A Phase 1b/2 Open-Label, Multicenter Study to Evaluate the Safety and Efficacy of TAK-981 in Combination With Monoclonal Antibodies in Adult Patients With Relapsed and/or Refractory Multiple Myeloma
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 27
- 试验地点
- 13
- 主要终点
- Phase 1b, Part 1: Number of Participants With One or More Treatment Emergent Adverse Events (TEAEs)
研究概览
简要总结
TAK-981 is being tested in combination with anti-CD38 monoclonal antibodies (mAbs) to treat participants who have relapsed or refractory multiple myeloma (RRMM).
The main aims of the study are to evaluate the safety and efficacy of TAK-981 in combination with anti-CD38 (mAbs) and to determine the recommended Phase 2 dose (RP2D).
Participants will be on this combination treatment for 28-day cycles. They will continue with this treatment until disease progression or unacceptable toxicity.
详细描述
The drug being tested in this study is called TAK-981. TAK-981 in combination with an anti-CD38 monoclonal antibody (mAbs) is being tested to treat people who have RRMM. The study will include a dose escalation phase and a dose expansion phase.
The study will enroll approximately 81 participants; approximately 30 participants in the dose escalation phase (Part 1) approximately 15 participants in (Part 2) and up to 36 participants in dose expansion phase (Part 2). Participants will receive escalating doses of TAK-981 in combination with fixed doses as follows:
- Phase 1b, Part 1 - Dose Escalation: Arm A - TAK-981 Twice Weekly (BIW) + Mezagitamab
- Phase 1b, Part 1 - Dose Escalation: Arm B - TAK-981 Weekly (QW) + Mezagitamab
- Phase 1b, Part 2 - Dose Escalation: TAK-981 + Daratumumab and Hyaluronidase-fihj
Once RP2D is determined in Phase 1, participants with RRMM will be enrolled in Phase 2.
• Phase 2 - Dose Expansion: TAK-981 + Daratumumab and Hyaluronidase-fihj or Mezagitamab
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants must have RRMM with measurable disease:
- •a) Has measurable disease defined as one of the following:
- •Serum M-protein ≥0.5 g/dL (≥5 g/L).
- •Urine M-protein ≥200 mg/24 hours.
- •In participants without measurable M-protein in serum protein electrophoresis (SPEP) or urine protein electrophoresis (UPEP), a serum free light chain (FLC) assay result with involved FLC level ≥10 mg/dL (≥100 mg/L), provided serum FLC ratio is abnormal.
- •Has undergone stem cell transplant or is considered transplant ineligible.
- •Has failed at least 3 prior lines of anti-myeloma treatments and is either refractory, or intolerant to at least 1 immunomodulatory drug ( IMiD); (ie, lenalidomide or pomalidomide [thalidomide excluded]), at least 1 proteasome inhibitor (ie, bortezomib, ixazomib or carfilzomib), and refractory to at least 1 anti-CD38 antibody and who have demonstrated disease progression with the last therapy.
- •5.Have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
- •6.Have recovered to Grade 1 or baseline from all toxicity associated with previous therapy or have the toxicity established as sequela.
排除标准
- •Received treatment with systemic anticancer treatments within 14 days before the first dose of study drug.
- •Current participation in another interventional study, including other clinical trials with investigational agents (including investigational vaccines or investigational medical device for disease under study) within 4 weeks of the first dose of TAK-981 and throughout the duration of this trial.
- •Prior radiation therapy within 14 days of the first dose of TAK-
- •Major surgery within 4 weeks before C1D
- •participants should be fully recovered from any surgically related complications.
- •Plasmapheresis within 28 days of randomization.
- •Diagnosis of primary amyloidosis, Waldenström's disease, monoclonal gammopathy of undetermined significance or smoldering multiple myeloma (SMM), plasma cell leukemia POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), myelodysplastic syndrome, or myeloproliferative syndrome.
- •With disease where the only measurable parameter is plasmacytoma.
- •Second malignancy within the previous 3 years, except treated basal cell or localized squamous skin carcinomas, localized prostate cancer, cervical carcinoma in situ, resected colorectal adenomatous polyps, breast cancer in situ, or other malignancy for which the participant is not on active anticancer therapy.
- •Prior treatment with more than 1 anti-CD38 antibody.
- •Requires the use of drugs known to prolong the corrected QT interval (QTc) (during Phase 1b only).
- •History of QT interval with Fridericia's correction (QTcF) >480 ms.
- •History of human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C infection.
