Clinical trial NCT02711137: Open-Label Safety and Tolerability Study of INCB057643 in Subjects With Advanced Malignancies
Official title: A Phase 1/2, Open-Label, Dose-Escalation/Dose-Expansion, Safety and Tolerability Study of INCB057643 in Subjects With Advanced Malignancies
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Solid Tumors
Keywords: 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
Lead sponsor: Incyte Corporation
Sponsor class: INDUSTRY
First posted: 2016-03-17
Enrollment: 137
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Number of Participants With Treatment Emergent Adverse Events (TEAE's).
timeFrame: From screening through at least 30 days after end of treatment, up to approximately 24 months
Secondary outcomes:
measure: Percent Inhibition of Total Cellular Myc Protein Concentrations Before and After Administration of INCB057643 When Administered as Monotherapy in an Ex-vivo Assay
timeFrame: 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
measure: Objective Response Rate (ORR) With INCB057643 in Solid Tumors
timeFrame: Efficacy measures from screening through end of treatment and follow-up (every 9 weeks), up to approximately 24 months
measure: Cmax: Maximum Observed Plasma Concentration of INCB057643.
timeFrame: Predose, 0.5, 1, 2, 4, 6, 8 hours on C1D1 and C1D8
measure: Tmax: Time to Maximum Plasma Concentration of INCB057643
timeFrame: Predose, 0.5, 1, 2, 4, 6, 8 hours on C1D1 and C1D8
measure: AUC0-t: Area Under the Single-dose Plasma Concentration-time Curve of INCB057643
timeFrame: Predose, 0.5, 1, 2, 4, 6, 8 hours on C1D1
measure: AUC0-24: Area Under the Steady-state Plasma Concentration-time Curve of INCB057643 Administered as Monotherapy
timeFrame: Predose, 0.5, 1, 2, 4, 6, 8 hours on C1D8
measure: Part 2 - Cmax: Maximum Observed Plasma Concentration of INCB057643.
timeFrame: C2D1
measure: Part 2-Tmax: Time to Maximum Plasma Concentration of INCB057643
timeFrame: C2D1
measure: AUC0-24: Area Under the Steady-state Plasma Concentration-time Curve of INCB057643 Administered as Monotherapy
timeFrame: C2D1
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: La Jolla
country: United States
facility: University of California
state: California
city: Denver
country: United States
facility: Sarah Cannon Research Institute at Health One
state: Colorado
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Miami
country: United States
facility: Sylvester Comprehensive Cancer Center
state: Florida
city: Port Saint Lucie
country: United States
facility: Hematology - Oncology Associates of Treasure Coast
state: Florida
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Rochester
country: United States
facility: University of Rochester, Wilmot Cancer Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Health
state: North Carolina
city: Houston
country: United States
facility: Oncology Consultants, P.A.
state: Texas
city: Houston
country: United States
facility: The Methodist Hospital
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Tacoma
country: United States
facility: MultiCare Institute for Research and Innovation
state: Washington
city: Brussels
country: Belgium
facility: Institut Jules Bordet, Clinical Trial Conduct Unit
city: Paris
country: France
facility: HÔPITAL SAINT-LOUIS, Service Hématologie Adultes
Study officials:
affiliation: Incyte Corporation
name: Fred Zheng, MD, PhD
role: STUDY_DIRECTOR
References:
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.