INCB001158 Combined With Subcutaneous (SC) Daratumumab, Compared to Daratumumab SC, in Relapsed or Refractory Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and antitumor activity of INCB001158 in combination with daratumumab SC, compared with daratumumab SC alone, in participants with relapsed or refractory multiple myeloma.

Official Title
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A Randomized Open-Label Phase 1/2 Study of INCB001158 Combined With Subcutaneous (SC) Daratumumab, Compared to Daratumumab SC, in Participants With Relapsed or Refractory Multiple Myeloma

Conditions
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Relapsed or Refractory Multiple Myeloma

Intervention / Treatment
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* Drug: INCB001158
* Biological: Daratumumab SC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Prior diagnosis of multiple myeloma according to IMWG diagnostic criteria. Measurable disease at screening. Has received at least 3 but not more than 5 prior lines of multiple myeloma treatment, including proteasome inhibitor, immunomodulatory drug, and anti-CD38 therapies. Eastern Cooperative Oncology Group performance status of 0 or 1. Willing to avoid pregnancy or fathering children. Willing to provide fresh and archival bone marrow aspiration and biopsy tissue. Exclusion Criteria: Receipt of any of the following treatment within the indicated interval before the first administration of study drug: Anti-myeloma treatment within 2 weeks or 5 half-lives (whichever is longer). Investigational drug (including investigational vaccines) or invasive investigational medical device within 4 weeks. Autologous stem cell transplant within 12 weeks, or allogeneic stem cell transplant at any time. Plasmapheresis within 4 weeks. Radiation therapy within 2 weeks. Major surgery within 2 weeks, or inadequate recovery from an earlier surgery, or surgery planned during the time the participant is expected to participate in the study or within 2 weeks after the last dose of study treatment. Toxicity ≥ Grade 2 from previous anti-myeloma therapy except for stable chronic toxicities (≤ Grade 2) not expected to resolve, such as stable Grade 2 peripheral neuropathy. Known additional malignancy (other than multiple myeloma) that is progressing or requires active treatment, or history of other malignancy within 2 years of study entry. Laboratory values at screening outside the protocol-defined range. Significant concurrent, uncontrolled medical condition including but not limited to known chronic obstructive pulmonary disease (COPD), persistent asthma, or history of asthma within the past 2 years; chronic or current active infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment; acute diffuse infiltrative pulmonary disease; clinically significant or uncontrolled cardiac disease. Plasma cell leukemia, Waldenström's macroglobulinemia, POEMS syndrome, or amyloidosis.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: An initial equal randomization of participants between INCB001158 in combination with daratumumab SC (Treatment Group A), daratumumab SC monotherapy (Treatment Group B), and INCB001158 monotherapy (Treatment Group C) will be conducted. Participants in the treatment groups B and C at confirmed disease progression will be crossed over to INCB001158 + daratumumab SC. After the equal randomization period, a response adaptive randomization design will be used to compare the objective response rate of Treatment Groups A and B with adjustments to the randomization rate based on the observed objective response rate.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: INCB001158 + daratumumab SC<br>INCB001158 + daratumumab | Drug: INCB001158<br>* Phase 1: INCB001158 administered orally twice daily at the protocol-defined starting dose, with dose escalation/de-escalation based on protocol-defined toxicity criteria to determine the maximum tolerated dose. INCB001158 is administered in combination with daratumumab SC. Phase 2: INCB001158 administered orally at the recommended dose from Phase 1 either as a monotherapy or in combination with daratumumab SC.<br>Biological: Daratumumab SC<br>* Daratumumab 1800 mg co-formulated with rHuPH20 (2000 U/mL) and administered subcutaneously once weekly for Cycles 1 and 2, once every 2 weeks for Cycles 3 to 6, and then once every 4 weeks. Daratumumab will be administered either as monotherapy or in combination with INCB001158.<br>|
