Ignite Creation Date:
2024-05-06 @ 8:55 AM
Last Modification Date:
2024-10-26 @ 12:07 PM
Study NCT ID:
NCT02858921
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2023-08-30
First Post:
2016-07-16
Brief Title:
Neoadjuvant Dabrafenib Trametinib andor Pembrolizumab in BRAF Mutant Resectable Stage III Melanoma
Sponsor:
Melanoma Institute Australia
Organization:
Melanoma Institute Australia
Study Overview
Official Title:
A Phase II Randomised Open Label Study of Neoadjuvant Dabrafenib Trametinib and or Pembrolizumab in BRAF V600 Mutant Resectable Stage IIIBC Melanoma
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2023-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
Neo Trio
Brief Summary:
This study aims to determine which of 3 drug combinations best reduces the size of tumour prior to surgery for advanced melanoma and prevents the recurrence of melanoma after surgery
Detailed Description:
The new drug options for advanced melanoma include oncogene-targeted therapy such as dabrafenib trametinib and vemurafenib and immune checkpoint blockade such as pembrolizumab nivolumab and ipilimumab These drugs have shown remarkable efficacy and have regulatory approval for metastatic disease However most patients with advanced disease eventually progress It is unknown if earlier treatment with systemic therapy after surgery improves long term survival or what is the optimal sequencing or combination of therapy An efficient method of assessing drugs and combinations in humans is critical particularly as combinations of molecularly targeted andor immune therapies may have similar signals for efficacy in pre-clinical models and recapitulation of the human immune system in animal models is limited
Neoadjuvant clinical trials in patients with resectable but bulky stage IIIIV melanoma allows for the rapid evaluation of drug activity in humans utilising multiple clinical endpoints metabolic response with Positron Emission Tomography PET clinical response with Computed Tomography CT imaging pathological response relapse-free survival and overall survival and translational endpoints morphological genetic and immunophenotyping of tumour and blood
Surgery remains the standard of care for resectable Stage III or IV melanoma despite the recent drug therapy advances described above The Food and Drug Administration FDA has recently expanded the approved use of ipilimumab to include a new use as adjuvant therapy for patients with resectable stage III IV melanoma to lower the risk of relapse following surgery Neoadjuvant therapy in this group of patients may also result in improved survival rates and in the duration of local and distant disease control with reduced surgical morbidity and the potential for early elimination of microscopic metastatic disease
There is an emerging and rapidly growing evidence base of the value of combining targeted and immunotherapies in a number of histological subtypes of cancers The support for a potential synergy between the two treatment modalities has been established as has the increased toxicity profile Both single agent BRAF inhibitors and combined BRAF and MEK inhibitors induce a marked clonal T cell infiltrate in responding melanoma metastases early during treatment day 7-15 which is transient and is not present at progression Concurrently melanoma tumour antigen and the programmed death-ligand 1 PDL1 expression increase early during treatment
It is unknown whether there is potential for converting a subset of patients who fail either immunotherapy or targeted therapy alone into long-term responders by treating with programmed cell death protein 1 PD-1 inhibitors in conjunction with mitogen-activated protein kinases MAPK targeted therapies Furthermore it is unclear whether the PD-1 inhibitor would be best combined sequentially or concurrently with MAPK inhibitors Mouse models have provided a clear rational for combining these treatments upfront however there is no human tissue evidence to guide best combination strategies
The question of how best to maximize clinical outcome via concurrent versus sequential targeted and immune therapy may be explored efficiently in the human neoadjuvant setting with detailed interrogation of multiple biopsies early during treatment Immunological proteomic and genetic features in tissue and blood provide an in vivo assessment of tumour responsiveness to therapy This may enable more selective application of therapeutic agents to patients who are more likely to benefit Such findings would improve the therapeutic index and cost effectiveness of these agents Earlier systemic therapy prior to surgery also means earlier targeting of distant micrometastases that could become the source of future disease relapse
The rationale for this study design is therefore based on the hypothesis that one week of targeted therapy may be sufficient to induce an enhanced tumoral immunity to result in a higher pathological and clinical response using the Response Evaluation Criteria In Solid Tumors RECIST guidelines when followed sequentially with pembrolizumab than either pembrolizumab alone or the combination of targeted therapy and pembrolizumab upfront
