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Vinorelbine in Advanced BRAF-like Colon Cancer (EORTC1616)

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ClinicalTrials.gov Identifier: NCT03482362
Recruitment Status : Recruiting
First Posted : March 29, 2018
Last Update Posted : August 27, 2018
Sponsor:
Collaborators:
Vall d'Hebron Institute of Oncology
Agendia
European Organisation for Research and Treatment of Cancer - EORTC
Azienda Ospedaliera Niguarda Cà Granda
Fundación para la Investigación del Hospital Clínico de Valencia
University of Campania "Luigi Vanvitelli"
University of Turin, Italy
Eli Lilly and Company
Catalan Institute of Health
Universitaire Ziekenhuizen Leuven
Information provided by (Responsible Party):
The Netherlands Cancer Institute

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.


Condition or disease Intervention/treatment Phase
Colon Cancer Drug: Vinorelbine Tartrate Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 82 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This is a two-stage, single-arm, multi-center, open-label, two-cohort, clinical, phase II, proof of principal study.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: MoTriColor: A Phase II Study of Vinorelbine in Advanced BRAF-like Colon Cancer
Actual Study Start Date : March 1, 2018
Estimated Primary Completion Date : December 1, 2019
Estimated Study Completion Date : March 1, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cohort A; KRASmt, BRAFwt, BRAF-like CC
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
Intravenous administration of vinorelbine on day 1 and day 8 in a dose of 30 mg/m2. One treatment cycle is 21 days.
Other Names:
  • Navelbine
  • Vinorelbine

Experimental: Cohort B; KRASwt, BRAFmt, BRAF-like CC
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
Intravenous administration of vinorelbine on day 1 and day 8 in a dose of 30 mg/m2. One treatment cycle is 21 days.
Other Names:
  • Navelbine
  • Vinorelbine




Primary Outcome Measures :
  1. Doubling of progression free survival [ Time Frame: 15 months ]
    This means that by vinorelbine treatment the rate of progression drops to 25%.


Secondary Outcome Measures :
  1. Incidence and severity of adverse events [ Time Frame: 15 months ]
  2. Overall response rate [ Time Frame: 15 months ]
  3. Duration of response [ Time Frame: 15 months ]
  4. Time to response [ Time Frame: 15 months ]
  5. Overall survival [ Time Frame: 15 months ]
  6. Baseline molecular status (mutation/ expression) in tumor tissue of potential predictive markers of tumor response [ Time Frame: 15 months ]
    The molecular status will be measured by NGS and IHC in tumor tissue.

  7. Gene alterations/expression profiles (i.e. baseline, relapse) in tumor tissue upon progression [ Time Frame: 15 months ]
    The molecular status will be measured by NGS and IHC in tumor tissue.


Other Outcome Measures:
  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. [ Time Frame: 15 months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Written informed consent for this clinical trial (+ 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 at least one or two lines of standard of care therapy, including BRAF inhibitors, for advanced disease
  6. WHO performance status of 0-1
  7. Able and willing to undergo blood sampling for pharmacodynamic (PD) analysis;
  8. Able and willing to undergo tumor biopsy prior to, during and upon treatment;
  9. Life expectancy > 3 months allowing adequate follow up of toxicity evaluation and antitumor activity
  10. Minimal acceptable safety laboratory values:

    1. ANC > 1.5 x 109 /L
    2. Platelet count > 100 x 109 /L
    3. Hemoglobin > 6.0 mmol/L
    4. 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
    5. Renal function as defined by serum creatinine < 1.5 x ULN
    6. creatinine clearance > 50 ml/min (by Cockcroft-Gault formula)
  11. Negative urine or serum pregnancy test (serum or urine) 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 (<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.
  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. Radio-, immuno- or chemotherapy within the last 4 weeks prior to receiving the first dose of investigational treatment. Palliative radiation (1x 8Gy) is allowed

10. 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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03482362


Contacts
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Contact: N Steeghs, MD, PhD +31(0)20-5129111 n.steeghs@nki.nl
Contact: Sanne Huijberts, MD +31(0)20-5129111 s.huijberts@nki.nl

Locations
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Netherlands
Antoni van Leeuwenhoek Recruiting
Amsterdam, Noord-Holland, Netherlands, 1066 CX
Contact: Sanne Huijberts, MD    +312051291111    s.huijberts@nki.nl   
Contact: N Steeghs, MD, PhD    +312051291111    n.steeghs@nki.nl   
Sponsors and Collaborators
The Netherlands Cancer Institute
Vall d'Hebron Institute of Oncology
Agendia
European Organisation for Research and Treatment of Cancer - EORTC
Azienda Ospedaliera Niguarda Cà Granda
Fundación para la Investigación del Hospital Clínico de Valencia
University of Campania "Luigi Vanvitelli"
University of Turin, Italy
Eli Lilly and Company
Catalan Institute of Health
Universitaire Ziekenhuizen Leuven
Investigators
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Principal Investigator: 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 INCLIVA
Principal Investigator: F Ciardiello, Prof INCLIVA
Principal Investigator: A Bardelli, Prof UNITO
Principal Investigator: S Tejpar, Prof UZ Leuven

Additional Information:
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Responsible Party: The Netherlands Cancer Institute
ClinicalTrials.gov Identifier: NCT03482362     History of Changes
Other Study ID Numbers: M16VIB
First Posted: March 29, 2018    Key Record Dates
Last Update Posted: August 27, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by The Netherlands Cancer Institute:
vinorelbine
Additional relevant MeSH terms:
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Colonic Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Colonic Diseases
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Vinorelbine
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action