多発性骨髄腫 Multiple Myeloma(MM)
研究ノート

■12. 分子標的療法

トリセノックス(Trisenox)


製品情報

製品名 トリセノックス(Trisenox)
一般名 三酸化ヒ素 (ATO: arsenic trioxide [As2O3])
慣用名 亜ヒ酸
開発 セル・セラピューティクス社(CTI: Cell Therapeutics, Inc.)
販売 日本新薬
製品 トリセノックス注(10mg1管)
薬価 35,230 (2004/12)
適応 再発難治性急性前骨髄性白血病(APL)
承認 日本新薬が2004年10月に輸入承認取得、12月から発売開始
(米FDAは、2000年に承認済み)

APL:Acute Promyelocytic Leukemia

作用機序

ATO併用療法

MAC療法

メルファラン+ATO(トリセノックス)+ビタミンC(アスコルビン酸)の併用療法

処方レジメン

2〜4時間かけて静脈内投与

APLレジメン:0.15mg/kg/日、60日間

MMレジメン:0.25mg/kg/日、月〜金曜、2週投薬/2週休薬

TA療法(トリセノックス+アスコルビン酸)
ATO(0.25mg/kg)+AA(1000mg)、25日間毎日
 
TAD療法(トリセノックス+アスコルビン酸+デキサメタゾーン)
1サイクル目:
第1週、ATO 0.25mg/kg(IV)1〜5日、各ATO点滴後30分以内にAA 1000mg(IV)、Dex 40mg(経口)1〜4日
第2〜12週、ATO 0.25mg/kg(IV)毎週2回、各ATO点滴後30分以内にAA 1000mg(IV)、Dex 40mg(経口)11〜14日、29〜32日、39〜42日、57〜60日、67〜70日。
第13〜15週、休止期間。
2および3サイクル目:
ATOとAAのレジメンは同じだが、Dex 40mg(経口)1〜4日、29〜32日、57〜60日、67〜70日に縮小。
 
MAC療法(メルファラン+トリセノックス+アスコルビン酸)
M 0.1mg/kg、4〜6週のサイクルの最初の4日間毎日、ATO 0.25mg/kg、毎週2回、そしてAA 1g、毎週2回

副作用

APL治療では
多形性心室頻拍および完全房室ブロックの起因となるQT時間の延長
低カリウム血症、高マグネシウム血症、高血糖、血小板減少(13%)
腹部痛、呼吸困難、低酸素症、骨痛、好中球減少(10%)
関節痛、熱性好中球現象、播種性血管内血液凝固(8%)
MAC療法:
骨髄抑制(貧血n=6、白血球減少症n=5および血小板減少症n=4)、QT間隔の延長(n=3)、胃腸の苦情(n=2)、帯状疱疹の復活(n=2)および頭痛(n=2)

臨床試験

Investigator
研究者
Treatment
治療法
Patients/ Evaluable
総患者/評価可能患者
Objective Responses*
有意反応
Stable Disease
疾病安定化
Bahlis (2002)[5] ATO(0.125/0.25mg/kg)
+AA(1g)
6 PR=2 (33%)
SD=4 (67%)
G3白血球減少症1
Hussein (2004)[6] ATO(0.25 mg/kg) 24 MR= 8(33%)
SD=6(25%)
G3/4白血球減少症16
Rousselot (2004)[7] ATO(0.15 mg/kg) 10 MR= 3(33%)
SD=4(25%)
G3白血球減少症4
Borad (2005)[8] ATO(0.25 mg/kg)
+AA(1g)
+Melphalan
10 >MR= 10(100%) 骨髄抑制、QTc延長
Berenson (2004)[9] ATO(0.25 mg/kg)
+AA(1g)
6 PR= 2(33%)
SD=4(67%)
白血球減少症
Berenson (ASH2004) ATO(0.25 mg/kg)
+AA(1g)
+Melphalan
14(20) PR=4/14(29%)
MR=4/14(29%)
SD=3/14(21%)
白血球減少症
Hussein TAD 19/17 MR=7 (41%)
SD= 7 (41%)
 
Lee [4] TA 6/6 MR=2 (33%)
SD=4 (67%)
 
Berenson MAC 7/7 MR=7 (100%)  
Hussein [3] T 24/21 MR=9 (43%)
SD= 8 (38%)
 
Berenson T + Steroids 16/13 MR=3 (23%)
SD= 4 (31%)
 
Munshi [1,2] T 14/14 MR=3 (21%)
SD= 1 (7%)
 

[1] Munshi N, Desikan R, Zangari M et al. Marked antitumor effect of arsenic trioxide (As2O3) in high risk refractory multiple myeloma. Blood 1999;94(suppl 10, pt 2):123a.

