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Trial registered on ANZCTR


Registration number
ACTRN12616001639415
Ethics application status
Approved
Date submitted
14/11/2016
Date registered
28/11/2016
Date last updated
28/11/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Improving sunitinib efficacy and tolerability in patients with metastatic clear cell carcinoma of the kidney by using a 14/7 day schedule and toxicity-adjusted dosing
Scientific title
Improving sunitinib efficacy and tolerability in patients with metastatic clear cell carcinoma of the kidney by using a 14/7 day schedule and toxicity-adjusted dosing
Secondary ID [1] 290500 0
WI200619
Universal Trial Number (UTN)
Trial acronym
ISE TAD 14-7
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic Renal Cell Cancer 300893 0
Condition category
Condition code
Cancer 300712 300712 0 0
Kidney

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Sunitinib malate, hard gel capsules, on a schedule of 14days (2weeks) on and 7days (1week) off
Sunitib is to be taken once daily for 14 days followed by no dosing for 7 days until disease progression or intolerable adverse events (dosing will continue indefinitely until progression or intolerable toxicity)
The investigator deciding the starting doses and dose adjustments will be a qualified and currently registered medical oncologist.

Recommended starting dose of sunitinib is 50mg daily, if the investigator has safety concerns then a starting dose of 37.5mg daily is allowable. Drug dose will be adjusted to ensure patients achieve grade 1 to 2 toxicity on at least 4 days of every 21 day cycle. Dose may be increased or decreased by increments of 12.5mg. Dose range between patients is expected to be 12.5 to 82.5mg/d with the majority of patients on 37.5 or 50mg daily. Regarding dose adjustment
- if patient has no toxicity OR Grade 1 toxicity for <4 days of the 21 days then the dose will be increase by 12.5mg/d
- if patient experiences Grade 1 - 2 toxicity for at least 4 days of the 21 days then the same dose will be continued
- if patient experiences Grade 3 or 4 toxicity for more than 6 days of the 21 days then drug will be stopped wait until less than Grade 1 Toxicity then recommence with 12.5 mg/d dose reduction (if Grade 4 toxicity the recommence with 25mg/d dose reduction)
- any other scenario will be left to the discretion of the investigator to guide treatment adjustment.
Medical history and records will be used to monitor adherence
Intervention code [1] 296357 0
Treatment: Drugs
Comparator / control treatment
No Control Group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 300131 0
To determine the progression free survival (PFS) in patients with mRCC treated with sunitinib on a 14/7 schedule with dose adjusted according to toxicity and TTL.
PFS will be assessed via CT scans
Timepoint [1] 300131 0
One year post enrolment
Secondary outcome [1] 329161 0
Determine time on sunitinib treatment from patient dosing records
Timepoint [1] 329161 0
One year post enrolment
Secondary outcome [2] 329162 0
Determine toxicity and quality of life (QoL) (These are composite secondary outcomes)
Health-related quality of life will be assessed using Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) and Toxicity will be based on CTCAE v4.03
Timepoint [2] 329162 0
QoL: Baseline
Toxicity and QoL: 6 weeks, 3 months, 6 months, 9 months, 12 months
Secondary outcome [3] 329163 0
Determine Response via CT scans
Timepoint [3] 329163 0
Assessed three-monthly or when clinically indicated until 12 months post commencement of study drug
Secondary outcome [4] 329164 0
Determine Overall Survival
Timepoint [4] 329164 0
Five years post enrolment
Secondary outcome [5] 329165 0
Explore potential pharmacogenomic correlation with toxicity, assessed by serum assay for genomic evaluation and review of medical records for toxicity data
(This is a composite secondary outcome)
Timepoint [5] 329165 0
One year post enrolment

