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

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ClinicalTrials.gov Identifier: NCT04157517
Recruitment Status : Recruiting
First Posted : November 8, 2019
Last Update Posted : October 22, 2021
Sponsor:
Information provided by (Responsible Party):
Takeda

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Neoplasms Melanoma Drug: Modakafusp Alfa Drug: Pembrolizumab Phase 1 Phase 2

Detailed Description:

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 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 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-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. 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 114 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: 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
Actual Study Start Date : December 12, 2019
Estimated Primary Completion Date : August 2, 2023
Estimated Study Completion Date : August 2, 2023

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: 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.
Drug: Modakafusp Alfa
Modakafusp alfa intravenous infusion.
Other Name: TAK-573

Experimental: 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.

Drug: Modakafusp Alfa
Modakafusp alfa intravenous infusion.
Other Name: TAK-573

Drug: Pembrolizumab
Pembrolizumab intravenous infusion.

Experimental: 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.
Drug: Modakafusp Alfa
Modakafusp alfa intravenous infusion.
Other Name: TAK-573

Drug: Pembrolizumab
Pembrolizumab intravenous infusion.

Experimental: 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.
Drug: Modakafusp Alfa
Modakafusp alfa intravenous infusion.
Other Name: TAK-573

Drug: Pembrolizumab
Pembrolizumab intravenous infusion.

Experimental: 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.
Drug: Modakafusp Alfa
Modakafusp alfa intravenous infusion.
Other Name: TAK-573

Drug: Pembrolizumab
Pembrolizumab intravenous infusion.




Primary Outcome Measures :
  1. Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting one or More Treatment-emergent Adverse Events (TEAEs) [ Time Frame: Up to 55 months ]
  2. Phase 1b and Phase 2 Safety Lead-in: Number of Participants with Grade 3 or Higher TEAEs [ Time Frame: Up to 55 months ]
    TEAEs Grades will be evaluated as per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.

  3. Phase 1b and Phase 2 Safety Lead-in: Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: Cycle 1 (Cycle length is equal to [=] 21 days) ]
    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 version 5.0.

  4. Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting one or More Serious Adverse Event (SAEs) [ Time Frame: Up to 55 months ]
  5. Phase 1b and Phase 2 Safety Lead-in: Number of Participants With one or More TEAEs Leading to Dose Modifications and Treatment Discontinuations [ Time Frame: Up to 55 months ]
  6. Phase 2 Expansion: Overall Response Rate (ORR) [ Time Frame: Up to 55 months ]
    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 modified Response Evaluation Criteria in Solid Tumor (mRECIST) version 1.1 for melanoma participants.


Secondary Outcome Measures :
  1. Phase 1b: Maximum Tolerated Dose (MTD) or Pharmacologically Active Dose (PAD) [ Time Frame: Cycle 1 (Cycle length is equal to [=] 21 days) ]
  2. Phase 1b and Phase 2 Safety Lead-in: Recommended Phase 2 Dose (RP2D) for Single Agent (SA) and in Combination With Pembrolizumab [ Time Frame: Cycle 1 (Cycle length is equal to [=] 21 days) ]
  3. Phase 2 Expansion: Number of Participants Reporting one or More TEAEs [ Time Frame: Up to 55 months ]
  4. Phase 2 Expansion: Number of Participants With Grade 3 or Higher TEAEs [ Time Frame: Up to 55 months ]
    TEAEs Grades will be evaluated as per the NCI CTCAE Version 5.0.

  5. Phase 2 Expansion: Number of Participants Reporting one or More SAEs [ Time Frame: Up to 55 months ]
  6. Phase 2 Expansion: Number of Participants With one or More TEAEs Leading to Dose Modifications and Treatment Discontinuations [ Time Frame: Up to 55 months ]
  7. Phase 1b and Phase 2 Safety Lead-in: Cmax: Maximum Observed Serum Concentration for Modakafusp Alfa [ Time Frame: Phase 1b: Cycles(C) 1-2 Day(D) 1: predose, at multiple timepoints (up to 72 hours [h]) postdose; Phase 2 Safety Lead-in: C1 and C3 D1: predose and at multiple timepoints (up to 336h) postdose (Cycle=21 days) ]
  8. Phase 1b and Phase 2 Safety Lead-in: Tmax: Time to Reach the Maximum Serum Concentration (Cmax) for Modakafusp Alfa [ Time Frame: Phase 1b: Cycles(C) 1-2 Day(D) 1: predose, at multiple timepoints (up to 72 hours [h]) postdose; Phase 2 Safety Lead-in: C1 and C3 D1: predose and at multiple timepoints (up to 336h) postdose (Cycle=21 days) ]
  9. 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 [ Time Frame: Phase 1b: Cycles(C) 1-2 Day(D) 1: predose, at multiple timepoints (up to 72 hours [h]) postdose; Phase 2 Safety Lead-in: C1 and C3 D1: predose and at multiple timepoints (up to 336h) postdose (Cycle=21 days) ]
  10. Phase 1b and Phase 2 Safety Lead-in: AUCinf: Area Under the Serum Concentration-time Curve From Time 0 to Infinity for Modakafusp Alfa [ Time Frame: Phase 1b: Cycles(C) 1-2 Day(D) 1: predose, at multiple timepoints (up to 72 hours [h]) postdose; Phase 2 Safety Lead-in: C1 and C3 D1: predose and at multiple timepoints (up to 336h) postdose (Cycle=21 days) ]
  11. Phase 1b and Phase 2 Safety Lead-in: t1/2z: Terminal Disposition Phase Half-life for Modakafusp Alfa [ Time Frame: Phase 1b: Cycles(C) 1-2 Day(D) 1: predose, at multiple timepoints (up to 72 hours [h]) postdose; Phase 2 Safety Lead-in: C1 and C3 D1: predose and at multiple timepoints (up to 336h) postdose (Cycle=21 days) ]
  12. Phase 1b and Phase 2 Safety Lead-in: CL: Total Clearance After Intravenous Administration for Modakafusp Alfa [ Time Frame: Phase 1b: Cycles(C) 1-2 Day(D) 1: predose, at multiple timepoints (up to 72 hours [h]) postdose; Phase 2 Safety Lead-in: C1 and C3 D1: predose and at multiple timepoints (up to 336h) postdose (Cycle=21 days) ]
  13. Phase 1b and Phase 2 Safety Lead-in: Vss: Volume of Distribution at Steady State for Modakafusp Alfa [ Time Frame: Phase 1b: Cycles(C) 1-2 Day(D) 1: predose, at multiple timepoints (up to 72 hours [h]) postdose; Phase 2 Safety Lead-in: C1 and C3 D1: predose and at multiple timepoints (up to 336h) postdose (Cycle=21 days) ]
  14. Phase 1b: Overall Response Rate (ORR) [ Time Frame: Up to 55 months ]
    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 mRECIST v1.1. for participants in dose escalation.

  15. Phase 1b and Phase 2: Disease Control Rate (DCR) [ Time Frame: Up to 55 months ]
    DCR is defined as the percentage of participants who achieve CR, PR, or SD of at least 6 weeks (determined by the investigator) during the study in response-evaluable population. The DCR will be assessed as per mRECIST v1.1.

  16. Phase 1b and Phase 2: Duration of Response (DOR) [ Time Frame: Up to 55 months ]
    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 mRECIST v1.1.

  17. Phase 1b and Phase 2: Time to Progression (TTP) [ Time Frame: Up to 55 months ]
    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 mRECIST v1.1.

  18. Phase 1b and Phase 2: Progression Free Survival (PFS) [ Time Frame: Up to 55 months ]
    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 mRECIST v.1.1 in participants with solid tumors and according to PCWG3 criteria for CRPC participants, or death due to any cause, whichever occurs first. Participants without documentation of progressive disease (PD) or death will be censored at the date of the last response assessment that is stable disease (SD) or better.

  19. Phase 1b and Phase 2: Overall Survival (OS) [ Time Frame: Up to 55 months ]
    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 mRECIST v1.1.

  20. Phase 2 Expansion: ORR Based on Immune Response Evaluation Criteria in Solid Tumors (iRECIST) [ Time Frame: Up to 55 months ]
  21. Phase 2 Expansion: DCR Based on iRECIST [ Time Frame: Up to 55 months ]
  22. Phase 2 Expansion: DOR Based on iRECIST [ Time Frame: Up to 55 months ]
  23. Phase 2 Expansion: TTP Based on iRECIST [ Time Frame: Up to 55 months ]
  24. Phase 2 Expansion: PFS Based on iRECIST [ Time Frame: Up to 55 months ]
  25. Phase 1b and Phase 2: Incidence and Titer of Modakafusp Alfa Antibodies [ Time Frame: Up to 55 months ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
  2. 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.
  3. Measurable disease per mRECIST 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 patients (safety lead-in and expansion) with subgroup III melanoma.
  4. 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, the initiation of treatment in the current study should be within the 12 months of the completion of the last anti-PD1 containing treatment.
  • 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:

  1. 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.
  2. 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.
  3. 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.
  4. Ongoing or active infection.
  5. 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.
  6. 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.
  7. Autoimmune disease requiring systemic immunosuppressive therapy. Participants with immune mediated endocrine deficiency from previous therapy with stable hormone replacement are exceptions.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04157517


Contacts
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Contact: Takeda Contact +1-877-825-3327 medinfoUS@takeda.com

Locations
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United States, North Carolina
Levine Cancer Institute Recruiting
Charlotte, North Carolina, United States, 28204
United States, Tennessee
Sarah Cannon Research Institute Recruiting
Nashville, Tennessee, United States, 37203
United States, Texas
Mary Crowley Cancer Research Recruiting
Dallas, Texas, United States, 75230
NEXT Oncology Recruiting
San Antonio, Texas, United States, 78240
Sponsors and Collaborators
Takeda
Investigators
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Study Director: Study Director Takeda
Additional Information:
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Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT04157517    
Other Study ID Numbers: TAK-573-1001
U1111-1238-9163 ( Registry Identifier: WHO )
First Posted: November 8, 2019    Key Record Dates
Last Update Posted: October 22, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
URL: https://vivli.org/ourmember/takeda/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Takeda:
Drug Therapy
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents