A Phase 1/2a Open-label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of Modakafusp Alfa in Combination With Daratumumab Subcutaneous in Patients With Relapsed or Refractory Multiple Myeloma
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 15
- 试验地点
- 45
- 主要终点
- Phase 1: Number of Participants With Dose Limiting Toxicities (DLT)
研究概览
简要总结
The main aim of this study is to determine safety and tolerability of modakafusp alfa given together with daratumumab to find out the best treatment dose. Another aim of this study is to learn more about the characteristics of modakafusp alfa.
详细描述
The drug being tested in this study is called modakafusp alfa (TAK-573). Modakafusp alfa is being tested to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy in combination with daratumumab in participants with relapsed or refractory multiple myeloma (RRMM). The study will consist of 2 phases: Phase 1 Dose Escalation and a Phase 2a Dose Finding.
The study will enroll approximately 58 patients. Approximately 18 participants will be enrolled in the Phase 1 Dose Escalation/De-escalation and two dose levels of modakafusp alfa in combination with daratumumab SC will be selected to be further explored in the randomized Phase 2a Dose Finding part of the study wherein, approximately 40 participants will be randomly assigned by chance (like flipping a coin) to one of the two treatment groups:
- Phase 2a Dose Finding: Modakafusp Alfa (DL1) + Daratumumab
- Phase 2a Dose Finding: Modakafusp Alfa (DL2) + Daratumumab This multi-center trial will be conducted worldwide. The overall time to participate in this study is approximately 60 months. Participants who discontinue study drug treatment for reasons other than progressive disease will continue progression-free survival (PFS) follow-up every 4 weeks from the end of treatment (EOT) visit until the occurrence of progressive disease, death, the start of subsequent systemic antineoplastic therapy, study termination, whichever occurs first.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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
- •Documented multiple myeloma (MM) diagnosis per IMWG criteria.
- •Measurable disease, defined as at least 1 of the following:
- •Serum M protein ≥0.5 grams per deciliter [g/dL] (≥5 g/L) on serum protein electrophoresis (SPEP).
- •Urine M protein ≥200 mg/24 hours on urine protein electrophoresis (UPEP).
- •Serum free light chain (FLC) assay with involved FLC level ≥10 mg/dL (≥100 mg/L) provided serum FLC ratio is abnormal.
- •For participants in the Phase 1 Dose Escalation only:
- •Must have received at least 3 prior lines of therapy, including at least 1 proteosome inhibitor (PI), 1 immunomodulatory imide drug (IMiD), and 1 anti-CD38 monoclonal antibody (mAb) drug; or who are triple refractory to a PI, an IMiD, and an anti-CD38 mAb drug, regardless of the number of prior line(s) or therapy.
- •For participants in Phase 2a Dose Finding only:
- •Received 1 to 3 prior line(s) of antimyeloma therapy.
- •Must be refractory to prior lenalidomide treatment.
- •Participants must be sensitive (nonrefractory) or naïve to prior anti-CD38 mAb treatment.
- •Documented progressive disease on or after the last regimen.
- •Participants must have PR or better to at least 1 line of prior therapy.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 at screening.
排除标准
- •Prior exposure to modakafusp alfa.
- •Participant has polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, solitary plasmacytoma, amyloidosis, Waldenström macroglobulinemia, plasma cell leukemia, or lymphoplasmacytic lymphoma.
- •Participant has not recovered from adverse reactions to prior myeloma treatment or procedures (chemotherapy, immunotherapy, radiation therapy) to NCI CTCAE, Version 5 Grade ≤1 or baseline, except for alopecia.
- •Previous allogeneic stem cell transplant at any time or autologous stem cell transplant (ASCT) within 12 weeks of planned start of dosing.
- •Seropositive for hepatitis B, or known history of seropositivity for hepatitis C or of seropositivity for human immunodeficiency virus (HIV).
- •Participant has congestive heart failure (New York Heart Association Grade ≥II), cardiac myopathy, active ischemia, or any other uncontrolled cardiac condition such as angina pectoris, clinically significant arrhythmia requiring therapy including anticoagulants, or clinically significant uncontrolled hypertension.
- •Participant has QT interval corrected by the Fridericia method >480 milliseconds [msec] (Grade ≥2).
- •Participant has a chronic condition that will require the chronic use of systemic corticosteroids >10 milligrams per day (mg/d) of prednisone or equivalent on top of any required corticosteroids for multiple myeloma (MM).
