Clinical trial NCT04157517: A Study of Modakafusp Alfa (TAK-573) Given by Itself and Together With Pembrolizumab in Adults With Advanced or Metastatic Solid Tumors
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Neoplasms
Melanoma
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2019-11-08
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: OTHER

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.

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 (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.

Eligibility 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 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.
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, 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:

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, or autoimmune endocrinopathies with stable replacement therapy.
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. Patients with acral lentiginous melanoma are excluded in phase 2 except for the safety lead-in phase.
5. Ongoing or active infection.
6. 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.
7. 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.
8. Autoimmune disease requiring systemic immunosuppressive therapy. Participants with immune mediated endocrine deficiency from previous therapy with stable hormone replacement are exceptions.

Primary outcomes:
measure: Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)
timeFrame: 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)
measure: Phase 1b and Phase 2 Safety Lead-in: Number of Participants With Grade 3 or Higher TEAEs
timeFrame: 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)
measure: Phase 1b and Phase 2 Safety Lead-in: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Cycle 1 (Cycle length is equal to [=] 21 days)
measure: Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting One or More Serious Adverse Event (SAEs)
timeFrame: 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)
measure: Phase 1b and Phase 2 Safety Lead-in: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuations
timeFrame: 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)
measure: Phase 2 Expansion: Overall Response Rate (ORR) Based on RECIST v1.1
timeFrame: From the first dose of study drug up to end of treatment or end of study (up to 2 years)
Secondary outcomes:
measure: Phase 1b: Maximum Tolerated Dose (MTD) of Modakafusp Alfa
timeFrame: Cycle 1 (Cycle length = 21 days)
measure: 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
timeFrame: Cycle 1 (Cycle length = 21 days)
measure: Phase 2 Expansion: Number of Participants Reporting One or More TEAEs
timeFrame: 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)
measure: Phase 2 Expansion: Number of Participants With Grade 3 or Higher TEAEs
timeFrame: 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)
measure: Phase 2 Expansion: Number of Participants Reporting One or More SAEs
timeFrame: 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)
measure: Phase 2 Expansion: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuations
timeFrame: 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)
measure: Phase 1b and Phase 2 Safety Lead-in: Maximum Observed Serum Concentration (Cmax) for Modakafusp Alfa
timeFrame: 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)
measure: Phase 1b and Phase 2 Safety Lead-in: Time to Reach the Cmax (Tmax) for Modakafusp Alfa
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: Phase 1b and Phase 2 Safety Lead-in: Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf) for Modakafusp Alfa
timeFrame: 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)
measure: Phase 1b and Phase 2 Safety Lead-in: Terminal Disposition Phase Half-life (t1/2z) for Modakafusp Alfa
timeFrame: 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)
measure: Phase 1b and Phase 2 Safety Lead-in: Total Clearance (CL) After Intravenous Administration for Modakafusp Alfa
timeFrame: 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)
measure: Phase 1b and Phase 2 Safety Lead-in: Volume of Distribution at Steady State (Vss) for Modakafusp Alfa
timeFrame: 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)
measure: Phase 1b and Phase 2 Safety Lead-in: ORR Based on RECIST v1.1
timeFrame: 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)
measure: Phase 1b and Phase 2: Disease Control Rate (DCR) Based on RECIST v1.1
timeFrame: 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)
measure: Phase 1b and Phase 2: Duration of Response (DOR) Based on RECIST v1.1
timeFrame: 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])
measure: Phase 1b and Phase 2: Time to Progression (TTP) Based on RECIST v1.1
timeFrame: 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])
measure: Phase 1b and Phase 2: Progression Free Survival (PFS) Based on RECIST v1.1
timeFrame: 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])
measure: Phase 1b and Phase 2: Overall Survival (OS) Based on RECIST v1.1
timeFrame: 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])
measure: Phase 2 Expansion: ORR Based on Based on Immune Response Evaluation Criteria in Solid Tumors (iRECIST)
timeFrame: 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])
measure: Phase 2 Expansion: DCR Based on iRECIST
timeFrame: 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])
measure: Phase 2 Expansion: DOR Based on iRECIST
timeFrame: 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])
measure: Phase 2 Expansion: TTP Based on iRECIST
timeFrame: 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])
measure: Phase 2 Expansion: PFS Based on iRECIST
timeFrame: From first dose of study drug until confirmed iCPD or death (up to end of treatment or end of study [up to 2 years])
measure: Phase 1b and Phase 2: Number of Participants With Positive Anti-Modakafusp Alfa Antibodies (ADA) Status
timeFrame: Baseline up to end of treatment or end of study (up to 1 year for Phase 1b and 2 years for Phase 2)
measure: Phase 1b and Phase 2: Titer of Anti-Modakafusp Alfa Antibodies (ADA)
timeFrame: Baseline up to end of treatment or end of study (up to 1 year for Phase 1b and 2 years for Phase 2)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center - Duarte
state: California
city: La Jolla
country: United States
facility: University of California San Diego Moores Cancer Center
state: California
city: Los Angeles
country: United States
facility: The Angeles Clinic and Research Institute - West Los Angeles Office
state: California
city: Colorado Springs
country: United States
facility: University of Colorado Health Memorial Hospital Central
state: Colorado
city: Miami
country: United States
facility: Sylvester Comprehensive Cancer Center
state: Florida
city: Orlando
country: United States
facility: Orlando Health Cancer Institute
state: Florida
city: Lebanon
country: United States
facility: Norris Cotton Cancer Center Lebanon
state: New Hampshire
city: Morristown
country: United States
facility: Morristown Medical Center
state: New Jersey
city: Cleveland
country: United States
facility: Cleveland Clinic Main Campus
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Sioux Falls
country: United States
facility: Avera Cancer Institute
state: South Dakota
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Dallas
country: United States
facility: Texas Oncology - Baylor Charles A. Sammons Cancer Center
state: Texas
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Morgantown
country: United States
facility: West Virginia University Health Sciences Campus
state: West Virginia
city: Woodville South
country: Australia
facility: The Queen Elizabeth Hospital
state: South Australia
city: Ballarat
country: Australia
facility: Ballarat Regional Integrated Cancer Center
state: Victoria
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References: