Potentiation of Cetuximab by Tregs Depletion With CSA in Advanced Head & Neck Cancer

Potentiation of Cetuximab by Tregs Depletion With Metronomic Cyclophosphamide in Metastatic Squamous Cell Cancers of Head and Neck

This is a feasibility study to assess the effectiveness of cetuximab when administered with low dose oral cyclophosphamide. Patients with metastatic squamous cell cancer of head and neck who have progressed on first line chemotherapy other than a cetuximab containing regimen will be treated with standard of care weekly cetuximab and twice daily low dose oral cyclophosphamide for 12 weeks.

Study Overview

• Status: Completed
• Conditions: Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Cetuximab

Detailed Description

In this study, patients with head and neck squamous cell carcinoma (HNSCC) will be given low-dose cyclophosphamide in combination with standard of care cetuximab. Tumor biopsies will be collected before and six weeks after treatment for measurement of tumor infiltration by effector cells, including CD8+ T cells, natural killer (NK) cells, and monocytes. In addition, the proportion of Regulatory T Cells (Tregs) to effector cells will be measured in peripheral blood at the same time points.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Masonic Cancer Center, University of Minnesota

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Histologically documented squamous cell carcinoma of the head and neck (irrespective of site of primary - nasopharyngeal, oral cavity, oropharyngeal, laryngeal or unknown primary) that is metastatic/incurable and has progressed on a first line chemotherapy regimen.
• Progression of measurable disease within the last 6 weeks based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria
• If the patient has received prior treatment with anti-epidermal growth factor receptor (EGFR) therapy as a part of definitive therapy concurrent with radiation, the time from the last cetuximab exposure must be > 180 days.
• Must be at least 30 days from prior treatment and have recovered from the reversible effects of previous anti-cancer treatment
• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1 or 2

• Adequate bone marrow, renal and hepatic function within 14 days of study enrollment defined as:

  • Bone marrow: White blood cells (WBC) > 3,000/uL; absolute neutrophil count > 1,500/uL; platelets > 100,000/uL
  • Renal: creatinine ≤ 2.5 times the institutional upper limit of normal (ULN)
  • Hepatic: total bilirubin < 1.5 X institutional ULN; aspartate aminotransferase/alanine aminotransferase (AST[SGOT] and ALT[SGPT]) < 2.5 X institutional ULN
  • Albumin > 3.0 gm/dL
• Women of childbearing potential and fertile men must be willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study and for 60 days after the last dose of study drug.
• Voluntary written consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care

Exclusion Criteria:

• Pregnant or lactating - females of child bearing potential must have a negative pregnancy test within 14 days of study enrollment as cyclophosphamide is Pregnancy Category D
• History of another active primary invasive cancer within the previous 2 years, excluding non-melanoma skin cancer
• The patient is receiving concurrent treatment with other anticancer therapy, including chemotherapy, immunotherapy, hormonal therapy, radiotherapy (RT), chemoembolization, or targeted therapy. Patients receiving palliative radiation therapy to bony metastases prior to the first dose of study medication are eligible.
• Chronic steroid dependence
• Known HIV-positive patients and those with other acquired/inherited immunodeficiency hepatitis B, hepatitis C, connective tissue disease, or other clinical diagnosis, ongoing or intercurrent illness that in the Investigator's opinion should preclude the subject from participation
• History of gastrointestinal disease causing malabsorption or obstruction such as, but not limited to Crohn's disease, celiac sprue, tropical sprue, bacterial overgrowth/blind loop syndrome, gastric bypass surgery, strictures, adhesions, achalasia, bowel obstruction, or extensive small bowel resection
• Inability to take medications by mouth
• History of allergic reactions attributed to compounds of similar chemical or biologic composition
• Active autoimmune disease, chronic inflammatory condition, conditions requiring concurrent use of any systemic immunosuppressants or steroids. Mild-intermittent asthma requiring only occasional beta-agonist inhaler use or mild localized eczema will not be excluded.
• Previous allo-transplant of any kind

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Cetuximab/low dose Cyclophosphamide; Safety population as defined by all patients receiving at least one treatment with cyclophosphamide on Day 1.

Drug: Cyclophosphamide; Patients will be given oral cyclophosphamide 50 mg twice daily to be self-administered starting the first day of therapy with weekly cetuximab for 12 weeks or until disease progression.; Other Names: Cytoxan; Drug: Cetuximab; The initial dose of cetuximab 400 mg/m^2 is administered over 120 minutes followed by weekly infusions of cetuximab 250 mg/m^2 intravenously (IV) over 60 minutes.; Other Names: Erbitux

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression	The number of patients without disease progression two years out from study enrollment. Progression of disease is defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria and is as at least a 20% increase in size of the lesion(s) being followed and/or the appearance of one or more new lesions.	At 2 Years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Aggregate Ratio of Tregs to Effector Cells for All Participants	The ratio of Tregs to effector cells (NK cells, CD 8+ lymphocytes, macrophages/monocytes) in tumor tissue as measured by immune-histochemistry (IHC) of tumor tissue for all Participants. Measure of central tendency was collected but the data is not accessible anymore because PI left institution and did not respond to requests for data.	6 Weeks Post Treatment with Cyclophosphamide
Aggregate Ratio of Tregs to Natural Killer (NK) Cells for All Participants	the Ratio of Tregs to NK cells in peripheral blood as measured by flow cytometry for all Participants. Measure of central tendency was collected but the data is not accessible anymore because the PI left institution and did not respond to requests for data.	6 Weeks Post Treatment with Cyclophosphamide
Myeloid-derived Suppressor Cells in Tumor Tissue	Myeloid-derived suppressor cells in tumor tissue as measured by immune-histochemistry (IHC)	Week 6
Quality of Life Scores	Comparison of health related quality of life scores as measured by FACT-G: Functional Assessment of Cancer Therapy - General (constitutes the core of all subscales; the FACT-G can be used with patients of any tumor type)questionnaire. At this point, the data is not able to be analyzed because the PI left the institution and did not respond to requests for data.	Comparison from Baseline to Week 6 and Week 12
Overall Survival	Defined as the number of patients alive two years out from study enrollment.	2 years

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota
• Investigators: Principal Investigator: Gautam Jha, M.D., Masonic Cancer Center, University of Minnesota

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (Actual): September 1, 2015
• Study Completion (Actual): September 1, 2015

Study Registration Dates

• First Submitted: April 18, 2012
• First Submitted That Met QC Criteria: April 19, 2012
• First Posted (Estimate): April 20, 2012

Study Record Updates

• Last Update Posted (Actual): September 11, 2019
• Last Update Submitted That Met QC Criteria: September 10, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: head and neck cancer; metastatic squamous cell cancer
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Carcinoma, Squamous Cell; Head and Neck Neoplasms; Squamous Cell Carcinoma of Head and Neck; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Cyclophosphamide; Cetuximab
• Other Study ID Numbers: 2012LS002