Ignite Creation Date:
2024-05-06 @ 3:58 PM
Last Modification Date:
2024-10-26 @ 2:01 PM
Study NCT ID:
NCT04825990
Status:
RECRUITING
Last Update Posted:
2022-04-07
First Post:
2021-03-29
Brief Title:
Pembrolizumab and Olaparib in RecurrentMetastatic Platinum Resistant Nasopharyngeal Cancer
Sponsor:
Gruppo Oncologico del Nord-Ovest
Organization:
Gruppo Oncologico del Nord-Ovest
Study Overview
Official Title:
Pembrolizumab and Olaparib in RecurrentMetastatic Platinum Resistant Nasopharyngeal Cancer
Status:
RECRUITING
Status Verified Date:
2022-03
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:
POINT
Brief Summary:
Recurrence rate after curative treatment for locally advanced Nasopharyngeal carcinoma NPC is reported varying from 15 to 30 of cases while approximately 5-11 of patients present with de novo metastatic disease
In NPC the immunogenicity of the cancer cell is derived from accumulated somatic mutations but also from genomic and proteomic differences between host and Epstein Barr Virus EBV However anti-cancer immune response tends to be feeble This impaired anti-cancer immunity could be attributed to multiple factors including strategies to escape anti-cancer immunity One of this is switch to immunosuppressive microenvironment as well as aberrant negative co-stimulatory signals like PD-L1 that is over expressed in NPC In 2017 the landmark KEYNOTE-028 trial firstly reported promising antitumor activities and safety profiles of pembrolizumab in previously treated RM-NPC Overall after the treatment of PD-1 inhibitors about 25 and 60 of the recurrent or metastatic nasopharyngeal carcinoma patients achieved ORR and DCR respectively with a profile of toxicities in line with the use of immune checkpoint inhibitors in other diseases
Recently it was found that some non-BRCA-mutated tumors often harbor other alterations in HR genes except for germline BRCA deleterious mutations thus making these tumors could benefit from PARPi treatment
PARP could contribute to resistance to chemotherapy induced DNA damage NPC cell platinum resistant could use PARP to repair and escape apoptosis In nasopharyngeal carcinoma PARP1 is overexpressed in comparison with normal nasopharyngeal cells LMP1 latent membrane protein one activates PARP1 and increases PolyADP-ribosylation PARylation through PARP1 A preclinical study demonstrates that LMP1 cells are more sensitive to PARP1 inhibition
After receiving PARPi treatment accumulated chromosome rearrangements generate plenty of neoantigens and elevate the immunogenicity of tumor PARPi-mediated acute inflammation remodels tumor immune microenvironment and drives a systemic Th1-skewing immune response
Patients in the POINT trial will receive pembrolizumab 200 mg intravenously IV on Day 1 of every 3-week dosing cycle Q3W and olaparib 300 mg capsules twice a day BID every day starting from Day 1 of Cycle 1 Treatment with protocol therapy will continue until objective disease progression any prohibitive toxicity or until a maximum of 35 treatment cycles up to 2 years
In NPC the immunogenicity of the cancer cell is derived from accumulated somatic mutations but also from genomic and proteomic differences between host and Epstein Barr Virus EBV However anti-cancer immune response tends to be feeble This impaired anti-cancer immunity could be attributed to multiple factors including strategies to escape anti-cancer immunity One of this is switch to immunosuppressive microenvironment as well as aberrant negative co-stimulatory signals like PD-L1 that is over expressed in NPC In 2017 the landmark KEYNOTE-028 trial firstly reported promising antitumor activities and safety profiles of pembrolizumab in previously treated RM-NPC Overall after the treatment of PD-1 inhibitors about 25 and 60 of the recurrent or metastatic nasopharyngeal carcinoma patients achieved ORR and DCR respectively with a profile of toxicities in line with the use of immune checkpoint inhibitors in other diseases
Recently it was found that some non-BRCA-mutated tumors often harbor other alterations in HR genes except for germline BRCA deleterious mutations thus making these tumors could benefit from PARPi treatment
PARP could contribute to resistance to chemotherapy induced DNA damage NPC cell platinum resistant could use PARP to repair and escape apoptosis In nasopharyngeal carcinoma PARP1 is overexpressed in comparison with normal nasopharyngeal cells LMP1 latent membrane protein one activates PARP1 and increases PolyADP-ribosylation PARylation through PARP1 A preclinical study demonstrates that LMP1 cells are more sensitive to PARP1 inhibition
After receiving PARPi treatment accumulated chromosome rearrangements generate plenty of neoantigens and elevate the immunogenicity of tumor PARPi-mediated acute inflammation remodels tumor immune microenvironment and drives a systemic Th1-skewing immune response
