| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| colorectal cancer |
| colorectaal carcinoom |
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| E.1.1.1 | Medical condition in easily understood language |
| colorectal cancer |
| dikkedarmkanker |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase I
The main objective of the phase I part is to determine safety and the recommended phase II dose (RP2D) of the triple combination.
Phase II
The main objective of the phase II part is to determine efficacy of the triplet combination defined by objective response rate according to RECIST 1.1.
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| E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
Phase I dose escalation
- To describe safety and tolerability of the triplet combination
- To describe the pharmacokinetic profile of vinorelbine, lapatinib and binimetinib.
Phase II
- To describe safety and tolerability of the triplet combination
- To evaluate additional antitumor activity parameters including clinical benefit rate and progression-free survival.
- To describe the pharmacokinetic profile of vinorelbine, lapatinib and binimetinib.
Exploratory objectives:
Exploratory pharmacodynamics (inhibition of downstream targets and apoptosis) and the use of organoids as predictive biomarker will be assessed.
Intratumoral drug levels will be compared with pharmacokinetics.
Furthermore a sub study will be performed on the correlation between cardiotoxicity (LVEF decline) and the release of cardiac biomarkers. Finally, blood samples will be stored to allow the analyses of additional biomarkers including circulating tumor DNA (ctDNA). |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histological or cytological proof of CRC.
2. After failure of a minimum of 2 lines of standard of care regimens. Prior lines of treatment must include: a minimum of 2 lines of prior systemic treatment for metastatic disease, including at least fluoropyrimidine, oxaliplatin and irinotecan based treatment (unless contra-indications for either oxaliplatin and/or irinotecan). Adjuvant treatment completed < 6 months before development of metastatic disease will be counted as 1st line for metastatic disease.
3. Written documentation of a known pathogenic RAS mutation.
4. Age 18 years.
5. Able and willing to give written informed consent.
6. Measurable disease according to RECIST 1.1
7. WHO performance status of 0 or 1.
8. Able to swallow and retain orally administered medications and does not have clinically significant gastrointestinal abnormalities that may alter absorption (e.g. malabsorption syndrome, ileostomy or major resection of the stomach or bowel)
9. Able and willing to undergo blood sampling.
10. Able and willing to undergo a tumor biopsy prior to start and after two weeks on therapy. Tumor biopsy should be histological. Cytological biopsies are not accepted.
11. All toxicities related to prior treatment should have resolved to CTCAE grade 1 or less (excluding alopecia)
12. Life expectancy 3 months allowing adequate follow up of toxicity evaluation and antitumor activity.
13. Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to registration and agree to use effective contraception, throughout the treatment period, and for 4 months after the last dose of study treatment.
14. Adequate organ functions as defined by table 2.
Table 2 Definitions for adequate baseline organ function
Absolute neutrophil count ≥ 1.5 x 109/L
Hemoglobin ≥ 6.0 mmol/L
Platelets ≥ 100 x 109/L
PT/INR and aPTT within normal limits (unless anti-coagulant treatment)
Hepatic:
Total bilirubin ≤ 1.5 x ULN
AST and ALT ≤ 2.5 x ULN
Albumin ≥ 30.0 g/L
Lactate dehydrogenase ≤ 2x ULN
Renal:
Serum creatinine ≤ 1.5 x ULN
Or Calculated creatinine clearance
by Cockcroft-Gault formula: ≥ 50 mL/min
Cardiac:
Left Ventricular Ejection Fraction (LVEF) by ECHO or MUGA ≥ 50%
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| E.4 | Principal exclusion criteria |
1. Any treatment with investigational drugs within 30 days or 5 half-lives prior to receiving the first dose of investigational treatment.
2. History of another malignancy. Exceptions: Patients who have been disease-free for at least 3 years after treatment with curative intent, or patients with a history of completely resected non-melanoma skin cancer, in situ carcinoma of the cervix and/or patients with indolent completely resected second malignancies are eligible.
3. Symptomatic or untreated leptomeningeal disease.
4. Symptomatic brain metastases. Patients previously treated or untreated for these conditions that are asymptomatic in the absence of corticosteroid and anticonvulsant therapy (for at least 6 weeks) are allowed to enrol. Radiotherapy for brain metastases 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 anti-epileptic drugs or corticosteroids.
