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Trial registered on ANZCTR


Registration number
ACTRN12621001436864
Ethics application status
Approved
Date submitted
13/08/2021
Date registered
25/10/2021
Date last updated
22/08/2022
Date data sharing statement initially provided
25/10/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A study of a new combination of drugs (cetuximab, cobimetinib and palbociclib) in subjects with advanced or metastatic colorectal cancer who have failed all available standard therapies
Scientific title
A two-part open label Phase 1/2 study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of the combination of cetuximab, cobimetinib and palbociclib in subjects with K-RAS wild-type BRAF V600E mutated, or K-RAS mutated, advanced or metastatic colorectal cancer who have failed all available standard therapies
Secondary ID [1] 304963 0
CTB-02-01
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Colorectal Cancer 323111 0
Condition category
Condition code
Cancer 320725 320725 0 0
Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Combination treatment using cetuximab, cobimetinib and palbociclib.
This is a two part open label study using escalating doses of these drugs.
Phase 1 will enroll 3-6 patients in one of 6 Cohorts, for dose escalation.
The initial dose escalation will start at cetuximab 150mg/m2 intravenously (IV) + cobimetinib 20 mg orally once daily (po qd) + palbociclib 50mg orally once daily (po qd), for Cohort 1.

Cohort 2 = cetuximab 150mg/m2 IV + cobimetinib 20 mg po qd + palbociclib 75mg po qd.
Cohort 3 = cetuximab 150mg/m2 IV + cobimetinib 40 mg po qd + palbociclib 75mg po qd.
Cohort 4 = cetuximab 150mg/m2 IV + cobimetinib 60 mg po qd + palbociclib 75mg po qd.
Cohort 5 = cetuximab 200mg/m2 IV + cobimetinib 60 mg po qd + palbociclib 75mg po qd.
Cohort 6 = cetuximab 250mg/m2 IV + cobimetinib 60 mg po qd + palbociclib 100mg po qd.

Cetuximab will be administered weekly via intravenous infusion.
Cobimetinib will be taken orally once daily for the first 21 consecutive days in a 28 day treatment cycle. Cobimetinib will be taken in tablet form.
Palbociclib will be taken orally once daily for first 21 consecutive days in a 28 day treatment cycle. Palbociclib will be taken in capsule form.
Neither of these two drugs will be given in the last 7 days of this 28 day cycle.

Cohorts of 3 patients will be enrolled at each dose level (with the option of up to six patients for each cohort if necessary) to assess toxicity. Each patient will participate in only one cohort to determine dose limiting toxicities of the combination. Patients at each dose level will be treated and observed through the end of the first cycle before treatment of subjects at the next higher dose level can begin.
Cohorts 1 to 6 will randomly assign consecutive patients to each new cohort until between 3 and 6 patients have been enrolled in that cohort and treated and observed through the end of the first cycle before treatment of patients at the next higher dose. Dose limiting toxicities (DLTs) will be observed during this time. If no more than one patient out of six has experienced a DLT during the first cycle of treatment, dose escalation to the next higher dose level may occur.

Each patient will receive at least two cycles of treatment. Additional cycles may be administered at the doctor's discretion and providing the treatment is tolerated with no evidence of DLT. Treatment may continue until disease progression, at the doctor's discretion.

The patient will be required to present to the clinic weekly for the intravenous infusions. All oral medications will be given to the patient to take at home, recording on a patient diary when the doses were taken or if they were missed and why. All oral medication and diaries will be returned to clinic for review to assess compliance.

Phase 1 is a dose finding study using escalation doses in a classical 3+3 design. Phase 2 is an expansion study using the maximum tolerated dose from phase 1.

Phase 2 of the study will use the combination of three drugs (CTB-02) to evaluate the clinical activity and safety profile of the three drug combination at the best tolerated dose assessed from the Phase 1 portion of the study.
All elements of the Phase 2 will be the same as Phase 1 with regard to frequency, number of cycles, duration of cycles etc. Phase 2 patients, as with Phase 1, can continue until disease progression.

Participants will be able to enroll in either phase 1 or phase 2. Each patient will participate in one cohort only.
Intervention code [1] 321387 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 328545 0
Phase 1: Determination of Dose Limiting Toxicity (DLT). A DLT will be defined using the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) v 5.0
Timepoint [1] 328545 0
Phase 1 DLTs will be assessed during the first cycle of treatment (28 days) and are events that are considered possiby related to the study drug combination for each cohort. After the treatment of each cohort, data will be reviewed to assess patient status and study drug related toxicities from the current cohort before deciding the escalation plan and dose level for the next cohort.
Primary outcome [2] 329201 0
Phase 2: Determination of Objective Response Rate as determined by MRI scanning with RECIST criteria reporting
Timepoint [2] 329201 0
Phase 2: patients will be reviewed for objective response rate after at least 2 treatment cycles
Secondary outcome [1] 399370 0
To assess pharmacokinetics of the study drug triplet combination during Phase 1 portion of study. Parameters to be assessed will include maximum concentration (Cmax), time of maximum observed concentration (Tmax) and steady state concentration measured before the next dose of study drug (C trough)
Timepoint [1] 399370 0
PK blood draws will occur on Day 1 and Day 22 of Cycle 1 and Day 1 of Cycle 2. PK will be drawn pre dose and 1, 2, 4 and 6 hours post dose after the IV infusion of cetuximab.

