Novantrone clinical trial abstracts from ECTRIMS

[xo++]

Below find most of the clinical trial abstracts on Novantrone from ECTRIMS. Still not clear whether Novantrone is effective in primary progressive MS. Results have been mixed in trials.

However Novantrone appears to be the most effective FDA-approved drug for RRMS and SPMS, but carries with it a slight risk of leukemia and a larger risk of permanent heart damage. Novantrone was compared to Cytoxan in one study and found similar in effectiveness. The authors fail to mention that Cytoxan significantly increases the risk of particular cancers.

One trial below found that Novantrone produced an 89% greater reduction in enhancing lesions at months 6 and 9 after beginning treatment, than Copaxone, although Copaxone became more effective as the trial progressed.

A small study below is looking at a protocol for protecting ovarian tissue from Novantrone.

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Efficacy of mitoxantrone and intrathecal triamcinolone acetonide treatment in chronic progressive multiple sclerosis patients

K. Hellwig, T. Mueller, C. Lukas, S. Schimrigk (Bochum, D)

Treatment approaches are rare for chronic progressive patients with multiple sclerosis. Objective was to evaluate the clinical benefit of repeat intrathecal application of the sustained release steroid triamcinolone acetonide or the administration of mitoxantrone in two similar cohorts of chronic progressive patients with multiple sclerosis in an open label fashion. EDSS scores significantly decreased after the first six intraspinal triamcinolone acetonide injections, which were performed every third day, and then remained stable.

Walking distance significantly increased and did not reduce until the end of the one year lasting trial period. Mitoxantrone treatment did not improve the EDSS score, however no further significant deterioration appeared. Walking distance did not significantly decrease. Both treatment regimes were safe, the patients experienced nearly no side effects.

Triamcinolone acetonide application provided a clinical benefit, whereas mitoxantrone administration prevented further worsening of multiple sclerosis symptoms. We stress, that only specialists with a broad experience of intraspinal triamcinolone acetonide application and mitoxantrone administration should perform both kinds of therapy only after a careful information and risk-benefit evaluation in cooperation with the patient.

Future trials will show the efficacy of combination of both treatment approaches in chronic progressive patients with multiple sclerosis.

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Short-term induction with mitoxantrone preceding treatment with glatiramer acetate offers early and pronounced effects on MRI-disease activity in patients with relapsing forms of multiple sclerosis

T. Vollmer, H. Panitch, M.S. Freedman, S.K. Gasda, A. Bar-Or, D.L. Arnold (Phoenix, Burlington, USA; Ottawa, Montreal, CAN)

Induction therapy followed by maintenance therapy is used in treating some autoimmune diseases, but rarely used for MS. We hypothesized that treatment with glatiramer acetate after depletion of the autoaggressive T cell population with mitoxantrone might prevent or delay the regrowth of the autoaggressive T cell population and enhance the induction of regulatory GA-specific T-cells, possibly inducing a long-term remission.

Objectives: To ascertain whether short-term induction of immunosuppression using mitoxantrone in patients with MS accelerates the onset and enhances the efficacy of long-term glatiramer acetate treatment.

Methods: RMS patients age 18 and 55 years with a gadolinium enhancing lesion on screening MRI and EDSS score 0-6.5 were randomized to receive either IV infusions of mitoxantrone monthly for three month followed by sc injections of GA 20 mg/d two weeks after the last infusion for a total treatment period of 15 months (M-GA, n =21), or GA 20 mg/d for 15 months (GA, n = 19).

Brain MRIs were performed at screening, and months 6, 9, 12, and 15. Suspected on-trial relapses were confirmed at an unscheduled visit.

Primary outcomes were tolerability and safety as measured by laboratory assessments and the incidence of adverse events. Secondary efficacy measures were the number of Gd-enhanced lesions, relapse rate and changes in EDSS.

Results: Of 93 subjects screened, 43 were randomized, 3 discontinued prior to ever receiving study drug, leaving 40 (62.5% female) eligible. The majority of screen failures (54%) did not meet MRI inclusion criteria. Baseline age (mean ± SD) (37.2 ± 9.7 years), disease duration (3.5 ± 4.8 years), EDSS (2.4 ± 1.2), and number of Gd-enhancing lesions (3.75 ± 3.95), were well-matched in the two arms.