[2] Munshi NC. Arsenic trioxide: an emerging therapy for multiple myeloma. The Oncologist 2001;6(suppl 2):17-21.

[3] Hussein MA, Mason J, Ravandi F et al. A phase II clinical study of arsenic trioxide (ATO) in patients (Pts) with relapsed or refractory multiple myeloma (MM); a preliminary report. Blood 2001;98:378a.

[4] Bahlis NJ, Jordan-McMurry I, Grad JM et al. Phase I results from a phase I/II study of arsenic trioxide (As2O3) and ascorbic acid (AA) in relapsed and chemorefractory multiple myeloma. Blood 2001;98:375a.

[5] Bahlis NJ, et al. Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment of relapsed/refractory multiple myeloma. Clin Cancer Res. 2002 Dec;8(12):3658-68. [PubMed]

[6] Hussein MA, et al. Phase 2 study of arsenic trioxide in patients with relapsed or refractory multiple myeloma. Br J Haematol. 2004 May;125(4):470-6. [PubMed]

[7] Rousselot P, et al. A clinical and pharmacological study of arsenic trioxide in advanced multiple myeloma patients.
Leukemia. 2004 Sep;18(9):1518-21.
[PubMed]

[8] Borad MJ, et al. Efficacy of melphalan, arsenic trioxide, and ascorbic acid combination therapy (MAC) in relapsed and refractory multiple myeloma. Leukemia. 2005 Jan;19(1):154-6. [PubMed]

[9] Berenson JR, et al. A prospective, open-label safety and efficacy study of combination treatment with melphalan, arsenic trioxide, and ascorbic acid in patients with relapsed or refractory multiple myeloma. Clin Lymphoma. 2004 Sep;5(2):130-4. [PubMed]

[10] Berenson JR, et al. A Phase I/II Multicenter, Safety and Efficacy Study of Combination Treatment with Melphalan, Arsenic Trioxide and Vitamin C (MAC) in Patients with Relapsed or Refractory Multiple Myeloma. ASH[2398]

 

Chen YB, et al. Mechanism of arsenic trioxide-induced cytotoxicity on multiple myeloma cells. Ai Zheng. 2003 Dec;22(12):1276-9. Chinese. [PubMed]

McCafferty-Grad J, et al. Arsenic trioxide uses caspase-dependent and caspase-independent death pathways in myeloma cells. Mol Cancer Ther. 2003 Nov;2(11):1155-64. [PubMed]

Chen YB, et al. Effects of arsenic trioxide on cell cycle and expression of cyclin dependent kinase inhibitors of multiple myeloma cells. Zhonghua Xue Ye Xue Za Zhi. 2003 Apr;24(4):193-6. Chinese. [PubMed]

Akay C, Gazitt Y. Arsenic trioxide selectively induces early and extensive apoptosis via the APO2/caspase-8 pathway engaging the mitochondrial pathway in myeloma cells with mutant p53. Cell Cycle. 2003 Jul-Aug;2(4):358-68. [PubMed]

Liu Q, et al. Arsenic trioxide-induced apoptosis in myeloma cells: p53-dependent G1 or G2/M cell cycle arrest, activation of caspase-8 or caspase-9, and synergy with APO2/TRAIL. Blood. 2003 May 15;101(10):4078-87. Epub 2003 Jan 16. [PubMed]

Hayashi T, et al. Arsenic trioxide inhibits growth of human multiple myeloma cells in the bone marrow microenvironment. Mol Cancer Ther. 2002 Aug;1(10):851-60. [PubMed]

Munshi NC, et al. Clinical activity of arsenic trioxide for the treatment of multiple myeloma. Leukemia. 2002 Sep;16(9):1835-7. [PubMed]

ASH2003(12月)で報告されたアブストラクト:

ASH2004 [827]
「難治性で再発した多発性骨髄腫の治療において、メルファラン+三酸化砒素+アスコルビン酸(MAC)療法は有効である」

[827] Melphalan, Arsenic Trioxide and Ascorbic Acid (MAC) Is Effective in the Treatment of Refractory and Relapsed Multiple Myeloma (MM). Session Type: Oral Session