| Active Comparator: Daratumumab monotherapy and crossover to INC001158+ daratumumab SC<br>Daratumumab will be administered as monotherapy, once confirmed disease progression participants will be crossed over to INCB001158+daratumumad combination therapy. | Biological: Daratumumab SC<br>* Daratumumab 1800 mg co-formulated with rHuPH20 (2000 U/mL) and administered subcutaneously once weekly for Cycles 1 and 2, once every 2 weeks for Cycles 3 to 6, and then once every 4 weeks. Daratumumab will be administered either as monotherapy or in combination with INCB001158.<br>|
| Experimental: INCB001158 monotherapy and crossover to INC001158+ daratumumab SC<br>INCB001158 will be administered as monotherapy, once confirmed disease progression participants will be crossed over to INCB001158+daratumumad combination therapy. | Drug: INCB001158<br>* Phase 1: INCB001158 administered orally twice daily at the protocol-defined starting dose, with dose escalation/de-escalation based on protocol-defined toxicity criteria to determine the maximum tolerated dose. INCB001158 is administered in combination with daratumumab SC. Phase 2: INCB001158 administered orally at the recommended dose from Phase 1 either as a monotherapy or in combination with daratumumab SC.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | A TEAE was defined as an adverse event (AE) that was reported for the first time or the worsening of a pre-existing event after the first dose of study treatment. | up to 454 days | 
| Phase 2: Overall Response Rate (ORR): Number of Participants With a Documented Response of Complete Response (CR), Very Good Partial Response (VGPR), or PR, as Per International Myeloma Working Group (IMWG) Criteria | CR: negative immunofixation on serum/urine, disappearance of soft tissue plasmacytomas, <5% bone marrow plasma cells (PCs). VGPR: serum/urine M-component detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein (SMP) plus urine M-protein (UMP) <100 milligrams (mg)/24 hours. PR: ≥50% reduction of SMP and reduction in 24-hour UMP by ≥90% or to <200 mg/24 hours. SMP and UMP not measurable: decrease of ≥50% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria. SMP and UMP not measurable, and serum free light assay is not measurable: ≥50% reduction in bone marrow PCs is required in place of M-protein, if Baseline bone marrow PC percentage was ≥30%. If present at Baseline, a ≥50% reduction in the size of soft tissue plasmacytomas is required. | up to Day 386 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: ORR: Number of Participants With a Documented Response of CR, VGPR, or PR, as Per IMWG Criteria | CR: negative immunofixation on serum/urine, disappearance of soft tissue plasmacytomas, <5% bone marrow plasma cells (PCs). VGPR: serum/urine M-component detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein (SMP) plus urine M-protein (UMP) <100 milligrams (mg)/24 hours. PR: ≥50% reduction of SMP and reduction in 24-hour UMP by ≥90% or to <200 mg/24 hours. SMP and UMP not measurable: decrease of ≥50% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria. SMP and UMP not measurable, and serum free light assay is not measurable: ≥50% reduction in bone marrow PCs is required in place of M-protein, if Baseline bone marrow PC percentage was ≥30%. If present at Baseline, a ≥50% reduction in the size of soft tissue plasmacytomas is required. | up to Day 395 | 
| Phase 2: Number of Participants With Any TEAE | A TEAE was defined as an AE that was reported for the first time or the worsening of a pre-existing event after the first dose of study treatment. | up to 420 days | 
| Phase 1: Time to Response, Defined as the Time From the First Dose of Study Drug to the First Documented Response of PR or Better (CR, VGPR, or PR), as Per IMWG Criteria | CR: negative immunofixation on serum/urine, disappearance of soft tissue plasmacytomas, <5% bone marrow plasma cells (PCs). VGPR: serum/urine M-component detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein (SMP) plus urine M-protein (UMP) <100 milligrams (mg)/24 hours. PR: ≥50% reduction of SMP and reduction in 24-hour UMP by ≥90% or to <200 mg/24 hours. SMP and UMP not measurable: decrease of ≥50% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria. SMP and UMP not measurable, and serum free light assay is not measurable: ≥50% reduction in bone marrow PCs is required in place of M-protein, if Baseline bone marrow PC percentage was ≥30%. If present at Baseline, a ≥50% reduction in the size of soft tissue plasmacytomas is required. | up to Day 395 | 
