Open-Label Safety and Tolerability Study of INCB057643 in Subjects With Advanced Malignancies

Study Overview
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Brief Summary
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The purpose of the Study is to select a dose and assess the safety and tolerability of INCB057643 as a monotherapy (Part 1 and Part 2) and in combination with standard-of-care (SOC) agents (Part 3 and Part 4) for subjects with advanced malignancies. Part 1 will determine the maximum tolerated dose of INCB057643 and/or a tolerated dose that demonstrates sufficient pharmacologic activity. Part 2 will further evaluate the safety, preliminary efficacy, PK, and PD of the dose(s) selected in Part 1 in select tumor types including solid tumors, lymphomas and other hematologic malignancies. Part 3 will determine the tolerated dose of INCB057643 in combination with select SOC agents; and assess the safety and tolerability of the combination therapy in select advanced solid tumors and hematologic malignancies. Part 4 will further evaluate the safety, preliminary efficacy, PK, and PD of the selected dose combination from Part 3 in 4 specific advanced solid tumor and hematologic malignancies.

Official Title
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A Phase 1/2, Open-Label, Dose-Escalation/Dose-Expansion, Safety and Tolerability Study of INCB057643 in Subjects With Advanced Malignancies

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: INCB057643
* Drug: Gemcitabine
* Drug: Paclitaxel
* Drug: Rucaparib
* Drug: Abiraterone
* Drug: Ruxolitinib
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed diagnosis of relapsed or refractory advanced or metastatic malignancies: Part 1: solid tumors or lymphomas, or hematologic malignancies Part 2: histologically confirmed disease in specific tumor types Part 3: advanced solid tumor or hematologic malignancy Part 4: select advanced solid tumor or hematologic malignancy For Part 1 and 2, subjects must have progressed following at least 1 line of prior therapy and there is no further established therapy that is known to provide clinical benefit (including subjects who are intolerant to the established therapy) For Parts 3 and 4, subjects must have progressed following at least 1 line of prior therapy, and the treatment with the select SOC agent is relevant for the specific disease cohort. Life expectancy > 12 weeks, for MF subjects in Parts 3 and 4, life expectancy > 24 weeks Eastern Cooperative Oncology Group (ECOG) performance status Parts 1 and 3: 0 or 1 Parts 2 and 4: 0, 1, or 2 Willingness to avoid pregnancy or fathering children Exclusion Criteria: Inadequate bone marrow function per protocol-specified hemoglobin, platelet count, and absolute neutrophil count Inadequate organ function per protocol-specified total bilirubin, AST and ALT, creatinine clearance and alkaline phosphatase. Receipt of anticancer medications or investigational drugs within protocol-specified intervals Unless approved by the medical monitor, may not have received an allogeneic hematopoietic stem cell transplant within 6 months before treatment, or have active graft-versus-host-disease following allogeneic transplant Unless approved by the medical monitor, may not have received autologous hematopoietic stem cell transplant within 3 months before treatment Any unresolved toxicity ≥ Grade 2 (except stable Grade 2 peripheral neuropathy or alopecia) from previous anticancer therapy Radiotherapy within the 2 weeks before initiation of treatment. Palliative radiation treatment to nonindex or bone lesions performed less than 2 weeks before treatment initiation may be considered with medical monitor approval Currently active and uncontrolled infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment Untreated brain or central nervous system (CNS) metastases or brain/CNS metastases that have progressed History or presence of abnormal electrocardiogram (ECG) that, in the investigator's opinion, is clinically meaningful Type 1 diabetes or uncontrolled Type 2 diabetes HbA1c of ≥ 8% (all subjects will have HbA1c test at screening) Any sign of clinically significant bleeding Coagulation panel within protocol-specified parameters

