A Phase 1/2, Open-Label, Dose-Escalation/Dose-Expansion, Safety and Tolerability Study of INCB057643 in Subjects With Advanced Malignancies
Overview
- Phase
- Phase 1
- Status
- Terminated
- Sponsor
- Incyte Corporation
- Enrollment
- 137
- Locations
- 18
- Primary Endpoint
- Number of Participants With Treatment Emergent Adverse Events (TEAE's).
Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
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
Arms & Interventions
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
Intervention: INCB057643 (Drug)
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
Intervention: INCB057643 (Drug)
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
Intervention: INCB057643 (Drug)
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
Intervention: INCB057643 (Drug)
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.
Intervention: INCB057643 (Drug)
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
Intervention: INCB057643 (Drug)
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.
Intervention: INCB057643 (Drug)
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.
Intervention: INCB057643 (Drug)
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
Intervention: INCB057643 (Drug)
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
Intervention: Gemcitabine (Drug)
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.
Intervention: INCB057643 (Drug)
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.
Intervention: Paclitaxel (Drug)
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.
Intervention: INCB057643 (Drug)
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.
Intervention: Rucaparib (Drug)
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
Intervention: INCB057643 (Drug)
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
Intervention: Abiraterone (Drug)
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.
Intervention: INCB057643 (Drug)
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.
Intervention: Ruxolitinib (Drug)
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
Intervention: INCB057643 (Drug)
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
Intervention: Azacitidine (Drug)
Outcomes
Primary Outcomes
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 Outcomes
- AUC0-t: Area Under the Single-dose Plasma Concentration-time Curve of INCB057643(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(C2D1)
- Tmax: Time to Maximum Plasma Concentration of INCB057643(Predose, 0.5, 1, 2, 4, 6, 8 hours on C1D1 and C1D8)
- Part 2 - Cmax: Maximum Observed Plasma Concentration of INCB057643.(C2D1)
- Objective Response Rate (ORR) With INCB057643 in Solid Tumors(Efficacy measures from screening through end of treatment and follow-up (every 9 weeks), up to approximately 24 months)
- Percent Inhibition of Total Cellular Myc Protein Concentrations Before and After Administration of INCB057643 When Administered as Monotherapy in an Ex-vivo Assay(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)
- Part 2-Tmax: Time to Maximum Plasma Concentration of INCB057643(C2D1)
- Cmax: Maximum Observed Plasma Concentration of INCB057643.(Predose, 0.5, 1, 2, 4, 6, 8 hours on C1D1 and C1D8)