Predictive Biomarkers for Response to Nivolumab in Head and Neck Squamous Cell Carcinoma

Predictive Biomarkers For Response To Nivolumab In Head and Neck Squamous Cell Carcinoma

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.

Study Overview

• Status: Unknown
• Conditions: DNA Damage; HNSCC; DNA Double Strand Break
• Intervention / Treatment: Other: Biomarker Research; Drug: Nivolumab

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.

• Study Type: Observational
• Enrollment (Anticipated): 50

Contacts and Locations

• Study Contact: Name: ELENI PAPASTAMATIOU; Phone Number: +302105831256; Email: lenagpa@yahoo.com

Study Locations

• Greece
  • Chaidari
    • Athens, Chaidari, Greece
      • Recruiting
      • Attikon Hospital
      • Contact: AMANDA PSYRRI, MD; Phone Number: +2105831664; Email: psyrri237@yahool.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• 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.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Recurrent/metastatic HNSCC; The investigators will include recurrent/metastatic HNSCC patients who progressed after cisplatin-based chemotherapy and are to be treated with nivolumab. Tumor biopsies will be performed at baseline, after the second cycle and at progression with appropriate written informed consent and the samples will be analyzed. Biomarker research will be performed. The patients will receive intravenously nivolumab at dose of 240 mg every 2 weeks (240mg q2w). The patients will undergo tumor biopsy at baseline and within 24-72h after the second administration of treatment, and at progression of their disease.

Other: Biomarker Research; The investigators will include recurrent/metastatic HNSCC patients who progressed after cisplatin-based chemotherapy and are to be treated with nivolumab 240mg IV q 2 weeks. Patient samples will be collected with appropriate written informed consent and analyzed.; Drug: Nivolumab; The investigators will include recurrent/metastatic HNSCC patients who progressed after cisplatin-based chemotherapy and are to be treated with nivolumab 240mg IV q 2 weeks.; Other Names: Opdivo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the percentage of immune cells in post treatment compared to baseline biopsies	Primary endpoint will be the change in mean percentage of immune cells that is caused by the nivolumab treatment	2 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of performing a biopsy after second nivolumab dose	Incidence of adverse events attributable to nivolumab treatment	6 weeks
Best overall response rate (BOR) according to 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}	One year
Number of participants with tolerability to the treatment.	NCI common toxicity criteria will be used	From the 1st day of therapy and every week for 4 weeks maximum and 30 days after last therapy administration ]
The burden of somatic non-synonymous mutations in association with BOR and survival	Targeted gene sequencing using next generation sequencing will be performed	At baseline
The interferon-gamma gene signature in association with BOR and survival	Nanostring gene expression profiling, multiple tumor, inflammatory- and immune related genes will be analyzed by multiplex Nanostring technology by using the nCounter PanCancer Immune Profiling 770-plex gene expression Panel	At baseline
The expression of PD-L1 in association with BOR and survival	PD-L1 will be assessed in tumor cells and immune cells by immunohistochemistry	At baseline and at 4 weeks
The expression of human leukocyte antigens, HLA class I and HLA class II molecules in association with BOR and survival	It will be assessed at RNA and protein level	At baseline
The presence of adaptive immunity cell populations	The assessment will be performed using multiplex imaging	At baseline and at 4 weeks
The expression of PD-L2 in association with BOR and survival	PD-L2 will be assessed in tumor cells and immune cells by immunohistochemistry	At baseline and at 4 weeks
PD-L1 expression in circulating tumor cells (CTCs) in association with BOR and survival	The assessment will be performed with Parsotrix system	At baseline and at 4 weeks

Collaborators and Investigators

• Sponsor: Attikon Hospital
• Investigators: Principal Investigator: AMANDA PSYRRI, MD, ATTIKON HOSPITAL, NATIONAL AND KAPODISTRIAN UNIVERSITY OF ATHENS, GREECE

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2018
• Primary Completion (Anticipated): May 1, 2020
• Study Completion (Anticipated): May 1, 2020

Study Registration Dates

• First Submitted: June 20, 2018
• First Submitted That Met QC Criteria: August 27, 2018
• First Posted (Actual): August 29, 2018

Study Record Updates

• Last Update Posted (Actual): August 29, 2018
• Last Update Submitted That Met QC Criteria: August 27, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: PD-1; PD-L1; DNA damage; HNSCC; Head and Neck cancer; DDR; DNA damage repair; NIVOLUMAB
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Head and Neck Neoplasms; Neoplasms, Squamous Cell; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: CA209-8EN

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No