Ignite Creation Date:
2024-05-06 @ 2:12 PM
Last Modification Date:
2024-10-26 @ 1:27 PM
Study NCT ID:
NCT04247165
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-05-28
First Post:
2020-01-25
Brief Title:
Nivolumab Ipilimumab and Chemoradiation in Pancreatic Cancer
Sponsor:
Herlev Hospital
Organization:
Herlev Hospital
Study Overview
Official Title:
LAPTOP Phase 12 Study in Borderline Resectable Locally Advanced or Metastatic Pancreatic Cancer to Assess Safety and Potential Efficacy of Dual Checkpoint Inhibition in Combination With Gemcitabine and Nab-paclitaxel Followed by Immune-chemoradiation
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-05
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:
LAPTOP
Brief Summary:
Pancreatic ductal adenocarcinoma PDAC remains a dreadful disease due to its often advanced stage at diagnosis and poor sensitivity to chemotherapy A locally unresectable tumor locally advanced pancreatic cancer LAPC is present in 30 of the cases and is defined as a surgically unresectable tumor encasing the adjacent arteries celiac axis superior mesenteric artery SMA In these patients chemotherapy has been the standard treatment for decades optionally combined with radiotherapy Patients with borderline resectable pancreatic cancer BRPC comprise a group of patients with PDAC who are at a high risk of having positive margins if upfront resection is pursued In addition multiple studies have reported these patients have increased probability of early recurrence of local and systemic disease resulting in poorer outcomes Although some patients are treated with an aggressive surgery-first approach and adjuvant systemic therapies a preoperative chemotherapy andor chemoradiation approach is becoming more common for all patients with BRPC and this strategy is adapted in Danish and international guidelines Majority of patients present with metastatic pancreatic cancer mPC Therapy options are limited by chemotherapy in palliative setting The superiority of the FOLFIRINOX regimen demonstrated in the phase III mPC setting led many centers to investigate FOLFIRINOX with or without chemoradiotherapy in patients with LAPC tumor Gemcitabine combined with nab-paclitaxel is the approved first-line treatment for patients with advanced PC This regimen showed a median progression-free survival PFS of 55 months and a median overall survival OS of 85 months and is the predominantly used regimen in metastatic PC The role of radiation therapy in the management of nonresectable PC remains controversial The results of small randomized trials comparing chemoradiotherapy with chemotherapy of patients with LAPC are divergent
Immunotherapy has emerged as a therapeutic approach that offers effective and durable treatment options for subsets of patients with various types of cancer However these successes have not manifested similar benefits for PDAC patients mostly due to a lack of pre-existing T-cell immunity andor a highly immunosuppressive tumor microenvironment TME Considering the emerging role of the TME the combination of checkpoint blocking antibodies with agents that target the inhibitory effects of the TME could lead to better responses in tumor historically resistant to checkpoint blocking antibody approaches For example in heavily pretreated patients with advancedmetastatic PDAC preliminary data from the phase 2 study CHECKPAC NCT02866383 showed that checkpoint inhibition in combination with stereotactic body radiotherapy SBRT provided durable clinical benefit in a small proportion of patients including prolonged sustained partial responses Furthermore the addition of standard-of-care chemotherapy could further potentiate the anti-tumor effects of immunotherapy approaches by reducing the tumor burden exposing antigens and directly affecting the immunosuppressive TME compartment
To explore the safety and synergy of the proposed combinatorial approach participants with borderline resectable locally advanced or mPC will receive nivolumab and ipilimumab administered in combination with gemcitabine and nab-paclitaxel followed by immune-chemoradiation