M-GA induction produced an 89% greater reduction (relative risk = 0.11, 95% CI = 0.04-0.36, p = 0.0001) in the total number of Gd-enhancing lesions at months 6 and 9, compared to GA alone.

The efficacy of M-GA induction was sustained at 15 months, while that of GA increased progressively over the 15 months: Gd-enhancing lesion frequency was decreased by 47% at 9 months and 87% at 15 months. Mean relapse rate during the study period was 0.16 in the M-GA group and 0.32 in the GA group. Both treatments were safe.

Conclusions: Short term induction with mitoxantrone followed by daily injections GA 20 mg/d for 15 months is safe and very effective, producing an 89% decrease in MRI-disease activity that occurs early and is sustained.

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Clinical effect of mitoxantrone in patients with multiple sclerosis

E. Kkolou, J. Toufexis, E. Gaglia, M. Pantzaris (Nicosia, CY)

Purpose: To assess the efficacy of Mitoxantrone (MITO) in progressive Multiple Sclerosis (MS).

Methods: 75 patients with progressive MS were included. 34 patients (45.3%) had worsening relapsing remitting (RR) MS, 24 patients (32%) secondary progressive (SP) MS and 17 patients (22.7%) primary progressive (PP) MS.

Mean age of onset of the disease was 34 years. Mean duration of the disease was 13 years. The mean annual relapse rate was 2.17 and the mean worsening of the EDSS score was 0.76 for the worsening RR group for the 12 months before introducing MITO.

The mean worsening of the EDSS score was 0.71 for the SP group and 0.78 for the PP group for the 12 months before introducing MITO. All patients received 12 mg/m2 MITO intravenously every 3 months for a total of 12 months .All patients were evaluated by cardiac echo at baseline and every 6 months.

Results: 43 patients (57.3%) discontinued the study. Main causes of discontinuation were: patient’s decision/no drug effect (17.3%), worsening (10.7%), cardiovascular side effects (8%),psychological side-effects (6.75), infections ((4%), white blood cell dyscrasias (4 %), urogenital side-effects (2.7%), and liver dysfunction (2.7%).

Worsening relapsing remitting patients concluding study period (N=20):

The mean annual relapse rate was 1.12, a 48.4% reduction from baseline. 6 patients (30%) were relapse-free. 5 patients (25%) had a relapse reduction of 50% or greater. 9 patients (45%) did not show any significant change from baseline or had an increase in the number of relapses.

Two patients (10%) showed improvement on the EDSS by 0.5 point. Nine patients (45%) remained stable. The EDSS score of seven patients (35%) worsened by 0.5 points, and in another two patients (10%) worsened by 1 point.

Secondary progressive patients concluding study period (N= 7): The EDSS score of four patients (57.1%) worsened by 0.5 points, and in another three patients (42. 9%) worsened by 1 point.

Primary progressive patients concluding study period (N= 5): One patient (20 %) showed improvement on the EDSS by 1.5 point. One patient (20%) remained stable. The EDSS score of two patients (40%) worsened by 0.5 points, and in one patient (20) worsened by 1.5 point.

Conclusion: Mitoxantrone is beneficial in reducing the number of relapses as well as improving or stabilizing the EDSS score in some patients with worsening RR and PP multiple sclerosis.

Mitoxantrone is also beneficial to patients with SP Multiple Sclerosis delaying the progression of the disease.

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Long-term safety profile of mitoxantrone in a French cohort of 802 multiple sclerosis patients: final report

E. Le Page, E. Leray, B. Brochet, M. Clanet, P. Clavelou, C. Confavreux, M. Debouverie, C. Lebrun, C. Lubetzki, M. Madigand, J. Pelletier, E. Roullet, L. Rumbach, D. Brassat, G. Edan (Rennes, Bordeaux, Toulouse, Clermont-ferrand, Lyon, Nancy, Nice, Paris, Saint Brieuc, Marseille, Besan*on, F)

Objective: To determine the long term incidence of drug related adverse events in a cohort of multiple sclerosis (MS) patients treated with Mitoxantrone (MITOX).

