A Study of Modakafusp Alfa (TAK-573) Given by Itself and Together With Pembrolizumab in Adults With Advanced or Metastatic Solid Tumors

Study Overview
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Brief Summary
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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.

Detailed Description
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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. II. Unresectable/metastatic cutaneous melanoma with acquired resistance to no more than 2 prior lines of anti-PD1 containing treatments in the metastatic setting. III. Unresectable/metastatic cutaneous melanoma naïve to prior anti-PD1 containing treatments in the metastatic setting. This multi-center trial will be conducted in the United States and Australia. Participants with demonstrated clinical benefit may continue treatment beyond 1 year for Phase 1b and 2 years for Phase 2 if approved by the sponsor. The overall time to participate in this study is 55 months. All participants will make an end of treatment (EOT) visit 30 days after receiving their last dose of study drug or before the start of subsequent systemic anticancer therapy, whichever occurs first for a safety follow up assessment.

Official Title
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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

Conditions
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Neoplasms, Melanoma

Intervention / Treatment
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* Drug: Modakafusp Alfa
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. 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 v1.1. 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 2. 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). Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b SA Dose Escalation<br>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. | Drug: Modakafusp Alfa<br>* Modakafusp alfa intravenous infusion.<br>* Other names: TAK-573;|
| Experimental: Phase 2 Safety Lead-in Dose Expansion: Modakafusp Alfa + Pembrolizumab<br>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. | Drug: Modakafusp Alfa<br>* Modakafusp alfa intravenous infusion.<br>* Other names: TAK-573;Drug: Pembrolizumab<br>* Pembrolizumab intravenous infusion.<br>|
| Experimental: Phase 2 Dose Expansion: Modakafusp Alfa + Pembrolizumab (Melanoma With Primary Resistance)<br>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. | Drug: Modakafusp Alfa<br>* Modakafusp alfa intravenous infusion.<br>* Other names: TAK-573;Drug: Pembrolizumab<br>* Pembrolizumab intravenous infusion.<br>|
| Experimental: Phase 2 Dose Expansion: Modakafusp Alfa + Pembrolizumab (Melanoma With Acquired Resistance)<br>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. | Drug: Modakafusp Alfa<br>* Modakafusp alfa intravenous infusion.<br>* Other names: TAK-573;Drug: Pembrolizumab<br>* Pembrolizumab intravenous infusion.<br>|
| Experimental: Phase 2 Dose Expansion: Modakafusp Alfa + Pembrolizumab (Melanoma naïve to anti-PD1)<br>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. | Drug: Modakafusp Alfa<br>* Modakafusp alfa intravenous infusion.<br>* Other names: TAK-573;Drug: Pembrolizumab<br>* Pembrolizumab intravenous infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting one or More Treatment-emergent Adverse Events (TEAEs) | AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. A TEAE is 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 (90 days for immune-related adverse event [irAE]) of the last administration of study drug. | Up to 55 months | 
| Phase 1b and Phase 2 Safety Lead-in: Number of Participants with Grade 3 or Higher TEAEs | TEAEs Grades will be evaluated as per the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0. (NCI CTCAE v5). | Up to 55 months | 