| Phase 2: Time to Response, Defined as the Time From the First Dose of Study Drug to the First Documented Response of PR or Better (CR, VGPR, or PR), as Per IMWG Criteria | CR: negative immunofixation on serum/urine, disappearance of soft tissue plasmacytomas, <5% bone marrow plasma cells (PCs). VGPR: serum/urine M-component detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein (SMP) plus urine M-protein (UMP) <100 milligrams (mg)/24 hours. PR: ≥50% reduction of SMP and reduction in 24-hour UMP by ≥90% or to <200 mg/24 hours. SMP and UMP not measurable: decrease of ≥50% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria. SMP and UMP not measurable, and serum free light assay is not measurable: ≥50% reduction in bone marrow PCs is required in place of M-protein, if Baseline bone marrow PC percentage was ≥30%. If present at Baseline, a ≥50% reduction in the size of soft tissue plasmacytomas is required. | up to Day 386 | 
| Phase 1: Duration of Response, Defined as Time From First Documented Response of PR or Better (CR, VGPR, PR), as Per IMWG Criteria, Until Date of Disease Progression or Death, Whichever Occurred First | CR: negative immunofixation on serum/urine, disappearance of soft tissue plasmacytomas, <5% bone marrow plasma cells (PCs). VGPR: serum/urine M-component detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein (SMP) plus urine M-protein (UMP) <100 milligrams (mg)/24 hours. PR: ≥50% reduction of SMP and reduction in 24-hour UMP by ≥90% or to <200 mg/24 hours. SMP and UMP not measurable: decrease of ≥50% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria. SMP and UMP not measurable, and serum free light assay is not measurable: ≥50% reduction in bone marrow PCs is required in place of M-protein, if Baseline bone marrow PC percentage was ≥30%. If present at Baseline, a ≥50% reduction in the size of soft tissue plasmacytomas is required. | up to Day 395 | 
| Phase 2: Duration of Response, Defined as Time From First Documented Response of PR or Better (CR, VGPR, PR), as Per IMWG Criteria, Until Date of Disease Progression or Death, Whichever Occurred First | CR: negative immunofixation on serum/urine, disappearance of soft tissue plasmacytomas, <5% bone marrow plasma cells (PCs). VGPR: serum/urine M-component detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein (SMP) plus urine M-protein (UMP) <100 milligrams (mg)/24 hours. PR: ≥50% reduction of SMP and reduction in 24-hour UMP by ≥90% or to <200 mg/24 hours. SMP and UMP not measurable: decrease of ≥50% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria. SMP and UMP not measurable, and serum free light assay is not measurable: ≥50% reduction in bone marrow PCs is required in place of M-protein, if Baseline bone marrow PC percentage was ≥30%. If present at Baseline, a ≥50% reduction in the size of soft tissue plasmacytomas is required. | up to Day 386 | 
| Progression-free Survival (PFS), Defined as the Duration From the Date of the First Dose of Study Drug Until Either Progressive Disease, as Per IMWG Criteria, or Death, Whichever Occurred First | Progressive disease: increase of 25% from the lowest response value in any one of the following: (a) serum M-component (absolute increase must be ≥0.5 grams per deciliter [g/dL]); (b) urine M-component (absolute increase must be ≥200 mg/24 hours); (c) only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels (absolute increase must be > 10 mg/dL); (d) only in participants without measurable serum and urine M-protein levels and without measurable disease by FLC levels, bone marrow plasma cell (PC) percentage (absolute percentage must be ≥10%); (d) bone marrow PC percentage: the absolute percentage must be > 10%; (e) definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; (f) development of hypercalcemia (corrected serum calcium > 11.5 mg/dL) that can be attributed solely to the PC proliferative disorder. | up to approximately 2 years | 
| Phase 1: Minimal Residual Disease (MRD), Defined as the Percentage of MRD-negative Participants | Bone marrow aspirate was to be collected for MRD analysis. | up to approximately 2 years | 
| Phase 2: MRD, Defined as the Percentage of MRD-negative Participants | Bone marrow aspirate was to be collected for MRD analysis. | up to approximately 2 years | 
| Overall Survival | Overall survival was defined as the time from the first dose of study drug to death from any cause until study completion. | up to 923 days (approximately 2.5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Arginase inhibitor, multiple myeloma, Daratumumab