Immunotherapy has emerged as a therapeutic approach that offers effective and durable treatment options for subsets of patients with various types of cancer However these successes have not manifested similar benefits for PDAC patients mostly due to a lack of pre-existing T-cell immunity andor a highly immunosuppressive tumor microenvironment TME Considering the emerging role of the TME the combination of checkpoint blocking antibodies with agents that target the inhibitory effects of the TME could lead to better responses in tumor historically resistant to checkpoint blocking antibody approaches For example in heavily pretreated patients with advancedmetastatic PDAC preliminary data from the phase 2 study CHECKPAC NCT02866383 showed that checkpoint inhibition in combination with stereotactic body radiotherapy SBRT provided durable clinical benefit in a small proportion of patients including prolonged sustained partial responses Furthermore the addition of standard-of-care chemotherapy could further potentiate the anti-tumor effects of immunotherapy approaches by reducing the tumor burden exposing antigens and directly affecting the immunosuppressive TME compartment
To explore the safety and synergy of the proposed combinatorial approach participants with borderline resectable locally advanced or mPC will receive nivolumab and ipilimumab administered in combination with gemcitabine and nab-paclitaxel followed by immune-chemoradiation
Detailed Description:
Patients receive nivolumab and ipilimumab Nivolumab 3 mgkg will be given on Day 1 3 days of each 28-day treatment cycle Ipilimumab 1 mgkg will be given only on day 1 in cycle 1 Nivolumab will be administered as an IV infusion over 30 5 minutes and then after a 30 minutes rest period ipilimumab will be administered as an IV infusion over 30 5 minutes
Pre-medication for chemotherapy based on standard-of-care and local institutional standards and chemotherapy will then be administered after a further 30 minutes rest period The recommended dose of nab-paclitaxel is 100 mgm2 administered as an IV infusion over 30 to 40 minutes on Days 1 8 and 15 of each 28-day cycle Gemcitabine 800 mgm2 will be adminestered over 30 to 40 minutes immediately after nab-paclitaxel on Days 1 8 and 15 of each 28-day cycle
At the beginning of cycle 3 patients also undergo concurrent MRI-guided adaptive SBRT 8 Gy x 3 fractions delivered by ViewRay MR-Linear Accelerator
Cycles repeats every 4 weeks for 4 courses 16 weeks in the absence of disease progression unacceptable toxicity withdrawal of consent or study closure
Once 4 cycles of study treatment have been completed subjects without disease progression or unacceptable toxicity may continue as per Investigators Choice to either
Continuation of treatment with nivolumab nab-paclitaxel and gemcitabine or surgery Nivolumab can be continued until progressive disease PD unacceptable toxicity withdrawal of consent or up to 12 cycles in total Patients will receive chemotherapy until PD unacceptable toxicity or withdrawal of consent according to investigators judgment
If tumor response allows for surgical intervention the subject will be eligible for that treatment as deemed appropriate by the investigators Surgical intervention may not occur prior to completing the planned 4 cycles of nivolumab nab-paclitaxel gemcitabine and SBRT regardless the patient demonstrates a major response to therapy Patients after PC resection will receive treatment until recurrence unacceptable toxicity withdrawal of consent clear clinical deterioration or for a maximum of 6 cycles according to investigators judgment Patients who discontinue without PD stable disease SD partial response PR or complete response CR will have both the safety follow-up period and survival follow-up period to occur simultaneously during the 2-year follow-up period The duration of this follow-up is up to 2 years following the last dose of study treatment although a longer follow-up period could be considered in selected cases if an efficacy signal is apparent Patients will receive follow-up CTMRI scans every 2 months 14 days until documented progression of disease withdrawal of consent from active participation in the study lost to follow-up or for at least 2 years after start of treatment whichever is earliest Tumor evaluations will be assessed by the investigators and response to be determined according to response evaluation criteria in solid tumors RECIST v11 guidelines Tumor assessment scans for participants who have ongoing clinical benefit beyond the 2-year period from start of treatment may continue to be collected as part of standard-of-care treatment Subsequent therapies will also be recorded in this survival follow-up period
All subjects who discontinue treatment for any reason will have a safety follow-up visit about 30 60 and 100 days after treatment discontinuation and will be followed for OS and post-study anticancer therapies approximately every 90 days by phone or review of medical records until death withdrawal of consent or lost to follow-up