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: Part1/Treatment Group A : 8mg QD INCB057643<br>Initial cohort dose of INCB057643 monotherapy at the protocol specified starting dose in the TGA. Treatment Group A included solid tumors and lymphoma | Drug: INCB057643<br>* Initial cohort dose of INCB057643 at the protocol-specified starting dose (Part 1), with subsequent dose escalations based on protocol-specific criteria. The recommended treatment group-specific dose(s) will be taken forward into expansion cohorts (Part 2).<br>|
| Experimental: Part1/Treatment Group A : 12mg QD INCB057643<br>Initial cohort dose of INCB057643 monotherapy at the protocol specified starting dose in the TGA. Treatment Group A included solid tumors and lymphoma | Drug: INCB057643<br>* Initial cohort dose of INCB057643 at the protocol-specified starting dose (Part 1), with subsequent dose escalations based on protocol-specific criteria. The recommended treatment group-specific dose(s) will be taken forward into expansion cohorts (Part 2).<br>|
| Experimental: Part1/Treatment Group A : 16mg QD INCB057643<br>Initial cohort dose of INCB057643 monotherapy at the protocol specified starting dose in the TGA. Treatment Group A included solid tumors and lymphoma | Drug: INCB057643<br>* Initial cohort dose of INCB057643 at the protocol-specified starting dose (Part 1), with subsequent dose escalations based on protocol-specific criteria. The recommended treatment group-specific dose(s) will be taken forward into expansion cohorts (Part 2).<br>|
| Experimental: Part1/Treatment Group B : 8mg QD INCB057643<br>Initial cohort dose of INCB054763 monotherapy at the protocol-specified cohort escalation treatment group B (TGB), based on protocol-specific criteria. Treatment Group B included any acute leukemia, HRMDS, MDS/MPN, or MF | Drug: INCB057643<br>* Initial cohort dose of INCB057643 at the protocol-specified starting dose (Part 1), with subsequent dose escalations based on protocol-specific criteria. The recommended treatment group-specific dose(s) will be taken forward into expansion cohorts (Part 2).<br>|
| Experimental: Part1/Treatment Group B : 12mg QD INCB057643<br>Initial cohort dose of INCB054763 monotherapy at the protocol-specified cohort escalation treatment group B (TGB), based on protocol-specific criteria. Treatment Group B included any acute leukemia, HRMDS, MDS/MPN, or MF. | Drug: INCB057643<br>* Initial cohort dose of INCB057643 at the protocol-specified starting dose (Part 1), with subsequent dose escalations based on protocol-specific criteria. The recommended treatment group-specific dose(s) will be taken forward into expansion cohorts (Part 2).<br>|
| Experimental: Part1/Treatment Group C : 8mg QD INCB057643<br>Initial cohort dose of INCB054763 monotherapy at the protocol-specified cohort escalation treatment group C (TGC), based on protocol-specific criteria. Treatment Group C includes subjects with MM | Drug: INCB057643<br>* Initial cohort dose of INCB057643 at the protocol-specified starting dose (Part 1), with subsequent dose escalations based on protocol-specific criteria. The recommended treatment group-specific dose(s) will be taken forward into expansion cohorts (Part 2).<br>|
| Experimental: Part2/Treatment Group A : 12 mg INCB057643 Expansion Cohort<br>Initial cohort dose of INCB054763 monotherapy at the specified RP2D dose selected in Part 1 cohort escalation treatment group A (TGA), based on protocol-specific criteria. Part 2 Treatment Group A expansion included pancreatic adenocarcinoma, castration-resistant prostrate cancer, breast cancer, high grade serious ovarian cancer, glioblastoma multiform, non-hodgkin's lymphoma, ewing's sarcoma, and solid tumor or lymphoma. | Drug: INCB057643<br>* Initial cohort dose of INCB057643 at the protocol-specified starting dose (Part 1), with subsequent dose escalations based on protocol-specific criteria. The recommended treatment group-specific dose(s) will be taken forward into expansion cohorts (Part 2).<br>|
