Incidence of WHO Grade 4 Oral Mucositis

20%

62%

Median (25^th, 75^th percentile) Days of WHO Grade 2/3/4 Oral Mucositis

8 (4, 12)

14 (11, 19)

Opioid Analgesia for Oral Mucositis:    

Median (25^th, 75^th percentile) Days

7 (1, 10)

11 (8, 14)

Median (25^th, 75^th percentile) Cumulative Dose (morphine mg equivalents)

212 (3, 558)

535 (269, 1429)

* P < 0.001 compared to placebo, using Generalized Cochran-Mantel-Haenszel (CMH) test stratified for study center. P-values presented for primary endpoint only.

** WHO Oral Mucositis Scale: Grade 1 = soreness/erythema; Grade 2 = erythema, ulcers, can eat solids; Grade 3 = ulcers, requires liquid diet only; Grade 4 = alimentation not possible.

Figure 1. Incidence of Oral Mucositis by Maximum Grade in Study 1

In Study 1, patients used a daily diary to record the amount of mouth and throat soreness. Compared with placebo-treated patients, Kepivance® -treated patients reported less mouth and throat soreness.

Study 2 was a randomized, multi-center, placebo-controlled study comparing varying schedules of Kepivance® . All patients received high-dose cytotoxic therapy consisting of fractionated TBI (12cGy total dose), high-dose etoposide (60 mg/kg), and high-dose cyclophosphamide (75-100 mg/kg) followed by PBPC support for the treatment of hematological malignancies (NHL, Hodgkins disease, AML, ALL, CML, CLL, or multiple myeloma).

The results of Study 1 were supported by results observed in the subset of patients in Study 2 who received the same dose and schedule of Kepivance® as given in Study 1. Compared with placebo, there was a reduction in median days of WHO Grade 3/4 oral mucositis (4 vs. 6 days), lower incidence of WHO Grade 3/4 oral mucositis (67% vs. 80%) and lower incidence of WHO Grade 4 oral mucositis (26% vs. 50%) for Kepivance® .

One of the schedules tested in Study 2 randomized patients to receive Kepivance® for 3 consecutive days prior to initiation of cytotoxic therapy, a dose given on the last day of TBI prior to etoposide, and for 3 consecutive days following infusion of PBPC. This arm was prematurely closed by the Safety Committee after enrollment of 35 patients due to lack of efficacy and a trend towards increased severity and duration of oral mucositis as compared to placebo-treated patients. This finding was attributed to administration of Kepivance® within 24 hours of chemotherapy, resulting in an increased sensitivity of the rapidly dividing epithelial cells in the immediate post-chemotherapy period (see PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION).

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