計劃書編號DSP-5336-101
NCT Number(ClinicalTrials.gov Identfier)NCT04988555
試驗執行中
2023-06-01 - 2027-10-31
Phase I/II
召募中3
一項第 1/2 期、開放性、劑量遞增、劑量擴展試驗，評估Enzomenib (DSP-5336) 用於帶有或未帶有混合譜系白血病 (MLL)重排或核仁磷酸蛋白 1 (NPM1) 突變的急性白血病和其他選定的血液系統惡性腫瘤患者
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試驗申請者
百瑞精鼎國際股份有限公司
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試驗委託 / 贊助單位名稱
百瑞精鼎國際股份有限公司
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臨床試驗規模
多國多中心
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更新日期
2026/02/01
試驗主持人及試驗醫院
適應症
第1 期安全性：• 依據美國國家癌症研究所常見不良事件評價標準 (NCI CTCAE) 第 5.0 版評估的劑量限制毒性 (DLTs)• 治療中出現的不良事件 (TEAE) 和嚴重不良事件 (SAEs)• 生命徵象、臨床實驗室數值（血液學、臨床化學、尿液分析）、心電圖 (ECG)參數、心臟超音波 (ECHO) 參數的變化耐受性：• 劑量中斷、劑量調降和／或劑量中止生物性療效：• 請參閱 PK 和臨床活性的對應次要指標• 請參閱生物標記的對應探索性指標（基因表現量）對於急性白血病：根據ELN 2017 標準與FDA 指引定義之CRh標準達到反應• 完全緩解 (CR)；完全緩解伴隨部分血液學恢復 (CRh)；完全緩解伴隨血液學未完全恢復 (CRi)；部分緩解 (PR)；形態學無白血病狀態 (MLFS)；CR + CRh；複合性完全緩解（CRc [CR 或 CRh 或 CRi]）：客觀反應率（ORR [= CR 或 CRi 或MLFS]）；達到 CR/CRh 的時間；達到ORR 的時間；CR/CRh 持續時間；ORR 持續時間；輸血獨立性 (TI)；整體存活期(OS)；無事件存活期 (EFS)對於 MDS（在美國）：將根據 2023 IWG 標準評估初步活性並報告達到反應亞型及／或血液改善的患者比例（例如，完全緩解、完全緩解但計數恢復有限第2 期•FDA 指引定義之 CR + CRh
試驗目的
目標與指標的完整清單（包括探索性質之目標與指標）納入於完整試驗計畫書。
第 1 期
主要目標
•評估 DSP-5336 單一療法用於患有復發性或難治性 AML、ALL、譜系不明確急性白血病之患者的安全性和耐受性，還評估用於患有高風險復發性或難治性 MDS 或復發性／難治性 MM 患者的安全性和耐受性（在美國）
•根據產生最大生物和臨床效果的 DSP-5336 最低劑量或最大耐受劑量 (MTD)，確定 DSP-5336 的第 2 期建議劑量 (RP2D)，以較低者為準
•確認 DSP-5336 與 venetoclax/ azacitidine 併用對復發性或難治性 AML 成人患者的安全性、耐受性與RP2D
•確認 DSP-5336 與 gilteritinib 併用對復發性或難治性 AML 成人患者的安全性、耐受性與 RP2D
次要目標
•描述 DSP-5336 的藥物動力學特性，包括在併用選定 azole 類藥物，即：posaconazole、voriconazole 或 fluconazole 時的藥物動力學特性
•評估食物（高脂飲食）對 DSP-5336 藥物動力學／曝藥量的影響
•評估 DSP-5336 對 midazolam 和咖啡因之藥物動力學／曝藥量的影響
•評估 DSP-5336 與 venetoclax 及 azacitidine 併用的藥物動力學特性
•評估 DSP-5336 與 gilteritinib 併用的藥物動力學特性
•評估 venetoclax與 DSP-5336 併用的藥物動力學特性
