An Open-Label, Dose-Escalation/Dose-Expansion Safety Study of INCB059872 in Subjects With Advanced Malignancies

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1/2, Open-Label, Dose-Escalation/Dose-Expansion, Safety and Tolerability Study of INCB059872 in Subjects With Advanced Malignancies

Conditions
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Solid Tumors and Hematologic Malignancy

Intervention / Treatment
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* Drug: INCB059872
* Drug: all-trans retinoic acid (ATRA)
* Drug: azacitidine
* Drug: nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects, age 18 years or older. Presence of measurable disease that has been confirmed by histology or cytology. Must not be a candidate for potentially curative therapy or standard-of-care approved therapy Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. Exclusion Criteria: Receipt of anticancer medications, anticancer therapies, or investigational drugs within the defined interval before the first administration of study drug. Any unresolved toxicity ≥ Grade 2 from previous anticancer therapy except for stable chronic toxicities (≤ Grade 2) not expected to resolve. Laboratory and medical history parameters outside Protocol-defined range. Known additional malignancy that is progressing or requires active treatment.

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: INCB059872<br> | Drug: INCB059872<br>* 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.<br>|
| Experimental: INCB059872 in combination with other therapies<br>Initial cohort dose of INCB059872 to evaluate different doses of INCB0599872 in combination with other therapies in the following treatment groups: Combination with all-trans retinoic acid (ATRA) in subjects with relapsed/refractory AML. Combination with azacitidine in subjects with newly diagnosed, treatment-naive AML Combination with nivolumab in subjects with advanced SCLC previously progressed on platinum-based treatment. Upon identification of the recommended dose(s) for each treatment combination, expansion cohorts of approximately 30 subjects in each treatment group may begin enrollment to further determine safety, tolerability, efficacy, PK, and PD of the selected dose(s). | Drug: INCB059872<br>* 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.<br>Drug: all-trans retinoic acid (ATRA)<br> <br> Drug: azacitidine<br> <br> Drug: nivolumab<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | up to 1387 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | Baseline; Week 12 | 
| Cmax of INCB059872 in Plasma When Received as Monotherapy | Cmax was defined as the maximum observed plasma concentration of INCB059872. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | Cycle 1 Day 15: 0.5, 1, 2, 4, and 6 hours after INCB059872 dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), small cell lung cancer (SCLC), myelofibrosis (MF), solid tumor, lysine-specific demethylase 1 (LSD1) inhibitor