Mitesh Borad, Regina A. Swift, Karen Sadler, Hank Yang, James R. Berenson Institute for Myeloma and Bone Cancer Research, Los Angeles, CA, USA; Oncotherapeutics, Los Angeles, CA, USA; Tulane University School of Medicine, New Orleans, LA, USA

最近私達の研究所における生体外の研究で、三酸化砒素(ATO)がMM細胞株のメルファランの細胞毒性作用に対する感受性を高めることが実証されました。更に、アスコルビン酸は三酸化砒素の抗骨髄腫効果を増強します。そう言う訳で、私達は、10名の難治性MM患者を治療するために、メルファラン(0.05〜0.1mg/kg,4〜6週毎に4日間経口投与)とATO(0.25mg/kg,週に2回1〜2時間で静注)、およびアスコルビン酸(1g,ATO投与後15分以上で静注)の併用療法を評価しました。
Recent in vitro studies in our laboratory have demonstrated that arsenic trioxide (ATO) sensitizes MM cell lines to the cytotoxic effects of melphalan. In addition, ascorbic acid potentiates the anti-myeloma effects of arsenic trioxide. Thus, we have evaluated a combination of oral melphalan (0.05-0.1 mg/kg qd for four days every 4-6 weeks), ATO (0.25 mg/kg IV over 1-2 hours twice weekly) followed by ascorbic acid (1 g IV qd over 15 minutes after each ATO dose) to treat ten patients with refractory MM.
このレジメンを始める最後の5人の患者に、週二回のACスケジュールに加えてメルファランを投与するのと同じ4日間に、ATOとアスコルビン酸を投与しました。患者の特質には次のものがありました。年齢範囲は47歳〜76歳、男性が4名で女性が6名、IgG型(5名),IgA型(4名),軽鎖型(1名)、腎臓障害(5名;血清クレアチニン 各 2.3, 4.0, 5.1, 5.1, 6.1 mg/dL)。患者はMAC治療の前に、メルファラン(6名)、サリドマイド(7名)、ボルテゾミブ(5名)を含む多くの治療レジメンで効果が得られませんでした。

The last five patients starting on this regimen received the ATO and ascorbic acid on the same four days that melphalan was given in addition to the twice weekly AC schedule. Patient characteristics included the following: ages ranged from 47-76; four males and six females; IgG subtype (n=5), IgA subtype (n=4) and light chain only disease (n=1); and renal failure (n=5; serum creatinine 2.3, 4.0, 5.1, 5.1, and 6.1 mg/dL). The patients had failed multiple prior therapeutic regimens including melphalan (n=6), thalidomide (n=7) and bortezomib (n=5) prior to MAC administration.
MAC治療の開始時点で、最初の6名の患者は、継続中の経口グルココルチコイド(経口メチルプレドニゾロンやプレドニゾン、又はデキサメサゾン)を、MCA治療を開始する6〜8週間以内に中止しました。治療期間の範囲は14〜58週でした。すべての患者が反応し、血清Mタンパクレベルの減少は37-85%、および24時間尿Mタンパクレベルの減少は34-58%でした。
At the time of initiation of MAC therapy, the first six patients continued ongoing oral glucocorticoids (oral methylprednisolone, prednisone or dexamethasone), which were discontinued within 6-8 weeks of initiating MAC therapy. The duration of therapy ranged from 14-58 weeks. All patients responded with a reduction of 37-85% and 34-58% in the serum and 24-hour urine M-protein levels, respectively.
重要なことに、腎臓障害があった5名の患者すべてに、腎機能の改善が見られ、血清クレアチニンの減少率は35-68%に及びました。ゾレドロン酸による治療にもかかわらず重度の高カルシウム血症(初期の血清カルシウム19.4mg/dL)であった1名の患者では、MAC治療開始1週間以内に血清カルシウムが正常値に戻りました。
Importantly, in all five patients with renal failure, renal function improved with a reduction in the serum creatinine ranging from 35-68%. One patient with profound hypercalcemia (initial serum calcium 19.4 mg/dL) despite treatment with zoledronic acid normalized her serum calcium within one week of initiating MAC therapy.