•評估 gilteritinib 與 DSP-5336 併用的藥物動力學特性
•評估 DSP-5336 單一療法用於患有急性骨髓性白血病、急性淋巴球性白血病、譜系不明確急性白血病之成年患者的初步臨床活性，還評估用於患有高風險復發性或難治性 MDS 或復發性／難治性 MM 患者的初步臨床活性（在美國）
•評估 DSP-5336 與 venetoclax/ azacitidine 併用的初步臨床活性
•評估 DSP-5336 與 gilteritinib 併用的初步臨床活性
•透過 12 導程安全性和密集心電圖監測，以及在 azole 類藥物存在下透過 12 導程安全性心電圖監測，判定 DSP-5336 作為單一藥物給藥的心臟安全性
第 2 期
主要目標
• 評估 DSP-5336 單一療法用於患有復發性／難治性急性白血病且帶有MLLr 之患者，或患有復發性／難治性 AML 且帶有 NPM1m 之患者的臨床活性
次要目標
• 評估 DSP-5336 單一療法用於患有復發性／難治性急性白血病且帶有MLLr 之患者，或患有復發性／難治性 AML 且帶有 NPM1m 之患者其他臨床活性
• 進一步評估 DSP-5336 的安全性和耐受性
藥品名稱
錠劑
主成份
DSP-5336
劑型
110
劑量
NA
評估指標
第1 期
安全性：
• 依據美國國家癌症研究所常見不良事件評價標準 (NCI CTCAE) 第 5.0 版評估的
劑量限制毒性 (DLTs)
• 治療中出現的不良事件 (TEAE) 和嚴重不良事件 (SAEs)
• 生命徵象、臨床實驗室數值（血液學、臨床化學、尿液分析）、心電圖 (ECG)
參數、心臟超音波 (ECHO) 參數的變化
耐受性：
• 劑量中斷、劑量調降和／或劑量中止
生物性療效：
• 請參閱 PK 和臨床活性的對應次要指標
• 請參閱生物標記的對應探索性指標（基因表現量）
對於急性白血病：
根據ELN 2017 標準與FDA 指引定義之CRh
標準達到反應
• 完全緩解 (CR)；完全緩解伴隨部分血液學
恢復 (CRh)；完全緩解伴隨血液學未完全
恢復 (CRi)；部分緩解 (PR)；形態學無白
血病狀態 (MLFS)；CR + CRh；複合性完
全緩解（CRc [CR 或 CRh 或 CRi]）：客
觀反應率（ORR [= CR 或 CRi 或
MLFS]）；達到 CR/CRh 的時間；達到
ORR 的時間；CR/CRh 持續時間；ORR 持
續時間；輸血獨立性 (TI)；整體存活期
(OS)；無事件存活期 (EFS)
對於 MDS（在美國）：
將根據 2023 IWG 標準評估初步活性並報告達
到反應亞型及／或血液改善的患者比例（例
如，完全緩解、完全緩解但計數恢復有限
第2 期
•FDA 指引定義之 CR + CRh
安全性：
• 依據美國國家癌症研究所常見不良事件評價標準 (NCI CTCAE) 第 5.0 版評估的
劑量限制毒性 (DLTs)
• 治療中出現的不良事件 (TEAE) 和嚴重不良事件 (SAEs)
• 生命徵象、臨床實驗室數值（血液學、臨床化學、尿液分析）、心電圖 (ECG)
參數、心臟超音波 (ECHO) 參數的變化
耐受性：
• 劑量中斷、劑量調降和／或劑量中止
生物性療效：
• 請參閱 PK 和臨床活性的對應次要指標
• 請參閱生物標記的對應探索性指標（基因表現量）
對於急性白血病：
根據ELN 2017 標準與FDA 指引定義之CRh
標準達到反應
• 完全緩解 (CR)；完全緩解伴隨部分血液學
恢復 (CRh)；完全緩解伴隨血液學未完全
恢復 (CRi)；部分緩解 (PR)；形態學無白
血病狀態 (MLFS)；CR + CRh；複合性完
全緩解（CRc [CR 或 CRh 或 CRi]）：客
觀反應率（ORR [= CR 或 CRi 或
MLFS]）；達到 CR/CRh 的時間；達到
ORR 的時間；CR/CRh 持續時間；ORR 持
續時間；輸血獨立性 (TI)；整體存活期
(OS)；無事件存活期 (EFS)
對於 MDS（在美國）：
將根據 2023 IWG 標準評估初步活性並報告達
到反應亞型及／或血液改善的患者比例（例
如，完全緩解、完全緩解但計數恢復有限
第2 期
•FDA 指引定義之 CR + CRh
主要納入條件
本試驗第 1 期部分的參與者將是在先前治療後復發或對先前治療為難治性的 AML、ALL 或
