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

Phase 1

Active, not recruiting

Conditions: Xerostomia Following Radiotherapy

Interventions: Biological: Autologous bone-marrow derived, interferon gamma stimulated mesenchymal stromal cells

Registration Number: NCT04489732

Lead Sponsor: University of Wisconsin, Madison

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.

Per Amendment Approved 4/14/23: Sub-study added, all enrolled participants will be offered injection of MSCs into the contralateral submandibular gland upon completion of the trial's primary objective (1 month of follow-up after injection of MSCs without any DLTs). The MSC IMP will be injected into the contralateral submandibular gland under local anesthesia.

Participants will complete 5 follow-up visits over the course of 24 months - at 1, 3, 6, 12, and 24 months following the contralateral injection. Salivary collection for analysis as well as QoL surveys will be obtained at all visits, except the 24 month follow-up visit.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 6

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment with MSCs	Autologous bone-marrow derived, interferon gamma stimulated mesenchymal stromal cells	A single dose of MSCs injected into the submandibular glands of patients with radiation-induced xerostomia (primary objective) Following primary outcomes, a second injection of 10 (8 - 12) x 106 MSCs will be offered for injection into each participant's contralateral submandibular gland.

Primary Outcome Measures

Name	Time	Method
Percentage of Subjects Experiencing Dose Limiting Toxicity (DLT)	up to 1 month post injection (up to 3 months from consent)	Dose limiting toxicity is defined as: submandibular pain \> 5 on a 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.

Secondary Outcome Measures

Name	Time	Method
Saliva Composition Analysis: Change in Amylase Concentration in Saliva	baseline (up to 8 weeks before injection), 1, 3, 6, 12, and 24 months post-injection	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.
Saliva Composition Analysis: Change in Mucin Concentration in Saliva	baseline (up to 8 weeks before injection), 1, 3, 6, 12, and 24 months post-injection	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.
Change in Salivary Gland Stiffness Measured by Shear Wave Velocity	baseline (up to 8 weeks before injection), 3, 6, and 12 months post-injection	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)
Participant Drop Out Rate	up to 24 months post-injection (up to 26 months from consent)	Study feasibility will in part be measured by participant drop out rate.
Change in Saliva Production Rate	baseline (up to 8 weeks before injection), 1, 3, 6, 12, and 24 months post-injection	Whole saliva production rates will be measured under unstimulated and stimulated saliva collection conditions.
Saliva Composition Analysis: Change in Total Protein Concentration in Saliva	baseline (up to 8 weeks before injection), 1, 3, 6, 12, and 24 months post-injection	ELISA will be used to quantify total protein concentration in saliva. The normal range of total protein in saliva is 2-5 mg/mL.
Change in Salivary Gland Size	baseline (up to 8 weeks before injection), 3, 6, and 12 months post-injection	Salivary gland size measured by ultrasound imaging
Saliva Composition Analysis: Change in Salivary pH	baseline (up to 8 weeks before injection), 1, 3, 6, 12, and 24 months post-injection	Salivary pH will be measured using a pH meter. The normal range of saliva pH is 6.2-7.6 .
Change in Visual Analogue Scale (VAS) Xerostomia Score	baseline (up to 8 weeks before injection), 1, 3, 6, 12, and 24 months post-injection	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
Change in The University of Michigan Xerostomia Related Quality of Life (XeQOL) Score	baseline (up to 8 weeks before injection), 1, 3, 6, 12, and 24 months post-injection	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.
Change in The MD Anderson Dysphagia Index (MDADI) Score	baseline(up to 8 weeks before injection), 1, 3, 6, 12, and 24 months post-injection	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.