MSC in Patients With Xerostomia Post XRT in Head and Neck Cancer

Study Overview
=================
Brief Summary
-----------------
This is a single center pilot study designed to determine the safety and tolerability of autologous bone marrow-derived Mesenchymal Stromal Cells (MSCs) in patients with xerostomia (dry mouth) after undergoing radiation therapy (XRT) for head and neck cancer (HNC). Up to 12 participants will be enrolled and can expect to be on study for up to 2 years.

Detailed Description
-----------------
Following the completion of screening/baseline procedures, and written consent, eligible participants will undergo bone marrow aspirate in order to obtain MSCs. The MSC Investigational Medicinal Product (IMP) (dose level 0, n=6, staggered) will be injected into one submandibular gland under local anesthesia, in the gland that received the lowest radiation dose. Patients with only one submandibular gland will be ineligible. All participants will be called by a study coordinator 3 days (+/- 2 days) after injection to assess pain and will have a phone visit with a physician 1 week (+/- 2 days) after injection during which the investigator will assess pain and ask about the area of injection regarding redness and/or swelling. All participants will complete a pain diary with daily entries over the first month to record the occurrence and severity of pain using a 0-10 visual analog scale and occurrence and severity of other adverse events (e.g., redness, swelling, warmth, tenderness, rash, pruritis, nausea, vomiting, fatigue). Participants will also keep a log of all pain medications taken including both narcotic and non-narcotic medications (e.g. ibuprofen, acetaminophen, etc.) for the first month. Participants will complete 5 follow-up visits over the course of 24 months - at 1, 3, 6, 12, and 24 months following the intervention. Salivary collection for analysis as well as QoL surveys will be obtained at these visits. Dose Reduction: If dose limiting toxicity (DLT) in less than or equal to 1 participant (n=6 participants, staggered at least 14 days), Dose Level 0 will be recommended as starting dose for subsequent trial. If DLT in greater than 1 participant, dose level -1 will be administered, staggered at least 14 days in n=6 participants. If DLT in this cohort is in less than or equal to 1 participant, Dose Level -1 will be recommended as starting dose for subsequent trial. If DLT in greater than or equal to 2 participants, study will be stopped. Primary Objective To evaluate the safety and tolerability of MSCs for subjects with xerostomia after radiation therapy for HNC. Secondary Objectives To evaluate the efficacy of MSCs for treatment of xerostomia and salivary hypofunction via quality-of-life (QoL) questionnaires, salivary amount, and salivary compositional analysis. To assess the imaging characteristics in HNC patients after MSC injection using ultrasound. To assess the feasibility of a future Phase 1 dose-escalation study.

Official Title
-----------------
Pilot Study of Mesenchymal Stromal Cells in Patients With Xerostomia After Radiation Therapy for Head and Neck Cancer

Conditions
-----------------
Xerostomia Following Radiotherapy

Intervention / Treatment
-----------------
* Biological: Autologous bone-marrow derived, interferon gamma stimulated mesenchymal stromal cells


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Willing to provide informed consent Willing to comply with all study procedures and be available for the duration of the study Histological diagnosis of Head and Neck Cancer (HNC) and ≥ 2 years from completion of treatment for HNC, either clinically or radiologically No Evidence of Disease (NED), as assessed by ENT or Radiation Oncologist within 28 days of study registration Individuals at least 18 years of age and no older than 90 years of age Xerostomia defined as less than or equal to 80 percent of baseline (pre-radiation) salivary function per patient estimate Karnofsky performance status ≥ 70, patient eligible for bone marrow aspirate with wakeful anesthesia Radiographically confirmed bilateral submandibular glands Females of childbearing potential must agree to have a negative urine or serum pregnancy test within 7 days prior to bone marrow biopsy. A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months) Women of childbearing potential in sexual relationships with men must have used an acceptable method of contraception for 30 days prior to study registration and agree to use an acceptable method of contraception until 4 weeks after completing study treatment. Males must agree to avoid impregnation of women during and for four weeks after completing study treatment through use of an acceptable method of contraception. Note: Acceptable method of contraception includes, but is not limited to, barrier with additional spermicidal foam or jelly, intrauterine device, hormonal contraception (started at least 30 days prior to study enrollment), intercourse with men who underwent vasectomy) Exclusion Criteria: History of sialolithiasis Patients with one submandibular gland History of autoimmune diseases affecting salivary glands, including Sjögren's syndrome, lupus, scleroderma, type I diabetes, sarcoidosis, and amyloidosis Chronic graft vs host disease Untreated oral candidiasis Use of anti-cholinergic medications (e.g. atropine, ipratropium, oxybutynin, scopolamine, solifenacin, tiotropium, etc…) while enrolled on study Malignancy within the past 2 years, except adequately treated stage I lung cancer, low risk prostate cancer that has been treated or is undergoing active surveillance, adequately treated non-melanoma skin cancer, adequately treated ductal carcinoma in situ (DCIS), or adequately treated stage I cervical cancer Expected life expectancy ≤ 6 months Lidocaine allergy Use of investigational drugs, biologics, or devices within 30 days prior to enrollment Women who are pregnant, lactating or planning on becoming pregnant during the study Not suitable for study participation due to other reasons at the discretion of the investigators

