Clinical trial NCT03652142: Predictive Biomarkers for Response to Nivolumab in Head and Neck Squamous Cell Carcinoma
Official title: Predictive Biomarkers For Response To Nivolumab In Head and Neck Squamous Cell Carcinoma
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: HNSCC
DNA Damage
DNA Double Strand Break
Keywords: HNSCC
DDR
DNA damage
DNA damage repair
PD-L1
PD-1
NIVOLUMAB
Head and Neck cancer
Lead sponsor: Attikon Hospital
Sponsor class: OTHER
First posted: 2018-08-29
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: The investigators will include recurrent/metastatic HNSCC patients who progressed after cisplatin-based chemotherapy and are to be treated with nivolumab.

Brief summary: Nivolumab is FDA-approved for the treatment of patients with recurrent/metastatic Head and Neck Squamous Cell Carcinoma (HNSCC).

HNSCC whose disease has progressed within 6 months after platinum-based chemotherapy. The development of predictive biomarkers is needed to optimize patient benefit, minimize risk of toxicities and guide combination strategies.

Detailed description: Nivolumab is FDA-approved for the treatment of patients with recurrent/metastatic Head and Neck Squamous Carcinoma (HNSCC) whose disease has progressed within 6 months after platinum-based chemotherapy. The development of predictive biomarkers is needed to optimize patient benefit, minimize risk of toxicities and guide combination strategies. The greatest focus has been on tumor-cell programmed death Ligand 1 (PD-L1) expression. Although PD-L1 positivity enriches for populations with clinical benefit, PD-L1 testing alone is insufficient for patient selection in most malignancies. PD-L1 expression can be transient, and intrapatient and even intratumor heterogeneity in PD- L1 tumor expression can exist. Therefore, tumor sampling at one timepoint might not accurately reflect the state of PD1 axis in a patient. Another important aspect is that PD-L1 immunohistochemistry alone does not take into account factors that could impede the anti-PD1 therapy response such as whether or not active immune cell engagement of the PD1 axis occurs in the tumor microenvironment or other concurrent immune suppressive pathways are present.

Assessment of biomarkers at baseline may not predict benefit from immunotherapy. In a phase II study of ipilimumab in patients with metastatic melanoma baseline tumor infiltrating lymphocyte status was not associated with clinical activity. However, increase in tumor infiltrating lymphocyte density in tumor biopsy samples collected after the second dose of ipilimumab was associated with significantly greater clinical activity with ipilimumab compared to samples without increase in lymphocyte density. For a better understanding of the mechanisms of resistance to nivolumab in HNSCC, the investigators propose to study a cohort of longitudinal HNSCC samples from recurrent/metastatic HNSCC patients treated with nivolumab and identify biomarkers of response and resistance. The investigators will specifically focus on modulation of immune phenotype (ImmR) following two cycles of nivolumab as surrogate biomarker for response to nivolumab.

The primary endpoint will be the change in the percentage of immune cells that is caused by nivolumab treatment. Secondary endpoint will be safety of performing a biopsy after second nivolumab dose. Translational correlates will be tested in tumour tissue, plasma and germline DNA.

Investigator assessment of best overall response (BOR), determined between the date of first dose and the last tumor assessment (TA), will be image-based and scored using the RECIST 1.1. criteria. BOR will be defined as categorical variable with 3 levels { Benefit (complete response (CR), partial response (PR), stable disease (SD) lasting 6 months from the first nivolumab dose), no benefit (PD, progressive disease or SD lasting less than 6 months from the first nivolumab dose), and unknown} Longitudinal tissue biopsies will be collected from HNSCC patients treated with nivolumab . Biopsies will be taken at baseline, 24-72 hours after the second cycle of nivolumab and at progression.

Eligibility criteria: Inclusion Criteria:

* Signed written informed consent before any trial-related procedure is undertaken
* Male or female subjects aged ≥18 years
* Availability of a formalin-fixed, paraffin-embedded tissue sample (FFPE) containing tumor

Exclusion Criteria:

* no inform consent provided

Primary outcomes:
measure: Change in the percentage of immune cells in post treatment compared to baseline biopsies
timeFrame: 2 weeks
Secondary outcomes:
measure: Safety of performing a biopsy after second nivolumab dose
timeFrame: 6 weeks
measure: Best overall response rate (BOR) according to RECIST 1.1 criteria
timeFrame: One year
measure: Number of participants with tolerability to the treatment.
timeFrame: From the 1st day of therapy and every week for 4 weeks maximum and 30 days after last therapy administration ]
measure: The burden of somatic non-synonymous mutations in association with BOR and survival
timeFrame: At baseline
measure: The interferon-gamma gene signature in association with BOR and survival
timeFrame: At baseline
measure: The expression of PD-L1 in association with BOR and survival
timeFrame: At baseline and at 4 weeks
measure: The expression of human leukocyte antigens, HLA class I and HLA class II molecules in association with BOR and survival
timeFrame: At baseline
measure: The presence of adaptive immunity cell populations
timeFrame: At baseline and at 4 weeks
measure: The expression of PD-L2 in association with BOR and survival
timeFrame: At baseline and at 4 weeks
measure: PD-L1 expression in circulating tumor cells (CTCs) in association with BOR and survival
timeFrame: At baseline and at 4 weeks
Other outcomes:
Locations:
city: Athens
country: Greece
facility: Attikon Hospital
state: Chaidari
Study officials:
affiliation: ATTIKON HOSPITAL, NATIONAL AND KAPODISTRIAN UNIVERSITY OF ATHENS, GREECE
name: AMANDA PSYRRI, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hamid O, Schmidt H, Nissan A, Ridolfi L, Aamdal S, Hansson J, Guida M, Hyams DM, Gomez H, Bastholt L, Chasalow SD, Berman D. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med. 2011 Nov 28;9:204. doi: 10.1186/1479-5876-9-204.