Mitoxantrone HCl Rx

Acute Nonlymphocytic Leukemia

In two large randomized multicenter trials, remission induction therapy for acute nonlymphocytic leukemia (ANLL) with mitoxantrone 12 mg/m² daily for 3 days as a 10-minute IV infusion and cytarabine 100 mg/m² for 7 days given as a continuous 24-hour infusion was compared with daunorubicin 45 mg/m² daily by IV infusion for 3 days plus the same dose and schedule of cytarabine used with mitoxantrone. Patients who had an incomplete antileukemic response received a second induction course in which mitoxantrone or daunorubicin was administered for 2 days and cytarabine for 5 days using the same daily dosage schedule. 

Results showed that treatment with mitoxantrone plus cytarabine (MIT) achieved the following response rates and median survival days compared with daunorubicin plus cytarabine (DAUN), respectively: 

• US Trial:

• % Complete response (CR): 63% (n=62/98) vs 53% (n=54/102)

• Median time to CR (days): 35 vs 42

• Survival (days): 312 vs 237

• International Trial:

• % CR: 50% (n=56/112) vs 51% (n=62/123)

• Median time to CR (days): 36 vs 42

• Survival (days): 192 vs 230

In these studies, 2 consolidation courses were administered to complete responders on each arm. Consolidation therapy consisted of the same drug and daily dosage used for remission induction, but only 5 days of cytarabine and 2 days of mitoxantrone or daunorubicin were given. The first consolidation course was administered 6 weeks after the start of the final induction course if the patient achieved a complete remission. The second consolidation course was generally administered 4 weeks later. Full hematologic recovery was necessary for patients to receive consolidation therapy. 

For the US trial, median granulocyte nadirs for patients receiving mitoxantrone + cytarabine for consolidation courses 1 and 2 were 10/mm³ for both courses, and for those patients receiving daunorubicin + cytarabine nadirs were 170/mm³ and 260/mm³, respectively. Median platelet nadirs for patients who received mitoxantrone + cytarabine for consolidation courses 1 and 2 were 17,000/mm³ and 14,000/mm³, respectively, and were 33,000/mm³ and 22,000/mm³ in courses 1 and 2 for those patients who received daunorubicin + cytarabine. The benefit of consolidation therapy in ANLL patients who achieve a complete remission remains controversial. However, in the only well-controlled prospective, randomized multicenter trials with mitoxantrone in ANLL, consolidation therapy was given to all patients who achieved a complete remission. During consolidation in the U.S. study, two myelosuppression-related deaths occurred in the mitoxantrone arm and one on the daunorubicin arm. However, in the international study there were eight deaths on the mitoxantrone arm during consolidation which were related to the myelosuppression and none on the daunorubicin arm where less myelosuppression occurred.

Multiple Sclerosis (Study 1)

• Study 1 is a randomized, controlled study conducted in 188 patients with secondary progressive or progressive relapsing multiple sclerosis who had experienced a mean deterioration in EDSS (Kurtzke Expanded Disability Status Scale) of about 1.6 points over the 18 months prior to enrollment. Patients were randomized to receive placebo, 5 mg/m² mitoxantrone, or 12 mg/m² mitoxantrone administered IV every 3 months for 2 years. High-dose methylprednisolone was administered to treat relapses. 

• A multivariate analysis of five clinical variables (EDSS, Ambulation Index [AI], number of relapses requiring treatment with steroids, months to first relapse needing treatment with steroids, and Standard Neurological Status [SNS]) was used to determine primary efficacy.