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: single-center, open-label, non-randomized, non-placebo controlled, single-group assignment, pilot study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment with MSCs<br>A single dose of MSCs injected into the submandibular glands of patients with radiation-induced xerostomia | Biological: Autologous bone-marrow derived, interferon gamma stimulated mesenchymal stromal cells<br>* Single dose, starting at Dose Level 0: 10 x 10^6 injected into one submandibular gland on Day 1<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of subjects experiencing dose limiting toxicity (DLT) | Dose limiting toxicity is defined as: submandibular pain > 5 on a standard 10-point pain scale of 0-10 at 1-month after MSC injection OR any serious AE OR any of the selected toxicities listed per protocol within one-month post-injection. | up to 1 month post injection (up to 3 months from consent) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Saliva production rate | Whole saliva production rates will be measured under unstimulated and stimulated saliva collection conditions. | baseline (up to 8 weeks before injection), 1, 3, 6, 12, and 24 months post-injection | 
| Saliva composition analysis: Change in salivary pH | Salivary pH will be measured using a pH meter. The normal range of saliva pH is 6.2-7.6 . | baseline (up to 8 weeks before injection), 1, 3, 6, 12, and 24 months post-injection | 
| Saliva composition analysis: Change in total protein concentration in saliva | ELISA will be used to quantify total protein concentration in saliva. The normal range of total protein in saliva is 2-5 mg/mL. | baseline (up to 8 weeks before injection), 1, 3, 6, 12, and 24 months post-injection | 
| Saliva composition analysis: Change in amylase concentration in saliva | The enzyme-linked immunosorbent assay (ELISA) will be used to quantify amylase concentration in saliva. The normal range of amylase concentration in saliva is 10-150 U/mL. | baseline (up to 8 weeks before injection), 1, 3, 6, 12, and 24 months post-injection | 
| Saliva composition analysis: Change in mucin concentration in saliva | ELISA will be used to quantify mucin concentration in saliva.The normal range of mucin concentration in saliva is 1,000-3,000 ug/mL. | baseline (up to 8 weeks before injection), 1, 3, 6, 12, and 24 months post-injection | 
| Change in The University of Michigan Xerostomia Related Quality of Life (XeQOL) score | The University of Michigan Xerostomia Related Quality of Life (XeQOL) scale is a validated patient-reported assessment 15 item scale with 4 domains: physical functioning, pain/discomfort, personal/psychologic functioning, and social functioning. Participants will answer the questions on a scale of 1-5 (not a all, a little, somewhat, quite a bit, very much) for every item. Higher scores represent greater degree of symptoms. | baseline (up to 8 weeks before injection), 1, 3, 6, 12, and 24 months post-injection | 
| Change in The MD Anderson Dysphagia Index (MDADI) score | The MDADI is a 20-item questionnaire designed for evaluating the impact of dysphagia on the quality of life of patients with head and neck cancer. The MDADI score ranges from 20-100 with a lower scale representing worse dysphagia. | baseline(up to 8 weeks before injection), 1, 3, 6, 12, and 24 months post-injection | 
| Change in Visual Analogue Scale (VAS) xerostomia score | A Visual Analogue Scale questionnaire for subjective assessment of salivary dysfunction. The VAS xerostomia questionnaire is an 8-item questionnaire that provides a validated measure of the perception of dry mouth. Participants will be asked to mark their responses to each item by placing a vertical line on the 100-mm horizontal scale. The VAS ranges from 8-80 with a lower scale representing less dysphagia/symptoms | baseline (up to 8 weeks before injection), 1, 3, 6, 12, and 24 months post-injection | 
| Change in salivary gland size | Salivary gland size measured by ultrasound imaging | baseline (up to 8 weeks before injection), 3, 6, and 12 months post-injection | 
| Change in salivary gland stiffness measured by shear wave velocity | Salivary gland stiffness (fibrosis) will be measured by acoustic radiation force impulse imaging. Evaluators will be blinded to the time point of evaluation (pre- or post- MSC injection) | baseline (up to 8 weeks before injection), 3, 6, and 12 months post-injection | 
| Participant Drop out Rate | Study feasibility will in part be measured by participant drop out rate. | up to 24 months post-injection (up to 26 months from consent) |