Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT05373251 |
| Other study ID # |
H21-03699 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
August 2022 |
| Est. completion date |
August 2032 |
Study information
| Verified date |
May 2022 |
| Source |
British Columbia Cancer Agency |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
1. To determine genomic markers of radioresistance by comparing patients with H&N cancer
who develop recurrence within twelve months of curative intent radiation and/or
chemoradiotherapy to those without recurrence
2. To compare the genomic landscape of patients with and without EBV and HPV mediated H&N
cancer
3. To identify somatic mutations, gene expression changes or other potentially targetable
abnormalities in patients with recurrent H&N cancer that may provide information to
guide systemic therapy in these patients
Description:
Head and neck cancer is the 12th most common cancer in Canada, with 6450 patients diagnosed
per year.1 The majority of head and neck cancers are squamous cell carcinoma (H&N SCC). The
majority of H&N SCC patients present with locally advanced disease, however despite advances
in intensive combined multi-modality treatment, approximately 35% of patients diagnosed with
head and neck cancer will die of their disease.2 The primary curative intent treatment
modalities for head and neck cancer are surgery and radiotherapy (with or without concurrent
chemotherapy). Radiotherapy is used as the primary curative intent modality for H&N SCC for
organ preservation of the oral cavity, pharynx and larynx to maintain speech and swallowing
function. It is also used for unresectable cancers and in the adjuvant setting after surgery
for patients with locally advanced disease.
Despite modern radiotherapy technologies allowing the delivery of high doses of radiotherapy
(60-70 Gy) with curative intent, many patients have radioresistant SCC, with local, regional
or distant progression during or shortly after radiotherapy. There are very few, if any,
radiologic and pathologic predictors to determine which patients with H&N SCC will respond
well to radiotherapy. Varying clinical responses are seen, with some patients having complete
clinical resolution of their tumours within the first few weeks of radiotherapy, whereas
others have minimal response, or even progressive disease during treatment. The only
molecular marker used for patient stratification for definitive management is the presence of
Human Papilloma Virus-16 (HPV) in oropharyngeal cancer, although its impact is tempered by
smoking history (Ang DOI: 10.1056/NEJMoa0912217).
This study aims to assess genomic predictors of radioresistant and chemoresistant H&N SCC,
defined as diagnosis of local, regional or distant recurrence within twelve months of
completing curative intent radiotherapy with or without chemotherapy. Diagnosis of recurrent
disease after radiotherapy is associated with poor survival outcomes, with a median survival
of 8 months.3
Additionally, , this study aims to elucidate the genomic characteristics of virally-mediated
H&N cancers and their impact on chemoradiation response. Currently, 40-45% of H&N cancers
seen at BC Cancer are linked to viral infections, namely Epstein Barr virus (EBV) and human
papilloma virus (HPV). Through prior research at the Genome Sciences Centre, BC Cancer
experts are showing that the HPV genome can integrate into the human genome, resulting in
profound genomic disruptions. Because these disruptions are exceedingly complicated, methods
to study them did not exist until recently. The availability of Nanopore technology, a
cutting-edge new strategy that sequences longer strands of DNA to detect novel genomic
features will enable investigators to look at: how viral genomes integrate into human genomes
and how they change; how these genomic changes reveal new insights into H&N cancers and how
to treat them; and whether or not virally-mediated genomic changes lead to radio-resistance
or radio-sensitivity. Through the study of H&N cancers, we aim to gain valuable knowledge
that may be relevant to other virally-mediated cancers.
HPV positive oropharyngeal SCC has a distinct clinical phenotype, staging and biology
compared to HPV negative H&N SCC, however deeper understanding of underlying genomic
differences are lacking. The Cancer Genome Atlas (TCGA) has conducted the largest
comprehensive genomic study of 528 H&N SCC tumours to date, however only 36 HPV positive
tumors were included, resulting in limited comparison of genomic analysis between HPV
positive and HPV negative tumours (PMID 31703248). In addition, TCGA-HNSCC cohort is largely
derived from patients who underwent oral cavity surgery, rather than chemoradiation and lacks
clinical correlatives of response to treatment including chemoradiation. PIK3CA is the most
frequently mutated gene in HPV-associated oropharyngeal squamous cell carcinoma, however the
clinical significance of PIK3CA mutations and other genomic alterations in response to
chemoradiation is unclear.
