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

A Phase 1/2, Open-Label, Dose-Escalation/Dose-Expansion, 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.

Study Overview

• Status: Terminated
• Conditions: Solid Tumors
• Intervention / Treatment: Drug: INCB057643; Drug: Gemcitabine; Drug: Paclitaxel; Drug: Rucaparib; Drug: Abiraterone; Drug: Ruxolitinib; Drug: Azacitidine

• Study Type: Interventional
• Enrollment (Actual): 137
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

14

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	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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Incyte Corporation
• Investigators: Study Director: Fred Zheng, MD, PhD, Incyte Corporation

Publications and helpful links

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.

Study record dates

Study Major Dates

• Study Start (Actual): May 18, 2016
• Primary Completion (Actual): February 13, 2019
• Study Completion (Actual): February 13, 2019

Study Registration Dates

• First Submitted: March 9, 2016
• First Submitted That Met QC Criteria: March 12, 2016
• First Posted (Estimate): March 17, 2016

Study Record Updates

• Last Update Posted (Actual): April 28, 2022
• Last Update Submitted That Met QC Criteria: April 1, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: lymphoma; colorectal cancer; breast cancer; prostate cancer; non-small cell lung cancer; AML; ovarian cancer; pancreatic cancer; Solid tumor; non-Hodgkin lymphoma; MDS/MPN; multiple myeloma; leukemia; myelodysplastic syndrome (MDS); glioblastoma multiforme (GBM); myelofibrosis (MF); double-hit; triple-hit; diffuse large B-cell lymphoma (DLBCL); myeloproliferative neoplasm (MPN); NUT midline carcinoma; myc; bromodomain and extra-terminal (BET) inhibitor
• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Poly(ADP-ribose) Polymerase Inhibitors; Gemcitabine; Paclitaxel; Azacitidine; Rucaparib; INCB057643
• Other Study ID Numbers: INCB 57643-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No