Supersaturated Calcium Phosphate Rinse in Preventing Oral Mucositis in Young Patients Undergoing Autologous or Donor Stem Cell Transplant

PRIMARY OBJECTIVES:

I. To determine if topically administered supersaturated calcium phosphate (Caphosol), rinsed orally four times daily at the initiation of conditioning for hematopoietic stem cell transplantation (HSCT), reduces oral mucositis as demonstrated by a decrease in duration of severe oral mucositis (World Health Organization \[WHO\] grade 3 or 4), compared to placebo.

SECONDARY OBJECTIVES:

I. To determine whether Caphosol administration, when compared to placebo, reduces oral mucositis as demonstrated by a decrease in incidence of severe oral mucositis (WHO grade 3 or 4); severity of mucositis according to mouth pain categorical rating scale and Oral Mucositis Daily Questionnaire (OMDQ); incidence, total dose, and duration of parenteral opioid analgesic use (morphine equivalents); and incidence and duration of total parenteral nutrition (TPN) administration.

II. To determine whether Caphosol administration, when compared to placebo, reduces the incidence of febrile neutropenia and invasive bacterial infections.

III. To validate a new pediatric measure of oral mucositis termed the Children's International Mucositis Evaluation Scale (ChIMES).

OUTLINE: This is a multicenter study. Patients are stratified according to conditioning regimen (total-body irradiation (TBI) or melphalan vs neither TBI nor melphalan) and hematopoietic stem cell transplantation (HSCT) (autologous vs allogeneic). Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients rinse and gargle with supersaturated calcium phosphate rinse over 1 minute four* times daily (QID) beginning on the first day (about day -7) of the conditioning regimen.

ARM II: Patients rinse and gargle with placebo over 1 minute QID* beginning the first day (about day -7) of the conditioning regimen.

NOTE: * Patients who reach WHO grade 3 or 4 mucositis have the option to request a total of 6 rinses daily.

In both arms, treatment continues until day 20 post-transplantation OR until mucositis resolves to WHO grade =< 2 for two consecutive days OR on day 12 in patients who do not experience oral mucositis of at least WHO grade >= 1. Patients are assessed daily by trained healthcare professionals using the Oral Mucositis Daily Questionnaire (OMDQ), the Pain Rating Scale, the WHO Mucositis Scale, and the Children's International Mucositis Evaluation Scale (ChIMES) from day -1 and continuing until day 20. Patients are also observed for the incidence of total dose and duration of parenteral opioid analgesic use, duration of total parenteral nutrition (TPN) administration, febrile neutropenia, and invasive bacterial infections.

After completion of study therapy, patients are followed up for 30 days.

• supersaturated calcium phosphate rinse (Drug), also known as Caphosol: Mouth rinse
• placebo (Other), also known as PLCB: Mouth rinse
• questionnaire administration (Other): Ancillary studies
• quality-of-life assessment (Procedure), also known as quality of life assessment: Ancillary studies

Primary outcomes

• Duration of Severe Oral Mucositis (WHO Grade 3 or 4) [Day -1 (day prior to stem cell infusion) to Day 20 following transplantation.]: Mean days of severe (WHO Grade 3 or 4) Mucositis.

Secondary outcomes

• Incidence of Severe Oral Mucositis [Day -1 (day prior to stem cell infusion) to Day 20 following transplantation.]: Percentage of patients with Severe Oral Mucositis (WHO Grade 3 or 4) per arm.
• Oral Mucositis Daily Questionnaire (OMDQ) [Day -1 (day prior to stem cell infusion) to Day 20 following transplantation]: Area under the curve (AUC) of the Oral Mucositis Daily Questionnaire (OMDQ) subscales
• Incidence of Parenteral Opioid Analgesic Use (Morphine Equivalents). [Day -1 (day prior to stem cell infusion) to Day 20 following transplantation.]: Opioid Administration = yes
• Duration of Parenteral Opioid Analgesic Use (Morphine Equivalents). [Day -1 (day prior to stem cell infusion) to Day 20 following transplantation.]: Mean days of parenteral opioid analgesic use.
• Total Dose of Parenteral Opioid Analgesic Used (Morphine Equivalents). [Day -1 (day prior to stem cell infusion) to Day 20 following transplantation.]: Morphine equivalent dose in mg/kg/day
• Incidence of Total Parenteral Nutrition (TPN) Administration. [Day -1 (day prior to stem cell infusion) to Day 20 following transplantation.]: Total Parenteral Nutrition = yes
• Duration of Total Parenteral Nutrition (TPN) Administration. [Day -1 (day prior to stem cell infusion) to Day 20 following transplantation.]: Mean days of total parenteral nutrition (TPN) administration.
• Incidence of Febrile Neutropenia [Day -1 (day prior to stem cell infusion) to Day 20 following transplantation.]: Fever and Neutropenia = yes
• Incidence of Invasive Bacterial Infections [Day -1 (day prior to stem cell infusion) to Day 20 following transplantation.]: Invasive Bacterial Infection = yes
• Severity of Mucositis [Day -1 (day prior to stem cell infusion) to Day 20 following transplantation]: Area Under the Curve of Severity of Mucositis. According to mouth pain categorical rating scale ranges 0-10 with higher scores reflecting more severe pain.

Other outcomes

• Ancillary Validation Study of ChIMES [Day -1 (day prior to stem cell infusion) to Day 20 following transplantation.]

Sex: All, ages: 4 Years to 21 Years

Inclusion Criteria:

* Patients undergoing myeloablative autologous or allogeneic hematopoietic stem cell transplantation (HSCT) for any indication
* One or more of the following donor stem cell sources (autologous or allogeneic):

  * Bone marrow
  * Placental blood (umbilical cord blood)
  * Cytokine-mobilized peripheral blood
* Patients eligible for allogeneic HSCT must have one of the following types of donor stem cells:

  * Human leukocyte antigen (HLA)-matched sibling or parent
  * Partially matched family donor (mismatched for a single HLA locus \[Class I\])
  * Fully matched unrelated marrow or peripheral blood stem cell donor
  * HLA-matched or partially mismatched (at least 4 of 6 match) cord blood (Class I or II)
* Patients expecting to receive any type of myeloablative HSCT conditioning regimen are eligible

  * No non-myeloablative or reduced-intensity conditioning regimens
* Eligible patients must not have received palifermin within 30 days prior to enrollment
* Eligible patients must not have received prior treatment with Caphosol

Exclusion Criteria:

* Females of childbearing potential must have a negative pregnancy test; patients must agree to use an effective birth control method; lactating patients must agree not to nurse a child while on this trial

Participant flow

Outcome results

• Duration of Severe Oral Mucositis (WHO Grade 3 or 4) (Primary), Mean, Number of days: Arm I (Placebo) 4.5 +/- 4.8; Arm II (Supersaturated Calcium Phosphate Rinse) 4.5 +/- 5
• Incidence of Severe Oral Mucositis (Secondary), Number, percent of patients: Arm I (Placebo) 68; Arm II (Supersaturated Calcium Phosphate Rinse) 63
• Oral Mucositis Daily Questionnaire (OMDQ) (Secondary), Mean, units on a scale * day: Arm I (Placebo) 9.3 +/- 10.9; Arm II (Supersaturated Calcium Phosphate Rinse) 7.3 +/- 9
• Incidence of Parenteral Opioid Analgesic Use (Morphine Equivalents). (Secondary), Number, percentage of participants: Arm I (Placebo) 88.7; Arm II (Supersaturated Calcium Phosphate Rinse) 91.3
• Duration of Parenteral Opioid Analgesic Use (Morphine Equivalents). (Secondary), Mean, Days: Arm I (Placebo) 14.2 +/- 9.5; Arm II (Supersaturated Calcium Phosphate Rinse) 12.5 +/- 8.7
• Total Dose of Parenteral Opioid Analgesic Used (Morphine Equivalents). (Secondary), Median, mg/kg/day of opioid analgesics: Arm I (Placebo) 0.4 (0 to 33.2); Arm II (Supersaturated Calcium Phosphate Rinse) 0.3 (0 to 13.4)
• Incidence of Total Parenteral Nutrition (TPN) Administration. (Secondary), Number, percentage of participants: Arm I (Placebo) 78.3; Arm II (Supersaturated Calcium Phosphate Rinse) 72.1
• Duration of Total Parenteral Nutrition (TPN) Administration. (Secondary), Mean, Number of days: Arm I (Placebo) 13.6 +/- 9.9; Arm II (Supersaturated Calcium Phosphate Rinse) 11.4 +/- 8.9
• Incidence of Febrile Neutropenia (Secondary), Number, percentage of participants: Arm I (Placebo) 65.1; Arm II (Supersaturated Calcium Phosphate Rinse) 67.3
• Incidence of Invasive Bacterial Infections (Secondary), Number, percentage of participants: Arm I (Placebo) 6.6; Arm II (Supersaturated Calcium Phosphate Rinse) 7.7
• Severity of Mucositis (Secondary), Mean, units on a scale * day: Arm I (Placebo) 45.5 +/- 36; Arm II (Supersaturated Calcium Phosphate Rinse) 44 +/- 35.6
• Ancillary Validation Study of ChIMES (Other pre specified)

Adverse events

Serious adverse events by term

Other adverse events by term

• Treister N, Nieder M, Baggott C, Olson E, Chen L, Dang H, Krailo M, August A, Sung L. Caphosol for prevention of oral mucositis in pediatric myeloablative haematopoietic cell transplantation. Br J Cancer. 2017 Jan 3;116(1):21-27. doi: 10.1038/bjc.2016.380. Epub 2016 Nov 22. PMID 27875526

• Nathaniel Treister, MD, Principal investigator, Children's Oncology Group

NIH grants: U10CA095861