To minimize the risks of adding or nivolumab ipilimumab followed by nivolumab and chemo-radiation safety will be monitored by a Bayesian stopping rule for the rate of treatment-related AEs leading to discontinuation greater than 30 summarized baseline toxicity rate For example if 3 patients out of the first 6 or 4 out of the first 7 evaluable patients experience treatment-related AEs leading to discontinuation accrual to the trial will be temporarily suspended and the principle investigator and study team will review the toxicity data and recommend either modification or termination of the trial
Pre-medication for chemotherapy based on standard-of-care and local institutional standards and chemotherapy will then be administered after a further 30 minutes rest period The recommended dose of nab-paclitaxel is 100 mgm2 administered as an IV infusion over 30 to 40 minutes on Days 1 8 and 15 of each 28-day cycle Gemcitabine 800 mgm2 will be adminestered over 30 to 40 minutes immediately after nab-paclitaxel on Days 1 8 and 15 of each 28-day cycle
At the beginning of cycle 3 patients also undergo concurrent MRI-guided adaptive SBRT 8 Gy x 3 fractions delivered by ViewRay MR-Linear Accelerator
Cycles repeats every 4 weeks for 4 courses 16 weeks in the absence of disease progression unacceptable toxicity withdrawal of consent or study closure
Once 4 cycles of study treatment have been completed subjects without disease progression or unacceptable toxicity may continue as per Investigators Choice to either
Continuation of treatment with nivolumab nab-paclitaxel and gemcitabine or surgery Nivolumab can be continued until progressive disease PD unacceptable toxicity withdrawal of consent or up to 12 cycles in total Patients will receive chemotherapy until PD unacceptable toxicity or withdrawal of consent according to investigators judgment
If tumor response allows for surgical intervention the subject will be eligible for that treatment as deemed appropriate by the investigators Surgical intervention may not occur prior to completing the planned 4 cycles of nivolumab nab-paclitaxel gemcitabine and SBRT regardless the patient demonstrates a major response to therapy Patients after PC resection will receive treatment until recurrence unacceptable toxicity withdrawal of consent clear clinical deterioration or for a maximum of 6 cycles according to investigators judgment Patients who discontinue without PD stable disease SD partial response PR or complete response CR will have both the safety follow-up period and survival follow-up period to occur simultaneously during the 2-year follow-up period The duration of this follow-up is up to 2 years following the last dose of study treatment although a longer follow-up period could be considered in selected cases if an efficacy signal is apparent Patients will receive follow-up CTMRI scans every 2 months 14 days until documented progression of disease withdrawal of consent from active participation in the study lost to follow-up or for at least 2 years after start of treatment whichever is earliest Tumor evaluations will be assessed by the investigators and response to be determined according to response evaluation criteria in solid tumors RECIST v11 guidelines Tumor assessment scans for participants who have ongoing clinical benefit beyond the 2-year period from start of treatment may continue to be collected as part of standard-of-care treatment Subsequent therapies will also be recorded in this survival follow-up period
All subjects who discontinue treatment for any reason will have a safety follow-up visit about 30 60 and 100 days after treatment discontinuation and will be followed for OS and post-study anticancer therapies approximately every 90 days by phone or review of medical records until death withdrawal of consent or lost to follow-up
To minimize the risks of adding or nivolumab ipilimumab followed by nivolumab and chemo-radiation safety will be monitored by a Bayesian stopping rule for the rate of treatment-related AEs leading to discontinuation greater than 30 summarized baseline toxicity rate For example if 3 patients out of the first 6 or 4 out of the first 7 evaluable patients experience treatment-related AEs leading to discontinuation accrual to the trial will be temporarily suspended and the principle investigator and study team will review the toxicity data and recommend either modification or termination of the trial
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