Pembrolizumab and Olaparib in Recurrent/Metastatic, Platinum Resistant Nasopharyngeal Cancer — POINT  

Nasopharyngeal Carcinoma Clinical Trial

Official title: Pembrolizumab and Olaparib in Recurrent/Metastatic, Platinum Resistant Nasopharyngeal Cancer

Status Recruiting

Clinical Trial 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 Poly(ADP-ribos)ylation (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).

Clinical Trial 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 clinical/endoscopic 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 1.1 (RECIST 1.1).

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 5.0; 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. ;

Related Conditions & MeSH terms

• Nasopharyngeal Carcinoma
• Nasopharyngeal Neoplasms

• NCT number: NCT04825990
• Study type: Interventional
• Source: Gruppo Oncologico del Nord-Ovest
• Contact: Paolo Bossi, MD
• Phone: +390303998969
• Email: paolo.bossi@unibs.it
• Status: Recruiting
• Phase: Phase 2
• Start date: March 24, 2022
• Completion date: March 24, 2028