Eligibility
Key inclusion criteria
1. Histologically or cytologically confirmed metastatic renal cell cancer with a component of clear cell histology.
2. Evidence of unidimensionally measurable disease, defined as: greater than or equal to 1 malignant tumour mass that can be accurately measured in at least 1 dimension greater than or equal to 20 mm with conventional computerized tomography [CT] scan or Magnetic Resonance Imaging [MRI], or greater than or equal to 10 mm with spiral CT scan using a 5 mm or smaller contiguous reconstruction algorithm).
3. Bone lesions, ascites, peritoneal carcinomatosis or miliary lesions, pleural or pericardial effusions, lymphangitis of the skin or lung, cystic lesions, or irradiated lesions are not considered measurable.
4. Adequate organ function as defined by the following criteria:
(a) absolute neutrophil count (ANC) greater than or equal to1.5 x10^9/L and
(b) platelets greater than or equal to 75 x10^9/L and
(c) haemoglobin greater than or equal to 90 g/L and
(d) AST and ALT less than or equal to 2.5 x upper limit of normal (ULN), unless there are liver metastases in which case AST and ALT less than or equal to 5.0 x ULN and
(e) total bilirubin is less than or equal to 1.5 x ULN and
(f) Serum creatinine is greater than or equal to 2.0 x ULN or calculated creatinine clearance is greater than or equal to 30 mL/min;
5. ECOG performance status of 0 or 1.
6. Life expectancy of greater than or equal to 12 weeks.
7. No evidence of pre-existing uncontrolled hypertension
8. Women of childbearing potential must have a negative serum or urine pregnancy test within 3 days prior to treatment.
9. Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to enrolment.
10. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures, including completion of patient-reported outcome measures.
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Prior systemic treatment of metastatic renal cell cancer;
2. Patients treated with any neoadjuvant or adjuvant systemic therapy;
3. Major surgery <4 weeks or radiation therapy <2 weeks of starting the study treatment. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided there is at least one measurable lesion that has not been irradiated;
4. Gastrointestinal abnormalities including:
(a) inability to take oral medication;
(b) requirement for intravenous alimentation;
(c) prior surgical procedures affecting absorption including total gastric resection;
(d) treatment for active peptic ulcer disease in the past 6 months; active gastrointestinal bleeding, unrelated to cancer, as evidenced by haematemesis, haematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy;
(e) malabsorption syndromes;
(f) history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment;
5. CYP3A4 inhibitors or inducers: Use with drugs that are known potent CYP3A4 inhibitors or inducers should be avoided if possible. Patients may receive these agents if they are on a stable dose and are planned to continue throughout the study period
6. Requirement of anticoagulant therapy with oral vitamin K antagonists. Low-dose anticoagulants for maintenance of patency of central venous access devise or prevention of deep venous thrombosis is allowed. Therapeutic use of low molecular weight heparin is allowed.
7. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before randomization. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of randomization.
8. A serious uncontrolled medical disorder or active infection that would impair their ability to receive study treatment.
9. Any of the following within the 12 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack and 6 months for deep vein thrombosis or pulmonary embolism.
10. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
11. History of a malignancy (other than renal cell cancer) except those treated with curative intent for skin cancer (other than melanoma), in situ breast or in situ cervical cancer, or those treated with curative intent for any other cancer with no evidence of disease for 2 years.
12. Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol.
13. Female patients who are pregnant or lactating, or men and women of reproductive potential not willing or not able to employ an effective method of birth control/contraception to prevent pregnancy during treatment and for 6 months after discontinuing study treatment The definition of effective contraception should be in agreement with local regulation and based on the judgment of the principal investigator or a designated associate.
14.Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study.


Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
We estimate a median PFS of greater than 12 months in the toxicity-adjusted dose (TAD), 14/7 treated patients. We estimate that such patients treated with standard dose of sunitinib will have a prognostic-score adjusted median PFS of 9 months (weighted median estimate assuming a median PFS of 11 months in intermediate risk subjects and a median PFS of 4 months in poor risk subjects). Based on the A’Hern design, a sample size of 80 patients would have 80% power with 95% confidence to detect a 14% increase in progression free survival from 50% to 64% at 9 months. This will be sufficient to rule a median PFS of 9 months in favour of a median PFS of 14 months. At 9 months, this sample size will also have 80% power to exclude a PFS rate of 50% (median PFS 9 months) in favour of a 62% PFS rate (median PFS 13 months) with 90% confidence.

