Back to resultsAn Open-Label, Dose-Escalation Study of INCB054329 in Patients With Advanced Malignancies
Primary Purpose
Solid Tumors and Hematologic Malignancy
Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
INCB054329 Monotherapy
Sponsored by
About this trial
This is an interventional treatment trial for Solid Tumors and Hematologic Malignancy focused on measuring solid tumor, lymphoma, BET bromodomain inhibitor, BRD, Diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma, c-MYC, colorectal cancer, Non-small cell lung cancer, Pancreatic adenocarcinoma, castration-resistant prostate cancer, breast cancer, NUT midline carcinoma, leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasms, myelofibrosis (MF), multiple myeloma (MM), MDS/MPN
Eligibility Criteria
Key Inclusion Criteria:
Confirmed diagnosis of advanced malignancy:
- Treatment Group A (TGA): Part 1 and Part 2: Any advanced solid tumor or lymphoma; Part 3: Histologically confirmed disease in specific solid tumors and lymphomas
- Treatment Group B (TGB): Acute Leukemia (Part 3 - acute myeloid leukemia [AML] only), myelodysplastic syndrome (MDS), myelodysplastic /myeloproliferative neoplasms (MDS/MPN) and myelofibrosis (MF)
- Treatment Group C (TGC): Multiple myeloma
- Progressed following at least 1 line of prior therapy and there is no further approved therapy available that has been demonstrated to prolong survival (including subjects who are intolerant to the approved therapy)
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 in Parts 1 and 2 dose escalation and titration, and 0, 1, 2 in Part 3 dose expansion
Key Exclusion Criteria:
- Inadequate hematopoietic, liver, endocrine or renal function
Receipt of anticancer medications or investigational drugs within the following interval before the first administration of study drug:
- < 6 weeks for mitomycin-C or nitrosoureas
- < 5 half-lives or 14 days, whichever is longer, for any investigational agent (for any indication)
- < 28 days for any antibodies or biological therapies
- < 5 half-lives for all other anticancer medications, or sponsor approval
- Prior radiotherapy within 2 weeks prior to first dose of study drug
- Untreated brain or central nervous system (CNS) metastases
- Type 1 diabetes or uncontrolled Type 2 diabetes
- Any sign of clinically significant bleeding
Sites / Locations
- Cedars-Sinai Medical Center
- University of California, San Francisco, Medical Center at Mount Zion
- Sarah Cannon Research Institute Research Center
- Northwestern Memorial Hospital
- The University of Chicago Medical Center
- Horizon Oncology Center
- John Hopkins
- University of Michigan Comprehensive Cancer Center
- Washington University School of Medicine in St. Louis
- Vanderbilt University Medical Center
- The University of Texas MD Anderson Cancer Center
- Seattle Cancer Care Alliance
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
INCB054329 Monotherapy
Arm Description
Outcomes
Primary Outcome Measures
Number of Participants With a Treatment-emergent Adverse Event (TEAE)
TEAE is defined as an adverse event reported for the first time or worsening of a pre-existing event after the first dose of study treatment.
Secondary Outcome Measures
Maximum Plasma Concentration (Cmax) Analysis of INCB054329
Cmax is defined as the maximum observed serum concentration measured at steady state (Day 15).
Study drug was administered with 240 mL of water. Summary of Steady-State, Day 15, was evaluated by dosing regimen.
Time to Maximum Plasma Concentration (Tmax) Analysis of INCB054329
Tmax is the time to maximum (peak) drug serum concentration. Study drug was administered with 240 mL of water. Summary of Steady-State, Day 15, was evaluated by dosing regimen.
Minimum Observed Plasma Concentration Over the Dose Interval (Cmin) Analysis of INCB054329
Minimum observed plasma concentration measured at steady state (Day 15). Study drug was administered with 240 mL of water. Summary of Steady-State, Day 15, was evaluated by dosing regimen.
AUC0-t Analysis of INCB054329
AUC0-t is the area under the plasma or serum concentration-time curve from time = 0 to the last measurable concentration at time = t measured at steady state (Day 15).
Study drug was administered with 240 mL of water.
Cl/F Analysis of INCB054329
Cl/F is the apparent oral dose clearance measured at steady state (Day 15). Study drug was administered with 240 mL of water.
Pharmacodynamics (PD) Analysis - Total c-Myc % Inhibition Versus INCB054329
The half maximal inhibitory concentration (IC50) of INCB054329 was measured. The maximal inhibition of total c-Myc was correlated to the level of drug exposure and demonstrated a high degree of interparticipant variability, parallel to the PK data.