The potential for toxicities that could affect adherence to the combined study treatments are recognised as additive overlapping or unforeseen adverse events may occur with the triple combination The adverse event profiles and safety-related interruption to treatment will therefore be assessed in conjunction with the objective responses
The clinical and translational findings from this study have the potential to inform rational decisions regarding combinations of treatment both in the metastatic and the adjuvant settings This is a critical study to inform future practice and future phase 3 clinical trials The translational research performed on tissue biopsies and blood will provide mechanistic information to guide the selection of optimal combinations of therapies for phase 3 studies in the advanced and the adjuvant setting
This is a phase II randomised open label three arm parallel group clinical trial of neoadjuvant combined targeted and immune therapy for patients with BRAF V600 mutant resectable stage III bulky regional stage IIIB-D but excluding in transit disease melanoma
This translational study explores pathological and RECIST response rates for a 6-week duration of neoadjuvant therapy across 3 treatment arms The key secondary outcomes to be measured include a detailed analysis of immunologic proteomic and genetic biomarkers in tumour tissue and peripheral blood at weeks 1 2 and 6 compared to baseline and correlated with clinical metabolic and pathological response to neoadjuvant treatment and relapse and overall survival to adjuvant treatment In patients who relapse within 40 weeks of adjuvant treatment further analysis of tumour tissue if possible will be undertaken Relapse free and overall survival surgical outcomes and adverse event profile will also be determined
Sixty patients will be randomised to one of three treatment groups in a 111 ratio with 20 patients in each treatment arm
Sequential immunotherapy Dabrafenib 150mg orally twice a day Trametinib 2mg orally once a day for 1 week then followed by treatment with Pembrolizumab 2mgkg delivered intravenously at weeks 1 3 and 6 then once every 3 weeks from week 6 for 50 weeks
Concurrent immunotherapy Dabrafenib 150mg orally twice a day Trametinib 2mg orally once a day Pembrolizumab 200mg intravenously once every 3 weeks for 6 weeks then Pembrlizuamb alone for a further 46 weeks after surgery
Immunotherapy alone Pembrolizumab 200mg intravenously once every 3 weeks alone for 52 weeks
Allocation of treatment will be concealed prior to randomisation which will be performed via a web based system in permuted blocks and stratified by BRAF V600E mutation versus non BRAF V600E mutation ie V600D V600K V600R V600M
Neoadjuvant treatment for all three arms will be administered for 6 weeks followed by complete resection of tumour to no evidence of disease Surgery is followed by 46 weeks of pembrolizumab adjuvant therapy or until disease relapse death intolerable adverse drug reactions or by withdrawal of patient consent After 52 weeks of the study treatment phase patients will be followed 3 monthly for relapse and progression following relapse and survival for 5 years
The biomarker component of this study will require blood samples and core biopsies of tumour tissue at the following time points
Baseline PRE
Week 1 EDT 1
Week 2 EDT 2
Week 6 - complete lymph node dissection specimen POST
At Relapse RELAPSE if applicable and available
Surveillance of disease during the 6 week neoadjuvant period will be undertaken with surgical assessments and with ultrasounds of the affected lymph node basin
Neoadjuvant clinical trials in patients with resectable but bulky stage IIIIV melanoma allows for the rapid evaluation of drug activity in humans utilising multiple clinical endpoints metabolic response with Positron Emission Tomography PET clinical response with Computed Tomography CT imaging pathological response relapse-free survival and overall survival and translational endpoints morphological genetic and immunophenotyping of tumour and blood
Surgery remains the standard of care for resectable Stage III or IV melanoma despite the recent drug therapy advances described above The Food and Drug Administration FDA has recently expanded the approved use of ipilimumab to include a new use as adjuvant therapy for patients with resectable stage III IV melanoma to lower the risk of relapse following surgery Neoadjuvant therapy in this group of patients may also result in improved survival rates and in the duration of local and distant disease control with reduced surgical morbidity and the potential for early elimination of microscopic metastatic disease
There is an emerging and rapidly growing evidence base of the value of combining targeted and immunotherapies in a number of histological subtypes of cancers The support for a potential synergy between the two treatment modalities has been established as has the increased toxicity profile Both single agent BRAF inhibitors and combined BRAF and MEK inhibitors induce a marked clonal T cell infiltrate in responding melanoma metastases early during treatment day 7-15 which is transient and is not present at progression Concurrently melanoma tumour antigen and the programmed death-ligand 1 PDL1 expression increase early during treatment
