Open-Label Safety And Tolerability Study Of INCB057643 In Subjects With Advanced Malignancies

Study Overview

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

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.

N/A

Solid Tumors

DRUG: INCB057643
DRUG: Gemcitabine
DRUG: Paclitaxel
DRUG: Rucaparib
DRUG: Abiraterone
DRUG: Ruxolitinib
DRUG: Azacitidine

INCB 57643-101

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2016-03-09	Results First Submitted 2022-02-11	Last Update Submitted that met QC Criteria 2022-04-01
First Submitted that Met QC Criteria 2016-03-12	Results First Submitted that Met QC Criteria 2022-04-01	Last Update Posted (ACTUAL) 2022-04-28
First Posted (ACTUAL) 2016-03-17	Results First Posted 2022-04-28	Last Verified 2022-04

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Non Randomized

Interventional Model:
Single Group

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Part1/Treatment Group A : 8mg QD INCB057643 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 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
EXPERIMENTAL: Part1/Treatment Group A : 12mg QD INCB057643 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 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
EXPERIMENTAL: Part1/Treatment Group A : 16mg QD INCB057643 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 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
EXPERIMENTAL: Part1/Treatment Group B : 8mg QD INCB057643 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 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
EXPERIMENTAL: Part1/Treatment Group B : 12mg QD INCB057643 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 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
EXPERIMENTAL: Part1/Treatment Group C : 8mg QD INCB057643 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
EXPERIMENTAL: Part2/Treatment Group A : 12 mg INCB057643 Expansion Cohort 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-r
EXPERIMENTAL: Part2/Treatment Group B : 12 mg INCB057643 Expansion Cohort 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-r
EXPERIMENTAL: Part3/Treatment Group A : 8 mg INCB057643 + Gemcitabine 1000mg 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 metasta	DRUG: Gemcitabine Standard of Care (SOC) agents
EXPERIMENTAL: Part3/Treatment Group B : 8 mg INCB057643 + Paclitaxel 80mg 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 metastat	DRUG: Paclitaxel Standard of Care (SOC) agents
EXPERIMENTAL: Part3/Treatment Group C : 8 mg INCB057643 + Rucaparib 600mg 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 metastati	DRUG: Rucaparib Standard of Care (SOC) agents
EXPERIMENTAL: Part3/Treatment Group D : 8 mg INCB057643 + Abir +Predni 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 Prostrat	DRUG: Abiraterone Standard of Care (SOC) agents
EXPERIMENTAL: Part3/Treatment Group E : 8 mg INCB057643 + Ruxolitinib 20mg 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: Ruxolitinib Standard of Care (SOC) agents
EXPERIMENTAL: Part3/Treatment Group F : 8 mg INCB057643 + Azacitidine 75mg 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	DRUG: Azacitidine Standard of Care (SOC) agents

Primary Outcome Measures	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	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

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

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

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

STUDY_DIRECTOR: Fred Zheng, MD, PhD, Incyte Corporation

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Falchook G, Rosen S, LoRusso P, Watts J, Gupta S, Coombs CC, Talpaz M, Kurzrock R, Mita M, Cassaday R, Harb W, Peguero J, Smith DC, Piha-Paul SA, Szmulewitz R, Noel MS, Yeleswaram S, Liu P, Switzky J, Zhou G, Zheng F, Mehta A. Development of 2 Bromodomain and Extraterminal Inhibitors With Distinct Pharmacokinetic and Pharmacodynamic Profiles for the Treatment of Advanced Malignancies. Clin Cancer Res. 2020 Mar 15;26(6):1247-1257. doi: 10.1158/1078-0432.CCR-18-4071. Epub 2019 Sep 16.

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