Significance
If the TAD, 14/7 intervention has a PFS of 12 months or greater, this would inform a phase 3 trial using TAD vs standard dosing with PFS and OS endpoints.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
15/12/2016
Actual
Date of last participant enrolment
Anticipated
31/12/2018
Actual
Date of last data collection
Anticipated
31/12/2019
Actual
Sample size
Target
80
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA
Recruitment hospital [1] 6913 0
Macquarie University Hospital - Macquarie Park
Recruitment hospital [2] 6914 0
Westmead Hospital - Westmead
Recruitment hospital [3] 6915 0
Flinders Medical Centre - Bedford Park
Recruitment postcode(s) [1] 14582 0
2109 - Macquarie Park
Recruitment postcode(s) [2] 14583 0
2145 - Westmead
Recruitment postcode(s) [3] 14584 0
5042 - Bedford Park

Funding & Sponsors
Funding source category [1] 294920 0
Commercial sector/Industry
Name [1] 294920 0
Pfizer
Country [1] 294920 0
Australia
Primary sponsor type
University
Name
Macquarie University
Address
Balaclava Rd
North Ryde, NSW, 2109
Country
Australia
Secondary sponsor category [1] 293780 0
None
Name [1] 293780 0
N/A
Address [1] 293780 0
N/A
Country [1] 293780 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296298 0
Macquarie University Human Research Ethics Committee (Medical Sciences)
Ethics committee address [1] 296298 0
Ethics committee country [1] 296298 0
Australia
Date submitted for ethics approval [1] 296298 0
13/05/2015
Approval date [1] 296298 0
18/06/2015
Ethics approval number [1] 296298 0
5201500429

Summary
Brief summary
The primary purpose of this trial is to evaluate the efficacy and tolerability of sunitinib on a 14/7 schedule with toxicity-adjusted dosing for the treatment of metastatic renal cell cancer (mRCC).

Who is it for?
You may be eligible to enroll in this trial if you are aged 18-80 years and have been diagnosed with metastatic renal cell cancer with a component of clear cell histology.

Study details
All participants enrolled in this trial will receive sunitinib capsules to be taken in cycles of 14 days on, then 7 days off, until either the disease becomes resistant to the treatment (disease progression), or due to intolerable side effects despite dose adjustment, in which case treatment will be ceased. Based on the occurrence of any side effects to the medication, the dose may be increased or reduced as required by the treating doctor. The dose is adjusted so as to aim for some side effects for up to four days per cycle. Participants will be asked to complete questionnaires relating to toxicity and quality of life, and will undergo scans to monitor disease progression for up to one year following the start of treatment.

It is hoped that the findings from this trial will provide information on whether a 14/7 dosing schedule with toxicity-adjusted dosing is effective and tolerable for sunitinib treatment for mRCC.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 70310 0
Prof Howard Gurney
Address 70310 0
Suite 407, Level 4, Department of Clinical Medicine
Building F10A
2 Technology Place
Macquarie University, NSW 2109
Country 70310 0
Australia
Phone 70310 0
+61 2 9812 3526
Fax 70310 0
+61 2 9812 3533
Email 70310 0
[email protected]
Contact person for public queries
Name 70311 0
Mr Radhika Butala
Address 70311 0
Suite 407, Level 4, Department of Clinical Medicine
Building F10A
2 Technology Place
Macquarie University, NSW 2109
Country 70311 0
Australia
Phone 70311 0
+ 61 2 9812 3561
Fax 70311 0
+ 61 2 9812 3533
Email 70311 0
[email protected]
Contact person for scientific queries
Name 70312 0
Prof Howard Gurney
Address 70312 0
Suite 407, Level 4, Department of Clinical Medicine
Building F10A
2 Technology Place
Macquarie University, NSW 2109
Country 70312 0
Australia
Phone 70312 0
+ 61 2 9812 3526
Fax 70312 0
+ 61 2 9812 3533
Email 70312 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.