A Phase 1/2, Open-Label, Dose-Escalation/Dose-Expansion, Safety and Tolerability Study of INCB057643 in Subjects With Advanced Malignancies

Phase 1

• Conditions: Subjects with relapsed or refractory advanced or metastatic malignancies.; MedDRA version: 20.0 Level: LLT Classification code 10048683 Term: Advanced cancer System Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2017-002641-29-FR
• Lead Sponsor: Incyte Corporation

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2017-12-21
• Last Update Posted: 30 April 2019

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: Not specified
• Target Recruitment: 420

Inclusion Criteria

• Men and women aged 18 years or older.
• Histologically or cytologically confirmed diagnosis of advanced malignancy:

Part 1 – Monotherapy Dose Escalation:
- TGA: Advanced solid tumor or lymphoma
- TGB: Acute leukemia (any), HR-MDS, MDS/MPN, or MF
- TGC: MM

Part 2 – Monotherapy Dose Expansion:
- TGA:
o Pancreatic adenocarcinoma
o mCRPC
o Breast cancer
o High-grade serous ovarian cancer
o Glioblastoma multiforme
o NHL
o Ewing's sarcoma
o Any solid tumor or lymphoma (except specified above) with any pathway alteration relevant to BET protein signaling, such as MYC pathway activation, which is hypothesized to be susceptible to INCB057643 monotherapy (require approval by medical monitor).
- TGB: AML, HR-MDS, MDS/MPN, or MF
- TGC: Measureable/evaluable MM, defined as one or more of the following:
o Serum M-protein = 0.5 g/dL
o Urine M-protein = 200 mg/24 h
o Serum free light chain (FLC): Involved FLC level = 10 mg/dL provided serum FLC ratio is abnormal

Part 3 – Combination Dose Escalation (C-ES):
- C-ES-TGA: any solid tumor for which treatment with gemcitabine is relevant.
- C-ES-TGB: any solid tumor for which treatment with paclitaxel is relevant.
- C-ES-TGC (conducted in the United States only): any solid tumor for which treatment with rucaparib is relevant.
- C-ES-TGD: any mCRPC subjects eligible to receive abiraterone plus prednisone.
- C-ES-TGE (conducted in the United States only): any MF subjects currently receiving ruxolitinib with an inadequate response.
- C-ES-TGF: any AML and HR-MDS subjects eligible to receive azacitidine.

Part 4 Combination Dose Expansion (C-EX):
- C-EX-TGA (conducted in the United States only): any BRCA wild type platinum-resistant mHGSOC (epithelial ovarian/fallopian tube/primary peritoneal cancer) subjects eligible to receive rucaparib.
o Platinum-resistant disease is defined by disease progression within 6 months of completing platinum-based therapy.
o Known BRCA wild type by a validated assay before consenting.
o Subjects must be poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor naive or have had a clinical response (complete response or partial response) to a prior PARP inhibitor and progressed and have a BRCA status that was shown to be BRCA wild type at the time of consent.
- C-EX-TGB: any mCRPC subjects who have progressed on first-line enzalutamide for metastatic disease and who are eligible to receive abiraterone plus prednisone (chemotherapy treatment naive); OR any mCRPC who have demonstrated PSA progression with or without radiologic progression while being treated with abiraterone plus prednisone and who are clinically stable and will remain on abiraterone plus prednisone (prior chemotherapy is allowed).
o Progression is defined by the Prostate Cancer Working Group 3 (PCWG3) Guidelines (blood-based PSA or imaging [nodes, viscera

Exclusion Criteria

• Inadequate bone marrow function
• Inadequate organ function demonstrated by any of the following, unless due to the underlying disease and approved by the medical monitor:
- All Parts: Total bilirubin > 1.5 × upper limit of normal (ULN). Total bilirubin > 1.5 × ULN is acceptable if direct bilirubin = 1.2 × ULN or with a diagnosis of Gilbert's syndrome.
- Parts 1 and 3: Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 1.5 × ULN.
- Parts 2 and 4: AST and ALT > 2.5 × ULN or > 5 × ULN for subjects with liver metastases.
- All Parts: Creatinine clearance < 50 mL/min based on Cockroft-Gault formula or 24-hour urinalysis (< 30 mL/min for MM).
- All Parts: Alkaline phosphatase (ALP) = 2.5 × ULN.
o Subjects with 1) bone metastases AND 2) no hepatic parenchymal metastases on screening radiographic examinations may enroll if ALP is = 5 × ULN. Subjects with 1) bone metastases AND 2) hepatic parenchymal metastases on screening radiographic examinations may enroll if ALP is = 5 × ULN only with medical monitor approval.
• Receipt of anticancer medications or investigational drugs within the following intervals before the first administration of study drug, unless with medical monitor approval:
- < 5 half-lives or 14 days, whichever is longer, for any investigational agent.
- < 5 half-lives for all other chemotherapy or targeted small molecule anticancer medications.
- < 6 weeks for mitomycin-C or nitrosoureas.
- < 4 weeks for immunotherapy or antibody therapy.
- The following medications are allowed:
o Subjects with mCRPC may be maintained on androgen deprivation, chemical or surgical, at the discretion of the investigator, with a castrate level of testosterone documented (< 50 ng/dL) during the screening period and while on study.
o Low-dose corticosteroids (prednisone or the equivalent = 10 mg per day) may be administered. Use of inhaled or topical steroids and prophylactic corticosteroids for radiographic procedures is permitted.
o For hematologic malignancies: Hydroxyurea for controlling proliferative disease may be administered. Hydroxyurea should not be used within at least 48 hours before and on the day of the PD biomarker sample collection (bone marrow and blood) or during or 72 hours before or after azacitidine administration.
o For Parts 1 and 2/TGC: Receipt of less than 160 mg dexamethasone within 14 days before receiving the first dose of study drug is allowed.
o Denosumab and zoledronic acid are permitted to treat cancer-related bone diseases.
• 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, or have received immunosuppressive therapy following allogeneic transplant within 2 weeks of Cycle 1 Day 1.
• 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.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified