An Open-Label Study of a Novel JAK-inhibitor, INCB052793, Given to Patients With Advanced Malignancies

Study Overview
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Brief Summary
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This was a study of INCB052793 given to patients with advanced malignancies that was to be conducted in three phases; Phase 1a (Monotherapy) and Phase 1b (Combination Therapy) and Phase 2 (Combination therapy of INCB052793 with azacitidine and itacitinib with azacitidine). Phase 1 had two parts; a dose escalation (Part 1) and an expansion (Part 2).

Official Title
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A Phase 1/2, Open-Label, Dose-Escalation, Safety and Tolerability Study of INCB052793 in Subjects With Advanced Malignancies

Conditions
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Solid Tumors, Advanced Malignancies, Metastatic Cancer

Intervention / Treatment
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* Drug: INCB052793
* Drug: gemcitabine
* Drug: nab-paclitaxel
* Drug: dexamethasone
* Drug: Carfilzomib
* Drug: bortezomib
* Drug: lenalidomide
* Drug: azacitidine
* Drug: INCB052793
* Drug: pomalidomide
* Drug: INCB050465
* Drug: INCB039110


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Phase 1a Aged 18 years or older Histologically or cytologically confirmed solid tumor or hematologic malignancy Life expectancy of 12 weeks or longer Must have received ≥ 1 prior treatment regimen Must not be a candidate for potentially curative or standard of care approved therapy Phase 1b Aged 18 years or older Cohort A: Histologically or cytologically confirmed pancreatic adenocarcinoma, triple-negative breast cancer, urothelial cancer with at least 1 measurable or evaluable target lesion Cohorts B, C, D, E and G: Histologically confirmed multiple myeloma and measureable/evaluable disease Cohort F: Confirmed acute myeloid leukemia or myelodysplastic syndrome Cohort H: Individuals diagnosed with lymphoma Prior therapy: Cohort A: No more than 1 prior chemotherapy regimen for advanced or metastatic disease (not including neoadjuvant and/or adjuvant therapy) Cohorts B, C, D, E and G: Must have relapsed from or have been refractory to ≥ 2 prior treatment regimens Cohort F: May have received any number of prior treatment regimens or be treatment-naïve Cohort H: Must have relapsed from or have been refractory to available treatments Phase 2 Aged 18 years or older Cohorts I and J: Confirmed acute myeloid leukemia or high risk myelodysplastic syndrome Prior therapy: Cohorts I and J: Must have failed prior therapy with a hypomethylating agent (HMA) Exclusion Criteria: Prior receipt of a JAK1 inhibitor (Phase 1a only) Known active central nervous system metastases and/or carcinomatous meningitis Eastern Cooperative Oncology Group (ECOG) performance status > 2 Any known contraindications to the use of gemcitabine, nab-paclitaxel, dexamethasone, carfilzomib, bortezomib, lenalidomide, azacitidine, pomalidomide or PI3Kδ inhibitor (Phase 1b and Phase 2 only, as appropriate to treatment cohort) Known human immunodeficiency virus infection, or evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or risk of reactivation

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1a: INCB052793 Monotherapy<br> | Drug: INCB052793<br>* Initial cohort dose of INCB052793 monotherapy at the protocol-specified starting dose, with subsequent cohort escalations based on protocol-specific criteria.<br>|
| Experimental: Phase 1b: INCB052793 Combination Therapy<br> | Drug: gemcitabine<br>* Gemcitabine administered intravenously over 30 minutes at the protocol-specified dose and frequency.<br>* Other names: Gemzar®;Drug: nab-paclitaxel<br>* nab-paclitaxel administered intravenously over 30 minutes at the protocol-specified dose and frequency.<br>* Other names: Abraxane®;Drug: dexamethasone<br>* Dexamethasone administered orally at the protocol-specified dose and frequency.<br>Drug: Carfilzomib<br>* Carfilzomib administered intravenously at the protocol-specified dose and frequency.<br>* Other names: Kyprolis®;Drug: bortezomib<br>* Bortezomib administered intravenously or subcutaneously at the protocol-specified dose and frequency.<br>* Other names: Velcade®;Drug: lenalidomide<br>* Lenalidomide administered orally at the protocol-specified dose and frequency.<br>* Other names: Revlimid®;Drug: azacitidine<br>* Azacitidine administered subcutaneously at the protocol-specified dose and frequency.<br>* Other names: Vidaza®;Drug: INCB052793<br>* INCB052793 tablets administered orally at the protocol specified dose strength and frequency.<br>Drug: pomalidomide<br>* Pomalidomide administered orally at the protocol-specified dose and frequency.<br>* Other names: Pomalyst®;Drug: INCB050465<br>* INCB050465 tablets administered orally at the protocol specified dose strength and frequency.<br>|
| Experimental: Phase 2: INCB052793 and itacitinib Combination Therapy<br> | Drug: azacitidine<br>* Azacitidine administered subcutaneously at the protocol-specified dose and frequency.<br>* Other names: Vidaza®;Drug: INCB052793<br>* INCB052793 tablets administered orally at the protocol specified dose strength and frequency.<br>Drug: INCB039110<br>* INCB039110 tablets administered orally at the protocol specified dose strength and frequency.<br>* Other names: itacitinib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1a and 1b: Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) and Serious Adverse Event (SAE) | An AE is any untoward medical occurrence in a subject administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization. A 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 dose of study drug. | From first dose of study drug up to 30 days after last dose of study drug (Up to approximately 3.4 years) | 
| Phase 2: Objective Response Rate (ORR) in Hematological Malignancies | ORR is defined as the proportion of participants who achieved complete response (CR), CR with incomplete hematologic recovery (CRi), partial response (PR), or hematologic improvement (HI), using the IWG response criteria. | Baseline through end of study (Up to approximately 4.5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1A and 1B: Percentage of Participants With Response as Determined by Investigator's Assessment | Response rate is defined as the percentage of participants who achieved best overall response (BOR) as determined by IWG response criteria of investigator's assessment. A participant was considered an objective responder based on the following- Solid tumors: participant had a best overall response (BOR) of CR or PR, Lymphoma: participant had a BOR of complete radiologic response/complete metabolic response or partial remission/partial metabolic response, AML: participant had a BOR of CR, CRi, morphological leukemia-free state (MLFS), or PR, MDS: participant had a BOR of CR, PR, or marrow CR, MDS/myeloproliferative neoplasm (MPN): participant had a BOR of CR, PR, or marrow response, MM: participant had a BOR of stringent CR, CR, very good PR, PR, or MR. Subjects are combined by tumor type for this analysis. | Baseline through end of study (Up to approximately 4.5 years) | 
| Phase 2: Number of Participants With at Least One TEAE and SAE | An AE is any untoward medical occurrence in a subject administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization. A 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 dose of study drug. | From first dose of study drug up to 30 days after last dose of study drug (Up to approximately 1.3 years) | 
| Phase 1a, 1b, and Phase 2: Cmax: Maximum Observed Plasma Concentration for INCB052793 | Cmax is defined as the maximum observed plasma concentration measured at steady state (Day 15). For PK analyses subjects in TGA and TGB are combined by dosage group because only 3 subjects were enrolled in each dose group in TGB and 4 subject for first dose in TGB 50 mg. | Cycle 1, Day 15: predose and 0.5, 1, 2, 4, 6 hours postdose in Phase 1a; 0 (predose), 0.08, 0.5, 1, 2, 4, 6 and 8 hours postdose in Phase 1b and Phase 2 | 