譜系不明確急性白血病患者。此外，將在美國納入患有另外兩種疾病適應症的參與者：1) 復
發性或難治性 MDS 患者，其已試過所有現有的標準療法，包括至少 2 個週期的低甲基化藥
物 (HMA) 療法；以及 2) 復發性或難治性 MM 患者，這些患者在先前接受過 3 線療法（包括
PI、IMiD 和抗 CD38 mAb）後出現疾病惡化。患者不得是已確立臨床效益之現有療法的候選
者。
在允許的國家和試驗單位，將開放 2 個第 1 期併用組，這些組的參與者將包括：1) 患有復發
性或難治性 AML 且帶有 MLLr/NPM1m 的患者，其經試驗主持人確定為 venetoclax 和
azacitidine 治療的候選者，以及 2) 患有復發性或難治性 AML 且帶有 MLLr/NPM1m 和
FLT3m 的患者，其經試驗主持人確定為 gilteritinib 治療的候選者。
在第 2 期，將納入以下患者：1) J 組中：患有復發性或難治性急性白血病且帶有 MLLr 之患
者，以及 2) K 組中：患有復發性或難治性 AML 且帶有 NPM1m 之患者，並且依型態評估其
骨髓中含 ≥ 5% 芽細胞且先前未接受過 menin 抑制劑治療。
針對本試驗每個期別和組別之納入和排除條件的完整清單已納入於完整試驗計畫書。
譜系不明確急性白血病患者。此外，將在美國納入患有另外兩種疾病適應症的參與者：1) 復
發性或難治性 MDS 患者，其已試過所有現有的標準療法，包括至少 2 個週期的低甲基化藥
物 (HMA) 療法；以及 2) 復發性或難治性 MM 患者，這些患者在先前接受過 3 線療法（包括
PI、IMiD 和抗 CD38 mAb）後出現疾病惡化。患者不得是已確立臨床效益之現有療法的候選
者。
在允許的國家和試驗單位，將開放 2 個第 1 期併用組，這些組的參與者將包括：1) 患有復發
性或難治性 AML 且帶有 MLLr/NPM1m 的患者，其經試驗主持人確定為 venetoclax 和
azacitidine 治療的候選者，以及 2) 患有復發性或難治性 AML 且帶有 MLLr/NPM1m 和
FLT3m 的患者，其經試驗主持人確定為 gilteritinib 治療的候選者。
在第 2 期，將納入以下患者：1) J 組中：患有復發性或難治性急性白血病且帶有 MLLr 之患
者，以及 2) K 組中：患有復發性或難治性 AML 且帶有 NPM1m 之患者，並且依型態評估其
骨髓中含 ≥ 5% 芽細胞且先前未接受過 menin 抑制劑治療。
針對本試驗每個期別和組別之納入和排除條件的完整清單已納入於完整試驗計畫書。
主要排除條件
NAExclusion Criteria:
Has a left ventricular ejection fraction (LVEF) <50%, as determined by ECHO
Histological diagnosis of acute promyelocytic leukemia
Received systemic calcineurin inhibitors within 2 weeks prior to the first dose of DSP 5336
Have abnormal ECGs at screening that are clinically significant, such as (QTc >480 msec, with QTc corrected according to Fridericia's formula (QTcF). Note: In case of bundle branch block, QT interval correction can be performed.
Has an active anduncontrolled, bacterial, viral, or fungal infection requiring parenteral therapy. Note: Patients must be afebrile with negative blood cultures at least 72 hours prior to Cycle 1 Day 1.