It is unknown whether there is potential for converting a subset of patients who fail either immunotherapy or targeted therapy alone into long-term responders by treating with programmed cell death protein 1 PD-1 inhibitors in conjunction with mitogen-activated protein kinases MAPK targeted therapies Furthermore it is unclear whether the PD-1 inhibitor would be best combined sequentially or concurrently with MAPK inhibitors Mouse models have provided a clear rational for combining these treatments upfront however there is no human tissue evidence to guide best combination strategies
The question of how best to maximize clinical outcome via concurrent versus sequential targeted and immune therapy may be explored efficiently in the human neoadjuvant setting with detailed interrogation of multiple biopsies early during treatment Immunological proteomic and genetic features in tissue and blood provide an in vivo assessment of tumour responsiveness to therapy This may enable more selective application of therapeutic agents to patients who are more likely to benefit Such findings would improve the therapeutic index and cost effectiveness of these agents Earlier systemic therapy prior to surgery also means earlier targeting of distant micrometastases that could become the source of future disease relapse
The rationale for this study design is therefore based on the hypothesis that one week of targeted therapy may be sufficient to induce an enhanced tumoral immunity to result in a higher pathological and clinical response using the Response Evaluation Criteria In Solid Tumors RECIST guidelines when followed sequentially with pembrolizumab than either pembrolizumab alone or the combination of targeted therapy and pembrolizumab upfront
The potential for toxicities that could affect adherence to the combined study treatments are recognised as additive overlapping or unforeseen adverse events may occur with the triple combination The adverse event profiles and safety-related interruption to treatment will therefore be assessed in conjunction with the objective responses
The clinical and translational findings from this study have the potential to inform rational decisions regarding combinations of treatment both in the metastatic and the adjuvant settings This is a critical study to inform future practice and future phase 3 clinical trials The translational research performed on tissue biopsies and blood will provide mechanistic information to guide the selection of optimal combinations of therapies for phase 3 studies in the advanced and the adjuvant setting
This is a phase II randomised open label three arm parallel group clinical trial of neoadjuvant combined targeted and immune therapy for patients with BRAF V600 mutant resectable stage III bulky regional stage IIIB-D but excluding in transit disease melanoma
This translational study explores pathological and RECIST response rates for a 6-week duration of neoadjuvant therapy across 3 treatment arms The key secondary outcomes to be measured include a detailed analysis of immunologic proteomic and genetic biomarkers in tumour tissue and peripheral blood at weeks 1 2 and 6 compared to baseline and correlated with clinical metabolic and pathological response to neoadjuvant treatment and relapse and overall survival to adjuvant treatment In patients who relapse within 40 weeks of adjuvant treatment further analysis of tumour tissue if possible will be undertaken Relapse free and overall survival surgical outcomes and adverse event profile will also be determined
Sixty patients will be randomised to one of three treatment groups in a 111 ratio with 20 patients in each treatment arm
Sequential immunotherapy Dabrafenib 150mg orally twice a day Trametinib 2mg orally once a day for 1 week then followed by treatment with Pembrolizumab 2mgkg delivered intravenously at weeks 1 3 and 6 then once every 3 weeks from week 6 for 50 weeks
Concurrent immunotherapy Dabrafenib 150mg orally twice a day Trametinib 2mg orally once a day Pembrolizumab 200mg intravenously once every 3 weeks for 6 weeks then Pembrlizuamb alone for a further 46 weeks after surgery
Immunotherapy alone Pembrolizumab 200mg intravenously once every 3 weeks alone for 52 weeks
Allocation of treatment will be concealed prior to randomisation which will be performed via a web based system in permuted blocks and stratified by BRAF V600E mutation versus non BRAF V600E mutation ie V600D V600K V600R V600M
Neoadjuvant treatment for all three arms will be administered for 6 weeks followed by complete resection of tumour to no evidence of disease Surgery is followed by 46 weeks of pembrolizumab adjuvant therapy or until disease relapse death intolerable adverse drug reactions or by withdrawal of patient consent After 52 weeks of the study treatment phase patients will be followed 3 monthly for relapse and progression following relapse and survival for 5 years
The biomarker component of this study will require blood samples and core biopsies of tumour tissue at the following time points
Baseline PRE
Week 1 EDT 1
Week 2 EDT 2
Week 6 - complete lymph node dissection specimen POST
At Relapse RELAPSE if applicable and available
Surveillance of disease during the 6 week neoadjuvant period will be undertaken with surgical assessments and with ultrasounds of the affected lymph node basin
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None