患有復發及/或難治型多發性骨髓瘤的成年病患

主要目的： • 測定lenalidomide與dexamethasone的背景療法在加入口服MLN9708後，是否能提升復發及/或難治型多發性骨髓瘤(RRMM)病患的無惡化存活期(PFS)。 關鍵次要目的： • 測定lenalidomide與dexamethasone在加入口服MLN9708後是否可提升整體存活率(OS)。 • 測定lenalidomide與dexamethasone在加入口服MLN9708後是否可提升帶有del (17)缺失(deletion del [17])高風險病患的整體存活率(OS)。

MLN9708

Ixazomib citrate

膠囊劑

2.3; 3.0; 4.0

1. 評估病患服用MLN9708後是否能提升無惡化存活率。

-Overall Survival (OS) [ Time Frame: Date of randomization until death up to data cut-off: 30 October 2014 (approximate median follow-up 15 months) ] [ Designated as safety issue: No ]
Overall survival is defined as the time from the date of randomization to the date of death. Participants without documentation of death at the time of the analysis were censored at the date when they were last known to be alive.

-Overall Survival in High-Risk Participants Carrying Deletion 17 [Del(17)] [ Time Frame: At the time of screening; Day 1 of each cycle (every 4 weeks) until disease progression and thereafter every 12 weeks until death or study termination ] [ Designated as safety issue: No ]
Overall survival is defined as the time from the date of randomization to the date of death. The high-risk participants whose myeloma carried del(17) subgroup was defined as the cases reported as positive for del(17) by the central laboratory combined with those cases that lacked a central laboratory result but with known del (17) by local laboratory. Participants without documentation of death at the time of the analysis were censored at the date when they were last known to be alive.

-Overall Response Rate (ORR) as Assessed by the IRC [ Time Frame: Day 1 of each cycle (every 4 weeks) until disease progression up to data cut-off: 30 October 2014 (approximate median follow-up 15 months) ] [ Designated as safety issue: No ]
ORR was defined as the percentage of participants with Complete Response (CR) including stringent complete response (sCR), very good partial response (VGPR) and Partial Response (PR) assessed by the IRC using IMWG criteria.

-Percentage of Participants With Complete Response (CR) and Very Good Partial Response (VGPR) as Assessed by the IRC [ Time Frame: Day 1 of each cycle (every 4 weeks) until disease progression up to data cut-off: 30 October 2014 (approximate median follow-up 15 months) ] [ Designated as safety issue: No ]
Response was assessed by the IRC using International Myeloma Working Group (IMWG) Criteria. CR is defined as negative immunofixation on the serum and urine and; disappearance of any soft tissue plasmacytomas and; < 5% plasma cells in bone marrow. VGPR is defined as Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level < 100 mg per 24 hours.

-Duration of Response (DOR) [ Time Frame: Day 1 of each cycle (every 4 weeks) until disease progression up to data cut-off: 30 October 2014 (approximate median follow-up 15 months) ] [ Designated as safety issue: No ]
DOR was measured as the time in months from the date of first documentation of a confirmed response of PR or better (CR [including sCR] + PR+ VGPR) to the date of the first documented disease progression (PD) among participants who responded to the treatment. Response was assessed by the investigator using International Myeloma Working Group (IMWG) Criteria.

-Time to Progression (TTP) as Assessed by the IRC [ Time Frame: Day 1 of each cycle (every 4 weeks) until disease progression up to data cut-off: 30 October 2014 (approximate median follow-up 15 months) ] [ Designated as safety issue: No ]
TTP was measured as the time in months from the first dose of study treatment to the date of the first documented progressive disease (PD) as assessed by the IRC using IMWG criteria.

-Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: From the date of signing of the informed consent form through 30 days after the last dose of study drug up to data cut-off: 30 October 2014 (approximate median follow-up 15 months) ] [ Designated as safety issue: Yes ]
Eastern Cooperative Oncology Group (ECOG) performance score, laboratory values, vital sign measurements and reported adverse events (AEs) were collected and assessed to evaluate the safety of therapy throughout the study. An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event.

-Percentage of Participants Achieving Pain Response [ Time Frame: At screening; Day 1 of each cycle; and thereafter every 4 weeks until disease progression ] [ Designated as safety issue: No ]
Pain response was defined as 30% reduction from Baseline in Brief Pain Inventory-Short Form (BPI-SF) worst pain score over the last 24 hours without an increase in analgesic (oral morphine equivalents) use at 2 consecutive evaluations. The BPI-SF contains 15 items designed to capture the pain severity ("worst," "least," "average," and "now" [current pain]), pain location, medication to relieve the pain, and the interference of pain with various daily activities including general activity, mood, walking activity, normal work, relations with other people, sleep, and enjoyment of life. The pain severity items are rated on a 0 to 10 scale where: 0=no pain and 10=pain as bad as you can imagine and averaged for a total score of 0 (best) to 10 (Worst).

-Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) [ Time Frame: Baseline and Every 2 Cycles beginning with Cycle 2 during treatment period, End of Treatment (EOT), and every 4 Weeks in follow-up ] [ Designated as safety issue: No ]
The EORTC-QLQ-C30 is a 30-question tool used to assess the overall quality of life in cancer participants. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact).The EORTC-QLQ-C30 Global Health Status/QOL Scale is scored between 0 and 100, where higher scores indicate better Global Health Status/QOL. Negative changes from baseline indicate deterioration in QOL or functioning and positive changes indicate improvement.

-Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY-20) [ Time Frame: Baseline and Every 2 Cycles beginning with Cycle 2 during treatment period, End of Treatment (EOT), and every 4 Weeks in follow-up ] [ Designated as safety issue: No ]
The EORTC-QLQ-MY-20 is a patient-completed, 20-question quality of life questionnaire that has 4 independent subscales, 2 functional subscales (body image, future perspective), and 2 symptoms scales (disease symptoms and side-effects of treatment). The participant answers questions about their health during the past week using a 4-point scale where 1=Not at All to 4=Very Much. A negative change from Baseline indicates improvement.

-OS in High-Risk Participants [ Time Frame: At the time of screening; Day 1 of each cycle; every 4 weeks until disease progression and thereafter every 12 weeks until death or study termination ] [ Designated as safety issue: No ]
Overall survival (OS) is defined as the time from the date of randomization to the date of death. High-risk participants are defined as participants carrying cytogenic abnormalities: del(17), translocation t(4;14), or t(14;16) as reported by the central laboratory combined with those cases that lacked a central laboratory result but with known del (17), t(4;14), or t(14;16) by local laboratory. Cytogenetic abnormalities of del(13) and +1q are no longer considered to be high-risk abnormalities and are not included in the analysis. Participants without documentation of death at the time of the analysis were censored at the date when they were last known to be alive.

-PFS in High-Risk Participants [ Time Frame: From date of randomization until disease progression or death up to data cut-off: 30 October 2014 (approximate median follow-up 15 months) ] [ Designated as safety issue: No ]
Progression Free Survival (PFS) is defined as the time from the date of randomization to the date of first documentation of disease progression or death due to any cause, whichever occurs first. Response was assessed by independent review committee (IRC) using IMWG response criteria. High-risk participants are defined as participants carrying cytogenic abnormalities: del(17), translocation t(4;14), or t(14;16) as reported by the central laboratory combined with those cases that lacked a central laboratory result but with known del (17), t(4;14), or t(14;16) by local laboratory. Cytogenetic abnormalities of del(13) and +1q are no longer considered to be high-risk abnormalities and are not included in the analysis.

-Pharmacokinetic Parameters (Including Cmax, AUC and Tmax) of Ixazomib [ Time Frame: Days 1 & 14 of Cycles 1 & 2. Day 1 of Cycles 3 to 10 ] [ Designated as safety issue: No ]
•Association Between Response or Resistance to Ixazomib Treatment and Proteasome and Nuclear Factor-kB (NF-kB)-Related Genes [ Time Frame: At the time of screening; Day 1 of each cycle; at EOT; every 4 weeks until disease progression and thereafter every 12 weeks until death or study termination ] [ Designated as safety issue: No ]

納入條件
病患必須符合以下主要條件才可參與本試驗：

1.病患必須年滿20歲(台灣境內參與本試驗的受試者必須年滿20歲)

2.根據標準條件，目前或於初次診斷時確診患有多發性骨髓瘤(MM)。
注意：初次診斷必須為症狀性MM，而復發疾病則不一定需要表現症狀。

3.根據血清或尿液等特定實驗室測量可評估出以下疾病狀態：
• 血清M-蛋白≥ 1 g/dL ( 10 g/L)。
• 尿液M-蛋白≥ 200 mg/24小時。
• 血清游離輕鏈測定：反應的游離輕鏈濃度 ≥10 mg/dL (100 mg/L)，顯示血清游離輕鏈比異常。

4.復發與/或難治型MM，且過去曾接受1至3種治療。
注意：此病患群體包括以下三類病患：
• 病患過去在接受治療後復發，但對於先前任何治療均未表現出療效不佳。
• 病患對於過去所有系列治療均表現療效不佳(即：病患對於曾接受的治療均無反應)。
• 病患過去在接受治療後至少有1種復發，同時先前治療中也至少有1種療效不佳。為了達成本研究之目的，將難治型疾病定義為疾病在治療後惡化，或者在特定治療最後一劑藥物後60日內惡化。

系列治療的定義為1個週期以上的排定治療計畫。可能包括單一藥物治療或合併治療1個以上的排定週期，也可為排定的一系列治療。例如，安排先完成前導治療，接著進行自體幹細胞移植，然後給予維持治療，以上全部程序稱為一系列治療。准許自體與異體移植者加入試驗。