Receives concurrent sensitive substrates with a narrow safety window or strong inhibitors or inducers of CYP3A4/5, including specifically: ketoconazole, isavuconazole and itraconazole. Other antifungals that are used as standard of care to prevent or treat infections are permitted. If a patient is on one of the excluded azole class antifungals, he/she can be taken off or switched to a permitted azole 7 or more days prior to first dose, then the patient could be allowed on study (Arm B) with approval of the medical monitor.
Received immunotherapy, including tumor vaccines and checkpoint inhibitors, within 42 days prior to the first dose of DSP-5336
Had major surgery within 28 days prior to the first dose of DSP-5336
Has active central nervous system leukemia. Patients with a history of any CNS leukemia involvement are excluded from Phase 2 Arms G and H.
Underwent HSCT or chimeric antigen receptor cell (CAR-T) therapy or other modified T-cell therapy within 60 days prior to the first dose of DSP-5336. Patients who have received >1 prior HSCT are excluded from Phase 2 Arms G and H.
Received a donor lymphocyte infusion within 28 days prior to the first dose of DSP-5336, or receiving immunosuppressive therapy post-HSCT at the time of screening, or with clinically active GVHD or GVHD requiring active medical intervention other than the use of topical steroids for ongoing cutaneous GVHD
Received antineoplastic agents (except hormonal therapies as adjuvant maintenance for breast or prostate cancers if a patient is taking before starting study treatment, and hydroxyurea given for controlling blast cells) or other investigational treatment within 14 days or 5 half-lives, whichever is shortest, prior to the first dose of DSP-5336
In the opinion of the treating investigator, have any concurrent conditions that could pose an undue medical hazard or interfere with interpretation of study results
Have a known detectable viral load for human immunodeficiency virus or hepatitis C, or evidence of hepatitis B surface antigen, all being indicative of active infection.
For sites in Japan, Taiwan, and Korea only: Hepatitis B core (HBc) antibody or hepatitis B surface (HBs) antibody test should be performed if HBsAg is negative. If HBc antibody or HBs antibody test is positive, HBV DNA quantification test should be performed to confirm that HBV DNA is negative.
Have severe dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally, including the inability to swallow oral medication
Have cognitive, psychologic, or psychosocial impediment that would impair the ability of the patient o receive therapy according to the protocol, or adversely affect the ability of the patient to comply with the informed consent process, protocol, or protocol-required visits and procedures
Are pregnant or breastfeeding or planning to become pregnant. Note: Patients who are breastfeeding may be enrolled if they interrupt breastfeeding prior to the first dose of any study drugs and do not feed the baby with breast milk expressed after receiving the first dose of any study drugs. Breastfeeding should not be resumed for at least 6 months after the last dose of study drug
Have any history or complication of interstitial lung disease (for sites in Japan in Phase 1 dose escalation only).
For clinical sites in the EU, have a history of Grade ≥ 2 drug-induced interstitial lung disease or Grade ≥ 2 non-infectious pneumonitis within 6 months of starting study treatment.
Have a history of Torsades de Pointes
Received systemic calcineurin inhibitors within 4 weeks prior to the first dose of DSP-5336
Have plasma cell leukemia (>2.0 x 109 /L plasma cells in blood by standard differential) (for patients with MM only)
For patients intending to enroll into the combination cohort with gilteritinib: Patients must be gilteritinib-naïve or sensitive and have not received a FLT3 inhibitor in the relapsed refractory setting (prior FLT3 inhibitor in front line therapy is allowed)
Have a known intolerance of hypersensitivity reaction to components of the investigational medicinal product
Patients with LDH >500 U/L (>8.3 µkat/L) are excluded from Phase 2 Arms G and H
Has a left ventricular ejection fraction (LVEF) <50%, as determined by ECHO
Histological diagnosis of acute promyelocytic leukemia
Received systemic calcineurin inhibitors within 2 weeks prior to the first dose of DSP 5336
Have abnormal ECGs at screening that are clinically significant, such as (QTc >480 msec, with QTc corrected according to Fridericia's formula (QTcF). Note: In case of bundle branch block, QT interval correction can be performed.
