Melanoma, Neoplasms
Conditions
Keywords
Drug Therapy
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.
Interventions
DRUGModakafusp Alfa
Modakafusp alfa intravenous infusion.
DRUGPembrolizumab
Pembrolizumab intravenous infusion.
Sponsors
Teva Branded Pharmaceutical Products R&D LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 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 | 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) | 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) | 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 | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Maximum Tolerated Dose (MTD) of Modakafusp Alfa | Cycle 1 (Cycle length = 21 days) | The MTD was selected as the highest dose which has maximum probability of being in targeted toxicity interval. |
| 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) | The RP2D of modakafusp alfa as a single agent or in combination with pembrolizumab was determined based on safety (including DLTs), pharmacokinetic and clinical data. DLT was graded according to CTCAE v5.0. |
| 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) | 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 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) | 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 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) | 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 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) | 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 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) | Cmax for modakafusp alfa was reported. |
| 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) | Tmax for modakafusp alfa was reported. |
| 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) | AUClast for modakafusp alfa was reported. |
| 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) | AUCinf of modakafusp alfa was reported. |
| 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) | T1/2z of modakafusp alfa was reported. |
| 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) | CL was total clearance of the drug from the serum. CL of modakafusp alfa was reported. |
| 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) | Vss of modakafusp alfa was reported. |
| 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) | ORR was defined as the percentage of participants who achieved CR or PR as per 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 \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| 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) | DCR was defined as the percentage of participants who achieved CR, PR, or stable disease (SD) (determined by the investigator) as per RECIST v1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression (PD), taking as reference the smallest sum diameters while on study. |
| 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]) | DOR was defined as the time from the first documentation of a response (CR or PR) until PD or death, whichever occurred first as per RECIST v1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). |
| 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]) | TTP was 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. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). |
| 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]) | PFS was defined as the time from the date of the first dose of study drug to the date of first documentation of PD according to RECIST v.1.1, or death due to any cause, whichever occurred first. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). |
| 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]) | OS was defined as the time from the date of first dose of study drug to the date of death due to any cause. |
| 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]) | ORR was defined as the percentage of participants whose BOR was immune CR (iCR) or immune PR (iPR), according to iRECIST as per investigator assessment. iCR: immune complete response achieved with disappearance of all target lesions immune confirmed progressive disease (iCPD). (iCPD): immune confirmed progressive disease when there is either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. iSD: immune stable disease in the absence of iCR or immune PD (iPD). iUPD: immune unconfirmed progressive disease (iUPD) when iCPD is unconfirmed NE: not evaluable. |
| 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]) | DCR was defined as percentage of participants who have achieved the best response of iCR, iPR, iSD based on iRECIST as per investigator assessment. iCR: achieved with disappearance of all target lesions, iPR: achieved with disappearance of partial target lesions. iSD: in the absence of iCR or iCPD. iUPD: when iPD is unconfirmed NE: not evaluable. |
| 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]) | DOR was defined as time from date of first observation of response (iPR or iCR) to date of the first observation of progression (iCPD) based on iRECIST as per investigator assessment, or date of death, whatever the cause. iCR: immune complete response achieved with disappearance of all target lesions iCPD: immune confirmed progressive disease when there is either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| 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]) | TTP was defined as the time from the date of the first dose of study drug to the date of the first documentation of iCPD based on iRECIST as per investigator assessment. iCPD: immune confirmed progressive disease when there is either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| 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]) | PFS was defined as the time from the first dose date to the date of iCPD or date of death (whichever occurred first) based on iRECIST as per investigator assessment. iCPD was defined as immune confirmed progressive disease when there is either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| 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) | ADA samples scoring equal to or above the cut-point (titer of 75) were defined as ADA positive. |
| 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) | ADA titers were assessed by confirmatory assay. |
Countries
Australia, United States
Participant flow
Recruitment details
Participants took part in the study at 17 investigative sites in the United States and Australia from 12 December 2019 to 20 December 2023.
Pre-assignment details
Participants were enrolled to Phase 1b (Dose Escalation) to receive single agent modakafusp alfa, and combination therapy of modakafusp alfa and pembrolizumab in Phase 2 (Safety lead-in, and Expansion with 3 Cohorts \[Cohorts I, II and III). Cohort III had no enrolment due to strategic reason, therefore, no data was collected and reported for Cohort III in this report.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg Participants with advanced/metastatic tumors received modakafusp alfa 0.1 mg/kg, infusion, intravenously, once on Day 1 of each 21-days treatment cycle. | 3 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg Participants with advanced/metastatic tumors received modakafusp alfa 0.2 mg/kg, infusion, intravenously, once on Day 1 of each 21-days treatment cycle. | 3 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg Participants with advanced/metastatic tumors received modakafusp alfa 0.4 mg/kg, infusion, intravenously, once on Day 1 of each 21-days treatment cycle. | 3 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg Participants with advanced/metastatic tumors received modakafusp alfa 0.75 mg/kg, infusion, intravenously, once on Day 1 of each 21-days treatment cycle. | 3 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg Participants with advanced/metastatic tumors received modakafusp alfa 1.0 mg/kg, infusion, intravenously, once on Day 1 of each 21-days treatment cycle. | 3 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg Participants with advanced/metastatic tumors received modakafusp alfa 1.5 mg/kg, infusion, intravenously, once on Day 1 of each 21-days treatment cycle. | 6 |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg Participants with any of the 3-melanoma disease of expansion Cohort I, II or III received modakafusp alfa 1.0 mg/kg, infusion, intravenously, once on Day 1 of each 21-days treatment cycle and pembrolizumab 400 mg infusion, intravenously, once, every 6 weeks. | 3 |
| Phase 2, Expansion, Cohort I: Modakafusp Alfa 1.0 mg/kg + Pembrolizumab 400 mg Participants with unresectable/metastatic cutaneous melanoma with primary resistance to no more than 2 prior lines of anti- programmed cell death protein 1 (PD1) containing treatments in the metastatic setting received modakafusp alfa 1.0 mg/kg, infusion, intravenously, once on Day 1 of each 21-days treatment cycle and pembrolizumab 400 mg infusion, intravenously, once, every 6 weeks. | 9 |
