An Open-Label, Dose-Escalation Phase 1b/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Modakafusp Alfa (TAK-573) as a Single Agent and in Combination With Pembrolizumab in Adult Patients With Advanced or Metastatic Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 45
- 试验地点
- 33
- 主要终点
- Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)
研究概览
简要总结
This study has 2 phases.
The main aims of Phase 1b are:
- to check for side effects from modakafusp alfa in adults with locally advanced or metastatic solid tumors.
- to learn how much modakafusp alfa adults can receive without getting any major side effects from it.
The main aims of Phase 2 are:
- to check for side effects from modakafusp alfa when given together with pembrolizumab in adults with metastatic cutaneous melanoma which cannot be completely removed by surgery.
- to learn how these medicines improve their symptoms.
Participants will receive modakafusp alfa for up to 1 year (Phase 1b) or modakafusp alfa given together with pembrolizumab for up to 2 years (Phase 2). Those whose symptoms improve might continue treatment for longer.
In both phases of the study, participants will revisit the study clinic within 30 days after their last dose or before they start other cancer treatment, whichever happens first.
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 antitumor activity as single agent (SA) or in combination with pembrolizumab in participants with locally advanced or metastatic solid tumors. The study will consist of 2 phases: Phase 1b dose escalation and a Phase 2 dose expansion.
The study will enroll approximately 114 participants (approximately 30 participants in Phase 1b dose escalation phase; 3-9 participants in safety-lead in and 25 participants for each expansion cohort (3 cohorts) of Phase 2.
The dose escalation phase will enroll participants with solid tumors. The dose escalation phase is to evaluate SA recommended phase 2 dose (RP2D).
The dose expansion phase in combination with pembrolizumab will be initiated with a safety lead-in phase once the SA RP2D is determined for modakafusp alfa. The dose expansion will include participants with one of following 3 disease indications:
I. Unresectable/metastatic cutaneous melanoma with primary resistance to no more than 2 prior lines of anti-disease programmed cell death protein 1 (PD1) containing treatments in the metastatic setting.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Other
- 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
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-
- •For both the dose escalation and expansion cohort phases of the study, eligible participants must have histologically confirmed advanced (locoregionally recurrent, not amenable to curative therapy) or metastatic solid tumors.
- •Measurable disease per RECIST v1.
- •At least 1 target lesion amenable for biopsy is required for enrollment in phase 1b. A minimum of 1 target lesion for response assessment is required for enrollment in phase
- •A separate lesion amenable for biopsy is required for enrollment in phase 2 for cohorts I and II post futility analysis and for all participants (safety lead-in and expansion) with subgroup III melanoma.
- •Phase 1b Dose Escalation: Participants with histologically confirmed advanced locally (locoregionally recurrent, not amenable to curative therapy) or metastatic solid tumors.
- •Phase 2 Dose Expansion:
- •The combination cohorts, including participants in the safety-lead phase, will enroll participants with unresectable/metastatic melanoma in the following subgroups:
- •I. Unresectable/metastatic histologically confirmed cutaneous melanoma with primary resistance to no more than 2 prior lines of anti-PD1 containing treatments in the metastatic setting.
- •II. Unresectable/metastatic histologically confirmed cutaneous melanoma with acquired resistance to no more than 2 prior lines of anti-PD1 containing treatments in the metastatic setting.
- •III. Unresectable/metastatic histologically confirmed cutaneous melanoma naive to prior anti-PD1 containing treatments in the metastatic setting.
- •Participants with BRAF V600E mutant melanoma may have received prior BRAF inhibitor therapy.
- •For the expansion cohorts I and II, there is no limitation of total number of prior line(s) of therapy, but the number of prior line(s) containing anti-PD1 must be ≤2 in the metastatic setting.
- •For the expansion cohort III, participants who received an anti-PD-1 treatment in the adjuvant setting must have completed that treatment at least 6 months prior to enrollment and must not have progressed on the anti-PD1 adjuvant treatment.
- •Primary resistance is defined as a best response of PD or SD less than (<) 6 months to an anti-PD1 alone or in combination with other agents (that is, CTLA4) in the initial anti-PD1 containing treatment.
- •Acquired resistance is defined as a progression following a best response of CR, PR or SD>6 months to a prior anti-PD1 alone or in combination with other agents (that is, CTLA4).
排除标准
- •Persistent toxicity from previous treatments that has not resolved to less than or equal to (<=) CTCAE version 5.0 Grade 1 prior to administration of modakafusp alfa, except for alopecia, Grade 2 neuropathy, and Grade 2 asthenia/fatigue, or autoimmune endocrinopathies with stable replacement therapy.
- •History of any of the following <=6 months before first dose modakafusp alfa: New York Heart Association (NYHA) Grade III or IV congestive heart failure, unstable angina, myocardial infarction, unstable symptomatic ischemic heart disease, any ongoing symptomatic cardiac arrhythmias of Grade >2, pulmonary embolism, or symptomatic cerebrovascular events, or any other serious cardiac condition (example, symptomatic pericardial effusion or restrictive cardiomyopathy). Chronic, stable atrial fibrillation on stable anticoagulant therapy, including low molecular-weight heparin, is allowed.
- •Baseline QT interval with Fridericia's correction (QTcF) greater than (>) 480 millisecond (msec) (Grade >=2), history of congenital long QT syndrome, or torsades de pointes.
- •Patients with acral lentiginous melanoma are excluded in phase 2 except for the safety lead-in phase.
- •Ongoing or active infection.
- •Known history of human immunodeficiency virus (HIV) infection or any other relevant congenital or acquired immunodeficiency. Testing during screening period is required only if indicated by specific local regulations or investigator's criteria.
- •Known hepatitis B (HBV) surface antigen seropositive or detectable hepatitis C infection viral load. Note: Participants with a positive HBV core antibody can be enrolled but must have an undetectable hepatitis B viral load.
- •Autoimmune disease requiring systemic immunosuppressive therapy. Participants with immune mediated endocrine deficiency from previous therapy with stable hormone replacement are exceptions.
研究组 & 干预措施
Phase 1b SA Dose Escalation
Modakafusp alfa 0.1 to 6 milligram per kilogram (mg/kg), infusion, intravenously, once on Day 1 of each 21-days treatment cycle for up to 1 year.
干预措施: Modakafusp Alfa (Drug)
Phase 2 Safety Lead-in Dose Expansion: Modakafusp Alfa + Pembrolizumab
Melanoma with primary resistance to prior anti-PD1, acquired resistance to prior anti-PD1 or naïve to anti-PD1.
Modakafusp alfa, infusion, intravenously, once on Day 1 of each 21-days treatment cycle and pembrolizumab 400 mg infusion, intravenously, once every 6 weeks for up to 2 years. The starting dose of modakafusp alfa for dose expansion safety lead-in phase will be the RP2D determined in the previous Phase 1b dose escalation phase.
干预措施: Modakafusp Alfa (Drug)
Phase 2 Safety Lead-in Dose Expansion: Modakafusp Alfa + Pembrolizumab
Melanoma with primary resistance to prior anti-PD1, acquired resistance to prior anti-PD1 or naïve to anti-PD1.
Modakafusp alfa, infusion, intravenously, once on Day 1 of each 21-days treatment cycle and pembrolizumab 400 mg infusion, intravenously, once every 6 weeks for up to 2 years. The starting dose of modakafusp alfa for dose expansion safety lead-in phase will be the RP2D determined in the previous Phase 1b dose escalation phase.
干预措施: Pembrolizumab (Drug)
Phase 2 Dose Expansion: Modakafusp Alfa + Pembrolizumab (Melanoma With Primary Resistance)
Melanoma With Primary Resistance to prior anti-PD1. Modakafusp alfa, infusion, intravenously, once on Day 1 of each 21-days treatment cycle and pembrolizumab 400 mg infusion, intravenously, once every 6 weeks for up to 2 years, in participants with unresectable/metastatic cutaneous melanoma with primary resistance to no more than 2 prior lines of anti-PD1 containing treatments in the metastatic setting. The dose of modakafusp alfa for dose expansion phase will be the modakafusp alfa RP2D in combination with pembrolizumab determined in the previous Phase 2 dose expansion safety-lead in phase.
干预措施: Modakafusp Alfa (Drug)
Phase 2 Dose Expansion: Modakafusp Alfa + Pembrolizumab (Melanoma With Primary Resistance)
Melanoma With Primary Resistance to prior anti-PD1. Modakafusp alfa, infusion, intravenously, once on Day 1 of each 21-days treatment cycle and pembrolizumab 400 mg infusion, intravenously, once every 6 weeks for up to 2 years, in participants with unresectable/metastatic cutaneous melanoma with primary resistance to no more than 2 prior lines of anti-PD1 containing treatments in the metastatic setting. The dose of modakafusp alfa for dose expansion phase will be the modakafusp alfa RP2D in combination with pembrolizumab determined in the previous Phase 2 dose expansion safety-lead in phase.
