Neoadjuvant Encorafenib, Binimetinib and Cetuximab for Patients With BRAF V600E Mutated/pMMR Localized Colorectal Cancer

Studien-Informationen Einschlusskriterien Studien-Rationale Geprüfte Regime

Rekrutierend

NCT-Nummer:
NCT05510895

Studienbeginn:
September 2022

Letztes Update:
15.06.2023

Wirkstoff:
Binimetinib

Indikation (Clinical Trials):
Colorectal Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
AIO-Studien-gGmbH

Collaborator:
Pierre Fabre Pharma GmbH, Merck Serono GmbH, Germany, Universitätsklinikum Hamburg-Eppendorf,

Studienleiter

Alexander Stein, Prof. Dr.
Principal Investigator
Hämatologisch-Onkologische Praxis Eppendorf, 20249 Hamburg, Germany

Kontakt

Lea Maciolek
Kontakt:
Phone: +49 (0) 30 - 8145 344
Phone (ext.): 41
E-Mail: lea.maciolek@aio-studien-ggmbh.de» Kontaktdaten anzeigen

Katrin Krause
Kontakt:
Phone: +49 (0) 30 - 8145 344
Phone (ext.): 32
E-Mail: Katrin.Krause@aio-studien-ggmbh.de» Kontaktdaten anzeigen

Studienlocations
(1 von 1)

Hämatologisch-Onkologische Praxis Eppendorf
20249 Hamburg
(Hamburg)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Alexander Stein, Prof. Dr.» Ansprechpartner anzeigen

Studien-Informationen

Detailed Description:

This is a single arm, multicenter, phase II trial for patients with unresected BRAF V600E

mutated/pMMR localized colorectal cancer (CRC). Patients enrolled will be treated with

neoadjuvant encorafenib (300mg QD), binimetinib (45mg BID) and cetuximab (500mg/m² biweekly)

for 8 weeks. Neoadjuvant treatment will be followed by surgery. First Endpoint is TRG

(Tumor-Regression-Grade) which will be analyzed centrally. Patients with TRG>1 will receive

adjuvant treatment with encorafenib (300mg QD), binimetinib (45mg BID) and cetuximab

(500mg/m² biweekly) for up to 16 weeks. For patients with TRG<2 EOT will be reached 4-6 weeks

after last dosage of encorafenib, binimetinib and cetuximab and further treatment is at

investigator discretion (CAPOX recommended). All subjects will be followed every 3 months

after surgery for up to 4 years after start of recruitment.

Ein-/Ausschlusskriterien

Inclusion Criteria:

1. Biopsy-confirmed adenocarcinoma of the colon or upper rectum if too high for

radiotherapy.

2. Radiologically (CT/MRI) staged disease as: T3-4 (as invasion of surrounding tissue

structures or organs) and/or nodal positive (N+ defined as regional lymph node(s)

without fat hilus and short axis diameter of ≥1 cm), M0.

3. BRAF V600E mutation and pMMR or MSS (as determined by a validated test, preferably PCR

or NGS).

4. ECOG performance status ≤ 1.

5. Age ≥ 18 years.

6. Adequate hematologic function at screening as follows:

ANC ≥ 1.5 x 109/L, platelets ≥ 100 x109/L, hemoglobin ≥ 9.0 g/dL.

7. Adequate liver function at screening as measured by serum transaminases (AST & ALT) ≤

2.5 x ULN and total bilirubin ≤ 1.5 x ULN. Patients with known Gilbert disease who

have serum bilirubin level ≤ 3 × ULN may be enrolled.

8. Adequate renal function at screening: serum creatinine ≤ 1.5 x ULN.

9. Adequate serum electrolytes at screening defined as serum potassium and magnesium

levels within institutional normal limits (Note: replacement treatment to achieve

adequate electrolytes will be allowed.

10. Adequate cardiac function at screening characterized by left ventricular ejection

fraction (LVEF) ≥ 50% as determined by ECHO and QT interval corrected for heart rate

using Fridericia's formula (QTcF) value ≤ 480 msec.

11. Negative serum pregnancy test at screening for women of childbearing potential.

12. Highly effective contraception for both male and female subjects if the risk of

conception exists. (Note: The effects of the trial drugs on the developing human fetus

are unknown; thus, women of childbearing potential and men able to father a child must

agree to use highly effective contraception, defined as methods with a failure rate of

less than 1 % per year, containing at least 1 form of non-hormonal contraception.

Highly effective contraception is required at least 28 days prior, throughout and for

at least 6 months after interventional study treatment (encorafenib, binimetinib and

cetuximab).

13. Signed and dated written informed consent.

14. Ability to take oral medication.

15. Ability to comply with the protocol for the duration of the study, including

hospital/office visits for treatment and scheduled follow-up visits and examinations.

Exclusion Criteria:

1. Any prior systemic therapy, surgery or radiotherapy of the colorectal cancer disease.

2. History or current evidence of retinal vein occlusion (RVO) or current risk factors

for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity

or hypercoagulability syndromes).

3. Malignancies other than disease under study within 5 years prior to inclusion, with

the exception of those with a negligible risk of metastasis or death (e.g., expected

5-year OS >90%) treated with expected curative outcome (such as adequately treated

carcinoma in situ of the cervix, localized prostate cancer treated surgically with

curative intent, ductal carcinoma in situ treated surgically with curative intent).