Four patients eventually progressed after 14, 21, 26, and 40 weeks of MAC therapy and two of these patients died with progressive disease. The remaining six patients remain on treatment at 15, 15, 20, 44, 52, and 58 weeks including three of the patients with renal failure. In general, the treatment has been well-tolerated. Three patients required a reduction in the melphalan dose because of cytopenias. The dose of arsenic trioxide was decreased by 50% in one patient and two other patients were changed to a weekly dosing schedule of AC due to constitutional symptoms, skin rash, or peripheral neuropathy. The most common adverse events noted with this combination were fatigue (n=7, grade 1), marrow suppression (anemia n=7, grade 1-3, leukopenia n=7, grade 1-3 and thrombocytopenia n=4, grade 1-3), prolongation of the QT interval (n=5, grade 1), gastrointestinal complaints (n=4, grade 1), pulmonary and peripheral edema responsive to diuretic treatment (n=2, grade 3), reactivation of herpes zoster (n=2, grade 2), headache (n=2, grade 1), and skin rash (n=3, grade 2). The combination of low-dose oral melphalan, arsenic trioxide and ascorbic acid appears to be an effective treatment for patients with refractory myeloma, and can reverse renal failure among heavily pre-treated MM patients.

ASH2004(12月)で報告されたアブストラクト:

ASH2004[2398]
「再発又は難治性の多発性骨髄腫患者を対象としたメルファラン+三酸化砒素+ビタミンCによるMAC併用療法の安全性と有効性に関する第I/II相多施設共同研究」

Berenson JR, et al.
A Phase I/II Multicenter, Safety and Efficacy Study of Combination Treatment with Melphalan, Arsenic Trioxide and Vitamin C (MAC) in Patients with Relapsed or Refractory Multiple Myeloma. ASH[2398]

James R. Berenson. Oncology, Oncotherapeutics, Inc., Los Angeles, CA, USA

Background: An urgent need exists for new treatments to overcome chemoresistance in MM patients. Recent in vitro and In vivo studies in our laboratory show that arsenic trioxide (ATO) can sensitize chemoresistant MM cells to melphalan-induced cytotoxic effects. Pre-clinical studies also show the most profound anti-MM effects when ATO, ascorbic acid and melphalan are used in combination compared with the effects observed when the drugs are used alone or combinations of any two of these agents. Based on encouraging results from a pilot study1, a larger, multicenter trial was recently started.

Methods: MM patients who showed relapse after responding to first-line chemotherapy and/or having proved to be refractory to chemotherapy are enrolled. Patients received a loading dose of ATO at 0.25 mg/kg IV followed by ascorbic acid 1 g IV days 1-4 of week 1 of each six-week cycle. ATO/ascorbic acid was given twice-weekly for the next 4 weeks of each cycle. Low-dose melphalan (0.10 mg/kg) was administered orally for the first 4 days of each cycle. Patients received a maximum of 6 cycles followed by weekly maintenance treatment with weekly ATO followed by ascorbic acid. The primary objectives of this study are to determine response rate and safety and tolerability of MAC therapy.

Results: Twenty patients have received at least one treatment cycle. Preliminary data show that eight (4 PR, 4 MR) of the 14 evaluable patients (57%) had an objective response, an additional three patients achieved stable disease, resulting in a total of 11 patients (79%) with disease control. Since responses were seen after 2 to 5 treatment cycles, it is possible that some patients with stable disease may experience additional disease response. Seven of the eight responding patients had failed two or more treatments: five patients had received prior thalidomide therapy, two had received melphalan and bortezomib, and two patients had undergone autologous peripheral stem cell transplantation. Of the six patients who have now completed the maximal numbers of cycles, four achieved PR, one MR, and one SD. The regimen was well tolerated with few significant side effects reported; mild cytopenias were reported as reversible. Conclusions: These preliminary results in this treatment group of heavily pre-treated MM patients who had either relapsed or were refractory to standard and/or investigational multiple myeloma treatments suggests that the MAC treatment regimen (1) shows efficacy using a low dose of melphalan supporting the preclinical evidence that ATO can sensitize tumors to chemotherapy; (2) is well tolerated; (3) may require multiple cycles before response.

対象患者 20名
反応評価患者 14名
反応 PR=4/14(29%),MR=4/14(29%),SD=3/14(21%)
全サイクル終了者 PR=4/6(67%),MR=1/6(17%),SD=1/6(17%)

References:
1. Borad M, Swift R, Sadler K, Yang H, Berenson JR. Melphalan, Arsenic Trioxide and Ascorbic Acid (MAC) is Effective in the Treatment of Refractory and Relapsed Multiple Myeloma (MM). ASH 2003.
Abstract #2398 appears in Blood, Volume 104, issue 11, November 16, 2004
Keywords: Relapse|Trisenox|Myeloma

Sunday, December 5, 2004, 06:00 PM

Poster Session: Myeloma Therapy - Non-Transplant III (6:00 PM-7:30 PM)