- •Systemic infection requiring systemic antibiotic therapy.
- •Active or history pneumonitis.
- •Receipt of any live vaccine (eg, varicella, pneumococcus) within 4 weeks of initiation of study drug.
- •Receiving strong or moderate Cytochrome P450 (CYP) 3A4/5 inhibitors or inducers.
- •History of unstable cardiac comorbidities in the following 6 months.
研究组 & 干预措施
Phase 1b, Part 1 - Dose Escalation: Arm A - TAK-981 Twice Weekly (BIW) + Mezagitamab
Mezagitamab: A fixed dose of 600 mg subcutaneous (SC) injection once weekly in Cycles 1 and 2 (each cycle is of 28 days), followed by once every 2 weeks in Cycle 3 through 6, then every 4 weeks up to Cycle 24 or until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first.
TAK-981: Escalating doses of TAK-981 BIW intravenous (IV) infusion on Days 1, 4, 8, 11 and 15 in Cycle 1 and 2 (each Cycle is of 28 days) followed by every 2 weeks in Cycles 3 through 6, followed by once every 4 weeks up to Cycle 24 or until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first.
干预措施: TAK-981 (Drug)
Phase 1b, Part 1 - Dose Escalation: Arm A - TAK-981 Twice Weekly (BIW) + Mezagitamab
Mezagitamab: A fixed dose of 600 mg subcutaneous (SC) injection once weekly in Cycles 1 and 2 (each cycle is of 28 days), followed by once every 2 weeks in Cycle 3 through 6, then every 4 weeks up to Cycle 24 or until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first.
TAK-981: Escalating doses of TAK-981 BIW intravenous (IV) infusion on Days 1, 4, 8, 11 and 15 in Cycle 1 and 2 (each Cycle is of 28 days) followed by every 2 weeks in Cycles 3 through 6, followed by once every 4 weeks up to Cycle 24 or until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first.
干预措施: Mezagitamab (Drug)
Phase 1b, Part 1 - Dose Escalation: Arm B - TAK-981 Weekly (QW) + Mezagitamab
Mezagitamab: A fixed dose of 600 mg SC injection once weekly in Cycles 1 and 2 (each cycle is of 28 days), followed by once every 2 weeks from Cycle 3 through 6, then every 4 weeks up to Cycle 24 or until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first.
TAK-981: Escalating doses of TAK-981 QW IV infusion on Days 1, 8, 15, and 22 in Cycles 1 and 2 (each cycle is of 28 days), followed by every 2 weeks in Cycles 3 through 6, followed by once every 4 weeks. up to Cycle 24 or until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first.
干预措施: TAK-981 (Drug)
Phase 1b, Part 1 - Dose Escalation: Arm B - TAK-981 Weekly (QW) + Mezagitamab
Mezagitamab: A fixed dose of 600 mg SC injection once weekly in Cycles 1 and 2 (each cycle is of 28 days), followed by once every 2 weeks from Cycle 3 through 6, then every 4 weeks up to Cycle 24 or until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first.
TAK-981: Escalating doses of TAK-981 QW IV infusion on Days 1, 8, 15, and 22 in Cycles 1 and 2 (each cycle is of 28 days), followed by every 2 weeks in Cycles 3 through 6, followed by once every 4 weeks. up to Cycle 24 or until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first.
干预措施: Mezagitamab (Drug)
Phase 1b, Part 2 - Lead-in Cohort: TAK-981 + Daratumumab and Hyaluronidase-fihj
Daratumumab and hyaluronidase-fihj: 1800 mg SC injection QW once weekly in Cycles 1 and 2 , (each cycle is of 28 days) followed by every 2 weeks in Cycle 3 through 6 , followed by every 4 weeks up to Cycle 24 until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first.
TAK-981: As per dose and schedule of TAK-981 defined in Phase 1b Part 1.
干预措施: TAK-981 (Drug)
Phase 1b, Part 2 - Lead-in Cohort: TAK-981 + Daratumumab and Hyaluronidase-fihj
Daratumumab and hyaluronidase-fihj: 1800 mg SC injection QW once weekly in Cycles 1 and 2 , (each cycle is of 28 days) followed by every 2 weeks in Cycle 3 through 6 , followed by every 4 weeks up to Cycle 24 until disease progression or unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first.
TAK-981: As per dose and schedule of TAK-981 defined in Phase 1b Part 1.
