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

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ClinicalTrials.gov Identifier: NCT02711137

Recruitment Status : Terminated (Study terminated due to safety issues.)

First Posted : March 17, 2016

Results First Posted : April 28, 2022

Last Update Posted : April 28, 2022

Sponsor:

Information provided by (Responsible Party):

Incyte Corporation

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Solid Tumors	Drug: INCB057643 Drug: Gemcitabine Drug: Paclitaxel Drug: Rucaparib Drug: Abiraterone Drug: Ruxolitinib Drug: Azacitidine	Phase 1 Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	137 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase 1/2, Open-Label, Dose-Escalation/Dose-Expansion, Safety and Tolerability Study of INCB057643 in Subjects With Advanced Malignancies
Actual Study Start Date :	May 18, 2016
Actual Primary Completion Date :	February 13, 2019
Actual Study Completion Date :	February 13, 2019

Resource links provided by the National Library of Medicine

Genetic and Rare Diseases Information Center resources: Pancreatic Cancer Lymphosarcoma Diffuse Large B-Cell Lymphoma B-cell Lymphoma Ovarian Cancer Ovarian Epithelial Cancer Myelodysplastic Syndromes Glioblastoma Multiple Myeloma Primary Myelofibrosis Chronic Myeloproliferative Disorders

U.S. FDA Resources

Arms and Interventions

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	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: 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-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 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: 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-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 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: 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 metastatic solid tumors and hematologic malignancies where Gemcitabine is relevant	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). 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 metastatic solid tumors and hematologic malignancies.	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). 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 metastatic solid tumors and hematologic malignancies.	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). 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 Prostrate Cancer	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). 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: 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). 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 Syndrome	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). Drug: Azacitidine Standard of Care (SOC) agents

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

Percent Inhibition of Total Cellular Myc Protein Concentrations Before and After Administration of INCB057643 When Administered as Monotherapy in an Ex-vivo Assay [ Time Frame: 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 ]
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.
Objective Response Rate (ORR) With INCB057643 in Solid Tumors [ Time Frame: Efficacy measures from screening through end of treatment and follow-up (every 9 weeks), up to approximately 24 months ]
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)].
Cmax: Maximum Observed Plasma Concentration of INCB057643. [ Time Frame: Predose, 0.5, 1, 2, 4, 6, 8 hours on C1D1 and C1D8 ]
Maximum Observed Plasma Concentration INCB057643 administered as monotherapy in fasted state.
Tmax: Time to Maximum Plasma Concentration of INCB057643 [ Time Frame: Predose, 0.5, 1, 2, 4, 6, 8 hours on C1D1 and C1D8 ]
Time to maximum plasma concentration of INCB057643 administered as monotherapy in fasted state
AUC0-t: Area Under the Single-dose Plasma Concentration-time Curve of INCB057643 [ Time Frame: Predose, 0.5, 1, 2, 4, 6, 8 hours on C1D1 ]
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
AUC0-24: Area Under the Steady-state Plasma Concentration-time Curve of INCB057643 Administered as Monotherapy [ Time Frame: Predose, 0.5, 1, 2, 4, 6, 8 hours on C1D8 ]
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
Part 2 - Cmax: Maximum Observed Plasma Concentration of INCB057643. [ Time Frame: C2D1 ]
Maximum Observed Plasma Concentration INCB057643 administered as monotherapy in fed state.
Part 2-Tmax: Time to Maximum Plasma Concentration of INCB057643 [ Time Frame: C2D1 ]
Time to maximum plasma concentration of INCB057643 administered as monotherapy in fed state
AUC0-24: Area Under the Steady-state Plasma Concentration-time Curve of INCB057643 Administered as Monotherapy [ Time Frame: C2D1 ]
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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02711137

Locations

Show 18 study locations

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United States, Alabama
University of Alabama
Birmingham, Alabama, United States, 35294-3300
United States, California
University of California
La Jolla, California, United States, 92093
United States, Colorado
Sarah Cannon Research Institute at Health One
Denver, Colorado, United States, 80218
United States, Connecticut
Yale University
New Haven, Connecticut, United States, 06510
United States, Florida
Sylvester Comprehensive Cancer Center
Miami, Florida, United States, 33136
Hematology - Oncology Associates of Treasure Coast
Port Saint Lucie, Florida, United States, 34952
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
United States, Minnesota
University of Minnesota
Minneapolis, Minnesota, United States, 55455
United States, Missouri
Washington University
Saint Louis, Missouri, United States, 63110
United States, New York
University of Rochester, Wilmot Cancer Center
Rochester, New York, United States, 14642
United States, North Carolina
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States, 27599
Wake Forest Baptist Health
Winston-Salem, North Carolina, United States, 27157
United States, Texas
Oncology Consultants, P.A.
Houston, Texas, United States, 77030
The Methodist Hospital
Houston, Texas, United States, 77030
United States, Utah
Huntsman Cancer Institute
Salt Lake City, Utah, United States, 84112
United States, Washington
MultiCare Institute for Research and Innovation
Tacoma, Washington, United States, 98405
Belgium
Institut Jules Bordet, Clinical Trial Conduct Unit
Brussels, Belgium, B-1000
France
HÔPITAL SAINT-LOUIS, Service Hématologie Adultes
Paris, France, 75010

Sponsors and Collaborators

Incyte Corporation

Investigators

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Study Director:	Fred Zheng, MD, PhD	Incyte Corporation

Study Documents (Full-Text)

Documents provided by Incyte Corporation:

Study Protocol and Statistical Analysis Plan [PDF] October 22, 2018

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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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Responsible Party:	Incyte Corporation
ClinicalTrials.gov Identifier:	NCT02711137
Other Study ID Numbers:	INCB 57643-101
First Posted:	March 17, 2016 Key Record Dates
Results First Posted:	April 28, 2022
Last Update Posted:	April 28, 2022
Last Verified:	April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

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Studies a U.S. FDA-regulated Drug Product:	Yes
Studies a U.S. FDA-regulated Device Product:	No

Keywords provided by Incyte Corporation:


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

Additional relevant MeSH terms:

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Neoplasms Gemcitabine Paclitaxel Azacitidine Rucaparib INCB057643 Antineoplastic Agents, Phytogenic Antineoplastic Agents Tubulin Modulators Antimitotic Agents Mitosis Modulators	Molecular Mechanisms of Pharmacological Action Antimetabolites, Antineoplastic Antimetabolites Antiviral Agents Anti-Infective Agents Enzyme Inhibitors Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Poly(ADP-ribose) Polymerase Inhibitors

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