干预措施: Pembrolizumab (Drug)
Phase 2 Dose Expansion: Modakafusp Alfa + Pembrolizumab (Melanoma With Acquired Resistance)
Melanoma With Acquired Resistance to prior anti-PD1. Modakafusp alfa, infusion, intravenously, once on Day 1 of each 21-days treatment cycle and pembrolizumab 400 mg infusion, intravenously, once every 6 weeks for up to 2 years, in participants with unresectable/metastatic cutaneous melanoma with acquired resistance to no more than 2 prior lines of anti-PD1 containing treatments in the metastatic setting. The dose of modakafusp alfa for dose expansion phase will be the modakafusp alfa RP2D in combination with pembrolizumab determined in the previous Phase 2 dose expansion safety lead-in phase.
干预措施: Modakafusp Alfa (Drug)
Phase 2 Dose Expansion: Modakafusp Alfa + Pembrolizumab (Melanoma With Acquired Resistance)
Melanoma With Acquired Resistance to prior anti-PD1. Modakafusp alfa, infusion, intravenously, once on Day 1 of each 21-days treatment cycle and pembrolizumab 400 mg infusion, intravenously, once every 6 weeks for up to 2 years, in participants with unresectable/metastatic cutaneous melanoma with acquired resistance to no more than 2 prior lines of anti-PD1 containing treatments in the metastatic setting. The dose of modakafusp alfa for dose expansion phase will be the modakafusp alfa RP2D in combination with pembrolizumab determined in the previous Phase 2 dose expansion safety lead-in phase.
干预措施: Pembrolizumab (Drug)
Phase 2 Dose Expansion: Modakafusp Alfa + Pembrolizumab (Melanoma naïve to anti-PD1)
Modakafusp alfa, infusion, intravenously, once on Day 1 of each 21-days treatment cycle and pembrolizumab 400 mg infusion, intravenously, once every 6 weeks for up to 2 years, in participants with unresectable/metastatic cutaneous melanoma naive to prior line of anti-PD1 containing treatments in the metastatic setting. The dose of modakafusp alfa for dose expansion phase will be the modakafusp alfa RP2D in combination with pembrolizumab determined in the previous Phase 2 dose expansion safety lead-in phase.
干预措施: Modakafusp Alfa (Drug)
Phase 2 Dose Expansion: Modakafusp Alfa + Pembrolizumab (Melanoma naïve to anti-PD1)
Modakafusp alfa, infusion, intravenously, once on Day 1 of each 21-days treatment cycle and pembrolizumab 400 mg infusion, intravenously, once every 6 weeks for up to 2 years, in participants with unresectable/metastatic cutaneous melanoma naive to prior line of anti-PD1 containing treatments in the metastatic setting. The dose of modakafusp alfa for dose expansion phase will be the modakafusp alfa RP2D in combination with pembrolizumab determined in the previous Phase 2 dose expansion safety lead-in phase.
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)
时间窗: From signing of the informed consent form (ICF) through 30 days after last dose of study drug or the start of subsequent anticancer therapy, whichever occurred first (up to 1 year 1 month for Phase 1b and 2 years 1 month for Phase 2)
Adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence did not necessarily have a causal relationship with this treatment. A TEAE was any AE either reported for the first time or worsening of a pre-existing event after first dose of study drug and within 30 days of the last administration of study drug.
Phase 1b and Phase 2 Safety Lead-in: Number of Participants With Grade 3 or Higher TEAEs
时间窗: From signing of the ICF through 30 days after last dose of study drug or the start of subsequent anticancer therapy, whichever occurred first (up to 1 year 1 month for Phase 1b and 2 years 1 month for Phase 2)
TEAEs Grades were evaluated as per the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0. (NCI CTCAE v5), where Grade 3: 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: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE.
Phase 1b and Phase 2 Safety Lead-in: Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: Cycle 1 (Cycle length is equal to [=] 21 days)
A DLT was defined as any of the following AEs that occurred in the escalation phase or in the combination safety lead-in phase during Cycle 1 unless they were considered by the investigator to be clearly unrelated to therapy with modakafusp alfa according to NCI CTCAE version 5.0. Any Grade 5 TEAE. Febrile neutropenia: Grade \>=3 or 4 neutropenia. Grade 4 thrombocytopenia. Grade \>=3 thrombocytopenia. Any Grade 3 immune-related AEs such as pericarditis, pneumonitis, cardiotoxicity, hepatitis, or neurotoxicity. Delay in the initiation of Cycle 2 by more than 14 days from the calculated start date due to a lack of adequate recovery of treatment-related hematological or nonhematologic toxicities. Any Grade \>=3 nonhematologic toxicity with some exception. Any Grade 2 nonhematologic toxicity that was considered by the investigator to be related to study drug and dose-limiting.
Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting One or More Serious Adverse Event (SAEs)
时间窗: From signing of the ICF through 30 days after last dose of study drug even if the participants start non-protocol systemic therapy (up to 1 year 1 month for Phase 1b and 2 years 1 month for Phase 2)
SAE was defined as any untoward medical occurrence that resulted in death; was life-threatening; required inpatient hospitalization or prolongation of an existing hospitalization; resulted in persistent or significant disability or incapacity; was a congenital anomaly/birth defect; was a medically important event that might not result in death, be immediately life-threatening, or required hospitalization, but might be considered serious when, on the basis of appropriate medical judgment, it might jeopardize the participant, required medical or surgical intervention to prevent one of the outcomes listed above, or involves suspected transmission via a medicinal product of an infectious agent.
Phase 1b and Phase 2 Safety Lead-in: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuations
时间窗: From signing of the ICF through 30 days after last dose of study drug or the start of subsequent anticancer therapy, whichever occurred first (up to 1 year 1 month for Phase 1b and 2 years 1 month for Phase 2)
TEAE was defined as any AE either reported for the first time or worsening of a pre-existing event after first dose of study drug and within 30 days of the last administration of study drug.
Phase 2 Expansion: Overall Response Rate (ORR) Based on RECIST v1.1
时间窗: From the first dose of study drug up to end of treatment or end of study (up to 2 years)
ORR was defined as the percentage of participants who achieved complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 millimeter (mm). PR: At least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
次要结局
- Phase 1b and Phase 2: Progression Free Survival (PFS) Based on RECIST v1.1(From the date of the first dose of study drug to the date of first documentation of PD or death, whichever occurred first (up to end of treatment or end of study [1 year for Phase 1b and 2 years for Phase 2]))
- Phase 1b and Phase 2: Overall Survival (OS) Based on RECIST v1.1(From the date of first dose of study drug to the date of death due to any cause (up to end of treatment or end of study [1 year for Phase 1b and 2 years for Phase 2]))
- Phase 2 Expansion: ORR Based on Based on Immune Response Evaluation Criteria in Solid Tumors (iRECIST)(From date of first dose of study drug until confirmed iCR or iPR (up to end of treatment or end of study [up to 2 years]))
- Phase 2 Expansion: DCR Based on iRECIST(From date of first dose of study drug until confirmed iCR or iPR (up to end of treatment or end of study [up to 2 years]))
- Phase 2 Expansion: DOR Based on iRECIST(From first documented confirmed iCR or iPR until first documentation of iCPD or death (up to end of treatment or end of study [up to 2 years]))
- Phase 2 Expansion: TTP Based on iRECIST(From the date of the first dose of study drug to the date of the first documentation of iCPD (up to end of treatment or end of study [up to 2 years]))
- Phase 2 Expansion: PFS Based on iRECIST(From first dose of study drug until confirmed iCPD or death (up to end of treatment or end of study [up to 2 years]))
- Phase 1b and Phase 2: Number of Participants With Positive Anti-Modakafusp Alfa Antibodies (ADA) Status(Baseline up to end of treatment or end of study (up to 1 year for Phase 1b and 2 years for Phase 2))
- Phase 1b and Phase 2: Titer of Anti-Modakafusp Alfa Antibodies (ADA)(Baseline up to end of treatment or end of study (up to 1 year for Phase 1b and 2 years for Phase 2))
- Phase 1b: Maximum Tolerated Dose (MTD) of Modakafusp Alfa(Cycle 1 (Cycle length = 21 days))
- Phase 1b and Phase 2 Safety Lead-in: Recommended Phase 2 Dose (RP2D) for Single Agent (SA) Modakafusp Alfa in Phase 1b and in Combination With Pembrolizumab in Phase 2 Safety Lead-in(Cycle 1 (Cycle length = 21 days))
- Phase 2 Expansion: Number of Participants Reporting One or More TEAEs(From signing of the ICF through 30 days after last dose of study drug or the start of subsequent anticancer therapy, whichever occurred first (up to 2 years 1 month))
