| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with relapsed or refractory advanced or metastatic malignancies. |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10048683 |
| E.1.2 | Term | Advanced cancer |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To assess the safety and tolerability of INCB057643 as monotherapy and in combination with standard of care (SOC) agents in subjects with advanced malignancies.
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the pharmacokinetics (PK) of INCB057643 when administered as monotherapy in the fasted state and in the fed state (food effect; Part 2 only) and when administered in combination with SOC agents in the fasted state.
• To assess the pharmacodynamics (PD) of INCB057643 when administered as monotherapy in subjects with advanced malignancies.
• To evaluate preliminary efficacy of INCB057643 when administered as monotherapy and in combination with SOC agents based on the investigator assessment of response using criteria appropriate for each disease in subjects with advanced malignancies.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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, and bone] at study entry).
o mCRPC subjects must maintain a castrate level of testosterone documented (< 50 ng/dL) during the screening period and while on study.
- C-EX-TGC (conducted in the United States only): any MF subjects currently receiving ruxolitinib with an inadequate response, as defined below:
o Palpable spleen of > 10 cm below the left subcostal margin on physical examination at screening OR
o Palpable splenomegaly of 5 to 10 cm below left subcostal margin on physical examination AND active symptoms of MF at screening as demonstrated by presence of 1 symptom score ≥ 5 or 2 symptom scores ≥ 3 using the Screening Symptom Form.
o MF subjects must be receiving ruxolitinib for ≥ 6 months with a stable dose for ≥ 8 weeks (acceptable doses are 5 to 25 mg BID).
- C-EX-TGD: any AML and HR-MDS subjects eligible to receive azacitidine.
o Confirmed AML or high-risk MDS (International Prognostic Scoring System -2, or high risk) in accordance with WHO diagnostic criteria
o Failure of prior therapy with HMA, defined as one of the following:
Progression to AML
% increase in bone marrow blasts
Relapsed disease after response
At least 4 cycles of treatment without clinical benefit (hematological improvement or better)
Please refer to the protocol for complete list of inclusion criteria |
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| E.4 | Principal 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.
• 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. In Part 3/C-ES-TGE and Part 4/C-EX-TGC, MF subjects may not have had splenic irradiation within 6 months of the first dose of INCB057643.
• Type 1 diabetes or uncontrolled Type 2 diabetes.
- All Parts: HbA1c ≥ 8% (all subjects will have HbA1c test at screening).
- For Parts 1 and 3 only: fasting blood glucose > 160 mg/dL (> 8.9 mmol/L).
• Known human immunodeficiency virus infection (HIV; HIV 1/2 antibodies).
• Evidence of hepatitis B virus or hepatitis C virus infection.
• 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 (eg, evidence of new or enlarging brain metastasis or new neurological symptoms attributable to brain/CNS metastases). Subjects with previously treated and clinically stable brain/CNS metastases and off all corticosteroids for ≥ 2 weeks before Cycle 1 Day 1 are eligible. Primary CNS lymphoma will only be permitted in Part 2/TGA. Subjects with glioblastoma are not subjected to this criterion with medical monitor approval.
Please refer to the protocol for complete list of exclusion criteria |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Safety and tolerability of INCB057643 as monotherapy and in combination with SOC agents as assessed by clinical laboratory assessments, physical examinations, 12-lead electrocardiograms (ECGs), and adverse events (AEs).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Adverse events will be monitored from the time the subject signs the ICF. Subjects will be instructed to report all AEs during the study and will be assessed for the occurrence of AEs throughout the study. A single 12-lead ECG will be performed at each timepoint indicated in the appropriate schedule of assessments. All local laboratory assessments will be performed using standard procedures on the days indicated in the appropriate schedule of assessments. |
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| E.5.2 | Secondary end point(s) |
• Cmax, Tmax, Cmin, AUC0-t, and AUC0-τ of INCB057643 at Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 2 Day 1 (food effect; Part 2 only).
• Pharmacodynamic profile of INCB057643 using a plasma PD assay.
• Objective response rate (ORR) in subjects with measurable or evaluable diseases as determined by the investigator assessment of response using the criteria appropriate for each disease.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Pharmacokinetic assessments will be performed according to the appropriate schedule of assessments.
Efficacy assessments will be performed at screening (this will be considered the baseline disease assessments) and at the intervals defined in the appropriate schedule of assessments throughout the study. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| France |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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