| Phase 2, Expansion, Cohort II: Modakafusp Alfa 1.0 mg/kg + Pembrolizumab 400 mg 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 received modakafusp alfa 1.0 mg/kg, infusion, intravenously, once on Day 1 of each 21-days treatment cycle and pembrolizumab 400 mg infusion, intravenously, once, every 6 weeks. | 12 |
| Total | 45 |
Baseline characteristics
| Characteristic | Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 2, Expansion, Cohort I: Modakafusp Alfa 1.0 mg/kg + Pembrolizumab 400 mg | Phase 2, Expansion, Cohort II: Modakafusp Alfa 1.0 mg/kg + Pembrolizumab 400 mg | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 74.0 years STANDARD_DEVIATION 5.2 | 51.3 years STANDARD_DEVIATION 11.37 | 68.0 years STANDARD_DEVIATION 10.44 | 62.0 years STANDARD_DEVIATION 8.19 | 55.0 years STANDARD_DEVIATION 4.58 | 61.8 years STANDARD_DEVIATION 9.13 | 74.3 years STANDARD_DEVIATION 4.04 | 53.4 years STANDARD_DEVIATION 17.91 | 60.3 years STANDARD_DEVIATION 12.11 | 60.7 years STANDARD_DEVIATION 13 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 2 Participants | 2 Participants | 2 Participants | 1 Participants | 5 Participants | 2 Participants | 8 Participants | 8 Participants | 33 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) White | 3 Participants | 3 Participants | 2 Participants | 3 Participants | 2 Participants | 5 Participants | 3 Participants | 8 Participants | 9 Participants | 38 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 4 Participants | 2 Participants | 4 Participants | 1 Participants | 16 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 3 Participants | 2 Participants | 1 Participants | 2 Participants | 1 Participants | 5 Participants | 11 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 2 / 3 | 2 / 3 | 3 / 3 | 3 / 3 | 4 / 6 | 1 / 3 | 2 / 9 | 4 / 12 |
| other Total, other adverse events | 3 / 3 | 2 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 6 / 6 | 3 / 3 | 8 / 9 | 12 / 12 |
| serious Total, serious adverse events | 3 / 3 | 1 / 3 | 2 / 3 | 1 / 3 | 2 / 3 | 4 / 6 | 0 / 3 | 2 / 9 | 6 / 12 |
Outcome results
Primary
Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting One or More Serious Adverse Event (SAEs)
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.
Time frame: 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)
Population: The safety analysis set included all enrolled participants who received at least one dose (even incomplete) of modakafusp alfa.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting One or More Serious Adverse Event (SAEs) | 3 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting One or More Serious Adverse Event (SAEs) | 1 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting One or More Serious Adverse Event (SAEs) | 2 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting One or More Serious Adverse Event (SAEs) | 1 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting One or More Serious Adverse Event (SAEs) | 2 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting One or More Serious Adverse Event (SAEs) | 4 Participants |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting One or More Serious Adverse Event (SAEs) | 0 Participants |
Primary
Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)
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.
Time frame: 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)
Population: The safety analysis set included all enrolled participants who received at least one dose (even incomplete) of modakafusp alfa.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 3 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 3 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 3 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 3 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 3 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 6 Participants |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 3 Participants |
Primary
Phase 1b and Phase 2 Safety Lead-in: Number of Participants With Dose Limiting Toxicities (DLTs)
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.
Time frame: Cycle 1 (Cycle length is equal to [=] 21 days)
Population: DLT evaluable analysis set included participants who received all Cycle 1 doses of modakafusp alfa or experience a DLT in Cycle 1 in the dose-escalation portion of the study; or participants who received all Cycle 1 doses of modakafusp alfa in combination with pembrolizumab or experience a DLT in Cycle 1 in the safety lead-in portion of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With Dose Limiting Toxicities (DLTs) | 2 Participants |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
Primary
Phase 1b and Phase 2 Safety Lead-in: Number of Participants With Grade 3 or Higher TEAEs
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.
Time frame: 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)
Population: The safety analysis set included all enrolled participants who received at least one dose (even incomplete) of modakafusp alfa.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With Grade 3 or Higher TEAEs | 2 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With Grade 3 or Higher TEAEs | 1 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With Grade 3 or Higher TEAEs | 2 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With Grade 3 or Higher TEAEs | 2 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With Grade 3 or Higher TEAEs | 3 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With Grade 3 or Higher TEAEs | 4 Participants |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With Grade 3 or Higher TEAEs | 2 Participants |
Primary
Phase 1b and Phase 2 Safety Lead-in: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuations
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.
Time frame: 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)
Population: The safety analysis set included all enrolled participants who received at least one dose (even incomplete) of modakafusp alfa.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuations | TEAEs Leading to Dose Modifications | 0 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuations | TEAEs Leading to Treatment Discontinuations | 0 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuations | TEAEs Leading to Dose Modifications | 0 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuations | TEAEs Leading to Treatment Discontinuations | 0 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuations | TEAEs Leading to Dose Modifications | 2 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuations | TEAEs Leading to Treatment Discontinuations | 1 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuations | TEAEs Leading to Dose Modifications | 1 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuations | TEAEs Leading to Treatment Discontinuations | 0 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuations | TEAEs Leading to Dose Modifications | 1 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuations | TEAEs Leading to Treatment Discontinuations | 0 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuations | TEAEs Leading to Dose Modifications | 4 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuations | TEAEs Leading to Treatment Discontinuations | 2 Participants |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuations | TEAEs Leading to Dose Modifications | 1 Participants |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2 Safety Lead-in: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuations | TEAEs Leading to Treatment Discontinuations | 0 Participants |
Primary
Phase 2 Expansion: Overall Response Rate (ORR) Based on RECIST v1.1
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.
Time frame: From the first dose of study drug up to end of treatment or end of study (up to 2 years)
Population: The response evaluable analysis set included participants with measurable disease at baseline and at least 1 post-treatment evaluation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 2 Expansion: Overall Response Rate (ORR) Based on RECIST v1.1 | 0.0 percentage of participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 2 Expansion: Overall Response Rate (ORR) Based on RECIST v1.1 | 16.7 percentage of participants |
Secondary
Phase 1b and Phase 2: Disease Control Rate (DCR) Based on RECIST v1.1
DCR was defined as the percentage of participants who achieved CR, PR, or stable disease (SD) (determined by the investigator) as per RECIST v1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression (PD), taking as reference the smallest sum diameters while on study.
