To determine the anti-tumor activity, as defined as doubling of progression free survival (PFS) of vinorelbine treatment in patients with BRAF-like colon cancer.
ID
Source
Brief title
Condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy, as defined as doubling of progression free survival (PFS) of
vinorelbine treatment in patients with BRAF-like colon cancer. This means that
by vinorelbine treatment the rate of progression at 6 weeks drops to 25%.
Secondary outcome
* To characterize the safety and tolerability of vinorelbine, as assessed by
the incidence and severity of adverse events.
* To assess efficacy of vinorelbine, as measured by overall response rate,
duration of response, time to response and overall survival (OS).
* To compare the activity of vinorelbine in patients with KRAS mutant, BRAF
wildtype, BRAF-like colon cancer vs. KRAS wildtype, BRAF mutant, BRAF-like
colon cancer.
* To explore determinants (gene alteration/expression) of response to
vinorelbine, as measured by baseline molecular status (mutation/ expression) in
tumor tissue of potential predictive markers of tumor response.
* To explore the potential mechanism of resistance to vinorelbine, as measured
by gene alterations/expression profiles (i.e. baseline, relapse) in tumor
tissue upon progression.
Background summary
Approximately 8-10% of colon cancer (CC) patients carry an activating mutation
in BRAF. This CC subtype is associated with poor outcome and with resistance,
both to current chemotherapeutic treatments and to tailored drugs.
Popovici et al.and Sun et al. showed that BRAF (V600E) colon cancers (CCs) have
a characteristic gene expression signature which is found also in subsets of
KRAS mutant (30%) and KRAS-BRAF wild type (18%) (WT2) tumors. Tumors having
this gene signature are referred to as *BRAF-like* and have a similar poor
prognosis irrespective of the presence of BRAF(V600E) mutation.
By using a lentiviral-based short hairpin RNA (shRNA) approach targeting the
genes belonging to the BRAF signature Vecchione et al identified RANBP2 to be
straight lethal with BRAF V600E gene mutation in a panel of colorectal cancer
(CRC) cell lines. RANBP2 is implicated in mitotic spindle formation, chromosome
segregation, mitotic progression and kinetochore function. In particular,
RANBP2 depletion induces abnormal chromosomal segregation, improper mitotic
progression and mitotic catastrophe. Vecchione et al showed that suppression of
RANBP2 results in mitotic defects only in BRAF-like CC cells, which leads to
cell death. Mechanistically, RANBP2 silencing reduces microtubule outgrowth
from the kinetochores, thereby inducing spindle perturbations, providing an
explanation for the observed mitotic defects.
Vinorelbine prevents the microtubule polymerization, thus by inducing loss of
dynamic stability and lack of normal microtubule function, it leads to cell
death following prolonged mitotic arrest.
In particular, the preclinical work shows BRAF V600E and BRAF-like CRC cell
lines to be 10-100000-fold more sensitive to vinorelbine than wild type CC cell
lines. Moreover, this exquisite sensitivity of BRAF-like CC cell lines to
vinorelbine is not related to an increased proliferation rate since the
proliferation rate of BRAF-like CC cell lines is not significantly different
from that of non-BRAF-like cell lines and importantly, BRAF(V600E) CC cells
lines have an IC50 for vinorelbine that is similar to that of breast and lung
cancer cell lines, two solid tumors for which vinorelbine is used in clinical
practice.
These preclinical data represent a strong rationale to also explore the
anti-tumor activity of vinorelbine in patients with advanced BRAF-like (both
BRAFm and BRAF wild type) CC. Since vinorelbine is standard of care in advanced
breast and NSCLC, there is ample experience with the dose and schedule as well
as with the safety profile and supportive measures required to prevent
side-effects.
In 2017 new clinical data were published regarding the efficacy of vinorelbine
in BRAFV600E mutated metastatic colorectal cancer. In a multicenter, phase II
trial in Italy a small group of 20 patients was treated with vinorelbine and
the primary endpoint was objective response rate. No responses were observed,
only one patient revealed stable disease. (4) Based on this new results two
cohorts will be explored in the current clinical trial in which BRAF-like
BRAFmt or BRAF-like KRASmt colorectal cancer patients will be enrolled and
treated with vinorelbine. These 2 cohorts will have the same primary endpoint,
namely progression free survival at 6 weeks, and will be compared in this
study.
Study objective
To determine the anti-tumor activity, as defined as doubling of progression
free survival (PFS) of vinorelbine treatment in patients with BRAF-like colon
cancer.
Study design
Two-stage double arm multi-center open-label phase II study with 40 patients
with BRAF-like CC treated with vinorelbine 30 mg/m2 day 1, 8, Q day 21.
Study burden and risks
- Blood will be drawn for pharmacokinetic, pharmacodynamic and pharmacogenetic
research
- Tumor biopsies will be taken pre-, upon and at end of treatment for
histological analyses of biomarkers, genetics and immune infiltration
- Patients will be asked to keep a diary and note daily what they ate and when
they took the medication.
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
1. Written informed consent (+ TR (translational research)) must be given according to ICH/GCP and national/local regulations
2. Written documentation of BRAF-like signature CC, including BRAFm and BRAFwt, as determined by the validated assay of Agendia
3. written documentation of KRAS and BRAF mutational status
4. Age * 18 years
5. Histologically proven and measurable (RECIST criteria v.1.1) metastatic adenocarcinoma of the colon not in a previously irradiated area, treated with one or two lines of standard of care therapy, including BRAF inhibitors, for locally advanced disease and metastatic disease
6. WHO performance status of 0-1
7.Life expectancy > 3 months allowing adequate follow up of toxicity evaluation and antitumor activity
8. Negative urine pregnancy test for female patients with childbearing potential
Exclusion criteria
1. Any treatment with investigational drugs, including BRAF inhibitors, within 28 days prior to receiving the first dose of investigational treatment
2. Symptomatic or untreated leptomeningeal disease;3. Symptomatic brain metastasis. Patients previously treated or untreated for these conditions that are asymptomatic in the absence of corticosteroid and anticonvulsant therapy (for at least 4 weeks) are allowed to enroll. Radiotherapy for brain metastasis must have been completed at least 6 weeks prior to start of study treatment. Brain metastasis must be stable with verification by imaging (e.g. brain MRI or CT completed at screening demonstrating no current evidence of progressive brain metastases). Patients are not permitted to receive enzyme inducing anti-epileptic drugs or corticosteroids;4. Impairment of gastrointestinal (GI) function or GI disease (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, any condition inducing malabsorption, small bowel resection);5. Other uncontrolled concomitant illness, including serious uncontrolled intercurrent infection;6. Known allergy or any other adverse reaction to any of the drugs or to any related compound;7. Women who are pregnant or breast feeding;8. Unreliable contraceptive methods. Both men and women enrolled in this trial must agree to use a reliable contraceptive method throughout the study (adequate contraceptive methods are: condom, sterilization, other barrier contraceptive measures preferably in combination with condoms);9. Patients who have undergone any major surgery within the last 2 weeks prior to starting study drug or who would not have fully recovered from previous surgery;10. Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients;11. Patients with a known history of hepatitis B or C;12. Known hypersensitivity to study drug or excipients
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-002364-13-NL |
| CCMO | NL59133.031.16 |