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Trial registered on ANZCTR


Trial ID
ACTRN12614000486628
Ethics application status
Approved
Date submitted
17/04/2014
Date registered
9/05/2014
Date last updated
2/02/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
EVICT: The erlotinib and vemurafenib in combination trial.
A Phase I/II Trial of the combination of BRAF and EGFR inhibition in BRAF V600E mutant colorectal, advanced or metastatic lung adenocarcinoma and other cancers.
Scientific title
A Phase I/II Trial of the combination of BRAF and EGFR inhibition in BRAF V600E mutant colorectal, advanced or metastatic lung adenocarcinoma and other cancers.
Secondary ID [1] 284458 0
Protocol Number: 2014.019
Secondary ID [2] 284523 0
Roche Study Number: ML28737
Universal Trial Number (UTN)
U1111-1155-9208
Trial acronym
EVICT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Colorectal Cancer (metastatic) 291683 0
Lung Cancer (metastatic) 291684 0
Condition category
Condition code
Cancer 292064 292064 0 0
Bowel - Back passage (rectum) or large bowel (colon)
Cancer 292065 292065 0 0
Lung - Non small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Tarceva (erlotinib) and Zelboraf (vemurafenib) are the intervention being studied. Both are provided in tablet form and are taken orally everyday until disease progression or unacceptable toxicity (anticipated this will be for approximately 6 months).


There will be 3 dose levels:
a) Dose level D-1 = erlotinib (100 mg/day) and vemurafenib (720 mg twice a day)

b) Dose level D1 = erlotinib (100 mg/day) and vemurafenib (960 mg twice a day)

c) Dose level D2 = erlotinib (150 mg/day) and vemurafenib (960 mg twice a day).

Please note; this is a dose escalation study in the first phase, proceeding to dose expansion in the second phase.

Strategies used to monitor adherence will be via a patient diary, where patients are asked to complete a daily diary entry recording drug use, as well as, standard drug tablet return and accountability logs.
Intervention code [1] 289214 0
Treatment: Drugs
Comparator / control treatment
Not Applicable
Control group
Uncontrolled

Outcomes
Primary outcome [1] 291941 0
Primary outcome is to determine the safety of the combination of vemurafenib and erlotinib in the first 4 weeks of treatment in BRAF V600E mutant metastatic CRC and identify the dosing regimen to be evaluated in Phase II.

This outcome will be assessed via the incidence of dose-limiting toxicities (DLTs) reported within the first 4 weeks of treatment with the combination of erlotinib and vemurafenib in a cohort of 3 patients. After each cohort of 3 patients completes the DLT observation period, a clinical synthesis of the available toxicity information will be reviewed by the trials safety monitoring committee.
Timepoint [1] 291941 0
Post first 4 weeks of treatment.
Primary outcome [2] 291942 0
Secondary primary outcome is to evaluate the clinical efficacy of the combination of vemurafenib and erlotinib in BRAF V600E mutant metastatic CRC as measured by the proportion of patients achieving a complete or partial response (CR or PR) within the first 24 weeks of treatment.

This outcome will be assessed using the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 within the first 24 weeks of treatment with the combination of erlotinib and vemurafenib.
Timepoint [2] 291942 0
Post the first 24 weeks of treatment.
Secondary outcome [1] 307885 0
To evaluate the clinical efficacy of the combination of vemurafenib and erlotinib in BRAF V600E mutant advanced or metastatic cancers (lung adenocarcinoma and other) as measured by the proportion of patients achieving a complete or partial response (CR or PR) within the first 24 weeks of treatment.

This outcome will be assessed using the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 within the first 24 weeks of treatment with the combination of erlotinib and vemurafenib.
Timepoint [1] 307885 0
Post the first 24 weeks of treatment.
Secondary outcome [2] 307886 0
To evaluate other measures of clinical efficacy of the combination of vemurafenib and erlotinib in the two patient groups (mCRC, lung adenocarcinoma and other) including: the clinical benefit rate at 16 weeks after treatment commencement (CR, PR and SD).
Timepoint [2] 307886 0
16 weeks after treatment commencement (CR, PR and SD)
Secondary outcome [3] 307887 0
To determine the safety of the combination of vemurafenib and erlotinib over the course of treatment within each of the two patient groups (mCRC, lung adenocarcinoma and other).

Safety will be assessed throughout various timepoints during treatment and will include the following investigations:
a) Physical examination;
b) Haematology assessments;
c) Biochemistry assessments;
d) Performance status assessments;
e) ECGs
f) Toxicity assessments;
g) Tumour response assessments according to RECIST v1.1
h) FDG-PET (where applicable).
Timepoint [3] 307887 0
Assessments will occur at various timepoints throughout the study, and include (but are not limited to):

a) Screening;
b) Weeks 1,2,4,6,8,12,16,20 and 24; and
c) Every 8 weeks thereafter until end of treatment.