• At month 24, results showed that treatment with mitoxantrone 12 mg/m² met the primary efficacy multivariate analysis vs placebo (P <.0001). Moreover, treatment with mitoxantrone 5 mg/m² and 12 mg/m² achieved the following results at month 24 from baseline vs placebo, respectively: 

• EDSS change (mean): -0.23 and -0.13 vs 0.23 (P =.0194)

• Ambulation Index change (mean): 0.41 and 0.30 vs 0.77 (P =.0306)

• Mean number of relapses per patient requiring corticosteroid treatment (adjusted for discontinuation): 0.73 and 0.40 vs 1.20 (P =.0002)

• Months to first relapse requiring corticosteroid treatment (median [1st quartile]): Not reached (NR) [6.9] and NR [20.4] vs 14.2 [6.7] (P =.0004)

• Standard Neurological Status change (mean): -0.38 and -1.07 vs 0.77 (P =.0269)

• MRI (Number of patients with new Gd-enhancing lesions): 11% (n=4/37) and 0% (n=0/31) vs 16% (n=5/32) (P =.022)

• MRI (Change in number of T2-weighted lesions, mean [n]): 0.68 (34) and 0.29 (28) vs 1.94 (32) (P =.027)

Multiple Sclerosis (Study 2)

• A second randomized, controlled study (Study 2) evaluated mitoxantrone in combination with methylprednisolone (MP) and was conducted in patients with secondary progressive or worsening relapsing-remitting multiple sclerosis who had residual neurological deficit between relapses. All patients had experienced at least two relapses with sequelae or neurological deterioration within the previous 12 months. The average deterioration in EDSS was 2.2 points during the previous 12 months. 

• During the screening period, patients were treated with two monthly doses of 1 g of IV MP and underwent monthly MRI scans. Only patients who developed at least one new Gd-enhancing MRI lesion during the 2-month screening period were eligible for randomization. A total of 42 evaluable patients received monthly treatments of 1 g of IV MP alone (n = 21) or ~12 mg/m² of IV mitoxantrone plus 1 g of IV MP (n = 21) (MIT + MP) for 6 months. Patients were evaluated monthly, and study outcome was determined after 6 months. 

• The primary measure of effectiveness in this study was a comparison of the proportion of patients in each treatment group who developed no new Gd-enhancing MRI lesions at 6 months; these MRIs were assessed by a blinded panel. Additional outcomes were measured, including EDSS and number of relapses, but all clinical measures in this trial were assessed by an unblinded treating physician. 

• At month 6, results showed that 90% (n=19/21) of patients treated with MIT+ MP met the primary endpoint with no new Gd-enhancing lesions on MRI compared with 31% (n=5/21) of those treated with MP alone (P =.001). Moreover, treatment with MIT + MP achieved the following secondary endpoints at month 6 vs MP alone, respectively: 

• EDSS change: -1.1 vs -0.1 (P =.013)

• Annualized relapse rate (mean per patient): 0.7 vs 3.0 (P =.003)

• Patients (%) without relapses: 14 (67%) vs 7 (33%) (P =.031)

Advanced Hormone-Refractory Prostate Cancer

Phase 2 Trial

• A multicenter trial of mitoxantrone and low-dose prednisone (M + P) was conducted in 27 symptomatic patients with hormone-refractory prostate cancer. Using NPCP (National Prostate Cancer Project) criteria for disease response, there was 1 partial responder and 12 patients with stable disease. However, 9 patients or 33% achieved a palliative response defined on the basis of reduction in analgesic use or pain intensity.

• These findings led to the initiation of a randomized multicenter trial (CCI-NOV22) comparing the effectiveness of (M + P) to low-dose prednisone alone (P) in 161 patients with metastatic or locally advanced disease that had progressed on standard hormonal therapy, a castrate serum testosterone level, and at least mild pain at study entry. Patients received either mitoxantrone 12 mg/m² by short IV infusion every 3 weeks (n=80) or prednisone 5 mg twice a day (n=81). Patients randomized to the prednisone arm were crossed over to the M + P arm if they progressed or if they were not improved after a minimum of 6 weeks of therapy with prednisone alone.

• Results showed that 29% of patients treated with M + P achieved a primary palliative response (defined as a 2-point decrease in pain intensity in a 6-point pain scale, associated with stable analgesic use, and lasting a minimum of 6 weeks) compared with 12% of patients treated with P alone (P =.011). Two responders left the study after meeting primary response criterion for two consecutive cycles. For the purposes of this analysis, these two patients were assigned a response duration of zero days. 