| Experimental: Part2/Treatment Group B : 12 mg INCB057643 Expansion Cohort<br>Initial cohort dose of INCB057463 monotherapy at the specified RP2D dose selected in Part 1 cohort escalation treatment group B (TGB), based on protocol-specific criteria. Part 2 Treatment Group B expansion included pancreatic adenocarcinoma, castration-resistant prostrate cancer, breast cancer, high grade serious ovarian cancer, glioblastoma multiform, non-hodgkin's lymphoma, ewing's sarcoma, and solid tumor or lymphoma. | Drug: INCB057643<br>* Initial cohort dose of INCB057643 at the protocol-specified starting dose (Part 1), with subsequent dose escalations based on protocol-specific criteria. The recommended treatment group-specific dose(s) will be taken forward into expansion cohorts (Part 2).<br>|
| Experimental: Part3/Treatment Group A : 8 mg INCB057643 + Gemcitabine 1000mg<br>Initial cohort dose of INCB057643 monotherapy based on protocol-specific criteria. Part 3 will determine the MTD and/or a tolerated dose of the combination of INCB057643 and one of the SOC agents (Gemcitabine) in relapsed or refractory advanced or metastatic solid tumors and hematologic malignancies where Gemcitabine is relevant | Drug: INCB057643<br>* Initial cohort dose of INCB057643 at the protocol-specified starting dose (Part 1), with subsequent dose escalations based on protocol-specific criteria. The recommended treatment group-specific dose(s) will be taken forward into expansion cohorts (Part 2).<br>Drug: Gemcitabine<br>* Standard of Care (SOC) agents<br>|
| Experimental: Part3/Treatment Group B : 8 mg INCB057643 + Paclitaxel 80mg<br>Initial cohort dose of INCB054763 monotherapy based on protocol-specific criteria. Part 3 will determine the MTD and/or a tolerated dose of the combination of INCB057643 and one of the SOC agents (Paclitaxel) in relapsed or refractory advanced or metastatic solid tumors and hematologic malignancies. | Drug: INCB057643<br>* Initial cohort dose of INCB057643 at the protocol-specified starting dose (Part 1), with subsequent dose escalations based on protocol-specific criteria. The recommended treatment group-specific dose(s) will be taken forward into expansion cohorts (Part 2).<br>Drug: Paclitaxel<br>* Standard of Care (SOC) agents<br>|
| Experimental: Part3/Treatment Group C : 8 mg INCB057643 + Rucaparib 600mg<br>Initial cohort dose of INCB054763 monotherapy based on protocol-specific criteria. Part 3 will determine the MTD and/or a tolerated dose of the combination of INCB057643 and one of the SOC agents (Rucaparib) in relapsed or refractory advanced or metastatic solid tumors and hematologic malignancies. | Drug: INCB057643<br>* Initial cohort dose of INCB057643 at the protocol-specified starting dose (Part 1), with subsequent dose escalations based on protocol-specific criteria. The recommended treatment group-specific dose(s) will be taken forward into expansion cohorts (Part 2).<br>Drug: Rucaparib<br>* Standard of Care (SOC) agents<br>|
| Experimental: Part3/Treatment Group D : 8 mg INCB057643 + Abir +Predni<br>Initial cohort dose of INCB054763 monotherapy based on protocol-specific criteria. Part 3 will determine the MTD and/or a tolerated dose of the combination of INCB057643 and one of the SOC agents (Abiraterone + Prednisone) in Castration Resistant Prostrate Cancer | Drug: INCB057643<br>* Initial cohort dose of INCB057643 at the protocol-specified starting dose (Part 1), with subsequent dose escalations based on protocol-specific criteria. The recommended treatment group-specific dose(s) will be taken forward into expansion cohorts (Part 2).<br>Drug: Abiraterone<br>* Standard of Care (SOC) agents<br>|
| Experimental: Part3/Treatment Group E : 8 mg INCB057643 + Ruxolitinib 20mg<br>Initial cohort dose of INCB054763 monotherapy based on protocol-specific criteria. Part 3 will determine the MTD and/or a tolerated dose of the combination of INCB057643 and one of the SOC agents (Ruxolitinib) in Myelofibrosis. | Drug: INCB057643<br>* Initial cohort dose of INCB057643 at the protocol-specified starting dose (Part 1), with subsequent dose escalations based on protocol-specific criteria. The recommended treatment group-specific dose(s) will be taken forward into expansion cohorts (Part 2).<br>Drug: Ruxolitinib<br>* Standard of Care (SOC) agents<br>|