Time frame: 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)
Population: The response evaluable analysis set included participants with measurable disease at baseline and at least 1 post-treatment evaluation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2: Disease Control Rate (DCR) Based on RECIST v1.1 | 0 percentage of participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2: Disease Control Rate (DCR) Based on RECIST v1.1 | 50.0 percentage of participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2: Disease Control Rate (DCR) Based on RECIST v1.1 | 0 percentage of participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2: Disease Control Rate (DCR) Based on RECIST v1.1 | 33.3 percentage of participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2: Disease Control Rate (DCR) Based on RECIST v1.1 | 0 percentage of participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2: Disease Control Rate (DCR) Based on RECIST v1.1 | 50.0 percentage of participants |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2: Disease Control Rate (DCR) Based on RECIST v1.1 | 33.3 percentage of participants |
| Phase 2, Expansion, Cohort I: Modakafusp Alfa 1.0 mg/kg + Pembrolizumab 400 mg | Phase 1b and Phase 2: Disease Control Rate (DCR) Based on RECIST v1.1 | 33.3 percentage of participants |
| Phase 2, Expansion, Cohort II: Modakafusp Alfa 1.0 mg/kg + Pembrolizumab 400 mg | Phase 1b and Phase 2: Disease Control Rate (DCR) Based on RECIST v1.1 | 41.7 percentage of participants |
Secondary
Phase 1b and Phase 2: Duration of Response (DOR) Based on RECIST v1.1
DOR was defined as the time from the first documentation of a response (CR or PR) until PD or death, whichever occurred first as per RECIST v1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).
Time frame: 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])
Population: The response evaluable analysis set included participants with measurable disease at baseline and at least 1 post-treatment evaluation. Here, overall number of participants analyzed signified participants who had CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2, Expansion, Cohort II: Modakafusp Alfa 1.0 mg/kg + Pembrolizumab 400 mg | Phase 1b and Phase 2: Duration of Response (DOR) Based on RECIST v1.1 | NA months |
Secondary
Phase 1b and Phase 2: Number of Participants With Positive Anti-Modakafusp Alfa Antibodies (ADA) Status
ADA samples scoring equal to or above the cut-point (titer of 75) were defined as ADA positive.
Time frame: Baseline up to end of treatment or end of study (up to 1 year for Phase 1b and 2 years for Phase 2)
Population: Immunogenicity-evaluable analysis set included participants with a baseline and at least one post-baseline immunogenicity assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2: Number of Participants With Positive Anti-Modakafusp Alfa Antibodies (ADA) Status | 2 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2: Number of Participants With Positive Anti-Modakafusp Alfa Antibodies (ADA) Status | 2 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2: Number of Participants With Positive Anti-Modakafusp Alfa Antibodies (ADA) Status | 3 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2: Number of Participants With Positive Anti-Modakafusp Alfa Antibodies (ADA) Status | 3 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2: Number of Participants With Positive Anti-Modakafusp Alfa Antibodies (ADA) Status | 3 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2: Number of Participants With Positive Anti-Modakafusp Alfa Antibodies (ADA) Status | 4 Participants |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2: Number of Participants With Positive Anti-Modakafusp Alfa Antibodies (ADA) Status | 3 Participants |
| Phase 2, Expansion, Cohort I: Modakafusp Alfa 1.0 mg/kg + Pembrolizumab 400 mg | Phase 1b and Phase 2: Number of Participants With Positive Anti-Modakafusp Alfa Antibodies (ADA) Status | 9 Participants |
| Phase 2, Expansion, Cohort II: Modakafusp Alfa 1.0 mg/kg + Pembrolizumab 400 mg | Phase 1b and Phase 2: Number of Participants With Positive Anti-Modakafusp Alfa Antibodies (ADA) Status | 10 Participants |
Secondary
Phase 1b and Phase 2: Overall Survival (OS) Based on RECIST v1.1
OS was defined as the time from the date of first dose of study drug to the date of death due to any cause.
Time frame: 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])
Population: The safety analysis set included all enrolled participants who received at least one dose (even incomplete) of modakafusp alfa.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2: Overall Survival (OS) Based on RECIST v1.1 | NA months |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2: Overall Survival (OS) Based on RECIST v1.1 | 9.8 months |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2: Overall Survival (OS) Based on RECIST v1.1 | 7.0 months |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2: Overall Survival (OS) Based on RECIST v1.1 | 6.3 months |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2: Overall Survival (OS) Based on RECIST v1.1 | 4.3 months |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2: Overall Survival (OS) Based on RECIST v1.1 | 3.1 months |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2: Overall Survival (OS) Based on RECIST v1.1 | NA months |
| Phase 2, Expansion, Cohort I: Modakafusp Alfa 1.0 mg/kg + Pembrolizumab 400 mg | Phase 1b and Phase 2: Overall Survival (OS) Based on RECIST v1.1 | NA months |
| Phase 2, Expansion, Cohort II: Modakafusp Alfa 1.0 mg/kg + Pembrolizumab 400 mg | Phase 1b and Phase 2: Overall Survival (OS) Based on RECIST v1.1 | NA months |
Secondary
Phase 1b and Phase 2: Progression Free Survival (PFS) Based on RECIST v1.1
PFS was defined as the time from the date of the first dose of study drug to the date of first documentation of PD according to RECIST v.1.1, or death due to any cause, whichever occurred first. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).