Eligibility
Key inclusion criteria
1. Male or female patients greater than or equal to 18 years of age at the time of study entry
2. All patients must have histological or cytological confirmed metastatic colorectal cancer with a BRAF V600E mutation of their primary cancer or related metastases. Patients with other tumour types with a proven BRAF V600E mutation can be considered for enrolment into the Expansion Phase exploratory cohort with the permission of the Study Chair.
3. Patients with BRAF V600E mCRC are permitted to have had a maximum of 2-lines of therapy for metastatic disease. A maintenance strategy post 1st-line treatment is not considered as an additional line of therapy, nor is rechallenge with oxaliplatin. Patients with lung adenocarcinoma are required to have received prior treatment with a platinum doublet. There is no requirement for previous treatment for other tumour types.
4. All patients must have measurable disease per RECIST 1.1 criteria.
5. A tumour paraffin tissue block or 20 - 30 unstained slides from the tumour tissue block must be available for the purpose of biomarker analyses. Obtaining archived tumour material or unstained slides from an archived tumour block will suffice to meet this requirement. The availability of the tumour tissue block must be confirmed at screening for a patient to be considered eligible. If no tissue block and fewer than 20 unstained slides are available, eligibility must be confirmed with the Study Chair or delegate.
6. ECOG performance status 0 to 1 inclusive.
7. Participants must have adequate organ and marrow function as defined below:
a) Absolute neutrophil count greater than or equal to 1.5 x 109/L
b) Platelets greater than or equal to 100 x 109/L
c) ALT and AST less than or equal to 2.5 x upper limit of normal (ULN), or less than or equal to 5 x ULN if liver metastases are present
d) Total serum bilirubin less than or equal to 1.5 x ULN
e) Serum creatinine less than or equal to 1.5 x ULN, or creatinine clearance > 50ml/min
8. Participants must be suitable for oral drug administration.
9. Life expectancy > 3 months.
10. Female patients of childbearing potential (see below) must:
a) Be on highly effective contraception. Highly effective contraception methods include:
* total abstinence, or
* sterilisation (see below), or
* combination of any two of the following (a+b, or a+c, or b+c):
* Use of oral, injected or implanted hormonal methods of contraception. Hormonal contraceptives include any marketed contraceptive agent that includes an oestrogen and/or a progestin.
* Placement of an intrauterine device (IUD)
* Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/cream/ vaginal suppository
b) Have a negative serum or urine pregnancy test performed within the 7 days before start of treatment.
c) Highly effective contraception for females of child bearing potential must be maintained throughout the study and for 6 months after study drug discontinuation.
11. Female patients not of child-bearing potential. Women are considered not of child bearing potential if they have had either:
a) 12 months of natural (spontaneous) amenorrhoea with an appropriate clinical profile (eg. age appropriate, history of vasomotor symptoms), or
b) A surgical bilateral oophorectomy (with or without hysterectomy), or
c) Tubal ligation at least 6 weeks ago.
In the case of unilateral oophorectomy alone, a woman is considered not of child-bearing potential only once the reproductive status has been confirmed by follow up hormone level assessment.
12. Sexually active males must use a condom during intercourse while taking the drug and for 6 months after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomised men in order to prevent delivery of the drug via seminal fluid.
13. Absence of any psychological, familial or sociological condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before trial entry.
14. Ability to understand and the willingness to sign a written informed consent. Before study entry, written informed consent must be obtained from patient prior to performing any study-related procedures.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Active CNS lesions are excluded (i.e. those with radiographically unstable, symptomatic lesions). Patients treated with stereotactic therapy or surgery are eligible if patient remains without evidence of disease progression within the CNS for greater than or equal to 1 month. Previous whole brain radiotherapy is not allowed with the exception of patients who have had definitive resection or stereotactic therapy of all radiologically detectable parenchymal lesions.
2. History of or known spinal cord compression, or carcinomatous meningitis.
3. Patients who have had any systemic cytotoxic/biologic or investigational therapies within 4 weeks prior to study entry or who have not recovered from the side effects of such earlier therapy.
4. Previous malignancies within the past 5 years are excluded except for adequately treated carcinoma in-situ of the cervix. Isolated elevation in PSA in the absence of radiographic evidence of metastatic prostate cancer is allowed.
5. Participants who have had radiotherapy and/or major surgery within 2 weeks prior to study entry.
6. Anticipated or concurrent use of any other anti-cancer therapies or study agents.
7. Clinical significant cardiac disease including any of the following:
a. unstable angina,
b. symptomatic or otherwise uncontrolled arrhythmia requiring medication (does not include stable, lone atrial fibrillation),
c. QTcF > 480 msecs or a history of congenital long QT syndrome,
d. uncontrolled hypertension,
e. symptomatic congestive heart failure
f. myocardial infarction less than or equal to 6 months prior to first study treatment,
g. serious uncontrolled cardiac arrhythmia.
8. Patients with active uncontrolled infection.
9. Known history of human immunodeficiency virus (HIV) infection.
10. Known history of active hepatitis B or C.
11. 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, which in the judgment of the investigator would make the patient inappropriate for entry into this study.
12. Patients who are receiving treatment with medications known to be strong CYP3A4 inhibitors within 7 days before starting treatment with erlotinib and vemurafenib or strong inducers of CYP3A4 within 14 days before starting treatment with erlotinib and vemurafenib.
A comprehensive list of inhibitors, inducers and substrates may be found at http://medicine.iupui.edu/flockhart/table.htm.
13. Nursing (lactating) women.
14. Severe hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of either erlotinib or vemurafenib.
15. Patients with EGFR mutant lung adenocarcinoma.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 2341 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [2] 2342 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [3] 2344 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [4] 2345 0
Western Hospital - Footscray
Recruitment hospital [5] 2346 0
Peter MacCallum Cancer Institute - East Melbourne
Recruitment hospital [6] 2347 0
Barwon Health - Geelong Hospital campus - Geelong