Background: MITOX is approved for the treatment of MS in the US and several European countries. In 2001, a French multicenter study was set up to determine the long-term safety profile of MITOX in a large cohort of MS patients. Since then, data were up-dated yearly. Every patient has currently a minimal follow-up duration of 5 years after MITOX start.

Design/Patients/Methods: 802 MS patients (308 Relapsing-Remitting MS, 352 Secondary Progressive MS, and 142 Primary Progressive MS) were treated with MITOX in 12 French MS centers. MITOX was administered either monthly over six months in 87 % or every 3 months in 13 % of the cohort.

Patients underwent clinical and hematological evaluations before every MITOX infusion and every 6 months after MITOX treatment end, up to 5 years. Echocardiograms were performed at MITOX treatment start and end and thereafter every year up to 5 years.

Results: The cohort had a follow-up duration of 5361 patient-years. 1/802 patients presented with acute congestive heart failure (0.1 %). 39/794 patients (4.9%) experienced at least once an asymptomatic LVEF reduction under 50%: persisting in 10 patients, transitory in 26 patients and to be followed in 3 patients.

There were also 2 cases of therapy-related leukemia (0.25 %), detected 20 and 22 months after initiating MITOX treatment (1 death and 1 remission). 17.3% of 317 women treated before 45 years old developed a persistent amenorrhea (5.4% treated before and 30.7% treated after age of 35 years). Final updates concerning cardiac and hematological tolerance, reproductive function will be presented.

Conclusion: This large cohort with at least 5 years of follow-up gave good insights into the long-term safety profile of Mitoxantrone in MS.

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Clinical follow-up of 304 patients with multiple sclerosis three years after mitoxantrone treatment

M. Sauvee, S. Pittion-Vouyovitch, M. Debouverie, L. Taillandier on behalf of the Lorsep Group

Objective: To assess the benefits of (1) mitoxantrone after three years of follow-up and (2) disease-modifying treatment (DMT) after stopping mitoxantrone.

Methods: A retrospective analysis was performed on 304 patients with active relapsing remitting, or progressive MS who were treated with one of two different regimens of mitoxantrone: either a monthly intravenous infusion of mitoxantrone (20 mg) for 6 months (relapsing-remitting MS-RRMS), or an intravenous bolus (12 mg/m2) every 3 months for 2 years (progressive MS-PMS).

After mitoxantrone therapy, some patients received DMT (interferon-beta or glatiramer acetate) while others did not. The disease course of the two groups was evaluated by the Expanded Disability Status Scale (EDSS) before and after mitoxantrone and then every year for three years.

Results: The mean EDSS at starting mitoxantrone and three years after stopping mitoxantrone respectively, were: 3.3 (1.3) and 3.2 (1.7) for the RRMS patients and 5.9 (1.2) and 6.4 (1.4) for the PMS patients. At one, two and three years after the end of the mitoxantrone therapy, disability was no significant difference between patients who were treated with DMT and those who were not.

Before starting mitoxantrone, demographic and clinical parameters of predictive disability were not significantly different between patients who received DMT or not. The variation of EDSS between time of stopping mitoxantrone and three years later was significantly different (+0.9 vs +0.3; p=0.03) for patients with RRMS.

Conclusions: We found a clinical benefit of mitoxantrone for RRMS patients 3 years after stopping treatment. Overall, there was no significant difference between the group of patients treated with DMT and those who were not. A moderate benefit of DMT was found for patients with RRMS during the 3rd year after the end of mitoxantrone therapy.

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Intravenous cyclophosphamide and mitoxantrone therapy in multiple sclerosis: a comparative study of efficacy and safety

V. Zipoli, E. Portaccio, B. Hakiki, G. Siracusa, S. Sorbi, M.P. Amato (Florence, I)

Background: Among immunosuppressive therapies considered to be efficacy in very active and rapidly progressive multiple sclerosis (MS), mitoxantrone (MTX) has been approved; however, its long-term use is limited due to its cardiotoxicity.

