Vinorelbine in Advanced BRAF-like Colon Cancer

NCT03482362 | Completed Phase 2 DMC

• 1 other identifier: M16VIB
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

Brief Summary

Vecchione et al showed that suppression of RANBP2 results in mitotic defects only in BRAF-like colon cancer (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 mimics RANPB2 silencing in BRAF-like and BRAFV600E CC cell lines. 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. 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. 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.

Conditions

Colon Cancer

Keywords

vinorelbine

Outcome Measures

Primary Outcomes (1)

• Doubling of progression free survival

  This means that by vinorelbine treatment the rate of progression drops to 25%.

  15 months

Secondary Outcomes (7)

• Incidence and severity of adverse events

  15 months

• Overall response rate

  15 months

• Duration of response

  15 months

• Time to response

  15 months

• Overall survival

  15 months

Other Outcomes (1)

• Overall response rate of vinorelbine in patients with KRAS mutant, BRAF wildtype, BRAF-like colon cancer vs. KRAS wildtype, BRAF mutant, BRAF-like colon cancer.

  15 months

Study Arms (2)

Cohort A; KRASmt, BRAFwt, BRAF-like CC

EXPERIMENTAL

Patients with KRAS mutant and BRAF wildtype colon cancer that met the BRAF-like signature according to the validated test of Agendia will be treated with vinorelbine tartrate.

Drug: Vinorelbine Tartrate

Cohort B; KRASwt, BRAFmt, BRAF-like CC

EXPERIMENTAL

Patients with KRAS wildtype and BRAF mutant colon cancer that met the BRAF-like signature according to the validated test of Agendia will be treated with vinorelbine tartrate.

Drug: Vinorelbine Tartrate

Interventions

Vinorelbine Tartrate DRUG

Intravenous administration of vinorelbine on day 1 and day 8 in a dose of 30 mg/m2. One treatment cycle is 21 days.

Also known as: Navelbine, Vinorelbine

Cohort A; KRASmt, BRAFwt, BRAF-like CC; Cohort B; KRASwt, BRAFmt, BRAF-like CC

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent for this clinical trial (+ TR (translational research)) must be given according to ICH/GCP and national/local regulations
• Written documentation of BRAF-like signature CC, including BRAFm and BRAFwt, as determined by the validated assay of Agendia
• Written documentation of KRAS and BRAF mutational status.
• Age \> 18 years
• Histologically proven and measurable (RECIST criteria v.1.1) metastatic adenocarcinoma of the colon not in a previously irradiated area, treated with at least one or two lines of standard of care therapy, including BRAF inhibitors, for advanced disease
• WHO performance status of 0-1
• Able and willing to undergo blood sampling for pharmacodynamic (PD) analysis;
• Able and willing to undergo tumor biopsy prior to, during and upon treatment;
• Life expectancy \> 3 months allowing adequate follow up of toxicity evaluation and antitumor activity
• Minimal acceptable safety laboratory values:
• ANC \> 1.5 x 109 /L
• Platelet count \> 100 x 109 /L
• Hemoglobin \> 6.0 mmol/L
• Hepatic function as defined by serum bilirubin \< 1.5 x ULN, ALAT and ASAT \< 2.5 x ULN, or ALAT and ASAT \< 5 x ULN in patients with liver metastases
• Renal function as defined by serum creatinine \< 1.5 x ULN

You may not qualify if:

• Any treatment with investigational drugs, including BRAF inhibitors, within 28 days prior to receiving the first dose of investigational treatment
• Symptomatic or untreated leptomeningeal disease
• 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 (\<21 days before start of treatment) demonstrating no current evidence of progressive brain metastases). Patients are not permitted to receive enzyme inducing anti-epileptic drugs or corticosteroids.
• Impairment of gastrointestinal (GI) function or GI disease (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, any condition inducing malabsorption, small bowel resection)
• Other uncontrolled concomitant illness, including serious uncontrolled intercurrent infection
• Known allergy or any other adverse reaction to any of the drugs or to any related compound
• Women who are pregnant or breast feeding
• 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. Radio-, immuno- or chemotherapy within the last 4 weeks prior to receiving the first dose of investigational treatment. Palliative radiation (1x 8Gy) is allowed
• \. 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 11. Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients 12. Patients with a known history of hepatitis B or C 13. Patients with cardiac comorbidities (myocardial infarct within 6 months of study start, NYHA class ≥ III, congestive heart failure or instable angina pectoris), uncontrolled hypertension (systolic blood pressure \> 150 mm Hg and/or diastolic pressure \> 90 mm Hg) or prolonged QT-interval (\> 440 ms for men, \> 460 ms for women) 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 that may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for the study 15. Known hypersensitivity to study drug or excipients

Sponsors & Collaborators

• The Netherlands Cancer Institute: lead
• Vall d'Hebron Institute of Oncology: collaborator
• Agendia: collaborator
• European Organisation for Research and Treatment of Cancer - EORTC: collaborator
• Azienda Ospedaliera Niguarda Cà Granda: collaborator
• Fundación para la Investigación del Hospital Clínico de Valencia: collaborator
• University of Campania Luigi Vanvitelli: collaborator
• University of Turin, Italy: collaborator
• Eli Lilly and Company: collaborator
• Catalan Institute of Health: collaborator
• Universitaire Ziekenhuizen KU Leuven: collaborator

Study Sites (1)

Antoni van Leeuwenhoek

Amsterdam, North Holland, 1066 CX, Netherlands

Location

Related Links

• general information

MeSH Terms

Conditions

Colonic Neoplasms

Interventions

Vinorelbine

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines

Study Officials

• N Steeghs, MD, PhD

  NKI-AvL

  PRINCIPAL INVESTIGATOR

• J Tabernero, Prof

  VHIO

  PRINCIPAL INVESTIGATOR

• R Salazar, MD, PhD

  ICO

  PRINCIPAL INVESTIGATOR

• R Bernards, Prof

  Agendia

  PRINCIPAL INVESTIGATOR

• S Siena, Prof

  ONCG

  PRINCIPAL INVESTIGATOR

• A Cervantes, Prof

  Instituto de Investigacion Sanitaria INCLIVA

  PRINCIPAL INVESTIGATOR

• F Ciardiello, Prof

  Instituto de Investigacion Sanitaria INCLIVA

  PRINCIPAL INVESTIGATOR

• A Bardelli, Prof

  UNITO

  PRINCIPAL INVESTIGATOR

• S Tejpar, Prof

  UZ Leuven

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a two-stage, single-arm, multi-center, open-label, two-cohort, clinical, phase II, proof of principal study.

Study Record Dates

• First Submitted: March 13, 2018
• First Posted: March 29, 2018
• Study Start: March 1, 2018
• Primary Completion: March 17, 2020
• Study Completion: March 17, 2020
• Last Updated: August 3, 2025

Record last verified: 2018-08

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)