- Phase 2 Expansion: Number of Participants With Grade 3 or Higher TEAEs(From signing of the ICF through 30 days after last dose of study drug or the start of subsequent anticancer therapy, whichever occurred first (up to 2 years 1 month))
- Phase 2 Expansion: Number of Participants Reporting One or More SAEs(From signing of the ICF through 30 days after last dose of study drug even if the participants start non-protocol systemic therapy (up to 2 years 1 month))
- Phase 2 Expansion: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuations(From signing of the ICF through 30 days after last dose of study drug or the start of subsequent anticancer therapy, whichever occurred first (up to 2 years 1 month))
- Phase 1b and Phase 2 Safety Lead-in: Maximum Observed Serum Concentration (Cmax) for Modakafusp Alfa(Phase 1b, Cycles 1 and 2 Day 1: Pre-infusion and at multiple timepoints (up to 72 hours) post-infusion; Phase 2, Safety lead-in, Cycles 1 and 3 Day 1: Pre-infusion and at multiple timepoints (up to 72 hours) post-infusion (each cycle length=21 days))
- Phase 1b and Phase 2 Safety Lead-in: Time to Reach the Cmax (Tmax) for Modakafusp Alfa(Phase 1b, Cycles 1 and 2 Day 1: Pre-infusion and at multiple timepoints (up to 72 hours) post-infusion; Phase 2, Safety lead-in, Cycles 1 and 3 Day 1: Pre-infusion and at multiple timepoints (up to 72 hours) post-infusion (each cycle length=21 days))
- Phase 1b and Phase 2 Safety Lead-in: Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUClast) for Modakafusp Alfa(Phase 1b, Cycles 1 and 2 Day 1: Pre-infusion and at multiple timepoints (up to 72 hours) post-infusion; Phase 2, Safety lead-in, Cycles 1 and 3 Day 1: Pre-infusion and at multiple timepoints (up to 72 hours) post-infusion (each cycle length=21 days))
- Phase 1b and Phase 2 Safety Lead-in: Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf) for Modakafusp Alfa(Phase 1b, Cycles 1 and 2 Day 1: Pre-infusion and at multiple timepoints (up to 72 hours) post-infusion; Phase 2, Safety lead-in, Cycles 1 and 3 Day 1: Pre-infusion and at multiple timepoints (up to 72 hours) post-infusion (each cycle length=21 days))
- Phase 1b and Phase 2 Safety Lead-in: Terminal Disposition Phase Half-life (t1/2z) for Modakafusp Alfa(Phase 1b, Cycles 1 and 2 Day 1: Pre-infusion and at multiple timepoints (up to 72 hours) post-infusion; Phase 2, Safety lead-in, Cycles 1 and 3 Day 1: Pre-infusion and at multiple timepoints (up to 72 hours) post-infusion (each cycle length=21 days))
- Phase 1b and Phase 2 Safety Lead-in: Total Clearance (CL) After Intravenous Administration for Modakafusp Alfa(Phase 1b, Cycles 1 and 2 Day 1: Pre-infusion and at multiple timepoints (up to 72 hours) post-infusion; Phase 2, Safety lead-in, Cycles 1 and 3 Day 1: Pre-infusion and at multiple timepoints (up to 72 hours) post-infusion (each cycle length=21 days))
- Phase 1b and Phase 2 Safety Lead-in: Volume of Distribution at Steady State (Vss) for Modakafusp Alfa(Phase 1b, Cycles 1 and 2 Day 1: Pre-infusion and at multiple timepoints (up to 72 hours) post-infusion; Phase 2, Safety lead-in, Cycles 1 and 3 Day 1: Pre-infusion and at multiple timepoints (up to 72 hours) post-infusion (each cycle length=21 days))
- Phase 1b and Phase 2 Safety Lead-in: ORR Based on RECIST v1.1(From the first dose of study drug up to end of treatment or end of study (up to 1 year for Phase 1b and 2 years for Phase 2))
- Phase 1b and Phase 2: Disease Control Rate (DCR) Based on RECIST v1.1(From the first dose of study drug up to end of treatment or end of study (up to 1 year for Phase 1b and 2 years for Phase 2))
- Phase 1b and Phase 2: Duration of Response (DOR) Based on RECIST v1.1(From the date of first documentation of a CR or PR until PD or death, whichever occurred first (up to end of treatment or end of study [1 year for Phase 1b and 2 years for Phase 2]))
- Phase 1b and Phase 2: Time to Progression (TTP) Based on RECIST v1.1(From the date of the first dose of study drug to the date of the first documentation of PD (up to end of treatment or end of study [1 year for Phase 1b and 2 years for Phase 2]))