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Malignant MelanomaPhase 2BOTTOMNCT02410863

Biopsy- and Biology-driven Optimization of Targeted Therapy in Subjects With Advanced Melanoma

A Phase 2 study testing Dabrafenib and Trametinib in people with Malignant Melanoma, run by Prof. Dr. med. Dirk Schadendorf at 6 sites in Germany.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

This is an open-label, multi-center, clinical phase II study to explore the correlation of the genetic make-up of the treated tumor before start of therapy and to correlate clinical response at 8 weeks as well as metabolic response at 2 and 8 weeks with genetic features of the tumor. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Malignant Melanoma
What is being tested?
Dabrafenib and Trametinib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
10 participants
Where
6 sitesGermany
Study dates
Nov 2015to Aug 2018
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • ≥ 18 years of age.
  • Signed written informed consent.
  • Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive by the central laboratory. Subjects with ocular or mucosal melanoma are not eligible.
  • Assessable lesion for biopsy at week 2 not inferring with RECIST measurements (Biopsies for genetic/biomarker analyses must be taken from lesions not required for disease assessment)
  • Measurable disease, i.e., present with at least one measurable lesion per RECIST, version 1.1 for the definition of a measureable lesion.
  • For Cohort A: Must NOT have received prior treatment with BRAF or MEK inhibitor.
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  • If a prior systemic therapy (such as but not limited to chemotherapy, immunotherapy, biologic, vaccine and/or investigational treatment) in metastatic disease has been administered, four weeks or more since last systemic treatment must have passed. Must have recovered from any acute toxicity associated with prior therapy.
  • For Cohort B: Must have shown PR/CR during treatment with selective BRAF/MEK combination treatment that was discontinued due to tumor progression and received subsequent alternative treatment (such as but not limited to surgery, chemotherapy, immunotherapy, biologic, vaccine and/or investigational treatment), with a period of at least 3 months since last intake of BRAF/MEK inhibitor
  • All prior treatment-related toxicities (except alopecia) must be ≤ Grade 1 according to the Common Terminology Criteria of Adverse Events (CTCAE, Version 9. Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
  • 10. Women of childbearing potential must have a negative urin pregnancy test within 7 days prior to registration and agree to use effective contraception, as defined in Section 9.8 throughout the treatment period, and for 4 months after the last dose of study treatment.
  • Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception as described in Section 9.8 throughout the treatment period, and for 4 months after the last dose of study treatment. 11. An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 12. Adequate baseline organ function defined as Absolute Neutrophil Count ≥1.2 × 109/L Hemoglobin ≥ 9 g/dL Platelet count ≥ 100 x 109/L Prothrombinzeit (PT/INR) and Partial thromboplastin time ≤ 1.3 x upper laboratory norm (ULN) Albumin ≥ 2.5 g/dL Total bilirubin ≤ 1.5 x ULN Aspartate aminotransferase and Alanine Aminotransferase ≤ 2.5 x ULN Serum creatinine ≤ 1.5 mg/dL 13. A left ventricular ejection fraction (LVEF) ≥ the institutional lower limit of normal as measured by ECHO

Who cannot join

  • Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to registration and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to registration.
  • Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to registration.
  • Current use of a prohibited medication
  • History of another malignancy. Exception: Subjects who have been disease-free for 3 years, subjects with a history of completely resected non-melanoma skin cancer, and/or subjects with successfully treated in situ carcinoma are eligible. Subjects with second malignancies that are indolent or definitively treated may be enrolled.
  • Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the subject's safety, obtaining informed consent, or compliance with study procedures.
  • Known Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV), or active Hepatitis C Virus (HCV). Subjects with chronic or cleared HBV and/or HCV are eligible.
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  • A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.
  • Subjects with brain metastases are excluded, unless:
  • All known lesions must be previously treated with surgery or stereotactic radiosurgery, and
  • Brain lesion(s), if present, must be confirmed stable (ie, no increase in lesion size) for 90 days prior to first dose of study drug(s). This must be documented with two consecutive MRI or CT scans using contrast, and
  • Asymptomatic with no corticosteroids requirement for 30 days prior to first dose of study drug(s), and
  • No enzyme-inducing anticonvulsants for 30 days prior to first dose of study drug(s).
  • In addition, even in cases of no evidence of disease (NED), confirmation on two consecutive MRI or CT scans using contrast will be required. Enrollment of a subject with brain metastases who meet the above criteria requires approval of the sponsor
  • A history or evidence of cardiovascular risk including any of the following:
  • A QT interval corrected for heart rate using the Bazett's formula (QTcB; ³ 480 msec;
  • A history or evidence of current clinically significant uncontrolled arrhythmias; Exception: Subjects with controlled atrial fibrillation for > 30 days prior to registration are eligible.
  • A history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to registration; or
  • A history or evidence of current ≥ Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines.
  • A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including:
  • Presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes); or
  • Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO or CSR such as:
  • Evidence of new optic disc cupping; ii. Evidence of new visual field defects on automated perimetry; iii. Intraocular pressure > 21 mmHg as measured by tonography.
  • Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO).
  • Interstitial lung disease or pneumonitis
  • Pregnant or breast-feeding females.

