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

Incyte

Status and phase: Terminated; Phase 2; Phase 1

Conditions: Solid Tumors

Treatments: Drug: Abiraterone; Drug: Gemcitabine; Drug: Azacitidine; Drug: Paclitaxel; Drug: INCB057643; Drug: Ruxolitinib; Drug: Rucaparib

Study type: Interventional

Funder types: Industry

Identifiers

NCT02711137

INCB 57643-101

2017-002641-29 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 137 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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137 participants in 14 patient groups

Part1/Treatment Group A : 8mg QD INCB057643

Experimental group

Description:

Initial cohort dose of INCB057643 monotherapy at the protocol specified starting dose in the TGA. Treatment Group A included solid tumors and lymphoma

Treatment:

Drug: INCB057643

Part1/Treatment Group A : 12mg QD INCB057643

Experimental group

Description:

Initial cohort dose of INCB057643 monotherapy at the protocol specified starting dose in the TGA. Treatment Group A included solid tumors and lymphoma

Treatment:

Drug: INCB057643

Part1/Treatment Group A : 16mg QD INCB057643

Experimental group

Description:

Initial cohort dose of INCB057643 monotherapy at the protocol specified starting dose in the TGA. Treatment Group A included solid tumors and lymphoma

Treatment:

Drug: INCB057643

Part1/Treatment Group B : 8mg QD INCB057643

Experimental group

Description:

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

Treatment:

Drug: INCB057643

Part1/Treatment Group B : 12mg QD INCB057643

Experimental group

Description:

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.

Treatment:

Drug: INCB057643

Part1/Treatment Group C : 8mg QD INCB057643

Experimental group

Description:

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

Treatment:

Drug: INCB057643

Part2/Treatment Group A : 12 mg INCB057643 Expansion Cohort

Experimental group

Description:

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.

Treatment:

Drug: INCB057643

Part2/Treatment Group B : 12 mg INCB057643 Expansion Cohort

Experimental group

Description:

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.

Treatment:

Drug: INCB057643

Part3/Treatment Group A : 8 mg INCB057643 + Gemcitabine 1000mg

Experimental group

Description:

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

Treatment:

Drug: INCB057643

Drug: Gemcitabine

Part3/Treatment Group B : 8 mg INCB057643 + Paclitaxel 80mg

Experimental group

Description:

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.

Treatment:

Drug: INCB057643

Drug: Paclitaxel

Part3/Treatment Group C : 8 mg INCB057643 + Rucaparib 600mg

Experimental group

Description:

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.

Treatment:

Drug: Rucaparib

Drug: INCB057643

Part3/Treatment Group D : 8 mg INCB057643 + Abir +Predni

Experimental group

Description:

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

Treatment:

Drug: INCB057643

Drug: Abiraterone

Part3/Treatment Group E : 8 mg INCB057643 + Ruxolitinib 20mg

Experimental group

Description:

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.

Treatment:

Drug: Ruxolitinib

Drug: INCB057643

Part3/Treatment Group F : 8 mg INCB057643 + Azacitidine 75mg

Experimental group

Description:

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

Treatment:

Drug: INCB057643

Drug: Azacitidine