| Phase 1b and Phase 2 Safety Lead-in: Number of Participants With Dose Limiting Toxicities (DLTs) | DLT will be defined as any of the TEAEs that occur during Cycle 1 and are considered by the investigator to be at least possibly related to modakafusp alfa. Toxicity will be evaluated according to NCI CTCAE v5. | Cycle 1 (Cycle length is equal to [=] 21 days) | 
| Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting one or More Serious Adverse Event (SAEs) | SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, leads to a congenital anomaly/birth defect or is considered to be an important medical event that may not result in death, be immediately life-threatening, or require hospitalization but may be considered serious when, based on appropriate medical judgment, the event may jeopardize the participant or may require medical or surgical intervention. | Up to 55 months | 
| Phase 1b and Phase 2 Safety Lead-in: Number of Participants With one or More TEAEs Leading to Dose Modifications and Treatment Discontinuations | TEAE is 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 (90 days for irAE) of the last administration of study drug. | Up to 55 months | 
| Phase 2 Expansion: Overall Response Rate (ORR) | ORR is defined as the percentage of participants who achieve complete response (CR) or partial response (PR) during the study in response-evaluable population. ORR will be assessed as per Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1 for melanoma participants. | Up to 55 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Maximum Tolerated Dose (MTD) or Pharmacologically Active Dose (PAD) |  | Cycle 1 (Cycle length is equal to [=] 21 days) | 
| Phase 1b and Phase 2 Safety Lead-in: Recommended Phase 2 Dose (RP2D) for Single Agent (SA) and in Combination With Pembrolizumab | The RP2D may be either MTD based on dose limiting toxicities or a pharmacologically active dose defined by the PK/pharmacodynamic model or exposure-response (ER) analysis in place. | Cycle 1 (Cycle length is equal to [=] 21 days) | 
| Phase 2 Expansion: Number of Participants Reporting one or More TEAEs | TEAE is 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 (90 days for irAE) of the last administration of study drug. | Up to 55 months | 
| Phase 2 Expansion: Number of Participants With Grade 3 or Higher TEAEs | TEAEs Grades will be evaluated as per the NCI CTCAE v5. | Up to 55 months | 
| Phase 2 Expansion: Number of Participants Reporting one or More SAEs | SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, leads to a congenital anomaly/birth defect or is considered to be an important medical event that may not result in death, be immediately life-threatening, or require hospitalization but may be considered serious when, based on appropriate medical judgment, the event may jeopardize the participant or may require medical or surgical intervention. | Up to 55 months | 
| Phase 2 Expansion: Number of Participants With one or More TEAEs Leading to Dose Modifications and Treatment Discontinuations | TEAE is 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 (90 days for irAE) of the last administration of study drug. | Up to 55 months | 
| Phase 1b and Phase 2 Safety Lead-in: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa |  | Phase 1b (Cycles 1-2) and Phase 2 (Cycle 1 and Cycle 3) Day 1: predose, at multiple timepoints (up to 72 hours (hrs) or up to 6 hrs (Phase 1b, Cycles 3-6) or up to 24 hrs (Phase 2, Cycle 2 and Cycle 4 onwards) postdose (cycle length=21 days) | 
| Phase 1b and Phase 2 Safety Lead-in: Tmax: Time to Reach the Maximum Serum Concentration (Cmax) for Modakafusp Alfa |  | Phase 1b (Cycles 1-2) and Phase 2 (Cycle 1 and Cycle 3) Day 1: predose, at multiple timepoints (up to 72 hours (hrs) or up to 6 hrs (Phase 1b, Cycles 3-6) or up to 24 hrs (Phase 2, Cycle 2 and Cycle 4 onwards) postdose (cycle length=21 days) | 
| Phase 1b and Phase 2 Safety Lead-in: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t for Modakafusp Alfa |  | Phase 1b (Cycles 1-2) and Phase 2 (Cycle 1 and Cycle 3) Day 1: predose, at multiple timepoints (up to 72 hours (hrs) or up to 6 hrs (Phase 1b, Cycles 3-6) or up to 24 hrs (Phase 2, Cycle 2 and Cycle 4 onwards) postdose (cycle length=21 days) | 
| Phase 1b and Phase 2 Safety Lead-in: AUCinf: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa |  | Phase 1b (Cycles 1-2) and Phase 2 (Cycle 1 and Cycle 3) Day 1: predose, at multiple timepoints (up to 72 hours (hrs) or up to 6 hrs (Phase 1b, Cycles 3-6) or up to 24 hrs (Phase 2, Cycle 2 and Cycle 4 onwards) postdose (cycle length=21 days) | 
| Phase 1b and Phase 2 Safety Lead-in: t1/2z: Terminal Disposition Phase Half-life for Modakafusp Alfa |  | Phase 1b (Cycles 1-2) and Phase 2 (Cycle 1 and Cycle 3) Day 1: predose, at multiple timepoints (up to 72 hours (hrs) or up to 6 hrs (Phase 1b, Cycles 3-6) or up to 24 hrs (Phase 2, Cycle 2 and Cycle 4 onwards) postdose (cycle length=21 days) | 
| Phase 1b and Phase 2 Safety Lead-in: CL: Total Clearance After Intravenous Administration for Modakafusp Alfa |  | Phase 1b (Cycles 1-2) and Phase 2 (Cycle 1 and Cycle 3) Day 1: predose, at multiple timepoints (up to 72 hours (hrs) or up to 6 hrs (Phase 1b, Cycles 3-6) or up to 24 hrs (Phase 2, Cycle 2 and Cycle 4 onwards) postdose (cycle length=21 days) | 
| Phase 1b and Phase 2 Safety Lead-in: Vss: Volume of Distribution at Steady State for Modakafusp Alfa |  | Phase 1b (Cycles 1-2) and Phase 2 (Cycle 1 and Cycle 3) Day 1: predose, at multiple timepoints (up to 72 hours (hrs) or up to 6 hrs (Phase 1b, Cycles 3-6) or up to 24 hrs (Phase 2, Cycle 2 and Cycle 4 onwards) postdose (cycle length=21 days) | 
| Phase 1b: Overall Response Rate (ORR) | ORR is defined as the percentage of participants who achieve CR or PR during the study in response-evaluable population. ORR will be assessed as per RECIST v1.1. for participants in dose escalation. | Up to 55 months | 
| Phase 1b and Phase 2: Disease Control Rate (DCR) | DCR is defined as the percentage of participants who achieve CR, PR, or stable disease (SD) (determined by the investigator) during the study in response-evaluable population. The DCR will be assessed as per RECIST v1.1. | Up to 55 months | 
| Phase 1b and Phase 2: Duration of Response (DOR) | DOR is the time from the date of first documentation of a PR or better to the date of first documentation of PD for responders (PR or better). Responders without documentation of PD will be censored at the date of last response assessment that is SD or better. DOR will be assessed as per RECIST v1.1. | Up to 55 months | 
| Phase 1b and Phase 2: Time to Progression (TTP) | TTP is defined as the time from the date of the first dose of study drug to the date of the first documentation of PD according to RECIST v1.1. | Up to 55 months | 
| Phase 1b and Phase 2: Progression Free Survival (PFS) | PFS is defined as the time from the date of the first dose of study drug to the date of first documentation of progressive disease according to RECIST v.1.1, or death due to any cause, whichever occurs first. Participants without documentation of PD or death will be censored at the date of the last response assessment that is SD or better. | Up to 55 months | 
| Phase 1b and Phase 2: Overall Survival (OS) | OS is defined as the time from the date of first dose of study drug to the date of death due to any cause. Participants without documentation of death at the time of analysis will be censored at the date last known to be alive. OS will be assessed as per RECIST v1.1. | Up to 55 months | 
| Phase 2 Expansion: ORR Based on Immune Response Evaluation Criteria in Solid Tumors (iRECIST) |  | Up to 55 months | 
| Phase 2 Expansion: DCR Based on iRECIST |  | Up to 55 months | 
| Phase 2 Expansion: DOR Based on iRECIST |  | Up to 55 months | 
| Phase 2 Expansion: TTP Based on iRECIST |  | Up to 55 months | 
| Phase 2 Expansion: PFS Based on iRECIST |  | Up to 55 months | 
| Phase 1b and Phase 2: Number of Participants With Anti-Modakafusp Alfa Antibodies |  | Up to 55 months | 
| Phase 1b and Phase 2: Titer of Anti-Modakafusp Alfa Antibodies |  | Up to 55 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug Therapy