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

Phase 2

Completed

Conditions: Head and Neck Cancer
Head and Neck Squamous Cell Carcinoma

Interventions: Drug: Cyclophosphamide
Drug: Cetuximab

Registration Number: NCT01581970

Lead Sponsor: Masonic Cancer Center, University of Minnesota

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 7

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Cetuximab/low dose Cyclophosphamide	Cyclophosphamide	Safety population as defined by all patients receiving at least one treatment with cyclophosphamide on Day 1.
Cetuximab/low dose Cyclophosphamide	Cetuximab	Safety population as defined by all patients receiving at least one treatment with cyclophosphamide on Day 1.

Primary Outcome Measures

Name	Time	Method
Progression	At 2 Years	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.

Secondary Outcome Measures

Name	Time	Method
Aggregate Ratio of Tregs to Effector Cells for All Participants	6 Weeks Post Treatment with Cyclophosphamide	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.
Myeloid-derived Suppressor Cells in Tumor Tissue	Week 6	Myeloid-derived suppressor cells in tumor tissue as measured by immune-histochemistry (IHC)
Overall Survival	2 years	Defined as the number of patients alive two years out from study enrollment.
Aggregate Ratio of Tregs to Natural Killer (NK) Cells for All Participants	6 Weeks Post Treatment with Cyclophosphamide	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.
Quality of Life Scores	Comparison from Baseline to Week 6 and Week 12	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.