5.可以接受的血液、肝臟與腎臟功能(根據實驗室數據)：
• 絕對嗜中性白血球計數(ANC) ≥ 1,000/mm3與血小板計數≥ 75,000/mm3。不得為了協助病患符合資格條件，而在隨機分配前3天內進行血小板輸注。
• 總膽紅素≤ 1.5 x正常值上限(ULN)。
• 丙胺酸轉胺酶(ALT)與天門冬胺酸轉胺脢(AST) ≤ 3 x ULN。
• 肌酐酸清除率計算值≥ 30 mL/min
注意：肌酸酐清除率為30至50 mL/min的病患將接受減量lenalidomide (10 mg)，若耐受良好且無反應，則可於隨後增加劑量。

6.具良好活動能力且能自我照護；

7.不論您目前是否因某種骨髓移植而產生特定併發症(即活性移植物對抗宿主疾病)；

8.您必須遵守特定避孕要求：
有生育能力的婦女應持續接受懷孕檢測，並符合以下條件：
-在試驗治療第1週期展開前10至14日間以及24小時內，接受血清或尿液懷孕檢測之結果須為陰性，且必須承諾自試驗治療開始前至少28日起，直到最後一劑試驗藥物後30日內，均不得與異性進行性行為，或採取2種許可的避孕方式(也就是1種高度有效避孕方式同時加上另1種有效避孕方式)。

男性受試者在與任何具生育能力的女性進行性行為時，必須同意使用乳膠保險套，即使您已成功完成輸精管結紮手術。包括全部試驗期間，直到接受最後一劑試驗藥物後4個月內，男性受試者在與任何具生育能力的女性進行性行為時，必須使用有效的屏障避孕措施。

9.必須能夠每日併服aspirin 325 mg (或者若對於aspirin過敏，則每日皮下注射enoxaparin 40 mg [或相等藥物])，作為預防性抗凝血劑之用。
注意：過去曾有深層靜脈栓塞(DVT)病史的病患必須接受低分子量肝素(LMWH)治療。

10.願意在進行任何與試驗相關且不屬於標準醫療照護的醫療程序前簽署同意書，並瞭解在任何時間退出臨床試驗也不會損害將來的治療。

11.您必須願意且有能力遵守試驗回診時間表及其他計畫書要求。

排除條件
符合下列任何一項排除條件的病患將無法接受隨機分配至該試驗：

1.在任何系列治療中，對於lenalidomide或蛋白酶體抑制劑療法反應不佳者。
注意：難治型疾病的定義為疾病在治療後惡化，或者在特定治療最後一劑藥物後60日內惡化。若病患在特定治療最後一劑藥物後60日後惡化，將視為疾病復發，且符合試驗納入條件。
對於thalidomide療法反應不佳的病患可納入本試驗。

2.懷孕或哺乳的女性病患。

3.前次化療影響尚未完全復原者(即未達毒性小於第1等級)，不論上次治療至今間隔多久。

4.隨機分配前14日內曾接受重大手術者。

5.隨機分配前14日內曾接受放射性治療。

6.中樞神經系統侵犯。

7.隨機分配前14日內曾發生需要進行全身性抗生素治療的感染或其他嚴重感染。

8.診斷患有Waldenstrom氏巨球蛋白血症、POEMS (多發性神經病變、臟器腫大、內分泌病變、單株γ球蛋白病變和皮膚改變)症候群、漿細胞白血病、原發性類澱粉沈積症、骨髓化生不良症候群或骨髓增生症候群。

9.證據顯示目前患有控制不良的心血管疾病，包括控制不良的高血壓、控制不良的心律不整、症狀性鬱血性心臟病、不穩定型心絞痛或過去6個月內曾心肌梗塞。

10.在試驗隨機分配前14日內，曾接受全身性的CYP1A2強效抑制劑(fluvoxamine、enoxacin、ciprofloxacin)、CYP3A強效抑制劑(clarithromycin、telithromycin、itraconazole、voriconazole、ketoconazole、nefazodone、posaconazole)或強效CYP3A誘導劑(rifampin、rifapentine、rifabutin、carbamazepine、phenytoin、phenobarbital)，或者使用銀杏或金絲桃。

11.持續或活性全身感染、活性B型肝炎病毒感、活性C型肝炎感染或已知人類免疫不全病毒(HIV)陽性反應。

12.病患患有全身性共病症狀或其他嚴重併存疾病，根據試驗主持人的判斷不適合參與本試驗，或者將會顯著干擾療程進行適當的安全性與毒性評估。

13.患有精神疾病/社交狀況，可能會限制試驗要求的遵囑性。

14.已知對於任何試驗藥物、類似物或任何藥劑各種配方之賦型劑過敏者。

15.無法吞嚥口服藥物、無法或不願遵循投藥要求，或曾接受可能影響口服吸收或治療耐受性的胃腸道(GI)程序。

16.接受隨機分配前2年內曾診斷出或接受其他全身性惡性腫瘤治療，或以前曾診斷出其他惡性腫瘤且顯示有殘餘癌細胞。若病患患有非黑色素皮膚癌或任何種類的原位癌但已完全切除，將不被排除。