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

Malignant Melanoma Clinical Trial

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

Status Terminated

Clinical 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.

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)

Clinical Trial 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. ;

Related Conditions & MeSH terms

• Malignant Melanoma
• Melanoma

• NCT number: NCT02410863
• Study type: Interventional
• Source: University Hospital, Essen
• Status: Terminated
• Phase: Phase 2
• Start date: November 2015
• Completion date: August 2018