Although intravenous (iv) cyclophosphamide (CTX) therapy may represent an alternative option, to date published studies have provided conflicting evidences on its efficacy and there are few studies comparing the two drugs.

Objective: To compare the clinical efficacy and safety of CTX and MTX in a cohort of patients with very active relapsing-remitting (RR) or secondary progressive (SP) MS.

Methods: The study sample consisted of patients with very active RRMS (>/= 2 relapses in the last year) or SPMS (>/= 0.5 or 1.0 point deterioration on the EDSS over the last year). MTX was administered iv at a dosage of 8 mg/m^2 monthly for 3 months, then every 3 months, until a cumulative dosage of 100 mg/m^2 was reached. CTX was administered iv at the dosage of 700 mg/ m^2 monthly for 12 months, then bimonthly for another 12 months.

We evaluated the treatment efficacy in terms of time to the first relapse in RR and relapsing SP patients, and of time to disease progression on the EDSS in the subgroup of patients with purely SPMS, using the Kaplan-Meier curves. Moreover, we assessed the frequency of side effects and the overall tolerability by the patient perspective using a visual analogue scale (VAS).

Results: 75 patients received MTX (49 female; 31 RR, 44 SP) and 78 CTX (50 female ;15 RR, 63 SP). The two groups did not significantly differ in terms of main demographic and clinical characteristics. The Kaplan-Meier curves did not demonstrate significant differences in terms of time to the first relapse (MTX 3.0±0.4, versus CTX 3.0±0.6 years; p=0.50), and in terms of disease progression (MTX 2.9±0.3, CTX 2.5+/-0.4years ; p=0.17).

On the whole, the safety profile of both therapy was acceptable. However, a significantly higher proportion of patients discontinued therapy due to side effects in the CTX group (22% versus 5%; p<0.01).

On the other hand, amenorrhea was significantly more frequent in the MTX group than in the CTX one (37% versus 12%; p<0.01). Finally, the overall tolerability assessed through the VAS score resulted to be comparable in the 2 groups.

Conclusions: In our sample, MTX and CTX therapy showed a comparable clinical efficacy. Both the drugs showed acceptable safety and tolerability profiles.

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Ongoing evaluation of the safety and tolerability of Novantrone® (mitoxantrone) worsening multiple sclerosis: the RENEW study

E. Fox, A. Al-Sabbagh, R. Bennett, P. Coyle, D. Mikol, H. Panitch, V. Rivera, L. Rolak, W. Sheremata, S.B. Elias on behalf of the RENEW Study Group

Background: Novantrone® (mitoxantrone) therapy is currently being evaluated for long-term safety and tolerability in patients with worsening relapsing-remitting MS (WRRMS), progressive relapsing MS (PRMS) and secondary progressive MS (SPMS) as part of the ongoing multicenter, open-label RENEW (Registry to Evaluate Novantrone Effects in Worsening MS) study.

Objectives: To evaluate the continuing safety and tolerability of mitoxantrone in MS patients using the dosing and monitoring guidelines specified in the Novantrone package insert.

Methods: 509 patients with WRRMS, PRMS, or SPMS who initiated Novantrone(12mg/m²) were included. Patients were excluded for: primary progressive MS (PPMS); history of congestive heart failure (CHF); left ventricular ejection fraction (LVEF) <50%; and previous treatment with mitoxantrone, other anthracenediones or anthracyclines. Patients were assessed every 3 months during treatment (3 years) and are being followed for an additional 2 years for safety evaluation (total:5 years).

Results: Data presented include data collected from April 2001 to Jan 2006 for 509 patients. Mean cumulative dose is 67.5mg/m² (8.0-148.6mg/m²) and mean treatment duration is 1.4 years (0.0-4.0). 16 patients have reached the recommended maximum cumulative dose (140mg/m²). 355 (70.0%) patients have received concomitant medications for MS.

Treatment discontinuation occurred in 404/508 (80%) subjects with validated data. Follow-up data are being collected for 361 patients regardless of treatment status (those receiving mitoxantrone [104] plus patients who discontinued mitoxantrone [257 of the 404]).

