H, Eisenhauer E, Vaughan M, Friedlander M, Gonzalez-Martin A, Stark D, Clark E, Farrelly L, Swart AM, Cook A, Kaplan RS, Parmar MKB; ICON6 collaborators. Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016 Mar 12;387(10023):1066-1074. doi: 10.1016/S0140-6736(15)01167-8. Erratum In: Lancet. 2016 Apr 23;387(10029):1722.

Recruitment Information

• Recruitment Status: Unknown status
• Actual Enrollment (submitted: March 11, 2015): 486
• Original Estimated Enrollment (submitted: September 19, 2007): 2000
• Estimated Study Completion Date: December 2016
• Actual Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Females aged >= 18 years with previous histologically proven diagnosis of

   • Epithelial ovarian carcinoma
   • Fallopian tube carcinoma
   • Primary serous peritoneal carcinoma requiring treatment with further platinum-based chemotherapy > 6 months after their last cycle of first-line chemotherapy and 6 weeks after maintenance that is not chemotherapy based.
2. Signed informed consent and ability to comply with the protocol
3. Ability to commence treatment within approximately 2 weeks of randomisation
4. CT or MRI proven relapsed disease (measurable or non-measurable)
5. ECOG performance status 0-1
6. Life expectancy more than 12 weeks
7. If there is a past history of a solid tumour (other than ovarian cancer), this must have been treated curatively more than five years ago with no evidence of recurrence, with the exception of patients who have synchronous endometrial cancer (stage I G1, G2) with their ovarian cancer
8. If prior anthracycline or chest radiotherapy, Left Ventricular Ejection Fraction (LVEF) > institutional lower limit of normal.

9. 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)

10. Adequate liver function (within 14 days before randomisation)

    • Serum bilirubin (BR) ≤ 1.5 x ULN
    • Serum transaminases ≤ 2.5 x ULN

11. Adequate renal function

    • Serum creatinine ≤ 1.5 ULN or calculated creatinine clearance > 50 ml/min
    • Urine dipstick for proteinuria <2+. If urine dipstick is >= 2+ on two occasions more than one week apart then a 24 hour urine must demonstrate <=1g of protein in 24 hours or protein/creatinine ratio <1.5

Exclusion Criteria:

1. Non-epithelial ovarian cancer, including malignant mixed Mullerian tumours and mucinous carcinoma of the peritoneum
2. Poorly controlled hypertension (persistently elevated > 150/100mmHg, either systolic or diastolic or both, despite anti-hypertensive medication)
3. History of inflammatory bowel disease (Crohn's disease or Ulcerative Colitis)
4. Malignancies other than ovarian cancer within 5 years prior to randomisation, except for synchronous endometrial cancer (Stage I G1,G2) with ovarian cancer,adequately treated carcinoma in situ of the cervix and/or basal cell skin cancer. Patients who have a past history of a solid tumour, treated curatively, more than five years prior to randomisation, with no evidence of recurrence, are still eligible to enter ICON6.
5. Previous radiotherapy within 21 days prior to anticipated start of treatment
6. Treatment with any other investigational agent within 6 weeks prior to entering this trial. Patients are still eligible for entry into ICON6 if they have received previous treatment for ovarian cancer with either bevacizumab, erlotinib, or a Cox-2 inhibitor as long as more than 6 weeks have elapsed since the last treatment.
7. Arterial thrombotic event (including transient ischaemic attack [TIA], cerebrovascular accident [CVA) and peripheral arterial embolus) within the previous 12 months.
8. GI impairment that could affect ability to take, or adsorption of, oral medicines including sub acute or complete bowel obstruction
9. Known hypersensitivity to cediranib or other VEGF inhibitors
10. Major surgery within 2 weeks before anticipated start of treatment
11. Significant haemorrhage of > 30ml in a single episode within 3 months or any haemoptysis

12. Evidence of severe or uncontrolled cardiac disease

    • Myocardial infarct [MI] or unstable angina within 12 months
    • New York Health Association (NYHA) ≥ grade 2 congestive heart failure (CHF)
    • Cardiac ventricular arrhythmias requiring medication.
    • History of 2nd or 3rd degree atrioventricular conduction defects.
13. Prolonged QTc (corrected) interval of > 470msec on ECG, or a family history of long QT syndrome.
14. Persisting ≥ Grade 2 CTC toxicity (except alopecia and neuropathy) from previous anti-cancer treatment. If peripheral sensory or motor neuropathy ≥ grade 2 then paclitaxel can be omitted from the chemotherapy at the discretion of the treating physician
15. 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 unstable, untreated brain or meningeal metastases are not eligible.
16. Inability to attend or comply with treatment or follow-up scheduling
17. Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contra-indicates the use of an investigational drug or puts the patient at high risk for treatment-related complications
18. Fertile women of childbearing potential not willing to use adequate contraception for the duration of trial treatment and at least 6 months after.
19. Any other severe uncontrolled medical condition or disease
20. Concomitant use of potent inhibitors of CYP3A4 and 2C8 which cannot be stopped without a 2 week washout period before starting Trial Drug.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT00532194
• Other Study ID Numbers: 2007-001346-41; ISRCTN68510403 ( Registry Identifier: ISRCTN ); 2007-001346-41 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Andrew Embleton, Medical Research Council
• Original Responsible Party: Not Provided
• Current Study Sponsor: Medical Research Council
• Original Study Sponsor: Same as current

Collaborators

• Cancer Research UK
• National Health and Medical Research Council, Australia
• Australia New Zealand Gynaecological Oncology Group
• NCIC Clinical Trials Group
• Grupo Español de Investigación en Cáncer de Ovario
• AstraZeneca

Investigators

• Principal Investigator: Jonathan Ledermann, Prof.; University College, London

• PRS Account: Medical Research Council
• Verification Date: September 2015