Treatment of advanced-stage malignancies harboring BRAF mutations with combination of Sorafenib and Trametinib: a multicenter study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Medical Center - University Of Freiburg

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

21 Oct 2020 → ongoing

Decision date (initial)

2024-10-07

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Bayer Vital GmbH · DKFZ (DKTK)

External identifiers

EU CT number

2024-512887-77-00

EudraCT number

2018-003237-16

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Safety, Efficacy, Therapy

Primary objective: is to determine the maximum tolerated dose (MTD) of
trametinib combined with sorafenib and the recommended phase II dose
(RP2D) for expansion part of the trial

Secondary objectives 1

1. Secondary objectives: • To further characterize safety and tolerability in the expansion part. • To give a preliminary estimate of efficacy of sorafenib and trametinib in advanced malignancies harboring a BRAF mutation with impaired BRAF kinase activity. • To characterize novel mutations with unknown BRAF activation status. • To demonstrate target inhibition in mutations with unknown BRAF activation status.

Conditions and MedDRA coding

advanced-stage malignancies harboring BRAF mutations with impaired kinase activity

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 1. Male or female patients aged ≥18 years without upper age limit;
2. 2. Metastatic malignancy
3. 3. Progression after standard treatment
4. 4. BRAF mutation with impaired kinase activity (according to Brummer laboratory at Medical Center – University of Freiburg)
5. 5. BRAF mutation with sensitivity to sorafenib in vitro (according to Brummer laboratory at Medical Center – University of Freiburg)
6. 6. At least one lesion that can be measured by CT, PET-CT, or MRI according to RECIST 1.1
7. 7. Adequate hepatic function with • AST and ALT < 3 ULN AND • Total bilirubin < 1.5 x ULN. Patient with Gilberts syndrome and in whom total bilirubin elevations are accompanied by elevated indirect bilirubin are eligible.
8. 8. Calculated creatinine clearance ≥ 50 mL/min by the Cockcroft-Gault- Equation
9. 9. Patient is able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
10. 10. Written informed consent obtained according to international guidelines and local laws
11. 11. Ability to understand the nature of the trial and the trial related procedures and to comply with them

Exclusion criteria 22

1. 1. Finding of a strongly activating BRAF mutation
2. 6. Uncontrolled bacterial, viral or fungal infection
3. 7. Radiation therapy, major surgery, other locoregional therapy, within 4 weeks prior to the first dose of study drug
4. 8. Serious cardiovascular disease (e.g. manifest heart failure, coronary heart disease, uncontrolled hypertension)
5. 9. Any serious disease interfering with a regular therapy according to the study protocol
6. 14. Ongoing interstitial lung disease or pneumonitis, which requires treatment/medication
7. 15. Known hypersensitivity to the active substances or any of the excipients
8. 16. Participation in any other interventional clinical trial within the last 30 days before the start of this trial; simultaneous participation in registry and diagnostic trials is allowed
9. 17. Patient without legal capacity who is unable to understand the nature, significance and consequences of the trial;
10. 18. Concurrent treatment with anticancer therapy (other than IMPs)
11. 19. Concomitant use of strong Cytochrome P450 3A4 inducers
12. 10. Patients who have received sorafenib in the past
13. 20. For female patient: current or planned pregnancy, nursing period
14. 21. Failure to use one of the following safe methods of contraception: hormonal contraception in combination with a mechanical method of contraception, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised partner, sexual abstinence
15. 11. Patient with a known history of aneurysms
16. 12. History of retinal vein occlusion (RVO)
17. 13. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression
18. 2. Life expectancy <3 months
19. 3. Patients with hepatocellular carcinoma (HCC) or hepatic cirrhosis
20. 4. Patient with ECOG >2
21. 5. Patients with known positivity for HIV, Hepatitis B or Hepatitis C at the time of screening
22. Treatment with therapeutic anticoagulation or dual platelets inhibition

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. MTD of trametinib given in combination with sorafenib

Secondary endpoints 1

1. Secondary endpoints: • Adverse (AEs), serious adverse events (SAEs) • Disease control rate (SD, PR or CR according to RECIST 1.1), best response during trial treatment) • Overall response rate (CR or PR according to RECIST 1.1) at the end of cycle 4 and cycle 7 • Overall survival from start of trial treatment • Translational parameter Exploratory endpoints: • Progression free survival ratio (PFSr)

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medical Center - University Of Freiburg

Sponsor organisation

Medical Center - University Of Freiburg

Address

Breisacher Strasse 153, Mooswald Mooswald

City

Freiburg Im Breisgau

Postcode

79110

Country

Germany

Scientific contact point

Organisation

Medical Center - University Of Freiburg

Contact name

Prod. Dr. Anna-Lena Illert

Public contact point

Organisation

Medical Center - University Of Freiburg

Contact name

ECTU

Locations

1 EU/EEA country · 10 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

Documents 7 files

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

Application history

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