研究组 & 干预措施
Phase 1 (Dose Escalation) Modakafusp Alfa 80 mg + Daratumumab
Modakafusp alfa 80 mg, infusion, intravenously (IV), once every 4 weeks (Q4W) with daratumumab 1800 mg, subcutaneously (SC), once weekly (QW) in Cycles 1 and 2, twice weekly (Q2W) in Cycles 3 to 6, and Q4W thereafter in each 28-day treatment cycle until disease progression.
干预措施: Modakafusp Alfa (Drug)
Phase 1 (Dose Escalation) Modakafusp Alfa 80 mg + Daratumumab
Modakafusp alfa 80 mg, infusion, intravenously (IV), once every 4 weeks (Q4W) with daratumumab 1800 mg, subcutaneously (SC), once weekly (QW) in Cycles 1 and 2, twice weekly (Q2W) in Cycles 3 to 6, and Q4W thereafter in each 28-day treatment cycle until disease progression.
干预措施: Daratumumab (Drug)
Phase 1 (Dose Escalation) Modakafusp Alfa 120 mg + Daratumumab
Modakafusp alfa 120 mg, infusion, IV, Q4W with daratumumab 1800 mg, SC, QW in Cycles 1 and 2, Q2W in Cycles 3 to 6, and Q4W thereafter in each 28-day treatment cycle until disease progression.
干预措施: Modakafusp Alfa (Drug)
Phase 1 (Dose Escalation) Modakafusp Alfa 120 mg + Daratumumab
Modakafusp alfa 120 mg, infusion, IV, Q4W with daratumumab 1800 mg, SC, QW in Cycles 1 and 2, Q2W in Cycles 3 to 6, and Q4W thereafter in each 28-day treatment cycle until disease progression.
干预措施: Daratumumab (Drug)
Phase 1 (Dose Escalation) Modakafusp Alfa 240 mg + Daratumumab
Modakafusp alfa 240 mg, infusion, IV, Q4W with daratumumab 1800 mg, SC, QW in Cycles 1 and 2, Q2W in Cycles 3 to 6, and Q4W thereafter in each 28-day treatment cycle until disease progression.
干预措施: Modakafusp Alfa (Drug)
Phase 1 (Dose Escalation) Modakafusp Alfa 240 mg + Daratumumab
Modakafusp alfa 240 mg, infusion, IV, Q4W with daratumumab 1800 mg, SC, QW in Cycles 1 and 2, Q2W in Cycles 3 to 6, and Q4W thereafter in each 28-day treatment cycle until disease progression.
干预措施: Daratumumab (Drug)
Phase 2a Dose Finding: Modakafusp Alfa (DL1) + Daratumumab
Modakafusp alfa at dose level 1 (DL1) [selected from Phase 1 Dose Escalation] with daratumumab SC 1800 mg, SC, QW in Cycles 1 and 2, Q2W in Cycles 3 to 6, and Q4W thereafter in each 28-day treatment cycle until disease progression.
干预措施: Modakafusp Alfa (Drug)
Phase 2a Dose Finding: Modakafusp Alfa (DL1) + Daratumumab
Modakafusp alfa at dose level 1 (DL1) [selected from Phase 1 Dose Escalation] with daratumumab SC 1800 mg, SC, QW in Cycles 1 and 2, Q2W in Cycles 3 to 6, and Q4W thereafter in each 28-day treatment cycle until disease progression.
干预措施: Daratumumab (Drug)
Phase 2a Dose Finding: Modakafusp Alfa (DL2) + Daratumumab
Modakafusp alfa at dose level 2 (DL2) [selected from Phase 1 Dose Escalation] with daratumumab SC 1800 mg, SC, QW in Cycles 1 and 2, Q2W in Cycles 3 to 6, and Q4W thereafter in each 28-day treatment cycle until disease progression.
干预措施: Modakafusp Alfa (Drug)
Phase 2a Dose Finding: Modakafusp Alfa (DL2) + Daratumumab
Modakafusp alfa at dose level 2 (DL2) [selected from Phase 1 Dose Escalation] with daratumumab SC 1800 mg, SC, QW in Cycles 1 and 2, Q2W in Cycles 3 to 6, and Q4W thereafter in each 28-day treatment cycle until disease progression.
干预措施: Daratumumab (Drug)
结局指标
主要结局
Phase 1: Number of Participants With Dose Limiting Toxicities (DLT)
时间窗: Phase 1: Cycle 1 (cycle length=28 days)
DLT was defined as any of the treatment-emergent adverse events (TEAEs) that occurred during Cycle 1 and were considered by the investigator to be at least possibly related to modakafusp alfa. Toxicity was evaluated according to national cancer institute common terminology criteria for adverse events (NCI CTCAE) Version 5.0.