Time frame: 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])
Population: The safety analysis set included all enrolled participants who received at least one dose (even incomplete) of modakafusp alfa.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2: Progression Free Survival (PFS) Based on RECIST v1.1 | 2.4 months |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2: Progression Free Survival (PFS) Based on RECIST v1.1 | 1.6 months |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2: Progression Free Survival (PFS) Based on RECIST v1.1 | 1.7 months |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2: Progression Free Survival (PFS) Based on RECIST v1.1 | 1.4 months |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2: Progression Free Survival (PFS) Based on RECIST v1.1 | 1.8 months |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2: Progression Free Survival (PFS) Based on RECIST v1.1 | 1.9 months |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2: Progression Free Survival (PFS) Based on RECIST v1.1 | 1.7 months |
| Phase 2, Expansion, Cohort I: Modakafusp Alfa 1.0 mg/kg + Pembrolizumab 400 mg | Phase 1b and Phase 2: Progression Free Survival (PFS) Based on RECIST v1.1 | 4.8 months |
| Phase 2, Expansion, Cohort II: Modakafusp Alfa 1.0 mg/kg + Pembrolizumab 400 mg | Phase 1b and Phase 2: Progression Free Survival (PFS) Based on RECIST v1.1 | 2.6 months |
Secondary
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
AUClast for modakafusp alfa was reported.
Time frame: 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)
Population: PK analysis set included participants who had sufficient data to calculate at least 1 PK parameter for modakafusp alfa. As planned, PK data at Cycles 1 and 2 Day 1 for Phase 1b, and Cycles 1 and 3 Day 1 for Phase 2 (Safety lead-in) was reported. Here, number analyzed signified participants who were evaluable at specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | 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 | Cycle 2 Day 1 | 535 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 1101.2 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | 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 | Cycle 1 Day 1 | 458 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 135.8 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | 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 | Cycle 1 Day 1 | 8450 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 70 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | 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 | Cycle 2 Day 1 | 8030 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 9.3 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | 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 | Cycle 1 Day 1 | 33100 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 72.4 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | 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 | Cycle 2 Day 1 | 20300 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 153.2 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | 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 | Cycle 1 Day 1 | 183000 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 74.1 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | 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 | Cycle 2 Day 1 | 86300 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 81.7 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | 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 | Cycle 2 Day 1 | 159000 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 219.2 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | 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 | Cycle 1 Day 1 | 262000 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 61.5 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | 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 | Cycle 1 Day 1 | 897000 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 57.1 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | 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 | Cycle 2 Day 1 | 360000 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 112.5 |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | 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 | Cycle 3 Day 1 | 165000 hour*nanogram per milliliter (h*ng/mL) | — |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | 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 | Cycle 1 Day 1 | 455000 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 21.8 |
Secondary
Phase 1b and Phase 2 Safety Lead-in: Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf) for Modakafusp Alfa
AUCinf of modakafusp alfa was reported.
Time frame: 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)
Population: PK analysis set included participants who had sufficient data to calculate at least 1 PK parameter for modakafusp alfa. As planned, PK data at Cycles 1 and 2 Day 1 for Phase 1b, and Cycles 1 and 3 Day 1 for Phase 2 (Safety lead-in) was reported. Here, overall number of participants analyzed signified participants who were evaluable for this outcome measure and number analyzed signified participants who were evaluable at specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf) for Modakafusp Alfa | Cycle 2 Day 1 | 2540 h*ng/mL | — |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf) for Modakafusp Alfa | Cycle 1 Day 1 | 1470 h*ng/mL | — |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf) for Modakafusp Alfa | Cycle 1 Day 1 | 8780 h*ng/mL | Geometric Coefficient of Variation 66.3 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf) for Modakafusp Alfa | Cycle 2 Day 1 | 8840 h*ng/mL | Geometric Coefficient of Variation 7.1 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf) for Modakafusp Alfa | Cycle 1 Day 1 | 33100 h*ng/mL | Geometric Coefficient of Variation 72.2 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf) for Modakafusp Alfa | Cycle 2 Day 1 | 21100 h*ng/mL | Geometric Coefficient of Variation 140.1 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf) for Modakafusp Alfa | Cycle 1 Day 1 | 217000 h*ng/mL | Geometric Coefficient of Variation 60.2 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf) for Modakafusp Alfa | Cycle 2 Day 1 | 86400 h*ng/mL | Geometric Coefficient of Variation 81.6 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf) for Modakafusp Alfa | Cycle 1 Day 1 | 263000 h*ng/mL | Geometric Coefficient of Variation 61.5 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf) for Modakafusp Alfa | Cycle 2 Day 1 | 160000 h*ng/mL | Geometric Coefficient of Variation 218.7 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf) for Modakafusp Alfa | Cycle 1 Day 1 | 1060000 h*ng/mL | Geometric Coefficient of Variation 62.1 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf) for Modakafusp Alfa | Cycle 2 Day 1 | 372000 h*ng/mL | Geometric Coefficient of Variation 121.3 |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2 Safety Lead-in: Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf) for Modakafusp Alfa | Cycle 3 Day 1 | 165000 h*ng/mL | — |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2 Safety Lead-in: Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf) for Modakafusp Alfa | Cycle 1 Day 1 | 455000 h*ng/mL | Geometric Coefficient of Variation 21.8 |
Secondary
Phase 1b and Phase 2 Safety Lead-in: Maximum Observed Serum Concentration (Cmax) for Modakafusp Alfa
Cmax for modakafusp alfa was reported.