干预措施: Daratumumab and Hyaluronidase-fihj (Drug)
Phase 2 - Dose Expansion: TAK-981 + Daratumumab and Hyaluronidase-fihj or Mezagitamab
TAK-981 at RP2D as determined in Phase 1b. Mezagitamab at a fixed dose of 600 mg SC injection or Daratumumab and Hyaluronidase-fihj at a fixed dose of 1800 mg weekly in Cycles 1 and 2 (each cycle is of 28 days), followed by every 2 weeks in Cycle 3 through 6, followed by every 4 weeks up to Cycle 24 or until disease progression unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first.
干预措施: TAK-981 (Drug)
Phase 2 - Dose Expansion: TAK-981 + Daratumumab and Hyaluronidase-fihj or Mezagitamab
TAK-981 at RP2D as determined in Phase 1b. Mezagitamab at a fixed dose of 600 mg SC injection or Daratumumab and Hyaluronidase-fihj at a fixed dose of 1800 mg weekly in Cycles 1 and 2 (each cycle is of 28 days), followed by every 2 weeks in Cycle 3 through 6, followed by every 4 weeks up to Cycle 24 or until disease progression unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first.
干预措施: Mezagitamab (Drug)
Phase 2 - Dose Expansion: TAK-981 + Daratumumab and Hyaluronidase-fihj or Mezagitamab
TAK-981 at RP2D as determined in Phase 1b. Mezagitamab at a fixed dose of 600 mg SC injection or Daratumumab and Hyaluronidase-fihj at a fixed dose of 1800 mg weekly in Cycles 1 and 2 (each cycle is of 28 days), followed by every 2 weeks in Cycle 3 through 6, followed by every 4 weeks up to Cycle 24 or until disease progression unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first.
干预措施: Daratumumab and Hyaluronidase-fihj (Drug)
结局指标
主要结局
Phase 1b, Part 1: Number of Participants With One or More Treatment Emergent Adverse Events (TEAEs)
时间窗: From the first dose of study drug through 30 days after the last dose of study drug (up to 13 months)
TEAEs were adverse events (AEs) that occurred after administration of the first dose of any study drug and through 30 days after the last dose of any study drug. Adverse event (AE) means any untoward medical occurrence in a participant administered a pharmaceutical product. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product.
Phase 1b, Part 1: Number of Participants With Grade 3 or Higher TEAEs
时间窗: From the first dose of study drug through 30 days after the last dose of study drug (up to 13 months)
The severity grade was evaluated as per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0, except for Cytokine Release Syndrome (CRS), which was assessed by American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading. Where Grade 3 was severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living (ADL), Grade 4 was 4 Life-threatening consequences; urgent intervention indicated. and Grade 5 was death related to AE. TEAEs were AEs that occurred after administration of the first dose of any study drug and through 30 days after the last dose of any study drug.
Phase 1b, Part 1: Number of Participants With Dose Limiting Toxicities (DLTs) Based on NCI CTCAE Version 5.0
时间窗: Cycle 1 (Cycle length = 28 Days)
DLTs were evaluated according to NCI CTCAE version 5.0. Grade 5 AE. Hematologic toxicity: Nonfebrile Grade 4 neutropenia/Grade greater than or equal to (\>=) 3 febrile neutropenia; Significant Grade 3 thrombocytopenia; Grade 4 anemia or thrombocytopenia. Nonhematologic Grade 3 or higher toxicities; Grade 2 nonhematologic toxicities leading to dose reduction/discontinuation. Delay in Cycle 2 by greater than (\>) 14 days or missed \>1 planned doses of TAK-981/monoclonal antibody (mAb) in Cycle 1 due to TEAEs.
Phase 2: Overall Response Rate (ORR)
时间窗: From date of treatment start to until date of first PD or death (whichever occurred first), up to 24 months
ORR: percentage of participants who achieve complete response (CR) or partial response (PR) or better per investigator assessment by IMWG.CR: Negative immunofixation on serum and urine and disappearance of any soft tissue plasmacytomas and \<5 percent (%) plasma cells in bone marrow (BM). PR: \>50 percent (%) reduction of serum M-protein and reduction in 24 hours (h) urinary M-protein by \>90% or to less than (\<) 200 milligrams per 24 hour (mg/24 h); If serum and urine M-protein were unmeasurable, \>50% decrease in difference between involved and uninvolved free light chain (FLC) levels was required in place of M-protein criteria; If serum and urine M-protein are not measurable, and serum free light assay was also not measurable, \>50% reduction in plasma cells is required in place of M-protein, provided baseline BM plasma cell percentage was \>30%. In addition to the above listed criteria, if present at baseline, a \>50% reduction in the size of soft tissue plasmacytomas is also required.