Phase 1: Number of Participants Reporting One or More TEAEs and Per Severity
时间窗: Phase 1: Up to 15.9 months
An adverse event (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 (e.g., 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 TEAE is defined as an adverse event with an onset that occurs after receiving study drug. Severity grades for TEAEs were evaluated as per the NCI CTCAE Version 5.0.
Phase 2a: Overall Response Rate (ORR)
时间窗: Phase 2a: Up to 15.9 months
ORR is defined as the percentage of participants who achieve a confirmed partial response (PR) or better during the study in the safety population. ORR will be assessed by the investigator per International Myeloma Working Group (IMWG) criteria.
次要结局
- Phase 1: Cmax: Single-Dose Maximum Observed Serum Concentration for Modakafusp Alfa(Phase 1: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days))
- Phase 1: Tmax: Time to First Occurrence of Maximum Serum Concentration (Cmax) for Modakafusp Alfa(Phase 1: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days))
- Phase 1: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa(Phase 1: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days))
- Phase 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration(Phase 1: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days))
- Phase 1: Apparent Serum Terminal Disposition Rate Constant for Modakafusp Alfa(Phase 1: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days))
- Phase 1: Apparent Serum Terminal Disposition Phase Half-life for Modakafusp Alfa(Phase 1: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days))
- Phase 1: Total Clearance After Intravenous Administration for Modakafusp Alfa(Phase 1: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days))
- Phase 1: Volume of Distribution at Steady State After Intravenous (IV) Administration for Modakafusp Alfa(Phase 1: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days))
- Phase 1: Cmax: Single-Dose Maximum Observed Serum Concentration for Daratumumab(Phase 1: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days))
- Phase 1: Tmax: Time to First Occurrence of Maximum Serum Concentration (Cmax) for Daratumumab(Phase 1: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days))
- Phase 1: Ctrough: Single-Dose and Multiple-dose Observed Concentration at the End of a Dosing Interval for Daratumumab(Phase 1: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days))
- Phase 1: AUC∞: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Daratumumab(Phase 1: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days))
- Phase 1: AUClast: Area Under the Serum Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration for Daratumumab(Phase 1: Days 1, 8, 15, and 22 of Cycles 1 and 2: Pre-dose, and at multiple time points up to 4 hours post-dose; Day 2 of Cycles 1 and 2: Post-dose (cycle length=28 days))
- Phase 1: Overall Response Rate (ORR)(Phase 1: Up to 15.9 months)
- Phase 1 and Phase 2a: Duration of Response (DOR)(Up to 15.9 months)
- Phase 1 and Phase 2a: Progression Free Survival (PFS)(Up to 15.9 months)
- Phase 1 and Phase 2a: Overall Survival (OS)(Up to 15.9 months)
- Phase 1 and Phase 2a: Number of Participants With Anti-drug Antibodies (ADA)(Up to 15.9 months)
- Phase 1 and Phase 2a: Titer of Anti-drug Antibodies(Up to 15.9 months)
- Phase 1 and Phase 2a: Number of Participants With Neutralizing Antibodies (NAb) Against Study Drug(Up to 15.9 months)
- Phase 1 and Phase 2a: Rate of Measurable [Minimal] Residual Disease Negative (MRD[-]) Complete Response (CR)(Up to 15.9 months)
- Phase 1 and Phase 2a: Duration of Measurable [Minimal] Residual Disease (MRD) Negativity(Up to 15.9 months)
- Phase 2a: Clinical Benefit Rate (CBR)(Phase 2a: Up to 15.9 months)
- Phase 2a: Duration of Clinical Benefit (DCB)(Phase 2a: Up to 15.9 months)
- Phase 2a: Disease Control Rate (DCR)(Phase 2a: Up to 15.9 months)
- Phase 2a: Duration of Disease Control(Phase 2a: Up to 15.9 months)
- Phase 2a: Time to Progression (TTP)(Phase 2a: Up to 15.9 months)
- Phase 2a: Time to Response (TTR)(Phase 2a: Up to 15.9 months)
- Phase 2a: Time to Next Treatment (TTNT)(Phase 2a: Up to 15.9 months)
- Phase 2a: Number of Participants Reporting One or More TEAEs and Per Severity(Phase 2a: Up to 15.9 months)