5. Patients previously treated with combination treatment of drugs known to interfere with EGFR, HER-2, HER-3, HER-4, or MAPK- and PI3K-pathway components, including inhibitors of PTEN, PI3K, AKT, mTOR, BRAF, MEK, and ERK. Single agent targeted therapies interfering with these pathways are allowed for inclusion in phase I.
Exclusion criteria in phase II: patients previously treated with drugs known to interfere with EGFR, HER-2, HER-3, HER-4, or MAPK- and PI3K-pathway components, including inhibitors of PTEN, PI3K, AKT, mTOR, BRAF, MEK, and ERK, both as single agent or in combination.
6. History of interstitial lung disease or pneumonitis
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 3 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 known, active, hepatitis B (HBV) or C virus (HCV).
13. Patients with retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), or with a history of uveitis, retinal vein occlusion, central serous retinopathy, or retinal detachment.
14. Patients with left ventricular ejection fraction (LVEF) < 50%.
15. History or evidence of cardiovascular risk including any of the following:
• A QT interval corrected for heart rate using the Bazett’s formula (QTcB; Appendix X) 480 msec;
• History or evidence of current clinically significant uncontrolled arrhythmias. Exception: Subjects with controlled atrial fibrillation for >30 days prior to randomization are eligible.
• History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization.
• History of or evidence of current congestive heart failure ≥ Class class II congestive heart failure as defined by the New York Heart Association.
• Treatment refractory hypertension defined as a blood pressure of systolic > 150 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by one maximally dosed anti-hypertensive therapy;
• Patients with intra-cardiac defibrillators;
16. 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.
17. Known hypersensitivity to one of the study drugs.
18. Use of any live vaccines against infectious diseases (e.g. varicella, pneumococcus or yellow fever) within 4 weeks of initiation of study treatment.
19. Use of prohibited co-medication or herbs and inability to discontinue this treatment or switch to an alternative drug at least 7 days prior to starting study treatment.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
For the phase I dose-escalation trial:
The primary endpoint is the incidence of DLTs leading to a RP2D. The RP2D of the triplet will be the MTD which is defined as the dose level that can be given to 6 subjects such that not more than 1 subject experiences a DLT.
For the phase II trial:
The primary endpoint is best overall response (OR), defined as complete response (CR) + partial response (PR) within 6 months, based on RECIST 1.1.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- evaluation of DLTs during first cycle (= 21 days)
- determining respons based on CT-scans every 6 weeks. |
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| E.5.2 | Secondary end point(s) |
Secondary study endpoints
• Safety and tolerability assessed by:
o Incidence and severity of adverse events (AEs) graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0
o Incidence of dose interruptions, dose modifications and discontinuations due to AEs
• The pharmacokinetic (PK) profile of vinorelbine, lapatinib and binimetinib.
• Clinical benefit, defined as CR + PR + stable disease (SD) for at least 6 months.
• Progression-free survival (PFS), defined as the time from the date of randomization until the date of the investigator-assessed radiological disease progression (RECIST 1.1) or death due to any cause.
Exploratory endpoints
The following exploratory endpoints will be evaluated:
• Predictive value of organoid cultures at baseline for response to therapy.
• To explore the pharmacodynamics (PD) profile of the lapatinib-binimetinib-vinorelbine combination as measured by expression levels of downstream targets (e.g. pERK, pMEK) and markers of apoptosis (e.g. caspase-3) in tumor tissue taken prior to treatment, while on treatment and upon progression.
• To correlate the PK with the PD and response.
• To evaluate the treatment response in different clinical subgroups including different types of RASmutation and left versus right sided primary tumors.
• To correlate cardiac biomarkers with the occurrence of a decline in LVEF
• Circulating biomarkers may be measured, including but not limited to ctDNA in order to predict response/resistance, investigate the mechanisms of resistance by evaluating the development of novel mutations in the ctDNA.
• To compare intratumoral drug levels after two weeks of treatments with pharmacokinetic measurements. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- evaluation of adverse events, continuous
- determining respons and progression-free survival based on CT-scans every 6 weeks.
- determining the pharmacokinetic profile in the first week of administration
- determining the pharmacodynamics based on tumor and skin biopsies obtained at baseline and on cycle 1 day 12.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| evaluation of a novel combination of drugs |
| onderzoek van een nieuwe combinatie van geneesmiddelen |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| last visit last subject |
| laatste visite van de laatste patient |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 36 |
| E.8.9.1 | In the Member State concerned days | |
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