Trial locations and contacts

6 sites in 1 country.

6 sites in 1 country

Germany6 sites

  • Elbe Kliniken Stade - Buxtehude GmbH, Clinic for Dermatology

    Buxtehude, Lower Saxony, 21614

  • Universitätsklinik Carl Gustav Carus der Technischen Universität Dresden

    Dresden, Saxony, 01307

  • University Hospital Essen

    Essen, North Rhine-Westphalia, 45147

  • National Centre for Tumour Diseases (NCT)

    Heidelberg, Baden-Wurttemberg, 69120

  • University Hospital Mainz, Clinic for Dermatology

    Mainz, Rhineland-Palatinate, 55131

  • University Hospital Tübingen

    Tübingen, Baden-Wurttemberg, 72076

Other trials in Germany

About this study

Official title: Biopsy- and Biology-driven Optimization of Targeted Therapy of Metastatic Melanoma in BRAF Inhibitor Non-pretreated and Pretreated Subjects With Advanced, Non-resectable (STAGE IIIC) or Metastatic (StAGE IV) BRAF Mutation-positive Melanoma

This is an open-label, multi-center, clinical phase II study to explore the correlation of the genetic make-up of the treated tumor before start of therapy and to correlate clinical response at 8 weeks as well as metabolic response at 2 and 8 weeks with genetic features of the tumor.

It will be conducted as a rationale optimization of targeted therapy in BRAF naïve and pretreated patients.

Prerequisite for all patients is the availability of tumor sample at start of treatment in order to determine the underlying driver mutation (BRAF mutational status) as well as molecular composition by next generation sequencing (NGS) and assessable lesions for biopsy at week 2. Melanoma patients in stage III (non-resectable) and stage IV are sorted into Cohort A or B according to their previous BRAF-treatment and treated with dabrafenib and trametinib (cohort A and B)

Read the detailed description

In this open-label, multi-center, clinical phase II study melanoma patients in stage III (non-resectable) and stage IV are sorted into Cohort A or B according to their previous BRAF-treatment:

Cohort A (BRAFi naïve): Patients who have not received prior BRAFi or MEKi-therapy. Dabrafenib (BRAFi) and trametinib (MEKi) will be administered orally at their recommended doses for combination therapy of 150 mg twice daily (BID) and 2 mg daily (QD). Clinical endpoint is clinical response at week 8. Metabolic response will be assessed at week 2 and 8. Treatment will continue until disease progression, death, unacceptable toxicity, or withdrawal of consent.

Cohort B (BRAFi / MEKi rechallenge): Patients with CR/PR as best response to previous BRAFi / MEKi combination therapy, discontinuation of this therapy after progression and different therapy for > 3 months prior to enrollment.

These patients will receive dabrafenib and trametinib at their recommended combination therapy doses of 150 mg twice daily (BID) and 2 mg daily (QD).

Treatment will continue until disease progression, death, unacceptable toxicity, or withdrawal of consent.

Survival will be assessed every 3 months after the final dose of BRAFi / MEKi until the end of the follow-up phase for the individual patient.

Follow up phase for each subject is 1 year following first treatment dose. End of study will be at recruitment finished plus 1 year post start of treatment of last patient thus ensuring that 1 year survival rate can be estimated.

Biopsies taken before start of treatment, after 2 weeks (+/- 4 days) and after progressive disease will be analyzed by Next generation sequencing (NGS), immunohistochemistry (IHC), phosphorplex Luminex as well as by reverse phase protein array in order to determine the magnitude of suppression of downstream signaling as well as reactivation of adaptative mechanisms.

Rebiopsy is mandatory after 2 weeks and in case of progressive disease in order to determine mechanisms of adaptation of the signaling pathway downstream.

The experimental molecular data will be analyzed in correlation with clinical response at week 8 (defined as partial or complete response according to RECIST) and metabolic responses at weeks 2 and 8 (responders are defined as those patients with changes of >66% in the Standard Uptake value (SUVmax) between interim PET and baseline PET.

Being tested
Dabrafenib, Trametinib
Keywords
Stage III or IV with BRAF V600E/K mutation
Medical subject headings
Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DabrafenibDrug

    Also called Tafinlar

    150 mg twice daily

  • TrametinibDrug

    Also called Mekinist

    2 mg daily

Study groups in NCT02410863
Study groupRoleWhat they receive
Cohort A (BRAFi naïve)ExperimentalDabrafenib (BRAFi) and trametinib (MEKi) will be administered orally at their recommended doses for combination therapy of 150 mg twice daily (BID) and 2 mg daily.
Receives: Drug: Dabrafenib; Drug: Trametinib
Cohort B (BRAFi / MEKi rechallenge)ExperimentalDabrafenib (BRAFi) and trametinib (MEKi) will be administered orally at their recommended doses for combination therapy of 150 mg twice daily (BID) and 2 mg daily
Receives: Drug: Dabrafenib; Drug: Trametinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Correlation of clinical response at week 8 of targeted therapy with molecular results of the biopsies.

    To broaden the understanding of molecular characterization of the melanoma in correlation to the clinical response (defined as partial or complete response according to RECIST) at week 8 of targeted therapy in different pre-treated patients with advanced/metastatic BRAF V600E/K mutation-positive cutaneous melanoma.

    Measured: Week 8

Secondary outcomes (7)

  1. Correlation of the tumor´s molecular composition to metabolic responses

    To correlate the tumor´s molecular composition to metabolic responses and biological effects on the downstream signaling cascade in order to get first insights into an adaptive mechanism in the downstream signaling of an oncogenic driver mutation upon its selective inhibition.

    Measured: Baseline, week 2 and 8

  2. Safety / toxicity according to the Common Toxicity Criteria (CTC, Version 4.0)

    Occurrence of adverse events and reactions

    Measured: 1 year

  3. Progression free survival rate

    Proportion of patients with PFS after date of the first dose of study medication until the first documented tumor progression date or date of death, whichever occurs first.

    Measured: 6 and 12 months

  4. Overall survival

    Time after date of the first dose of study medication until documented date of death

    Measured: 6 and 12 months

  5. Progression free survival according to RECIST criteria

    Time after date of the first dose of study medication until the first documented tumor progression date or date of death, whichever occurs

    Measured: 6 and 12 months

  6. Overall response rate according to RECIST criteria

    Proportion of patients with PR and CR

    Measured: 6 and 12 months

  7. Disease control rate according to RECIST criteria

    Proportion of patients with SD, PR and CR

    Measured: 6 and 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Apr 2015 (estimated)
  2. Study startNov 2015
  3. Primary completionAug 2018
  4. Study completionAug 2018

Why it stopped: lack of recruitment due to changed therapy options

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
10 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02410863
Sponsor's protocol ID
Bottom_2012
Acronym
BOTTOM
Status last verified
Oct 2020
First submitted
2 Apr 2015
Last updated
14 Oct 2020
Results posted
No
Data monitoring committee
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Dabrafenib and Trametinib in people with Malignant Melanoma, run by Prof. Dr. med. Dirk Schadendorf at 6 sites in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 14 Oct 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: lack of recruitment due to changed therapy options). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Correlation of clinical response at week 8 of targeted therapy with molecular results of the biopsies. (time frame: Week 8). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02410863.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Oct 2020.

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