None listed
Conditions
Brief summary
The purpose of this study is to look at the safety, tolerability and effectiveness of the combination of three drugs cetuximab, cobimetinib and palbociclib in patients with advanced or metastatic colorectal cancer with certain mutations, who have not responded to standard therapies. Who is it for? You may be eligible to join this study if you are aged 18 years and above, and have been diagnosed with advanced or metastatic colorectal cancer which has tumour expression of BRAF or KRAS mutations, and you have not responded to available standard therapies. Study details All participants in this study will receive cetuximab, cobimetinib and palbociclib. This study will have 2 stages: Phase 1 and Phase 2. In Phase 1, there will be up to 6 groups of participants. Each group receives different dosages of each drug. Cetuximab will be given intravenously once a week, while cobimetinib and palbociclib will be given orally once a day for 21 consecutive days for at least two 28-day cycles. In Phase 2, all participants will receive the same dose of cetuximab, cobimetinib and palbociclib; with the dose being determined by results from Phase 1. Cetuximab will be given intravenously once a week, while cobimetinib and palbociclib will be given orally once a day for 21 consecutive days for at least two 28-day cycles. Participants will be monitored for side effects, disease response and survival. Blood tests, physical exams, eye exams, electrocardiograms and CT scans may be performed at various timepoints including pre-treatment screening and Days 1, 4, 8, 15 and 22 of each 28-day cycle. It is hoped this trial will provide information on the safety and effectiveness of the proposed combination drug therapy in treating advanced or metastatic colorectal cancer, and be an option for patients who have not responded to current therapies.
Interventions
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
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.
Sponsors
Cothera Bioscience Pty ltd
Study design
Allocation
Non-randomised trial
Intervention model
Other
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
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
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
Outcome results
None listed