Clinical trial NCT04489732: MSC in Patients With Xerostomia Post XRT in Head and Neck Cancer
Official title: Pilot Study of Mesenchymal Stromal Cells in Patients With Xerostomia After Radiation Therapy for Head and Neck Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Xerostomia Following Radiotherapy
Lead sponsor: University of Wisconsin, Madison
Sponsor class: OTHER
Collaborators: name: National Institute of Dental and Craniofacial Research (NIDCR)
First posted: 2020-07-28
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: single-center, open-label, non-randomized, non-placebo controlled, single-group assignment, pilot study
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Percentage of Subjects Experiencing Dose Limiting Toxicity (DLT)
timeFrame: up to 1 month post injection (up to 3 months from consent)
Secondary outcomes:
measure: Change in Saliva Production Rate
timeFrame: baseline (up to 8 weeks before injection), 1, 3, 6, 12, and 24 months post-injection
measure: Saliva Composition Analysis: Change in Salivary pH
timeFrame: baseline (up to 8 weeks before injection), 1, 3, 6, 12, and 24 months post-injection
measure: Saliva Composition Analysis: Change in Total Protein Concentration in Saliva
timeFrame: baseline (up to 8 weeks before injection), 1, 3, 6, 12, and 24 months post-injection
measure: Saliva Composition Analysis: Change in Amylase Concentration in Saliva
timeFrame: baseline (up to 8 weeks before injection), 1, 3, 6, 12, and 24 months post-injection
measure: Saliva Composition Analysis: Change in Mucin Concentration in Saliva
timeFrame: baseline (up to 8 weeks before injection), 1, 3, 6, 12, and 24 months post-injection
measure: Change in The University of Michigan Xerostomia Related Quality of Life (XeQOL) Score
timeFrame: baseline (up to 8 weeks before injection), 1, 3, 6, 12, and 24 months post-injection
measure: Change in The MD Anderson Dysphagia Index (MDADI) Score
timeFrame: baseline(up to 8 weeks before injection), 1, 3, 6, 12, and 24 months post-injection
measure: Change in Visual Analogue Scale (VAS) Xerostomia Score
timeFrame: baseline (up to 8 weeks before injection), 1, 3, 6, 12, and 24 months post-injection
measure: Change in Salivary Gland Size
timeFrame: baseline (up to 8 weeks before injection), 3, 6, and 12 months post-injection
measure: Change in Salivary Gland Stiffness Measured by Shear Wave Velocity
timeFrame: baseline (up to 8 weeks before injection), 3, 6, and 12 months post-injection
measure: Participant Drop Out Rate
timeFrame: up to 24 months post-injection (up to 26 months from consent)
Other outcomes:
Locations:
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
Study officials:
affiliation: University of Wisconsin, Madison
name: Randall J Kimple, MD,PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Wisconsin, Madison
name: Jacques Galipeau, MD
role: STUDY_DIRECTOR
References:
citation: Blitzer GC, Rogus-Pulia NM, Mattison RJ, Varghese T, Ganz O, Chappell R, Galipeau J, McDowell KA, Meyers RO, Glazer TA, Kimple RJ. Marrow-Derived Autologous Stromal Cells for the Restoration of Salivary Hypofunction (MARSH): Study protocol for a phase 1 dose-escalation trial of patients with xerostomia after radiation therapy for head and neck cancer: MARSH: Marrow-Derived Autologous Stromal Cells for the Restoration of Salivary Hypofunction. Cytotherapy. 2022 May;24(5):534-543. doi: 10.1016/j.jcyt.2021.11.003. Epub 2022 Feb 16.