Clinical Trial Details
— Status: Active, not recruiting
Administrative data
NCT number |
NCT03734809 |
Other study ID # |
NPC032 |
Secondary ID |
|
Status |
Active, not recruiting |
Phase |
Phase 2
|
First received |
|
Last updated |
|
Start date |
May 3, 2019 |
Est. completion date |
December 31, 2025 |
Study information
Verified date |
February 2024 |
Source |
Chinese University of Hong Kong |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
This is an open label, single arm, non-randomized, multi-site, phase 2 clinical trial of
neoadjuvant pembrolizumab in combination with gemcitabine-cisplatin for 2 cycles,followed by
concurrent pembrolizumab-cisplain-radiation, and then maintainence pembrolizumab monotherpy
given every 3 weeks for a total treatment duration of 12 months, in previously untreated
stage IVA ( UICC 8 th Edition ) nasopharyngeal cancer(NPC).
Description:
Nasopharyngeal cancer (NPC) is a predominantly Asian disease, with approximately 80% of the
world's 86000 cases occurring in Asian countries (12). With advances in radiation technology
such as intensity modulation radiotherapy (IMRT), local and nodal control exceeds 85-90% in
most reported series. Distant metastasis remains the main mode of failure, particularly in
locally advanced NPC. As an example, in a study by Pan et al (13), 5 years local and nodal
control of 86% and 89% was achieved with concurrent chemo-IMRT respectively, but distant
failure free survival of 77% and 72% was reported for patients with T4 and N3 disease
respectively (AJCC 8th edition).
Current strategies to reduce distant metastasis, including the use of adjuvant chemotherapy
have been inconclusive. One major disadvantage of adjuvant chemotherapy following the
completion of chemoradiation is that approximately half of patients are unable to complete
the full 3 cycles of adjuvant chemotherapy, due to treatment related toxicities. The use of
induction chemotherapy has two potential benefits: the first is to downsize the tumour,
making radiotherapy more tolerable; the second, it allows for patients to be able to complete
the chemotherapy before the onset of chemoradiation associated toxicities.
There are at least two studies now supporting the use of induction chemotherapy. A recent
publication by Ma et al (14), showed the addition of induction docetaxel, cisplatin and
fluorouracil prior to concurrent chemoradiation resulted in 8% improvement (80% vs 72%) in
3-year failure-free survival. Similarly, Cao et al showed that 2 cycles of cisplatin and
fluorouracil prior to chemoradiation improved the 3 years disease free survival in patients
(15).
Gemcitabine and cisplatin has been shown to be more effective than 5-FU plus cisplatin as
first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (16). There are
currently no studies looking at the addition of anti-PD-1 monoclonal antibody such as
pembrolizumab either in the in the induction or maintenance setting. Hence, we are proposing
the use of pembrolizumab in combination with 2 cycles of gemcitabine and cisplatin
chemotherapy followed by concurrent chemoradiation. Following completion of chemoradiation,
patients will receive maintenance pembrolizumab for total treatment duration of one year. The
main objective of this Phase II study is to test the safety, efficacy and tolerability of
this combination in the setting of locally advanced NPC (limited to T4 or N3, stage IVA by
UICC 8th edition), as this group has the greatest risk of recurrence after the current
standard treatment.
Preliminary evidence supporting the clinical efficacy of pembrolizumab monotherapy in NPC
came from the KEYNOTE-028 trial, which was a global, nonrandomized, multi-cohort, phase Ib
trial of pembrolizumab in patients with PD-L1-positive advanced solid tumors (17). Key
eligibility criteria for the NPC cohort included unresectable or metastatic disease, failure
on prior standard therapy, and PD-L1 expression in 1% or more of tumor cells or
tumor-infiltrating lymphocytes. Patients received pembrolizumab 10 mg/kg every 2 weeks up to
2 years or until disease progression or unacceptable toxicity. In the initial report,
twenty-seven NPC patients was evaluated. Median age was 52.0 years (range, 18 to 68 years);
92.6% received prior therapies for recurrent or metastatic NPC; 70.4% had received three or
more therapies. Partial response and stable disease were observed in seven and 14 patients,
respectively, for an ORR of 25.9% (95% CI, 11.1 to 46.3) over a median follow-up of 20
months. Drug-related adverse events that occurred in 15% or more of patients included rash
(25.9%), pruritus (25.9%), pain (22.2%), hypothyroidism (18.5%), and fatigue (18.5%). Grade ≥
3 drug-related adverse events occurred in eight patients (29.6%), and there was one
drug-related death (sepsis). It was concluded that pembrolizumab demonstrated antitumor
activity and a manageable safety profile in patients with recurrent or metastatic NPC.