301 relapses were reported during treatment in 221 patients. Median time to first relapse was 155 days (range: 3-1215).

95 patients experienced 158 AEs. The most frequently reported SAEs were infectious (54/158 [34%]) and cardiac events (36/158 [23%]). CHF was reported in 8 patients, and LVEF <50% was observed in 24/340 (4.7%) patients with post-baseline LVEF tests. 9/46 patients with serious infections were severely neutropenic (ANC<500). There have been 7 deaths: 5 unrelated and 2 possibly related to treatment. One therapy-related leukemia case has been reported.

Conclusions: These results, reflecting patient treatment at higher cumulative mitoxantrone doses (mean: 67.5mg/m^2), appear consistent with the known safety profile. Continued patient observation will provide important longer-term safety and tolerability data for mitoxantrone use in clinical practice.

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Prevention of persistent ovarian failure after mitoxantrone in women with MS. Design of a treatment protocol with triptorelin

N. Téllez, J. Gris, M. Tintoré, J. Río, C. Nos, Í. Galán, R. Pelayo, X. Montalban (Barcelona, E)

Introduction: Mitoxantrone is an immunosuppressive agent currently used in MS patients non responders to immunomodulation. Many adverse events have been attributed to the drug. Leukaemia and cardiopathy are the most serious although the less frequent.

Other such as nausea and vomiting, hair loss and amenorrhoea are more common. The known odds ratio to develop persistent amenorrhoea after mitoxantrone is about 8.5 and consequences are double: infertility and early menopause.

Proposed options to protect the ovarian tissue in women at risk are cryopreservation of mature oocytes, embryos or ovarian tissue, although these options are not fully accepted yet. Alternatives such as gonadotropin-releasing hormone analogue (GnRH-a) have been used in oncohematological disorders showing a capacity to prevent gonadal damage after chemotherapy with no major side effects.

Objective: Our aim was to study the ovarian function after a GnRH-a treatment, the triptorelin, in MS women on mitoxantrone.

Protocol design: A protocol has been designed with the following inclusion criteria: women with relapsing remitting or secondary progressive MS, non responders to interferon beta, with an age between 18-45 that are invited to start mitoxantrone.

Patients are then planned to be on treatment with a monthly intramuscular injection of triptorelin for12 months. Serial gynaecological evaluations are performed at baseline visit, day 15, month 2, 12, 13 (end of study) and 14 (follow-up visit).

Before starting mitoxantrone the baseline visit include: 1. Plasma levels of luteinising and follicle-stimulating hormone, estradiol, prolactine, thyroid profile and inhibine, 2. Echography to assess the ovarian size, number of follicles >5 mm and endometrium characteristics, 3.

Doppler of the uterin and ovarian arteries and 4. Bone densitometry. At each visit time the hormonal analysis, the echography and the Doppler are repeated. Densitometry is repeated at the end of the study. Mitoxantrone is started after the first dose of triptorelin, and its efficacy and side effects are assessed every three months by the by neurologist.

Current status: Since 2004 we have started mitoxantrone in 10 women. Six of them were younger than 45 and were referred to gynaecology to start triptorelin. No dropouts or relevant side effects have been identified since then. At present only two women have finished the protocol. New results will be presented.

[Lazarus]

Since the novantrone discusson is back on the front burner for me, I selfishly and truly appreciate the posts here and the ones on IVIg which I have been studying for many hours now.

I'm having a bit more luck understanding how irrigating tomatoes just before the sun comes up when there has been a frost, will save the tomatoes from bursting their cells. I hope I have as much clear insight to what researchers are thinking about treating SPMS.

Linda Lazarus

[*Joy*]

XO

It's so very nice to see your informative posts again! Thank you.

:)

Joy

[xo++]

Hi Linda,

I just look forward to the day when members of our community do not have to choose between therapies with the potential for grave harm which may or may not work and highly probable disability progression.

Thanks Joy, good to see everyone returning. :)

Mark

[TheSleeper]

Thanks XO! you always seem to find good info!