Has an active anduncontrolled, bacterial, viral, or fungal infection requiring parenteral therapy. Note: Patients must be afebrile with negative blood cultures at least 72 hours prior to Cycle 1 Day 1.
Receives concurrent sensitive substrates with a narrow safety window or strong inhibitors or inducers of CYP3A4/5, including specifically: ketoconazole, isavuconazole and itraconazole. Other antifungals that are used as standard of care to prevent or treat infections are permitted. If a patient is on one of the excluded azole class antifungals, he/she can be taken off or switched to a permitted azole 7 or more days prior to first dose, then the patient could be allowed on study (Arm B) with approval of the medical monitor.
Received immunotherapy, including tumor vaccines and checkpoint inhibitors, within 42 days prior to the first dose of DSP-5336
Had major surgery within 28 days prior to the first dose of DSP-5336
Has active central nervous system leukemia. Patients with a history of any CNS leukemia involvement are excluded from Phase 2 Arms G and H.
Underwent HSCT or chimeric antigen receptor cell (CAR-T) therapy or other modified T-cell therapy within 60 days prior to the first dose of DSP-5336. Patients who have received >1 prior HSCT are excluded from Phase 2 Arms G and H.
Received a donor lymphocyte infusion within 28 days prior to the first dose of DSP-5336, or receiving immunosuppressive therapy post-HSCT at the time of screening, or with clinically active GVHD or GVHD requiring active medical intervention other than the use of topical steroids for ongoing cutaneous GVHD
Received antineoplastic agents (except hormonal therapies as adjuvant maintenance for breast or prostate cancers if a patient is taking before starting study treatment, and hydroxyurea given for controlling blast cells) or other investigational treatment within 14 days or 5 half-lives, whichever is shortest, prior to the first dose of DSP-5336
In the opinion of the treating investigator, have any concurrent conditions that could pose an undue medical hazard or interfere with interpretation of study results
Have a known detectable viral load for human immunodeficiency virus or hepatitis C, or evidence of hepatitis B surface antigen, all being indicative of active infection.
For sites in Japan, Taiwan, and Korea only: Hepatitis B core (HBc) antibody or hepatitis B surface (HBs) antibody test should be performed if HBsAg is negative. If HBc antibody or HBs antibody test is positive, HBV DNA quantification test should be performed to confirm that HBV DNA is negative.
Have severe dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally, including the inability to swallow oral medication
Have cognitive, psychologic, or psychosocial impediment that would impair the ability of the patient o receive therapy according to the protocol, or adversely affect the ability of the patient to comply with the informed consent process, protocol, or protocol-required visits and procedures
Are pregnant or breastfeeding or planning to become pregnant. Note: Patients who are breastfeeding may be enrolled if they interrupt breastfeeding prior to the first dose of any study drugs and do not feed the baby with breast milk expressed after receiving the first dose of any study drugs. Breastfeeding should not be resumed for at least 6 months after the last dose of study drug
Have any history or complication of interstitial lung disease (for sites in Japan in Phase 1 dose escalation only).
For clinical sites in the EU, have a history of Grade ≥ 2 drug-induced interstitial lung disease or Grade ≥ 2 non-infectious pneumonitis within 6 months of starting study treatment.
Have a history of Torsades de Pointes
Received systemic calcineurin inhibitors within 4 weeks prior to the first dose of DSP-5336
Have plasma cell leukemia (>2.0 x 109 /L plasma cells in blood by standard differential) (for patients with MM only)
For patients intending to enroll into the combination cohort with gilteritinib: Patients must be gilteritinib-naïve or sensitive and have not received a FLT3 inhibitor in the relapsed refractory setting (prior FLT3 inhibitor in front line therapy is allowed)
Have a known intolerance of hypersensitivity reaction to components of the investigational medicinal product
Patients with LDH >500 U/L (>8.3 µkat/L) are excluded from Phase 2 Arms G and H
試驗計畫預計收納受試者人數
-
台灣人數
NA 人
-
全球人數
NA 人