Patients in the POINT trial will receive pembrolizumab 200 mg intravenously IV on Day 1 of every 3-week dosing cycle Q3W and olaparib 300 mg capsules twice a day BID every day starting from Day 1 of Cycle 1 Treatment with protocol therapy will continue until objective disease progression any prohibitive toxicity or until a maximum of 35 treatment cycles up to 2 years
Detailed Description:
Before any study specific procedure is performed the patient will sign an informed consent form
Every effort should be done to obtain a new tumor biopsy from relapsed-metastatic disease but a new biopsy is not necessary to participate to the study
Patients will undergo radiologic staging investigations according to guidelines including pre-treatment head and neck MRI and whole body FDG-PET or thorax and abdomen CT scan and clinical evaluation with fiberendoscopy
Patients will receive pembrolizumab 200 mg intravenously IV on Day 1 of every 3-week dosing cycle Q3W and olaparib 300 mg capsules twice a day BID every day starting from Day 1 of Cycle 1 Treatment with protocol therapy will continue until objective disease progression any prohibitive toxicity or until a maximum of 35 treatment cycles up to 2 years
Patients who must discontinue one of the two drugs in the combination due to adverse events may continue the study with the other combination drug Once patients have been discontinued from study treatment other treatment options will be at the discretion of the investigator
Dose reductions will be allowed according to protocol-specified rules Tumor response will be evaluated by clinicalendoscopic evaluation every 3 weeks and by radiological imaging every 9 weeks 7 days since treatment start After the first year the radiological imaging frequency can be modified as clinically indicated Radiologic response will be assessed by Response Evaluation Criteria in Solid Tumors Version 11 RECIST 11
Blood samples for plasmatic EBV-DNA analysis will be performed at baseline and if positive at week 3 week 9 and then every 9 weeks since treatment start however in concomitance with the radiological imagining and at every follow up visit in case of EBER-positive tumor
Patients will be evaluated for treatment safety at each clinical visit by means of clinical and laboratory exams All adverse events will be recorded by Common Terminology Criteria for Adverse Events CTCAE version 50 the investigator will assess whether those events are drug related or not All enrolled patients will be included in overall safety analyses
Change in the Quality-of-Life QoL since baseline using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck Module EORTC QLQ-HN43 will be evaluated at first visit every 9 weeks during treatment and at the follow up visit
Every effort should be done to obtain a new tumor biopsy from relapsed-metastatic disease but a new biopsy is not necessary to participate to the study
Patients will undergo radiologic staging investigations according to guidelines including pre-treatment head and neck MRI and whole body FDG-PET or thorax and abdomen CT scan and clinical evaluation with fiberendoscopy
Patients will receive pembrolizumab 200 mg intravenously IV on Day 1 of every 3-week dosing cycle Q3W and olaparib 300 mg capsules twice a day BID every day starting from Day 1 of Cycle 1 Treatment with protocol therapy will continue until objective disease progression any prohibitive toxicity or until a maximum of 35 treatment cycles up to 2 years
Patients who must discontinue one of the two drugs in the combination due to adverse events may continue the study with the other combination drug Once patients have been discontinued from study treatment other treatment options will be at the discretion of the investigator
Dose reductions will be allowed according to protocol-specified rules Tumor response will be evaluated by clinicalendoscopic evaluation every 3 weeks and by radiological imaging every 9 weeks 7 days since treatment start After the first year the radiological imaging frequency can be modified as clinically indicated Radiologic response will be assessed by Response Evaluation Criteria in Solid Tumors Version 11 RECIST 11
Blood samples for plasmatic EBV-DNA analysis will be performed at baseline and if positive at week 3 week 9 and then every 9 weeks since treatment start however in concomitance with the radiological imagining and at every follow up visit in case of EBER-positive tumor
Patients will be evaluated for treatment safety at each clinical visit by means of clinical and laboratory exams All adverse events will be recorded by Common Terminology Criteria for Adverse Events CTCAE version 50 the investigator will assess whether those events are drug related or not All enrolled patients will be included in overall safety analyses
Change in the Quality-of-Life QoL since baseline using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck Module EORTC QLQ-HN43 will be evaluated at first visit every 9 weeks during treatment and at the follow up visit
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