Trial document




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  DRKS00015849

Trial Description

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Title



Cross-institutional, prospective, open label, single group basket study of combined
CRAF and MEK inhibition in advanced-stage malignancies harboring BRAF mutations
with impaired kinase activity

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Trial Acronym

SORATRAM

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URL of the Trial

[---]*

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Brief Summary in Lay Language

The study is designed for patients with an advanced tumor disease in whom a specific genetic change, a mutation in the BRAF gene, has been identified during further testing of tumor tissue samples.
The protein product of this gene is, among other things, part of a communication and signaling pathway in our cells (the so-called MAP kinase pathway), which is involved in the normal growth and survival of cells. Mutations in this gene can cause this signaling pathway to become overactive, which can accelerate tumor growth. Other mutations can lead to the signaling pathway being inactivated or restricted. In this case, the tumour cell switches on a bypass pathway (CRAF). This is done by activating another protein product (RAS), which can also accelerate the growth of the cancer cells.
BRAF is mutated in approximately one in 10 tumor patients (8%). There are already drugs available that specifically inhibit the overactivation (so-called BRAF inhibitors); these are approved, for example, for patients with black skin cancer or certain forms of lung cancer.
In every 4th to 5th patient with a BRAF mutation, however, there is no overactivity; the biological function of the protein molecule is either restricted or unknown here.
For this case of BRAF hypofunction and activation of the alternative pathway CRAF, there are still no approved effective drugs. Studies on tumor cells suggest that patients with corresponding BRAF mutations may benefit from combined treatment with a CRAF inhibitor and an inhibitor of MEK (also part of the MAP kinase signaling pathway).
The drug sorafenib inhibits CRAF and has shown some efficacy in laboratory tests alone. This effect could be further enhanced by additional MEK inhibition with the drug trametinib in laboratory trials. First case reports of so-called individualized healing trials on patients support this hypothesis.
The rationale for this clinical trial for therapy with sorafenib combined with trametinib is based on the findings available to date to test the tolerability and efficacy of this combined therapeutic approach.



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Brief Summary in Scientific Language

BRAF mutations are found in 7-8% of solid tumors. In 25% of cases, these mutations impair or inactivate the BRAF kinase. In these patients, BRAF leads to paradoxical CRAF activation and BRAF inhibitors are not active. These cases constitute an unmet medical need. Our previous work demonstrates that a combination of CRAF (sorafenib) and MEK (trametinib) inhibitors suppresses downstream MEK and ERK activation in vitro in cell lines expressing BRAF variants with impaired kinase activity. Treatment of a patient with metastatic melanoma harboring an inactivating BRAFD594G mutation with sorafenib and trametinib was tolerated well and led to a clinical and radiographic response lasting for 6 months. We thus propose that the combination of CRAF and MEK inhibition might offer a promising treatment strategy in patients with advanced solid tumors carrying BRAF mutations with impaired kinase activity. This multicenter prospective project is intended to demonstrate feasibility, safety and a first proof of concept that sorafenib in combination with trametinib is clinically active in advanced malignancies with BRAF mutations with impaired kinase activity. We will initiate a prospective multicenter phase I trial at all nine DKTK partner sites to evaluate the safety of trametinib in increasing doses in combination with of sorafenib in advanced malignancies with BRAF mutations impairing BRAF kinase activity.

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Do you plan to share individual participant data with other researchers?

Yes

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Description IPD sharing plan:

All patients will be informed about DKTK (german Cancer Consortium) MASTER program and only after their written consent
to this program BRAF mutations will be characterized and the patients for the clinical trial
identified. The data will be passed on to the Master program database in pseudonymised form. The centers involved in the DKTK and their researchers can use thiis pseudonymised data for scientific questions and evaluations without the data being merged using a pseudonym.

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Organizational Data

  •   DRKS00015849
  •   2020/08/28
  •   [---]*
  •   yes
  •   Approved
  •   564/19, Ethik-Kommission der Albert-Ludwigs-Universität Freiburg
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Secondary IDs

  •   2018-003237-16 
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Health Condition or Problem studied

  •   Malignancies harboring BRAF mutations with impaired kinase activity
  •   Solid tumors
  •   D03 -  Melanoma in situ
  •   C43 -  Malignant melanoma of skin
  •   C26 -  Malignant neoplasm of other and ill-defined digestive organs
  •   C73 -  Malignant neoplasm of thyroid gland
  •   C50 -  Malignant neoplasm of breast
  •   C56 -  Malignant neoplasm of ovary
  •   C16 -  Malignant neoplasm of stomach
  •   C44 -  Other malignant neoplasms of skin
  •   C24 -  Malignant neoplasm of other and unspecified parts of biliary tract
  •   C22 -  Malignant neoplasm of liver and intrahepatic bile ducts
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Interventions/Observational Groups