次要结局
- Phase 1b, Part 1: Observed Plasma Concentration of TAK-981(Cycle 1 Day 1: Pre-dose, at end of infusion (EOI), 2, 4, 6, and 24 hours post-dose; Cycle 1 Days 8 and 15: Pre-dose and EOI; Cycle 2 Days 1 and 15: Pre-dose and EOI (Cycle length = 28 days))
- Phase 1b, Part 1, Cmax: Maximum Observed Plasma Concentration for TAK-981(Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days))
- Phase 1b, Part 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981(Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days))
- Phase 1b, Part 1, AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time t for TAK-981(Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days))
- Phase 1b, Part 1, AUC0-inf: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-981(Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days))
- Phase 1b, Part 1, t1/2z: Terminal Disposition Phase Half-life for TAK-981(Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days))
- Phase 1b, Part 1, CL: Total Clearance for TAK-981(Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days))
- Phase 1b, Part 1, Vss: Volume of Distribution at Steady State for TAK-981(Cycle 1 Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days))
- Phase 1b, Part 1: Number of Participants With Positive Anti-drug Antibodies (ADA) for TAK-981 + Mezagitamab and >= 5-fold in ADA Titer(Baseline up to 12 months)
- Phase 1b, Part 1: Serum Concentration of Mezagitamab(Cycles 1, 2, 3, 4, 6, 7 and 12: Day 1 pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length = 28 days))
- Phase 1b, Part 1: ORR Based on International Myeloma Working Group (IMWG) Criteria(From the first dose of study drug until first disease progression (PD) or death, whichever occurred first (up to 12 months))
- Phases 1b, Part 1: Clinical Benefit Rate (CBR) Based on IMWG Criteria(From first dose of study drug until PD or death, whichever occurred first (up to 12 months))
- Phase 1b, Part 1: Duration of Response (DOR) Based on IMWG Criteria(From first documented confirmed CR or PR until first documentation of PD or death, whichever occurred first (up to 12 months))
- Phases 1b, Part 1: Time to Progression (TTP) Based on IMWG Criteria(From first dose of study drug to the date of the first documentation of PD or death, whichever occurred first (up to 12 months))
- Phases 1b, Part 1: Time to Next Treatment (TTNT)(From the date of first dose of study drug to the date of the first dose initiation of the next line of antineoplastic therapy (up to 12 months))
- Phases 1b, Part 1: Progression-free Survival (PFS) Based on IMWG Criteria(From the first dose of study drug to date of PD or death, whichever occurred first (up to 12 months))
- Phases 1b, Part 1: Overall Survival (OS)(From date of first dose of study drug up to death from any cause (up to 27 months))
- Phases 1b, Part 1: Fold Change From Baseline in Level of TAK-981-Small Ubiquitin-like Modifier (TAK-981-SUMO) Adduct Formation in Peripheral Blood Lymphocytes(Cycle 1 Day 1: 1, 4, and 24 hours post-dose; Cycle 1 Day 8: Pre-dose, and 1 hour post-dose; Cycle 1 Day 15: Pre-dose (Cycle length = 28 days))
- Phases 1b, Part 1: Fold Change From Baseline in SUMO Pathway Inhibition in Peripheral Blood Lymphocytes(Cycle 1 Day 1: 1, 4, and 24 hours post-dose; Cycle 1 Day 8: Pre-dose, and 1 hour post-dose; Cycle 1 Day 15: Pre-dose (Cycle length = 28 days))
- Phase 2: Number of Participants With TEAEs and TEAEs by Severity(Up to 24 months)
- Phase 2: CBR Based on IMWG Criteria(Up to 24 months)
- Phase 2: DOR Based on IMWG Criteria(Up to 24 months)
- Phase 2: Overall Survival (OS)(Up to 24 months)
- Phase 2: Percentage of Participants With MRD Negative Status as Determined by Next-Generation Sequencing (NGS)(Up to 24 months)
- Phase 2: Minimal Residual Disease (MRD) Negative Rate(Up to 12 months)
- Phase 2: Durable MRD Negative Rate(Up to 12 months)
- Phase 2: TTP Based on IMWG Criteria(Up to 24 months)
- Phase 2: Time to Next Treatment (TTNT)(Up to 24 months)
- Phase 2: PFS Based on IMWG Criteria(Up to 24 months)