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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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

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

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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


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




Primary Outcome Measures :
  1. 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 :
  1. 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.

  2. 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)].

  3. 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.

  4. 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

  5. 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

  6. 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

  7. Part 2 - Cmax: Maximum Observed Plasma Concentration of INCB057643. [ Time Frame: C2D1 ]
    Maximum Observed Plasma Concentration INCB057643 administered as monotherapy in fed state.

  8. 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

  9. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
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

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 Show 18 study locations
Sponsors and Collaborators
Incyte Corporation
Investigators
Layout table for investigator information
Study Director: Fred Zheng, MD, PhD Incyte Corporation
  Study Documents (Full-Text)

Documents provided by Incyte Corporation:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
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:
Layout table for MeSH terms
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