  •   Dosing Schedule:
    Dose allocation takes place upon registration in the study for the entire duration of max. 12 cycles or until relapse/progression,
    unacceptable toxicity, death , whatever occurs first.
    Dose Level 1: Trametinib 0.5 mg/d po in combination with sorafenib 600mg/d p.o.
    Dose level 1 (start): Trametinib 0.5 mg/d p.o. in combination with sorafenib 800mg/d p.o.
    Dose level 2: Trametinib 1.0 mg/d p.o. in combination with sorafenib 800mg/d p.o.
    Dose level 3: Trametinib 1.5 mg/d p.o. in combination with sorafenib 800mg/d p.o.
    After determination of the recommended phase II dose (RP2D) for expansion part of the trial for the duration of max. 12 cycles or until relapse/progression, unacceptable toxicity, death , whatever occurs first.
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Characteristics

  •   Interventional
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  •   Single arm study
  •   Open (masking not used)
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  •   Uncontrolled/Single arm
  •   Treatment
  •   Single (group)
  •   I
  •   Yes
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Primary Outcome

Determination of the maximum tolerated dose (MTD) of trametinib in combination with sorafenib and the recommended Phase II dose (RP2D) for the extension part of the study

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Secondary Outcome

- Characterization of safety and compatibility in the extension part.
- To provide a preliminary estimate of the efficacy of sorafenib and trametinib in advanced malignant diseases involving a BRAF mutation with impaired BRAF kinase activity
- Characterization of novel mutations with unknown BRAF activation status.
- To demonstrate target inhibition in mutations with unknown BRAF activation status.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Actual
  •   2020/12/15
  •   30
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

1. Male or female patients aged ≥18 years without upper age limit;
2. Metastatic malignancy
3. Patients must have received standard therapy or have no standard therapy available. Or, in the opinion of investigator have been considered ineligible for a particular form of standard therapy on medical grounds.
4. BRAF mutation with impaired kinase activity (according to Brummer laboratory at Medical Center – University of Freiburg)
5. BRAF mutation with sensitivity to sorafenib in vitro (according to Brummer laboratory at Medical Center – University of Freiburg)
6. At least one lesion that can be measured by CT, PET-CT, or MRI according to RECIST 1.1
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. Calculated creatinine clearance ≥ 50 mL/min by the Cockcroft-Gault-Equation
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. Written informed consent obtained according to international guidelines and local laws
11. Ability to understand the nature of the trial and the trial related procedures and to comply with them

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Exclusion Criteria

1. Finding of a strongly activating BRAF mutation (according to Brummer laboratory at Medical Center – University of Freiburg)
2. Life expectancy <3 months
3. Patients with hepatocellular carcinoma (HCC) or hepatic cirrhosis
4. Patient with ECOG >2
5. Patients with known positivity for HIV, Hepatitis B or Hepatitis C at the time of screening
6. Uncontrolled bacterial, viral or fungal infection
7. Radiation therapy, major surgery, other locoregional therapy, within 4 weeks prior to the first dose of study drug
8. Serious cardiovascular disease (e.g. manifest heart failure, coronary heart disease, uncontrolled hypertension)
9. Any serious disease interfering with a regular therapy according to the study protocol
10. Patients who have received sorafenib in the past
11. Patient with a known history of aneurysms
12. History of retinal vein occlusion (RVO)
13. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression
14. History of interstitial lung disease or pneumonitis
15. Known hypersensitivity to the active substances or any of the excipients
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
17. Patient without legal capacity who is unable to understand the nature, significance and consequences of the trial;
18. Concurrent treatment with anticancer therapy (other than IMPs)
19. Concomitant use of strong Cytochrome P450 3A4 inducers
20. For female patient: current or planned pregnancy, nursing period
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

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Addresses

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    • Universitätsklinikum FreiburgKlinik für Innere Medizin IHämatologie, Onkologie und StammzelltransplantationHugstetter Str. 55 · 79106 Freiburg
    • Hugstetter Str. 55
    • 79106  Freiburg
    • Germany
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    • Deutschen Krebsforschungszentrum, Stiftung des öffentlichen Rechts
    • DKFZ 
    • Neuenheimer Feld 280
    • 69210  Heidelberg
    • Germany
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    • UNIVERSITÄTSKLINIKUM FREIBURGKlinik für Innere Medizin I Schwerpunkt Hämatologie, Onkologie und Stammzelltransplantation
    • Ms.  PD Dr.  Lena  Illert 
    • Hugstetter Straße 55
    • 79106  Freiburg
    • Germany
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    • UNIVERSITÄTSKLINIKUM FREIBURGKlinik für Innere Medizin I Schwerpunkt Hämatologie, Onkologie und Stammzelltransplantation
    • Ms.  PD Dr.  Lena  Illert 
    • Hugstetter Straße 55
    • 79106  Freiburg
    • Germany
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Sources of Monetary or Material Support

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    • Deutschen Krebsforschungszentrum, Stiftung des öffentlichen Rechts
    • DKFZ 
    • Neuenheimer Feld 280
    • 69210  Heidelberg
    • Germany
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

  •   Initiales Votum CEC
  •   CTP V1.1
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* This entry means the parameter is not applicable or has not been set.