4. Known severe hypersensitivity reactions to monoclonal antibodies or

BRAF-/MEK-inhibitors (grade ≥ 3 NCI-CTCAE v 5), any history of anaphylaxis, or

uncontrolled asthma (that is, 3 or more features of partially controlled asthma).

5. Pregnancy or lactation.

6. Known alcohol or drug abuse.

7. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular

accident/stroke (≤ 6 months prior to enrolment); myocardial infarction (≤ 6 months

prior to enrolment), acute coronary syndromes [including unstable angina, coronary

artery bypass graft (CABG), coronary angioplasty or stenting) ≤ 6 months prior to

enrolment]; congestive heart failure (≥New York Heart Association Classification Class

II); or history or current evidence of clinically significant arrhythmia and/or

conduction abnormality (≤ 6 months prior to enrolment), except rate controlled atrial

fibrillation and paroxysmal supraventricular tachycardia.

8. Uncontrolled hypertension defined as persistent elevation of systolic blood pressure ≥

150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy.

9. Preexisting interstitial lung disease.

10. Impaired GI function or disease that may significantly alter the absorption of

encorafenib or binimetinib (e.g., ulcerative diseases, uncontrolled vomiting,

malabsorption syndrome, small bowel resection with decreased intestinal absorption).

11. History of thromboembolic or cerebrovascular events ≤ 6 months prior to enrolment,

including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis

or pulmonary emboli.

12. Concurrent neuromuscular disorder that is associated with the potential of elevated CK

(e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis,

spinal muscular atrophy).

13. Known human immunodeficiency virus (HIV) infection or active hepatitis B or C

infection.

14. All other significant diseases, which, in the opinion of the Investigator, might

impair the subject's tolerance of trial treatment.

15. Any psychiatric condition that would prohibit the understanding or rendering of

informed consent.

16. Any approved anticancer therapy, including chemotherapy, hormonal therapy or

radiotherapy, within 5 half-lives or 4 weeks (the longer period applies) prior to

initiation of study treatment.

17. Current treatment with a non-topical medication or current intake of herbal

preparations / supplements / foods known to be a strong inhibitor of CYP3A4. However,

patients who either discontinue such treatment/intake or switch to another medication

at least 7 days prior to starting study treatment are eligible.

18. Concomitant use of St. John's Wort (hypericum perforatum).

Studien-Rationale

Primary outcome:

1. Tumor regression grade (TRG) (Time Frame - immediately after the surgery):
Tumor regression will be centrally graded according to the grading system developed by Dworak et al (Dworak, Keilholz et al. 1997).

Secondary outcome:

1. Safety and tolerability (acc. to NCI CTC AE v5.0) incl. vital signs, clinical parameters and overall feasibility of the regimen (Time Frame - max 54 months):
Safety assessments will include physical examinations including visual and skin assessment as well as vital signs (blood pressure, heart rate, respiratory rate), performance status (ECOG), clinical laboratory profile, 12-lead ECG and ECHO, ophthalmologic assessment, concomitant medication/therapies/procedures and adverse events. All observed adverse events will be graded according to NCI CTCAE v5. Adverse events will be analysed overall and concerning their potential relationship to study treatment and surgical intervention. Serious adverse events (SAE) will be analysed in the same way.

2. Perioperative morbidity and mortality (Time Frame - max 24 months):
Perioperative morbidity and mortality are defined as prolongation of hospitalization (discharge >20 days after surgery), re-hospitalization or reoperation under general anaesthesia within 30 days of surgery or death during surgery or within 30 days of surgery; Other severe postoperative complications within 30 days of surgery including surgery-associated bleeding with replacement ≥ 4 units of erythrocyte concentrates, transient liver failure, defined as a bilirubin level >10 mg/dL lasting > 7 days, renal failure requiring dialysis, respiratory failure with renewed necessary mechanical ventilation or >26 h, necessary mechanical ventilation, deep venous thromboembolism, cardiac failure, major impaired wound healing necessitating re-operation or prolonging hospitalization (discharge >20 days after surgery); >8 weeks delay of surgery due to study treatment-related toxicity; and further.

3. R0-resection rate (Time Frame - max 24 months):
The R0 resection rate will be determined as the rate of R0 resections out of all resected patients. In addition, the R1 and/or R2 resection rates will be determined.

4. Overall Response Rate (ORR) according to RECIST v1.1 (Time Frame - max 54 months):
Response rate to preoperative treatment will be assessed according to RECIST v1.1.

5. Disease free survival (Time Frame - max 54 months):
Disease free survival will be determined as time from start of study treatment to date of first observed disease recurrence (either local or distant) or death from any cause.

6. Overall survival (OS) (Time Frame - max 54 months):
Overall survival will be determined as time from start of study treatment to date of death from any cause.

7. Translational research 1 (Time Frame - max 54 months):
Correlation of quantitative BRAF V600E levels (measured by ddPCR) with TRG

8. Translational research 2 (Time Frame - max 54 months):
Evaluation of mechanism of relative resistance in patients with less response (evaluated by tumor and liquid biopsy NGS profiling at baseline and after treatment)

9. Translational research 3 (Time Frame - max 54 months):
Comparison of ctDNA clearance and TRG with a BRAF mutant/pMMR cohort from the planned neoadjuvant PROTECTOR study receiving neoadjuvant chemotherapy

Geprüfte Regime

Binimetinib (Encorafenib / Cetuximab / ):
Triplet combination administered neoadjuvant and adjuvant, depending on TRG

Quelle: ClinicalTrials.gov

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