Finally, the current lack of biomarkers in H&N SCC impedes the advance of experimental
therapeutics in H&N SCC in which promising novel targeted or immunologic agents continue to
be tested in unselected patient populations with little effort to identify the molecular
markers associated with treatment response. Comprehensive characterization of clinically
annotated samples encompassing genomics, immune function assessments and establishment of
model systems is urgently needed. This study will aim to identify predictors of immunotherapy
response as the majority of patients with H&N SCC who experience cancer recurrence following
chemoradiation will be offered immune checkpoint inhibitor therapy as their next line of
treatment. Currently, there are no validated predictors of response to immune checkpoint
inhibitors in patients who experience cancer recurrence shortly following definitive
chemoradiation, and the presence of PD-L1 is not a requirement for receipt of immune
checkpoint inhibitor therapy in the early post-chemoradiotherapy setting (Checkmate-141,
Keynote-040). Currently clinical responses to single agent immune checkpoint inhibitors,
nivolumab or pembrolizumab, have been observed in H&N SCC patients regardless of PD-L1 status
or HPV status, however overall objective response rates remain low (<20%). Combination immune
checkpoint inhibitor clinical trials thus far have not demonstrated significant activity,
hence there is a critical unmet need to identify underlying genomic characteristics of immune
response and improve patient selection for immune checkpoint blockade in H&N SCC.
In 2014, BC Cancer launched the Personalized Onco-Genomics (POG) Program to investigate the
genomic characteristics of individual cancers with the goal of identifying more effective
treatments informed by genomic data. To date, POG has enrolled more than 1,200 patients with
a variety of metastatic cancers. This study has resulted in innovative and effective
treatments that would not otherwise have been found, and some of the most interesting and
successful POG cases have been patients with head and neck cancer.
With the PATH trial, we will leverage the established POG infrastructure and we will perform
comprehensive DNA and RNA sequencing on participant's tumour to identify unique underlying
oncogenic drivers and potential novel therapeutic targets. Similar to the POG study, tumour
and matched normal genomes and tumour transcriptome will be assembled for each patient. The
data analysis process that POG has established includes the assembly, annotation, and mining
of the genomic data to identify somatic aberrations, gene expression changes or other
abnormalities that might be cancer "drivers" or provide actionable (diagnostic) or druggable
targets. Results from the whole genome and transcriptome analysis (WGTA) are summarized in
two formats: the first is an automatically generated Targeted Gene Report (TGR) with the
common identifiable mutations and fusions, and the second is a final comprehensive report
with all notable abnormalities.
The TGR is a tool developed by the BC Cancer Genome Sciences Centre (GSC) genome analysts as
a means to deliver a rapid "high-level look" at the genomic and transcriptomic data for each
patient. Similar in concept to a panel, but derived from the entire genome and transcriptome
(unlike a panel), the findings reported in the TGR are identified a priori by the analytics
team and include the genes of interest that are commonly represented on a panel such as KRAS,
EGFR, P53 and also the transcriptomic findings such as ALK or RET fusions. This report is
linked to the Genome Sciences Centre's (GSC) GraphKB (previously called Knowledgebase), which
is a manually curated database of cancer associated genomic abnormalities and linkages to
targeted therapies, clinical trials and other academic knowledge bases in collaboration, such
as CiVIC (https://civicdb.org/home). The turnaround time for a TGR report from the time of
biopsy is 2- 3 weeks and the report is communicated to the ordering clinician. The current
version of the TGR (version: GSC7.3.0 (GR1.2.1:gkb1.3.5)) screens 785 genes and 19534 small
variants (SNVs and indels), it also screens for 566 fusion genes and 730 fusion variants.
Lastly, the in silico nature of the TGR probes facilitate a highly dynamic and flexible panel
that can incorporate the most up-to-date translational genomic discoveries. An additional and
critical advantage to the TGR is that it is based on data from the whole genome and
transcriptome; therefore, when new targeted therapies, variants or genes become relevant for
patient care, these are easily added to the list that would be routinely reported in the TGR;
in addition, previous TGR across the population can be scanned to identify patients who also
have these targets. This is simply not possible with panel data because if a target is not on
the panel there is no means to look for it retrospectively in the data nor to re-run samples
for additional new targets. This means that whole genome data, with a turnaround time of 2-3
weeks, can be used in the present for patient treatment decisions, such as clinical trials,
and retrospectively for patient care and research opportunities in the future. This will
personalize treatment approaches for patients whose cancer recurs; achieving results in real
time for study participants.
