This is an open-label, dose-escalation/dose-expansion study of INCB059872 in subjects with advanced malignancies. The study will be conducted in 4 parts. Part 1 (mono therapy dose escalation) will determine the recommended dose(s) of INCB059872 for dose expansion, based on maximum tolerated dose and/or a tolerated pharmacologically active dose. Part 2 (dose expansion) will further determine the safety, tolerability, efficacy, PK, and PD of the selected monotherapy dose(s) in AML/MDS, SCLC, myelofibrosis, Ewing sarcoma, and poorly differentiated neuroendocrine tumors. Part 3 will determine the recommended dose(s) of INCB059872 in combination with azacitadine and all-trans retinoic acid in AML and in combination with nivolumab in SCLC. Part 4 will further determine the safety, tolerability, efficacy, PK, and PD of the selected combination dose(s) in Part 3.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
116
Initial cohort dose of INCB059872 monotherapy at the protocol-specified starting dose, with subsequent cohort escalations based on protocol-specific criteria. The recommended dose(s) will be taken forward into expansion cohorts. INCB059872 tablets to be administered by mouth.
University of Alabama
Birmingham, Alabama, United States
Moores UCSD Cancer Center
La Jolla, California, United States
UCLA Medical Center
Los Angeles, California, United States
Northwestern University
Chicago, Illinois, United States
University of Kansas Center for Research, Inc.
Kansas City, Kansas, United States
Roswell Park Cancer Institute
Buffalo, New York, United States
Columbia University
New York, New York, United States
Oregon Health Science University
Portland, Oregon, United States
University of Pennsylvania
Philadelphia, Pennsylvania, United States
Vanderbilt University
Nashville, Tennessee, United States
...and 5 more locations
Number of Participants Receiving INCB059872 Monotherapy With Any Treatment-emergent Adverse Event (TEAE)
Adverse events (AEs) were defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurred after a participant provided informed consent. Abnormal laboratory values or test results occurring after informed consent constituted AEs only if they induced clinical signs or symptoms, were considered clinically meaningful, required therapy (e.g., hematologic abnormality that required transfusion), or required changes in the study drug(s). TEAEs were defined as AEs either reported for the first time or the worsening of pre-existing events after the first dose of study drug and within 30 days of the last administration of study drug.
Time frame: up to 588 days
Number of Participants Receiving INCB059872 Combination Therapy With Any TEAE
AEs were defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurred after a participant provided informed consent. Abnormal laboratory values or test results occurring after informed consent constituted AEs only if they induced clinical signs or symptoms, were considered clinically meaningful, required therapy (e.g., hematologic abnormality that required transfusion), or required changes in the study drug(s). TEAEs were defined as AEs either reported for the first time or the worsening of pre-existing events after the first dose of study drug and within 30 days of the last administration of study drug.
Time frame: up to 1387 days
Objective Response Rate (ORR) in Participants With the Indicated Type of Solid Tumors Who Received INCB059872 Monotherapy
ORR was defined as the percentage of participants who achieved a best overall response of complete response (CR) or a partial response (PR), per investigator assessment according to Response Evaluation Criteria in Solid Tumors version 1.1 (RESIST v1.1), recorded before and including the first event of progressive disease (PD). CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 millimeters (mm). PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions.
Time frame: up to 518 days
ORR for Altering the Natural History of the Disease in Participants With Acute Myeloid Leukemia (AML) Who Received INCB059872 Monotherapy
ORR was defined as the percentage of participants who achieved a best overall response of complete remission or complete remission with incomplete hematologic recovery (CRi), per the International Working Group Response Criteria for AML, recorded before and including the first event of progression (treatment failure, relapse, and PD) based on altering the natural history of the disease. Complete remission: absolute neutrophil count (ANC) ≥1.0 x 10\^9/Liter (L), platelet count ≥100 x 10\^9/L, bone marrow with less than 5% blast cells, Auer rods not detectable; no platelet, or whole blood transfusions for 7 days prior to the date of the hematology assessment. CRi: complete remission, but the ANC count may be \< 1.0 x 10\^9/L and/or the platelet count may be \<100 x 10\^9/L.
Time frame: up to 85 days
ORR for Altering the Natural History of the Disease in Participants With Myelodysplastic Syndrome (MDS) Who Received INCB059872 Monotherapy
ORR was defined as the percentage of participants who achieved a best overall response of complete remission, partial remission, or bone marrow complete remission, per the International Working Group Response Criteria for MDS, recorded before and including the first event of progression (treatment failure, relapse after CR or PR, disease transformation, and PD) based on altering the natural history of the disease. Complete remission: \<5% bone marrow blasts without evidence of dysplasia; peripheral blood counts: hemoglobin ≥11 grams per deciliter (g/dL), neutrophils ≥1 x 10\^9/L, platelets ≥100 x 10\^9/L. Partial remission: meeting complete remission criteria, but bone marrow blasts decreased by ≥50% from pre-treatment, but still ≥5%. Bone marrow complete remission: ≤5% bone marrow blasts and decrease by ≥50% from pre-treatment.
Time frame: up to 61 days
Change From Baseline in Spleen Volume Reduction (SVR) at Week 12 in Participants With Myelofibrosis (MF) Who Received INCB059872 Monotherapy
Change from Baseline was to have been calculated as the post-Baseline value minus the Baseline value. SVR was to have been measured by magnetic resonance imaging (MRI), or by computed tomography (CT) scan in participants who were not candidates for MRI or when MRI was not readily available.
Time frame: Baseline; Week 12
Cmax of INCB059872 in Plasma When Received as Monotherapy
Cmax was defined as the maximum observed plasma concentration of INCB059872.
Time frame: Cycle 1 Day 15: 0.5, 1, 2, 4, and 6 hours after INCB059872 dose
Tmax of INCB059872 in Plasma When Received as Monotherapy
tmax was defined as the time to the maximum observed plasma concentration of INCB059872.
Time frame: Cycle 1 Day 15: 0.5, 1, 2, 4, and 6 hours after INCB059872 dose
AUC(0-τ) of INCB059872 in Plasma When Received as Monotherapy
AUC(0-τ) was defined as the area under the plasma concentration-time curve from time = 0 to the end of the dosing period of INCB059872.
Time frame: Cycle 1 Day 15: 0.5, 1, 2, 4, and 6 hours after INCB059872 dose
t1/2 of INCB059872 in Plasma When Received as Monotherapy
t1/2 was defined as the half-life of INCB059872.
Time frame: Cycle 1 Day 15: 0.5, 1, 2, 4, and 6 hours after INCB059872 dose
CL/F of INCB059872 in Plasma When Received as Monotherapy
CL/F was defined as the apparent oral clearance of INCB059872.
Time frame: Cycle 1 Day 15: 0.5, 1, 2, 4, and 6 hours after INCB059872 dose
ORR in Participants With SCLC Who Received Combination Therapy
ORR was defined as the percentage of participants who achieved a best overall response of CR or a PR, per investigator assessment according to RESIST v1.1, recorded before and including the first event of PD. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions.
Time frame: up to 1353 days
ORR for Altering the Natural History of the Disease in Participants With AML Who Received Combination Therapy
ORR was defined as the percentage of participants who achieved a best overall response of complete remission or CRi, per the International Working Group Response Criteria for AML, recorded before and including the first event of progression (treatment failure, relapse, and PD) based on altering the natural history of the disease. Complete remission: ANC ≥1.0 x 10\^9/L, platelet count ≥100 x 10\^9/L, bone marrow with less than 5% blast cells, Auer rods not detectable; no platelet, or whole blood transfusions for 7 days prior to the date of the hematology assessment. CRi: complete remission, but the ANC count may be \< 1.0 x 10\^9/L and/or the platelet count may be \<100 x 10\^9/L.
Time frame: up to 208 days
ORR for Altering the Natural History of the Disease in Participants With MDS Who Received Combination Therapy
ORR was defined as the percentage of participants who achieved a best overall response of complete remission, partial remission, or bone marrow complete remission, per the International Working Group Response Criteria for MDS, recorded before and including the first event of progression (treatment failure, relapse after CR or PR, disease transformation, and PD) based on altering the natural history of the disease. Complete remission: \<5% bone marrow blasts without evidence of dysplasia; peripheral blood counts: hemoglobin ≥11 g/dL, neutrophils ≥1 x 10\^9/L, platelets ≥100 x 10\^9/L. Partial remission: meeting complete remission criteria, but bone marrow blasts decreased by ≥50% from pre-treatment, but still ≥5%. Bone marrow complete remission: ≤5% bone marrow blasts and decrease by ≥50% from pre-treatment.
Time frame: up to 85 days
Cmax of INCB059872 in Plasma When Received as Combination Therapy
Cmax was defined as the maximum observed plasma concentration of INCB059872.
Time frame: Cycle 1 Day 15: 0.5, 1, 2, 4, and 6 hours after INCB059872 dose
Tmax of INCB059872 in Plasma When Received as Combination Therapy
tmax was defined as the time to the maximum observed plasma concentration of INCB059872.
Time frame: Cycle 1 Day 15: 0.5, 1, 2, 4, and 6 hours after INCB059872 dose
AUC(0-τ) of INCB059872 in Plasma When Received as Combination Therapy
AUC(0-τ) was defined as the area under the plasma concentration-time curve from time = 0 to the end of the dosing period of INCB059872.
Time frame: Cycle 1 Day 15: 0.5, 1, 2, 4, and 6 hours after INCB059872 dose
t1/2 of INCB059872 in Plasma When Received as Combination Therapy
t1/2 was defined as the half-life of INCB059872.
Time frame: Cycle 1 Day 15: 0.5, 1, 2, 4, and 6 hours after INCB059872 dose
CL/F of INCB059872 in Plasma When Received as Combination Therapy
CL/F was defined as the apparent oral clearance of INCB059872.
Time frame: Cycle 1 Day 15: 0.5, 1, 2, 4, and 6 hours after INCB059872 dose
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