Funding & Sponsors
Funding source category [1] 289104 0
Government body
Name [1] 289104 0
Victorian Cancer Agency
c/o Department of Health
Address [1] 289104 0
GPO Box 4541 (Level 19)
MELBOURNE VIC 3001
Country [1] 289104 0
Australia
Primary sponsor type
Hospital
Name
Peter MacCallum Cancer Centre
Address
305 Grattan Street
Melbourne VIC 3000
Country
Australia
Secondary sponsor category [1] 287769 0
Commercial sector/Industry
Name [1] 287769 0
Roche Pharmaceuticals PTY LTD
Address [1] 287769 0
4-10 Inman Road
Dee Why NSW 2099
Country [1] 287769 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290890 0
Melbourne Health Human Research Ethics Committee
Ethics committee address [1] 290890 0
PO Royal Melbourne Hospital
Parkville Victoria 3050
Ethics committee country [1] 290890 0
Australia
Date submitted for ethics approval [1] 290890 0
Approval date [1] 290890 0
16/04/2014
Ethics approval number [1] 290890 0
HREC/13/MH/446

Summary
Brief summary
The aim of the study is to assess the safety and efficacy of chemotherapy treatment with a combination of erlotinib and vemurafenib in patients with BRAF V600E mutant colorectal and non-small lung cancer.

Who is it for?
You may be eligible to join this study if you aged 18 years or more and have a confirmed diagnosis of metastatic colorectal cancer or non-small cell lung cancer with a BRAF V600E mutation of your primary cancer or related metastases.

Study details:
There are two parts to this study. In the first part, participants with metastatic colorectal cancer will be treated with erlotinib and vemurafenib daily until disease progression or unacceptable toxicities. Both of these chemotherapy drugs are administered in tablet form and taken orally. The dose administered will be increased in subsequent patient groups in order to determine the maximum tolerated dose to be used in the second part of the study.

Patients with metastatic colorectal cancer or non-small cell lung cancer are eligible for the second part of the study. They will also be treated with oral erlotinib and vemurafenib daily until disease progression or unacceptable toxicities.

All participants will be regularly monitored and assessed for a period of up to 18 months in order to evaluate the safety and efficacy of treatment.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 47810 0
Dr Jayesh Desai
Address 47810 0
Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne VIC 3000
Country 47810 0
Australia
Phone 47810 0
+61 3 85595000
Fax 47810 0
Email 47810 0
jayesh.desai@petermac.org
Contact person for public queries
Name 47811 0
Dr Laura Galletta
Address 47811 0
Peter MacCallum Cancer Centre
Department of Biostatistics and Clinical Trials
305 Grattan St
Melbourne VIC 3000
Country 47811 0
Australia
Phone 47811 0
+61 3 85597532
Fax 47811 0
+61 3 8559 7539
Email 47811 0
laura.galletta@petermac.org
Contact person for scientific queries
Name 47812 0
Dr Jayesh Desai
Address 47812 0
Peter MacCallum Cancer Centre
305 Grattan St
Melbourne VIC 3000
Country 47812 0
Australia
Phone 47812 0
+61 3 8559 5000
Fax 47812 0
Email 47812 0
jayesh.desai@petermac.org