The measure was performed as a value across all cohorts. The entire dose escalation data set was used to create the relationship curve. Analysis of individual cohorts contained too few subjects and was biased toward one region of the curve so that the relationship was poorly defined.
Individual data points from all subjects were subjected to a nonlinear least squares regression analysis with no weighting, resulting in a sigmoidal dose response curve defining the relationship. The numerical value given is the projected INCB0054329 concentration in nM that produced 50% inhibition of c-myc expression.
Objective Response Rate (ORR)
Defined as the percentage of subjects having complete response (CR) or partial response (PR). The best overall response was defined as the best response recorded before and including the first event of Progressive disease (PD).
Duration of Response (DOR)
Defined as the time from earliest date of disease response until earliest date of disease progression or death.
Progression Free Survival (PFS)
PFS is the time from start of study treatment to first documentation of progression, or to death due to any cause, whichever comes first
Overall Survival (OS)
OS is defined as the time from the date of randomization to the date of the participant's death.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02431260
Brief Title
An Open-Label, Dose-Escalation Study of INCB054329 in Patients With Advanced Malignancies
Official Title
A Phase 1/2, Open-Label, Dose-Escalation, Safety and Tolerability Study of INCB054329 in Subjects With Advanced Malignancies
Study Type
Interventional
2. Study Status
Record Verification Date
May 2019
Overall Recruitment Status
Terminated
Why Stopped
As of 31 JAN 2018, the study was terminated by the sponsor due to PK variability.
Study Start Date
April 14, 2015 (Actual)
Primary Completion Date
January 31, 2018 (Actual)
Study Completion Date
January 31, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Incyte Corporation
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
This was a study of INCB054329 given to patients with advanced malignancies that were conducted in three treatment groups. Each treatment group had a dose escalation (Part 1) and a dose expansion (Part 3), two of the treatment groups also had an intra-patient dose titration (Part 2).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Solid Tumors and Hematologic Malignancy
Keywords
solid tumor, lymphoma, BET bromodomain inhibitor, BRD, Diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma, c-MYC, colorectal cancer, Non-small cell lung cancer, Pancreatic adenocarcinoma, castration-resistant prostate cancer, breast cancer, NUT midline carcinoma, leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasms, myelofibrosis (MF), multiple myeloma (MM), MDS/MPN
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Enrollment
69 (Actual)
8. Arms, Groups, and Interventions
Arm Title
INCB054329 Monotherapy
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
INCB054329 Monotherapy
Intervention Description
Initial cohort dose of INCB054329 monotherapy at the protocol-specified starting dose in the treatment group A (TGA), with subsequent cohort escalations in the three treatment groups (TGA, TGB, and TGC) based on protocol-specific criteria
Primary Outcome Measure Information:
Title
Number of Participants With a Treatment-emergent Adverse Event (TEAE)
Description
TEAE is defined as an adverse event reported for the first time or worsening of a pre-existing event after the first dose of study treatment.
Time Frame
up to 30 days
Secondary Outcome Measure Information:
Title
Maximum Plasma Concentration (Cmax) Analysis of INCB054329
Description
Cmax is defined as the maximum observed serum concentration measured at steady state (Day 15).
Study drug was administered with 240 mL of water. Summary of Steady-State, Day 15, was evaluated by dosing regimen.
Time Frame
Summary of steady-state PK parameters by dosing regimen at Day 15
Title
Time to Maximum Plasma Concentration (Tmax) Analysis of INCB054329
Description
Tmax is the time to maximum (peak) drug serum concentration. Study drug was administered with 240 mL of water. Summary of Steady-State, Day 15, was evaluated by dosing regimen.
Time Frame
Summary of steady-state PK parameters by dosing regimen at Day 15
Title
Minimum Observed Plasma Concentration Over the Dose Interval (Cmin) Analysis of INCB054329
Description
Minimum observed plasma concentration measured at steady state (Day 15). Study drug was administered with 240 mL of water. Summary of Steady-State, Day 15, was evaluated by dosing regimen.
Time Frame
Summary of steady-state PK parameters by dosing regimen at Day 15
Title
AUC0-t Analysis of INCB054329
Description
AUC0-t is the area under the plasma or serum concentration-time curve from time = 0 to the last measurable concentration at time = t measured at steady state (Day 15).
Study drug was administered with 240 mL of water.