| Phase 1a, 1b, and Phase 2: Tmax: Time to Maximum Plasma Concentration for INCB052793 | Tmax is the time to maximum (peak) observed plasma drug concentration. Summary of Steady-State, Day 15, was evaluated by dosing regimen. For PK analyses subjects in TGA and TGB are combined by dosage group because only 3 subjects were enrolled in each dose group in TGB and 4 subject for first dose in TGB 50 mg. | Cycle 1, Day 15: predose and 0.5, 1, 2, 4, 6 hours postdose in Phase 1a; 0 (predose), 0.08, 0.5, 1, 2, 4, 6 and 8 hours postdose in Phase 1b and Phase 2 | 
| Phase 1a, 1b, and Phase 2: AUC0-τ: Area Under the Plasma Concentration-time Curve Over Dosing Interval for INCB052793 | AUC0-τ is the area under the plasma concentration-time curve from time = 0 to the last measurable concentration at time = t measured at steady state (Day 15). For PK analyses subjects in TGA and TGB are combined by dosage group because only 3 subjects were enrolled in each dose group in TGB and 4 subject for first dose in TGB 50 mg. | Cycle 1, Day 15: predose and 0.5, 1, 2, 4, 6 hours postdose in Phase 1a; 0 (predose), 0.08, 0.5, 1, 2, 4, 6 and 8 hours postdose in Phase 1b and Phase 2 | 
| Phase 1a, 1b, and Phase 2: Cmax: Maximum Observed Plasma Concentration of Itacitinib | Cmax is defined as the maximum observed plasma concentration measured at steady state (Day 15). | Cycle 1, Day 15: predose and 0.5, 1, 2, 4, 6 hours postdose in Phase 1a; 0 (predose), 0.08, 0.5, 1, 2, 4, 6 and 8 hours postdose in Phase 1b and Phase 2 | 
| Phase 1a, 1b, and Phase 2: Tmax: Time to Maximum Plasma Concentration for Itacitinib | Tmax is the time to maximum (peak) observed plasma drug concentration. | Cycle 1, Day 15: predose and 0.5, 1, 2, 4, 6 hours postdose in Phase 1a; 0 (predose), 0.08, 0.5, 1, 2, 4, 6 and 8 hours postdose in Phase 1b and Phase 2 | 
| Phase 1a, 1b, and Phase 2: AUC0-τ: Area Under the Plasma Concentration-time Curve Over Dosing Interval for Itacitinib | AUC0-τ is the area under the plasma concentration-time curve from time = 0 to the last measurable concentration at time = t measured at steady state (Day 15). | Cycle 1, Day 15: predose and 0.5, 1, 2, 4, 6 hours postdose in Phase 1a; 0 (predose), 0.08, 0.5, 1, 2, 4, 6 and 8 hours postdose in Phase 1b and Phase 2 | 
| Phase 1a, Part 2: Cmax: Maximum Observed Plasma Concentration for INCB052793 | Cmax is defined as the maximum observed plasma concentration measured at Day 1. | Cycle 1, Day 1 | 
| Phase 1a, Part 2: Tmax: Time to Maximum Plasma Concentration for INCB052793 | Tmax is the time to maximum (peak) observed plasma drug concentration. | Cycle 1, Day 1 | 
| Phase 1a, Part 2: AUC[0-t]: Area Under the Plasma Concentration-Time Curve From Time 0 To the Last Measurable Concentration at Time t | AUC0-t is the area under the plasma concentration-time curve from time = 0 to the last measurable concentration at time = t. | Cycle 1, Day 1 | 
| Phase 1a, Part 2: Cmax: Maximum Observed Plasma Concentration for INCB052793 | Cmax is defined as the maximum observed plasma concentration measured at steady state (Day 15). | Cycle 1, Day 15 | 
| Phase 1a, Part 2: Cmin: Minimum Observed Plasma Concentration Over the Dose Interval | Minimum observed plasma concentration measured at steady state (Day 15). | Cycle 1, Day 15 | 
| Phase 1a, Part 2: Tmax: Time to Maximum Plasma Concentration for INCB052793 | Tmax is the time to maximum (peak) observed plasma drug concentration. | Cycle 1, Day 15 | 
| Phase 1a, Part 2: AUC[0-t]: Area Under the Plasma Concentration-Time Curve From Time 0 To the Last Measurable Concentration at Time | AUC0-t is the area under the plasma concentration-time curve from time = 0 to the last measurable concentration at time = t measured at steady state (Day 15). | Cycle 1, Day 15 | 
| Phase 1a, Part 2: AUC0-τ: Area Under the Plasma Concentration-time Curve Over Dosing Interval for INCB052793 | AUC0-τ is the area under the plasma concentration-time curve from time = 0 to the last measurable concentration at time = t. | Cycle 1, Day 15 | 
| Phase 1a, Part 2: Cmax: Maximum Observed Plasma Concentration for INCB052793 | Cmax is defined as the maximum observed plasma concentration measured at cycle 2 Day 1. | Cycle 2, Day 1 | 
| Phase 1a, Part 2: Cmin: Minimum Observed Plasma Concentration Over the Dose Interval | Cmin is defined as the minimal observed plasma concentration measured at cycle 2 Day 1 | Cycle 2, Day 1 | 
| Phase 1a, Part 2: Tmax: Time to Maximum Plasma Concentration for INCB052793 | Tmax is the time to maximum (peak) observed plasma drug concentration. | Cycle 2, Day 1 | 
| Phase 1a, Part 2: AUC[0-t]: Area Under the Plasma Concentration-Time Curve From Time 0 To the Last Measurable Concentration at Time | AUC0-t is the area under the plasma concentration-time curve from time = 0 to the last measurable concentration at time = t. | Cycle 2, Day 1 | 
| Phase 1a, Part 2: AUC0-τ: Area Under the Plasma Concentration-time Curve Over Dosing Interval for INCB052793 | AUC0-τ is the area under the plasma concentration-time curve from time = 0 to the last measurable concentration at time = t. | Cycle 2, Day 1 |