Time frame: 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)
Population: Pharmacokinetic (PK) analysis set included participants who had sufficient data to calculate at least 1 PK parameter for modakafusp alfa. As planned, PK data at Cycles 1 and 2 Day 1 for Phase 1b, and Cycles 1 and 3 Day 1 for Phase 2 (Safety lead-in) was reported. Here, number analyzed signified participants who were evaluable at specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Maximum Observed Serum Concentration (Cmax) for Modakafusp Alfa | Cycle 2 Day 1 | 336 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 540.2 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Maximum Observed Serum Concentration (Cmax) for Modakafusp Alfa | Cycle 1 Day 1 | 261 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 85 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Maximum Observed Serum Concentration (Cmax) for Modakafusp Alfa | Cycle 1 Day 1 | 2770 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 51.4 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Maximum Observed Serum Concentration (Cmax) for Modakafusp Alfa | Cycle 2 Day 1 | 2790 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 14.2 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Maximum Observed Serum Concentration (Cmax) for Modakafusp Alfa | Cycle 1 Day 1 | 4920 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 42.9 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Maximum Observed Serum Concentration (Cmax) for Modakafusp Alfa | Cycle 2 Day 1 | 3560 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 99.9 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Maximum Observed Serum Concentration (Cmax) for Modakafusp Alfa | Cycle 1 Day 1 | 17000 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 26.1 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Maximum Observed Serum Concentration (Cmax) for Modakafusp Alfa | Cycle 2 Day 1 | 9420 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 52.7 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Maximum Observed Serum Concentration (Cmax) for Modakafusp Alfa | Cycle 2 Day 1 | 14400 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 136.2 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Maximum Observed Serum Concentration (Cmax) for Modakafusp Alfa | Cycle 1 Day 1 | 17700 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 60.1 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Maximum Observed Serum Concentration (Cmax) for Modakafusp Alfa | Cycle 1 Day 1 | 37200 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 29.9 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Maximum Observed Serum Concentration (Cmax) for Modakafusp Alfa | Cycle 2 Day 1 | 25400 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 84.5 |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2 Safety Lead-in: Maximum Observed Serum Concentration (Cmax) for Modakafusp Alfa | Cycle 3 Day 1 | 13900 nanograms per milliliter (ng/mL) | — |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2 Safety Lead-in: Maximum Observed Serum Concentration (Cmax) for Modakafusp Alfa | Cycle 1 Day 1 | 21200 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 18.7 |
Secondary
Phase 1b and Phase 2 Safety Lead-in: ORR Based on RECIST v1.1
ORR was defined as the percentage of participants who achieved CR or PR as per 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 \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: 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)
Population: The response evaluable analysis set included participants with measurable disease at baseline and at least 1 post-treatment evaluation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2 Safety Lead-in: ORR Based on RECIST v1.1 | 0.0 percentage of participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2 Safety Lead-in: ORR Based on RECIST v1.1 | 0.0 percentage of participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2 Safety Lead-in: ORR Based on RECIST v1.1 | 0.0 percentage of participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2 Safety Lead-in: ORR Based on RECIST v1.1 | 0.0 percentage of participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2 Safety Lead-in: ORR Based on RECIST v1.1 | 0.0 percentage of participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2 Safety Lead-in: ORR Based on RECIST v1.1 | 0.0 percentage of participants |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2 Safety Lead-in: ORR Based on RECIST v1.1 | 0.0 percentage of participants |
Secondary
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
The RP2D of modakafusp alfa as a single agent or in combination with pembrolizumab was determined based on safety (including DLTs), pharmacokinetic and clinical data. DLT was graded according to CTCAE v5.0.
Time frame: Cycle 1 (Cycle length = 21 days)
Population: The safety analysis set included all enrolled participants who received at least one dose (even incomplete) of modakafusp alfa.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | 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 | 1.0 mg/kg |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | 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 | 1.0 mg/kg |
Secondary
Phase 1b and Phase 2 Safety Lead-in: Terminal Disposition Phase Half-life (t1/2z) for Modakafusp Alfa
T1/2z of modakafusp alfa was reported.
Time frame: 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)
Population: PK analysis set included participants who had sufficient data to calculate at least 1 PK parameter for modakafusp alfa. As planned, PK data at Cycles 1 and 2 Day 1 for Phase 1b, and Cycles 1 and 3 Day 1 for Phase 2 (Safety lead-in) was reported. Here, overall number of participants analyzed signified participants who were evaluable for this outcome measure and number analyzed signified participants who were evaluable at specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Terminal Disposition Phase Half-life (t1/2z) for Modakafusp Alfa | Cycle 1 Day 1 | 1.07 hour | — |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Terminal Disposition Phase Half-life (t1/2z) for Modakafusp Alfa | Cycle 2 Day 1 | 0.832 hour | — |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Terminal Disposition Phase Half-life (t1/2z) for Modakafusp Alfa | Cycle 1 Day 1 | 1.97 hour | Geometric Coefficient of Variation 33.9 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Terminal Disposition Phase Half-life (t1/2z) for Modakafusp Alfa | Cycle 2 Day 1 | 1.85 hour | Geometric Coefficient of Variation 9.1 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Terminal Disposition Phase Half-life (t1/2z) for Modakafusp Alfa | Cycle 1 Day 1 | 5.25 hour | Geometric Coefficient of Variation 13.7 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Terminal Disposition Phase Half-life (t1/2z) for Modakafusp Alfa | Cycle 2 Day 1 | 3.08 hour | Geometric Coefficient of Variation 38.6 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Terminal Disposition Phase Half-life (t1/2z) for Modakafusp Alfa | Cycle 2 Day 1 | 6.43 hour | Geometric Coefficient of Variation 11.3 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Terminal Disposition Phase Half-life (t1/2z) for Modakafusp Alfa | Cycle 1 Day 1 | 5.60 hour | Geometric Coefficient of Variation 28.5 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Terminal Disposition Phase Half-life (t1/2z) for Modakafusp Alfa | Cycle 1 Day 1 | 6.23 hour | Geometric Coefficient of Variation 14.4 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Terminal Disposition Phase Half-life (t1/2z) for Modakafusp Alfa | Cycle 2 Day 1 | 6.15 hour | Geometric Coefficient of Variation 7.7 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Terminal Disposition Phase Half-life (t1/2z) for Modakafusp Alfa | Cycle 1 Day 1 | 15.5 hour | Geometric Coefficient of Variation 71.8 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Terminal Disposition Phase Half-life (t1/2z) for Modakafusp Alfa | Cycle 2 Day 1 | 14.1 hour | Geometric Coefficient of Variation 85.6 |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2 Safety Lead-in: Terminal Disposition Phase Half-life (t1/2z) for Modakafusp Alfa | Cycle 3 Day 1 | 6.15 hour | — |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2 Safety Lead-in: Terminal Disposition Phase Half-life (t1/2z) for Modakafusp Alfa | Cycle 1 Day 1 | 6.44 hour | Geometric Coefficient of Variation 11 |
Secondary
Phase 1b and Phase 2 Safety Lead-in: Time to Reach the Cmax (Tmax) for Modakafusp Alfa
Tmax for modakafusp alfa was reported.
