A dose-esalation phase I/II study in patients with RAS-mutated metastatic colorectal cancer to investigate safety and clinical actvitiy of the triple combination of: MEK-inhibitor binimetinib, pan-EGFR inhibitor lapatinib and the microtubule targeting agent (MTA) vinorelbine (RASTRIC)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitair Medisch Centrum Utrecht

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

31 Jul 2020 → 17 Feb 2025

Decision date (initial)

2024-09-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-509732-25-00

EudraCT number

2019-004987-23

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Pharmacodynamic, Dose response, Efficacy, Safety

Phase I dose escalation: To determine safety and the recommended phase II dose (RP2D) of the triple combination.
Phase II: To determine efficacy of the triplet combination defined by objective response rate according to RECIST 1.1.

Conditions and MedDRA coding

metastatic colorectal cancer with a proven RAS mutation after failure of standard systemic treatment regimens including at least 5- FU/capecitabine-oxaliplatin and irinotecan based standard treatment (unless contra-indications for either oxaliplatin or irinotecan)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

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, major resection of the stomach or bowel, or ileostomy)
9. Able and willing to undergo blood sampling
10. Able and willing to undergo a tumor and skin 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 System Laboratory Values Hematologic 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 anticoagulant treatment or patient unable to undergo tumor biopsy) Hepatic Total bilirubin ≤ 1.5 x ULN AST and ALT ≤ 2.5 x ULN or ≤ 5x ULN in case of liver metastases Albumin ≥ 30.0 General 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%

Exclusion criteria 19

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 nonmelanoma 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 enroll. 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, RAS, 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) > 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)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. 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
2. For the phase II trial the primary endpoint is objective response rate according to RECIST 1.1

Secondary endpoints 1

1. the pharmacokinetic profile of the triple combination, safety and tolerability (frequencies of AEs, dose reductions) and additional anti-tumor efficacy parameters including clinical benefit rate and progression-free survival

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitair Medisch Centrum Utrecht

Sponsor organisation

Universitair Medisch Centrum Utrecht

Address

Heidelberglaan 100

City

Utrecht

Postcode

3584 CX

Country

Netherlands

Scientific contact point

Organisation

Universitair Medisch Centrum Utrecht

Contact name

Jeanine Roodhart

Public contact point

Organisation

Universitair Medisch Centrum Utrecht

Contact name

Jeanine Roodhart

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications