Primary Objective: Phase I dose escalationThe main objective of the phase I part is to determine safety and the recommended phase II dose (RP2D) of the triple combination.Phase IIThe main objective of the phase II part is to determine efficacy of…
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Brief title
Condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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.
Secondary outcome
• 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.
Background summary
Patients with RAS-mutated metastatic colorectal cancer (mCRC) have a poorer
overall survival and less therapeutic options compared to patients with
RAS-wildtype mCRC. RAS-mutated (RASm) tumors are found to be resistant to
anti-EGFR therapy. A combination of MEK-inhibition and pan-EGFR inhibition was
evaluated in a phase I trial for patients with RASm mCRC to overcome this
resistance. This combination has proven to be safe, however limited responses
were seen, although active drug levels were reached in tumor tissue. Drug
screens performed on a range of patient-derived RASm organoids showed that the
MEK-pan-EGFR combination is cytostatic rather than cytotoxic, and addition of a
low dose of a Microtubule Targeting Agent (MTA) like vinorelbine resulted in
remarkable synthetic lethality. We propose that addition of an MTA to the
combination of the MEK-inhibitor binimetinib and the pan-EGFR-inhibitor
lapatinib will result in anti-tumor efficacy in patients with RASm mCRC.
Study objective
Primary Objective:
Phase I dose escalation
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.
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. To compare the serum concentration measurements with drug
concentration measurements in the biopsy after two weeks of treatment.
Exploratory objectives:
Exploratory pharmacodynamics (inhibition of downstream targets and apoptosis)
and the use of organoids as predictive biomarker will be assessed. 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).
Study design
This is a single-centre dose-escalating phase I/II trial evaluating the triplet
combination of the MEK-inhibitor binimetinib, the pan-EGFR-inhibitor lapatinib
with vinorelbine in RAS-mutated metastatic colorectal cancer. The trial
consists of a phase I dose-finding study (3 + 3 classical design) evaluating
the RP2D of the triplet and a phase II study evaluating response rate and
safety following a Simon*s two stage design. The patients from the phase I
trial treated at the MTD will be included in the phase II analysis. In total
between 47-50 patients will be included depending on the dose escalation.
Intervention
In the initial dose levels, a rest week schedule was tested to reach an
appropriate level for the three drugs with manageable side-effects. In later
dose levels, an every-week schedule is tested to optimize efficacy of the
therapy.
Rest week schedule:
Treatment cycles consist of 21 days. Lapatinib and binimetinib are administered
orally, respectively once and twice a day, in a 5 days on/2 days off schedule
in the first and second week of every cycle. Vinorelbine is given in a day 3
and day 10 schedule intravenously. The third week is a rest week.
Every-week schedule:
Treatment cycles consist of 21 days. Lapatinib and binimetinib are administered
orally, respectively once and twice a day, in a 5 days on/2 days off schedule
every week of every cycle. Vinorelbine is given in a day 3, day 10 and day 17
schedule intravenously.
Adapted every-week schedule:
Treatment cycles consist of 21 days. Lapatinib and binimetinib are administered
orally, respectively once and twice a day, in a 5 days on/2 days off schedule
every week of every cycle. Vinorelbine is given in a day 3 and day 10 schedule
intravenously.
Study burden and risks
The combination of drugs can cause adverse effects. During visits to the
hospital, the patient will be regularly examined. In addition, patients will
have to follow strict instructions on how to monitor their health and when to
call to the hospital.
The burden within this study is that these visits ask for a large time
investments and will require more tests and examinations than they would be
subjected to if they would follow a regular new treatment line.
Heidelberglaan 100
Utrecht 3584 CX
NL
Heidelberglaan 100
Utrecht 3584 CX
NL
Listed location countries
Age
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:
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)
Total bilirubin <= 1.5 x ULN
AST and ALT <= 2.5 x ULN or <= 5x ULN in case of liver metastases
Albumin >= 30.0 g/L
Lactate dehydrogenase <= 2x ULN
Serum creatinine <= 1.5 x ULN or Calculated creatinine clearance
by Cockcroft-Gault formula: >= 50 mL/min
Left Ventricular Ejection Fraction (LVEF) by ECHO or MUGA >= 50%
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 current congestive heart failure >= class II 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. (see paragraph 5.8.
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 | EUCTR2019-004987-23-NL |
| CCMO | NL72638.041.20 |