Time frame: 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)
Population: PK analysis set included participants who had sufficient data to calculate at least 1 PK parameter for modakafusp alfa. As planned, PK data at Cycles 1 and 2 Day 1 for Phase 1b, and Cycles 1 and 3 Day 1 for Phase 2 (Safety lead-in) was reported. Here, overall number of participants analyzed signified participants who were evaluable for this outcome measure and number analyzed signified participants who were evaluable at specified timepoints.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Time to Reach the Cmax (Tmax) for Modakafusp Alfa | Cycle 2 Day 1 | 1.28 hour |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Time to Reach the Cmax (Tmax) for Modakafusp Alfa | Cycle 1 Day 1 | 1.53 hour |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Time to Reach the Cmax (Tmax) for Modakafusp Alfa | Cycle 1 Day 1 | 1.17 hour |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Time to Reach the Cmax (Tmax) for Modakafusp Alfa | Cycle 2 Day 1 | 1.03 hour |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Time to Reach the Cmax (Tmax) for Modakafusp Alfa | Cycle 2 Day 1 | 1.05 hour |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Time to Reach the Cmax (Tmax) for Modakafusp Alfa | Cycle 1 Day 1 | 1.05 hour |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Time to Reach the Cmax (Tmax) for Modakafusp Alfa | Cycle 1 Day 1 | 1.18 hour |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Time to Reach the Cmax (Tmax) for Modakafusp Alfa | Cycle 2 Day 1 | 1.07 hour |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Time to Reach the Cmax (Tmax) for Modakafusp Alfa | Cycle 1 Day 1 | 1.52 hour |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Time to Reach the Cmax (Tmax) for Modakafusp Alfa | Cycle 2 Day 1 | 1.77 hour |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Time to Reach the Cmax (Tmax) for Modakafusp Alfa | Cycle 1 Day 1 | 1.97 hour |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Time to Reach the Cmax (Tmax) for Modakafusp Alfa | Cycle 2 Day 1 | 1.97 hour |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2 Safety Lead-in: Time to Reach the Cmax (Tmax) for Modakafusp Alfa | Cycle 3 Day 1 | 2.90 hour |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2 Safety Lead-in: Time to Reach the Cmax (Tmax) for Modakafusp Alfa | Cycle 1 Day 1 | 3.13 hour |
Secondary
Phase 1b and Phase 2 Safety Lead-in: Total Clearance (CL) After Intravenous Administration for Modakafusp Alfa
CL was total clearance of the drug from the serum. CL of modakafusp alfa was reported.
Time frame: 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)
Population: PK analysis set included participants who had sufficient data to calculate at least 1 PK parameter for modakafusp alfa. As planned, PK data at Cycles 1 and 2 Day 1 for Phase 1b, and Cycles 1 and 3 Day 1 for Phase 2 (Safety lead-in) was reported. Here, overall number of participants analyzed signified participants who were evaluable for this outcome measure and number analyzed signified participants who were evaluable at specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Total Clearance (CL) After Intravenous Administration for Modakafusp Alfa | Cycle 1 Day 1 | 0.0682 liters per hour per kilograms (L/h/kg) | — |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Total Clearance (CL) After Intravenous Administration for Modakafusp Alfa | Cycle 2 Day 1 | 0.0394 liters per hour per kilograms (L/h/kg) | — |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Total Clearance (CL) After Intravenous Administration for Modakafusp Alfa | Cycle 1 Day 1 | 0.0228 liters per hour per kilograms (L/h/kg) | Geometric Coefficient of Variation 66.2 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Total Clearance (CL) After Intravenous Administration for Modakafusp Alfa | Cycle 2 Day 1 | 0.0226 liters per hour per kilograms (L/h/kg) | Geometric Coefficient of Variation 7.2 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Total Clearance (CL) After Intravenous Administration for Modakafusp Alfa | Cycle 1 Day 1 | 0.0121 liters per hour per kilograms (L/h/kg) | Geometric Coefficient of Variation 72.4 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Total Clearance (CL) After Intravenous Administration for Modakafusp Alfa | Cycle 2 Day 1 | 0.0190 liters per hour per kilograms (L/h/kg) | Geometric Coefficient of Variation 139.6 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Total Clearance (CL) After Intravenous Administration for Modakafusp Alfa | Cycle 1 Day 1 | 0.00345 liters per hour per kilograms (L/h/kg) | Geometric Coefficient of Variation 61 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Total Clearance (CL) After Intravenous Administration for Modakafusp Alfa | Cycle 2 Day 1 | 0.00872 liters per hour per kilograms (L/h/kg) | Geometric Coefficient of Variation 81.1 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Total Clearance (CL) After Intravenous Administration for Modakafusp Alfa | Cycle 1 Day 1 | 0.00383 liters per hour per kilograms (L/h/kg) | Geometric Coefficient of Variation 61.1 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Total Clearance (CL) After Intravenous Administration for Modakafusp Alfa | Cycle 2 Day 1 | 0.00632 liters per hour per kilograms (L/h/kg) | Geometric Coefficient of Variation 214.5 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Total Clearance (CL) After Intravenous Administration for Modakafusp Alfa | Cycle 1 Day 1 | 0.00142 liters per hour per kilograms (L/h/kg) | Geometric Coefficient of Variation 61.1 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Total Clearance (CL) After Intravenous Administration for Modakafusp Alfa | Cycle 2 Day 1 | 0.00407 liters per hour per kilograms (L/h/kg) | Geometric Coefficient of Variation 118.5 |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2 Safety Lead-in: Total Clearance (CL) After Intravenous Administration for Modakafusp Alfa | Cycle 1 Day 1 | 0.00220 liters per hour per kilograms (L/h/kg) | Geometric Coefficient of Variation 21.3 |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2 Safety Lead-in: Total Clearance (CL) After Intravenous Administration for Modakafusp Alfa | Cycle 3 Day 1 | 0.00610 liters per hour per kilograms (L/h/kg) | — |
Secondary
Phase 1b and Phase 2 Safety Lead-in: Volume of Distribution at Steady State (Vss) for Modakafusp Alfa
Vss of modakafusp alfa was reported.