| Experimental: Part3/Treatment Group F : 8 mg INCB057643 + Azacitidine 75mg<br>Initial cohort dose of INCB054763 monotherapy based on protocol-specific criteria. Part 3 will determine the MTD and/or a tolerated dose of the combination of INCB057643 and one of the SOC agents (Azacitidine) in Acute Myeloid Leukemia and Myelodysplastic Syndrome | Drug: INCB057643<br>* Initial cohort dose of INCB057643 at the protocol-specified starting dose (Part 1), with subsequent dose escalations based on protocol-specific criteria. The recommended treatment group-specific dose(s) will be taken forward into expansion cohorts (Part 2).<br>Drug: Azacitidine<br>* Standard of Care (SOC) agents<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAE's). | Adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug/treatment. | From screening through at least 30 days after end of treatment, up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Inhibition of Total Cellular Myc Protein Concentrations Before and After Administration of INCB057643 When Administered as Monotherapy in an Ex-vivo Assay | An ex vivo assay (utilized in monotherapy only), Measuring Total c-Myc protein expressed from an exogenously added cell line (KMS12BM) to patient plasma, before and after administration of INCB057643. | PD in plasma at pre-dose and 0.5, 1, 2, 4, 6 and 8 hours postdose, for C1D1 and C1D8, and 24hrs post dose for C1D1 | 
| Objective Response Rate (ORR) With INCB057643 in Solid Tumors | Objective response rate is defined as the proportion of subjects who have an objective response using the applicable disease assessment criteria. ORR was proportion of participants with best overall response [complete response (CR) or partial response (PR)]. | Efficacy measures from screening through end of treatment and follow-up (every 9 weeks), up to approximately 24 months | 
| Cmax: Maximum Observed Plasma Concentration of INCB057643. | Maximum Observed Plasma Concentration INCB057643 administered as monotherapy in fasted state. | Predose, 0.5, 1, 2, 4, 6, 8 hours on C1D1 and C1D8 | 
| Tmax: Time to Maximum Plasma Concentration of INCB057643 | Time to maximum plasma concentration of INCB057643 administered as monotherapy in fasted state | Predose, 0.5, 1, 2, 4, 6, 8 hours on C1D1 and C1D8 | 
| AUC0-t: Area Under the Single-dose Plasma Concentration-time Curve of INCB057643 | Area under the single-dose plasma concentration-time curve from Hour 0 to the last quantifiable measurable plasma concentration of INCB057643 administered as monotherapy in fasted state | Predose, 0.5, 1, 2, 4, 6, 8 hours on C1D1 | 
| AUC0-24: Area Under the Steady-state Plasma Concentration-time Curve of INCB057643 Administered as Monotherapy | Area under the steady-state plasma concentration-time curve over 1 dosing interval from Hour 0 to 24 for QD administration of INCB057643 administered as monotherapy in fasted state | Predose, 0.5, 1, 2, 4, 6, 8 hours on C1D8 | 
| Part 2 - Cmax: Maximum Observed Plasma Concentration of INCB057643. | Maximum Observed Plasma Concentration INCB057643 administered as monotherapy in fed state. | C2D1 | 
| Part 2-Tmax: Time to Maximum Plasma Concentration of INCB057643 | Time to maximum plasma concentration of INCB057643 administered as monotherapy in fed state | C2D1 | 
| AUC0-24: Area Under the Steady-state Plasma Concentration-time Curve of INCB057643 Administered as Monotherapy | Area under the steady-state plasma concentration-time curve over 1 dosing interval from Hour 0 to 24 for QD administration of INCB057643 administered as monotherapy in fed state. | C2D1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid tumor, lymphoma, leukemia, AML, myelodysplastic syndrome (MDS), multiple myeloma, myeloproliferative neoplasm (MPN), MDS/MPN, myelofibrosis (MF), pancreatic cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, breast cancer, ovarian cancer, glioblastoma multiforme (GBM), NUT midline carcinoma, non-Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL), double-hit, triple-hit, myc, bromodomain and extra-terminal (BET) inhibitor