Time Frame
Summary of steady-state PK parameters by dosing regimen at Day 15
Title
Cl/F Analysis of INCB054329
Description
Cl/F is the apparent oral dose clearance measured at steady state (Day 15). Study drug was administered with 240 mL of water.
Time Frame
Summary of steady-state PK parameters by dosing regimen at Day 15
Title
Pharmacodynamics (PD) Analysis - Total c-Myc % Inhibition Versus INCB054329
Description
The half maximal inhibitory concentration (IC50) of INCB054329 was measured. The maximal inhibition of total c-Myc was correlated to the level of drug exposure and demonstrated a high degree of interparticipant variability, parallel to the PK data.
The measure was performed as a value across all cohorts. The entire dose escalation data set was used to create the relationship curve. Analysis of individual cohorts contained too few subjects and was biased toward one region of the curve so that the relationship was poorly defined.
Individual data points from all subjects were subjected to a nonlinear least squares regression analysis with no weighting, resulting in a sigmoidal dose response curve defining the relationship. The numerical value given is the projected INCB0054329 concentration in nM that produced 50% inhibition of c-myc expression.
Time Frame
Day 15 in all cohorts
Title
Objective Response Rate (ORR)
Description
Defined as the percentage of subjects having complete response (CR) or partial response (PR). The best overall response was defined as the best response recorded before and including the first event of Progressive disease (PD).
Time Frame
Baseline through end of study, up to 6 months
Title
Duration of Response (DOR)
Description
Defined as the time from earliest date of disease response until earliest date of disease progression or death.
Time Frame
Baseline through end of study, up to 6 months
Title
Progression Free Survival (PFS)
Description
PFS is the time from start of study treatment to first documentation of progression, or to death due to any cause, whichever comes first
Time Frame
Baseline through end of study, up to 6 months
Title
Overall Survival (OS)
Description
OS is defined as the time from the date of randomization to the date of the participant's death.
Time Frame
Baseline through end of study, up to 6 months for participants in Part 2
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Key Inclusion Criteria:
Confirmed diagnosis of advanced malignancy:
Treatment Group A (TGA): Part 1 and Part 2: Any advanced solid tumor or lymphoma; Part 3: Histologically confirmed disease in specific solid tumors and lymphomas
Treatment Group B (TGB): Acute Leukemia (Part 3 - acute myeloid leukemia [AML] only), myelodysplastic syndrome (MDS), myelodysplastic /myeloproliferative neoplasms (MDS/MPN) and myelofibrosis (MF)
Treatment Group C (TGC): Multiple myeloma
Progressed following at least 1 line of prior therapy and there is no further approved therapy available that has been demonstrated to prolong survival (including subjects who are intolerant to the approved therapy)
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 in Parts 1 and 2 dose escalation and titration, and 0, 1, 2 in Part 3 dose expansion
Key Exclusion Criteria:
Inadequate hematopoietic, liver, endocrine or renal function
Receipt of anticancer medications or investigational drugs within the following interval before the first administration of study drug:
< 6 weeks for mitomycin-C or nitrosoureas
< 5 half-lives or 14 days, whichever is longer, for any investigational agent (for any indication)
< 28 days for any antibodies or biological therapies
< 5 half-lives for all other anticancer medications, or sponsor approval
Prior radiotherapy within 2 weeks prior to first dose of study drug
Untreated brain or central nervous system (CNS) metastases
Type 1 diabetes or uncontrolled Type 2 diabetes
Any sign of clinically significant bleeding
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Fred Zheng, M.D.
Organizational Affiliation
Incyte Corporation
Official's Role
Study Director
Facility Information:
Facility Name
Cedars-Sinai Medical Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90048
Country
United States
Facility Name
University of California, San Francisco, Medical Center at Mount Zion
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
Facility Name
Sarah Cannon Research Institute Research Center
City
Denver
State/Province
Colorado
ZIP/Postal Code
80218
Country
United States
Facility Name
Northwestern Memorial Hospital
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
The University of Chicago Medical Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
Horizon Oncology Center
City
Lafayette
State/Province
Indiana
ZIP/Postal Code
47905
Country
United States
Facility Name
John Hopkins
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287-0013
Country
United States
Facility Name
University of Michigan Comprehensive Cancer Center
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Washington University School of Medicine in St. Louis
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232-0021
Country
United States
Facility Name
The University of Texas MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Seattle Cancer Care Alliance
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
31527168
Citation
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.
Results Reference
derived
Learn more about this trial
An Open-Label, Dose-Escalation Study of INCB054329 in Patients With Advanced Malignancies
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