Time frame: 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)
Population: PK analysis set included participants who had sufficient data to calculate at least 1 PK parameter for modakafusp alfa. As planned, PK data at Cycles 1 and 2 Day 1 for Phase 1b, and Cycles 1 and 3 Day 1 for Phase 2 (Safety lead-in) was reported. Here, overall number of participants analyzed signified participants who were evaluable for this outcome measure and number analyzed signified participants who were evaluable at specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Volume of Distribution at Steady State (Vss) for Modakafusp Alfa | Cycle 2 Day 1 | 0.0546 liters per kilograms (L/kg) | — |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Volume of Distribution at Steady State (Vss) for Modakafusp Alfa | Cycle 1 Day 1 | 0.119 liters per kilograms (L/kg) | — |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Volume of Distribution at Steady State (Vss) for Modakafusp Alfa | Cycle 1 Day 1 | 0.0567 liters per kilograms (L/kg) | Geometric Coefficient of Variation 49.7 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Volume of Distribution at Steady State (Vss) for Modakafusp Alfa | Cycle 2 Day 1 | 0.0565 liters per kilograms (L/kg) | Geometric Coefficient of Variation 15.6 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Volume of Distribution at Steady State (Vss) for Modakafusp Alfa | Cycle 1 Day 1 | 0.0562 liters per kilograms (L/kg) | Geometric Coefficient of Variation 58.2 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Volume of Distribution at Steady State (Vss) for Modakafusp Alfa | Cycle 2 Day 1 | 0.0794 liters per kilograms (L/kg) | Geometric Coefficient of Variation 135.8 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Volume of Distribution at Steady State (Vss) for Modakafusp Alfa | Cycle 1 Day 1 | 0.0276 liters per kilograms (L/kg) | Geometric Coefficient of Variation 13.5 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Volume of Distribution at Steady State (Vss) for Modakafusp Alfa | Cycle 2 Day 1 | 0.0562 liters per kilograms (L/kg) | Geometric Coefficient of Variation 72.9 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Volume of Distribution at Steady State (Vss) for Modakafusp Alfa | Cycle 1 Day 1 | 0.0369 liters per kilograms (L/kg) | Geometric Coefficient of Variation 48.1 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Volume of Distribution at Steady State (Vss) for Modakafusp Alfa | Cycle 2 Day 1 | 0.0514 liters per kilograms (L/kg) | Geometric Coefficient of Variation 107.2 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Volume of Distribution at Steady State (Vss) for Modakafusp Alfa | Cycle 1 Day 1 | 0.0331 liters per kilograms (L/kg) | Geometric Coefficient of Variation 33.1 |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2 Safety Lead-in: Volume of Distribution at Steady State (Vss) for Modakafusp Alfa | Cycle 2 Day 1 | 0.0629 liters per kilograms (L/kg) | Geometric Coefficient of Variation 33.4 |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2 Safety Lead-in: Volume of Distribution at Steady State (Vss) for Modakafusp Alfa | Cycle 3 Day 1 | 0.0453 liters per kilograms (L/kg) | — |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2 Safety Lead-in: Volume of Distribution at Steady State (Vss) for Modakafusp Alfa | Cycle 1 Day 1 | 0.0313 liters per kilograms (L/kg) | Geometric Coefficient of Variation 13.3 |
Secondary
Phase 1b and Phase 2: Time to Progression (TTP) Based on RECIST v1.1
TTP was 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. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).
Time frame: 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])
Population: The safety analysis set included all enrolled participants who received at least one dose (even incomplete) of modakafusp alfa.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2: Time to Progression (TTP) Based on RECIST v1.1 | 2.4 months |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2: Time to Progression (TTP) Based on RECIST v1.1 | 4.5 months |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2: Time to Progression (TTP) Based on RECIST v1.1 | 1.7 months |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2: Time to Progression (TTP) Based on RECIST v1.1 | 1.4 months |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2: Time to Progression (TTP) Based on RECIST v1.1 | 1.5 months |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2: Time to Progression (TTP) Based on RECIST v1.1 | 2.3 months |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2: Time to Progression (TTP) Based on RECIST v1.1 | 1.7 months |
| Phase 2, Expansion, Cohort I: Modakafusp Alfa 1.0 mg/kg + Pembrolizumab 400 mg | Phase 1b and Phase 2: Time to Progression (TTP) Based on RECIST v1.1 | 2.8 months |
| Phase 2, Expansion, Cohort II: Modakafusp Alfa 1.0 mg/kg + Pembrolizumab 400 mg | Phase 1b and Phase 2: Time to Progression (TTP) Based on RECIST v1.1 | 2.3 months |
Secondary
Phase 1b and Phase 2: Titer of Anti-Modakafusp Alfa Antibodies (ADA)
ADA titers were assessed by confirmatory assay.
Time frame: Baseline up to end of treatment or end of study (up to 1 year for Phase 1b and 2 years for Phase 2)
Population: Immunogenicity-evaluable analysis set included participants with a baseline and at least one post-baseline immunogenicity assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b and Phase 2: Titer of Anti-Modakafusp Alfa Antibodies (ADA) | 150.0 titers |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 1b and Phase 2: Titer of Anti-Modakafusp Alfa Antibodies (ADA) | 164000.0 titers |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.4 mg/kg | Phase 1b and Phase 2: Titer of Anti-Modakafusp Alfa Antibodies (ADA) | 6070.0 titers |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.75 mg/kg | Phase 1b and Phase 2: Titer of Anti-Modakafusp Alfa Antibodies (ADA) | 6070.0 titers |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.0 mg/kg | Phase 1b and Phase 2: Titer of Anti-Modakafusp Alfa Antibodies (ADA) | 6070.0 titers |
| Phase 1b, Dose Escalation: Modakafusp Alfa 1.5 mg/kg | Phase 1b and Phase 2: Titer of Anti-Modakafusp Alfa Antibodies (ADA) | 109350.0 titers |
| Phase 2, Safety Lead-in: Modakafusp 1.0 mg/kg Alfa + Pembrolizumab 400 mg | Phase 1b and Phase 2: Titer of Anti-Modakafusp Alfa Antibodies (ADA) | 273350.0 titers |
| Phase 2, Expansion, Cohort I: Modakafusp Alfa 1.0 mg/kg + Pembrolizumab 400 mg | Phase 1b and Phase 2: Titer of Anti-Modakafusp Alfa Antibodies (ADA) | 492000.0 titers |
| Phase 2, Expansion, Cohort II: Modakafusp Alfa 1.0 mg/kg + Pembrolizumab 400 mg | Phase 1b and Phase 2: Titer of Anti-Modakafusp Alfa Antibodies (ADA) | 164000.0 titers |
Secondary
Phase 1b: Maximum Tolerated Dose (MTD) of Modakafusp Alfa
The MTD was selected as the highest dose which has maximum probability of being in targeted toxicity interval.
Time frame: Cycle 1 (Cycle length = 21 days)
Population: DLT evaluable analysis set included participants who received all Cycle 1 doses of modakafusp alfa or experience a DLT in Cycle 1 in the dose-escalation portion of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 1b: Maximum Tolerated Dose (MTD) of Modakafusp Alfa | NA milligrams per kilograms (mg/kg) |
Secondary
Phase 2 Expansion: DCR Based on iRECIST
DCR was defined as percentage of participants who have achieved the best response of iCR, iPR, iSD based on iRECIST as per investigator assessment. iCR: achieved with disappearance of all target lesions, iPR: achieved with disappearance of partial target lesions. iSD: in the absence of iCR or iCPD. iUPD: when iPD is unconfirmed NE: not evaluable.
Time frame: 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])
Population: The response evaluable analysis set included participants with measurable disease at baseline and at least 1 post-treatment evaluation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 2 Expansion: DCR Based on iRECIST | 37.5 percentage of participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 2 Expansion: DCR Based on iRECIST | 41.7 percentage of participants |
Secondary
Phase 2 Expansion: DOR Based on iRECIST
DOR was defined as time from date of first observation of response (iPR or iCR) to date of the first observation of progression (iCPD) based on iRECIST as per investigator assessment, or date of death, whatever the cause. iCR: immune complete response achieved with disappearance of all target lesions iCPD: immune confirmed progressive disease when there is either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: 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])
Population: The response evaluable analysis set included participants with measurable disease at baseline and at least 1 post-treatment evaluation. Here, overall number of participants analyzed signifies participants who had iCR or iPR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 2 Expansion: DOR Based on iRECIST | NA months |
Secondary
Phase 2 Expansion: Number of Participants Reporting One or More SAEs
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.
Time frame: 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)
Population: The safety analysis set included all enrolled participants who received at least one dose (even incomplete) of modakafusp alfa.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 2 Expansion: Number of Participants Reporting One or More SAEs | 2 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 2 Expansion: Number of Participants Reporting One or More SAEs | 6 Participants |
Secondary
Phase 2 Expansion: Number of Participants Reporting One or More TEAEs
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.
Time frame: 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)
Population: The safety analysis set included all enrolled participants who received at least one dose (even incomplete) of modakafusp alfa.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 2 Expansion: Number of Participants Reporting One or More TEAEs | 8 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 2 Expansion: Number of Participants Reporting One or More TEAEs | 12 Participants |
Secondary
Phase 2 Expansion: Number of Participants With Grade 3 or Higher TEAEs
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.
Time frame: 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)
Population: The safety analysis set included all enrolled participants who received at least one dose (even incomplete) of modakafusp alfa.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 2 Expansion: Number of Participants With Grade 3 or Higher TEAEs | 6 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 2 Expansion: Number of Participants With Grade 3 or Higher TEAEs | 7 Participants |
Secondary
Phase 2 Expansion: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuations
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.
Time frame: 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)
Population: The safety analysis set included all enrolled participants who received at least one dose (even incomplete) of modakafusp alfa.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 2 Expansion: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuations | TEAEs Leading to Dose Modifications | 1 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 2 Expansion: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuations | TEAEs Leading to Treatment Discontinuations | 0 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 2 Expansion: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuations | TEAEs Leading to Treatment Discontinuations | 1 Participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 2 Expansion: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuations | TEAEs Leading to Dose Modifications | 9 Participants |
Secondary
Phase 2 Expansion: ORR Based on Based on Immune Response Evaluation Criteria in Solid Tumors (iRECIST)
ORR was defined as the percentage of participants whose BOR was immune CR (iCR) or immune PR (iPR), according to iRECIST as per investigator assessment. iCR: immune complete response achieved with disappearance of all target lesions immune confirmed progressive disease (iCPD). (iCPD): immune confirmed progressive disease when there is either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. iSD: immune stable disease in the absence of iCR or immune PD (iPD). iUPD: immune unconfirmed progressive disease (iUPD) when iCPD is unconfirmed NE: not evaluable.
Time frame: 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])
Population: The response evaluable analysis set included participants with measurable disease at baseline and at least 1 post-treatment evaluation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 2 Expansion: ORR Based on Based on Immune Response Evaluation Criteria in Solid Tumors (iRECIST) | 0.0 percentage of participants |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 2 Expansion: ORR Based on Based on Immune Response Evaluation Criteria in Solid Tumors (iRECIST) | 16.7 percentage of participants |
Secondary
Phase 2 Expansion: PFS Based on iRECIST
PFS was defined as the time from the first dose date to the date of iCPD or date of death (whichever occurred first) based on iRECIST as per investigator assessment. iCPD was defined as immune confirmed progressive disease when there is either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: From first dose of study drug until confirmed iCPD or death (up to end of treatment or end of study [up to 2 years])
Population: The safety analysis set included all enrolled participants who received at least one dose (even incomplete) of modakafusp alfa.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 2 Expansion: PFS Based on iRECIST | 4.8 months |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 2 Expansion: PFS Based on iRECIST | 2.6 months |
Secondary
Phase 2 Expansion: TTP Based on iRECIST
TTP was defined as the time from the date of the first dose of study drug to the date of the first documentation of iCPD based on iRECIST as per investigator assessment. iCPD: immune confirmed progressive disease when there is either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: 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])
Population: The safety analysis set included all enrolled participants who received at least one dose (even incomplete) of modakafusp alfa.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.1 mg/kg | Phase 2 Expansion: TTP Based on iRECIST | 4.8 months |
| Phase 1b, Dose Escalation: Modakafusp Alfa 0.2 mg/kg | Phase 2 Expansion: TTP Based on iRECIST | NA months |