• Additionally, 38% of patients treated with M + P achieved an overall palliative response (defined as primary plus secondary responses; secondary response was defined as a 50% or greater decrease in analgesic use, associated with stable pain intensity, and lasting a minimum of 6 weeks) compared with 21% of patients treated with P alone (P =.025).

• The median duration of primary palliative response for patients randomized to M + P was 7.6 months compared with 2.1 months for patients randomized to P alone (P =.0009). The median duration of overall palliative response for patients randomized to M + P was 5.6 months compared with 1.9 months for patients randomized to P alone (P =.0004).

• Time to progression was defined as a 1-point increase in pain intensity, or a > 25% increase in analgesic use, or evidence of disease progression on radiographic studies, or requirement for radiotherapy. The median time to progression for all patients randomized to M + P was 4.4 months compared with 2.3 months for all patients randomized to P alone (P =.0001). Median time to death was 11.3 months for all patients on the M + P arm compared with 10.8 months for all patients on P alone (P =.2324).

• 48 patients on the P arm crossed over to receive M + P. Of these, thirty patients had progressed on P, while 18 had stable disease on P. The median cycle of crossover was 5 cycles (range of 2 to 16 cycles). Time trends for pain intensity prior to crossover were significantly worse for patients who crossed over than for those who remained on P alone (P =.012). Nine patients (19%) demonstrated a palliative response on M + P after crossover. The median time to death for patients who crossed over to M + P was 12.7 months.

• In the CCI-NOV22 trial, 33% of all patients randomized to the M + P arm had a PSA fall of 50% or greater for 2 consecutive follow-up assessments after baseline compared with 9% of all patients randomized to the P arm. These findings should be interpreted with caution since PSA responses were not defined prospectively. A number of patients were inevaluable for response, and there was an imbalance between treatment arms in the numbers of evaluable patients. In addition, PSA reduction did not correlate precisely with palliative response, the primary efficacy endpoint of this study. Also, among 42 evaluable patients on this arm who did not have this reduction in PSA, 8 nonetheless had a primary palliative response.

Phase 3 Comparative Trial

• Investigators at Cancer and Leukemia Group B (CALGB) conducted a phase 3 comparative trial of mitoxantrone plus hydrocortisone (M + H) vs hydrocortisone alone (H) in patients with hormone-refractory prostate cancer (CALGB 9182). Eligible patients were required to have metastatic disease that had progressed despite at least one hormonal therapy. Patients received mitoxantrone 14 mg/m² intravenously every 21 days and hydrocortisone was administered orally at a daily dose of 40 mg. A total of 242 patients were randomly assigned to receive M + H (n=119) or H (n=123). There were no differences in survival between the two arms, with a median of 11.1 months in the M + H arm and 12 months in the H arm (P = 0.3298).

• Using NPCP criteria for response, partial responses were achieved in 10 patients (8.4%) randomized to the M + H arm compared with 2 patients (1.6%) randomized to the H arm (P = 0.018). The median time to progression, defined by NPCP criteria, for patients randomized to the M + H arm was 7.3 months compared to 4.1 months for patients randomized to H alone (P =.0654).

• Approximately 60% of patients on each arm required analgesics at baseline. Analgesic use was measured in this study using a 5-point scale. The best percent change from baseline in mean analgesic use was -17% for 61 patients with available data on the M + H arm, compared with +17% for 61 patients on H alone (P = 0.014). A time trend analysis for analgesic use in individual patients also showed a trend favoring the M + H arm over H alone but was not statistically significant.

• Pain intensity was measured using the Symptom Distress Scale (SDS) Pain Item 2 (a 5-point scale). The best percent change from baseline in mean pain intensity was -14% for 37 patients with available data on the M + H arm, compared with +8% for 38 patients on H alone (P =.057). A time trend analysis for pain intensity in individual patients showed no difference between treatment arms.