Eligibility
Key inclusion criteria
* Males or females aged 18 years and older.
* Signed informed consent. 
* Histologically or cytologically confirmed advanced or metastatic colorectal cancer that is refactory to all available standard therapies
* Tumor expression of BRAF V600E mutation or KRAS mutation
* Females postmenopausal or willing to use effective birth control
* Males patients must use effective birth control
* Females with a negative pregnancy test at Screening 
* Have stopped previous anticancer therapy for at least 3 weeks or 5 half lives prior to Screening
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Concomitant anticancer therapy, systemic immune therapy, hormonal therapy, nontraditional and/or herbal therapy as cancer therapy.
* Unresolved NCI CTCAE (v5.0) greater than or equal to Grade 2 toxicity from any prior anticancer therapy
* Symptomatic brain metastases
* History of known spinal cord cell compression or carcinomatous meningitis
* Pregnant or actively breastfeeding.
* Active hepatitis B or hepatitis C infection
* Known history of HIV infection
* Documented malignancies other than CRC within 3 years prior
* Clinically significant cardiac disease
* Signs or symptoms of organ failure, major chronic illnesses other than cancer
* Treatment with medications known to be strong CYP3A4 inhibitors within 7 days prior to Day 1 of treatment or CYP3A4 inducers within 14 days prior to Day 1 of treatment.
* Previous history of keratitis, ulcerative keratitis or severe form of dry eye
* Known pre-existing interstitial lung disease
* History of or evidence of retinal pathology
* Treatment with another investigational drug, or investigational device within 30 days before dosing

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)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
All participants will receive the same combination of treatments just in escalating doses per cohort
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety
Statistical methods / analysis
Phase 1 will enroll between 18 and 36 patients and Phase 2 will enroll approximately 60 patients. These sample sizes have been based on clinical experience.
Study data will be analysed by ITT (intention to treat), Safety evaluable set (to include all subjects who received at least on dose) and Per Protocol.
Two sided 95% confidence intervals will be provided for the means and percentages as needed.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
The study was terminated due to a business decision by the sponsor to consider alternative triplet therapies.
Date of first participant enrolment
Anticipated
6/12/2021
Actual
10/12/2021
Date of last participant enrolment
Anticipated
11/12/2023
Actual
22/03/2022
Date of last data collection
Anticipated
19/03/2024
Actual
27/07/2022
Sample size
Target
96
Accrual to date
Final
3
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 20175 0
Calvary Mater Newcastle - Waratah
Recruitment postcode(s) [1] 34905 0
2298 - Waratah

Funding & Sponsors
Funding source category [1] 309350 0
Commercial sector/Industry
Name [1] 309350 0
Cothera Bioscience Pty Ltd
Country [1] 309350 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Cothera Bioscience Pty ltd
Address
c/- Seed Outsourcing
Suite 6, Level 7
122 Arthur St
North Sydney NSW 2060
Country
Australia
Secondary sponsor category [1] 310315 0
None
Name [1] 310315 0
Address [1] 310315 0
Country [1] 310315 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309167 0
Bellberry Limited
Ethics committee address [1] 309167 0
Ethics committee country [1] 309167 0
Australia
Date submitted for ethics approval [1] 309167 0
11/08/2021
Approval date [1] 309167 0
19/08/2021
Ethics approval number [1] 309167 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 113214 0
Dr James Lynam
Address 113214 0
Calvary Mater Newcastle
Platt Street
Waratah NSW 2298
Country 113214 0
Australia
Phone 113214 0
+61 2 4014 3558
Fax 113214 0
Email 113214 0
james.lynam@calvarymater.org.au
Contact person for public queries
Name 113215 0
Taylor Kilfoil
Address 113215 0
InClin Pty Ltd Suite 210, 25/29 Berry Street, North Sydney, NSW, 2060
Country 113215 0
Australia
Phone 113215 0
+61 408 880 403
Fax 113215 0
Email 113215 0
taylor.kilfoil@inclin.com
Contact person for scientific queries
Name 113216 0
Georgina Kilfoil
Address 113216 0
Cothera Bioscience Pty Ltd
Suite 6, Level 7
122 Arthur St
North Sydney NSW 2060
Country 113216 0
Australia
Phone 113216 0
+61 432 388 772
Fax 113216 0
Email 113216 0
georgina@ashcroftlsc.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Only aggregate participant data will be available from this study.


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.