| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Potential subjects include those with advanced or metastatic malignancies who are ineligible for all therapeutic options that are standard of care or known to confer clinical benefit, or who refuse these treatments. |
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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 |
• Part 1: To evaluate the safety and tolerability and determine the recommended dose(s) of INCB059872 for further study in advanced malignancies.
• Part 2: To further evaluate the safety and tolerability of INCB059872 for further study in advanced malignancies.
• Part 3: To evaluate the safety and tolerability and determine the recommended dose of INCB059872 in combination with other therapies for further study in advanced malignancies.
• Part 4: To further evaluate the safety and tolerability of INCB059872 in combination with other therapies in advanced malignancies. |
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| E.2.2 | Secondary objectives of the trial |
• Parts 1 and 2: To assess preliminary antitumor activity of INCB059872 as a monotherapy in subjects with advanced malignancies.
• Parts 3 and 4: To assess preliminary antitumor activity of INCB059872 in combination with other therapies in subjects with advanced malignancies.
• To evaluate the pharmacokinetics (PK) of INCB059872 and assess the effect of food (Treatment Group [TG] B1 only) on the PK of INCB059872. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female subjects, age 18 years or older.
2. Presence of measurable disease that has been confirmed by histology or cytology. Myelofibrosis subjects must have palpable spleen of ≥ 5 cm below the left subcostal margin on physical examination at the screening visit.
3. The following malignancy types will be included in each of the treatment groups:
Part 1 (Dose Escalation)
Treatment Group A: AML or myelodysplastic syndrome (MDS)
Treatment Group B: SCLC (other solid tumors, eg, endocrine tumors, are allowed with medical monitor approval)
Part 2 (Dose Expansion)
Treatment Group A1: Relapsed/refractory AML or MDS
Treatment Group A2: MF (PMF, PPV-MF, and PET-MF)
Treatment Group B1: SCLC
Treatment Group B2: Ewing's sarcoma and poorly differentiated neuroendocrine tumors
Parts 3 and 4 (Combination Dose Escalation/Expansion)
Treatment Group C/C1: Relapsed/refractory AML
Treatment Group D/D1: Subjects with newly diagnosed, treatment-naive AML who are unfit to tolerate standard intensive chemotherapy at study entry
Treatment Group E/E1: SCLC previously progressed on platinum-based treatment
4. Subjects must meet specific disease and treatment criteria as follows:
− TG A/A1/A2, TG B/B1/B2, C/C1, and TG E/E1: The subject must not be a candidate for potentially curative therapy or standard-of-care approved therapy.
− TG A2: The subjects must have confirmed diagnosis of PMF, PPV-MF, or PET-MF according to revised WHO 2016 criteria.
− TG D/D1: Subjects with newly diagnosed, treatment-naive AML who are unfit to tolerate standard intensive chemotherapy at study entry based on at least 1 of the following criteria:
Age ≥ 75 years old
History of congestive heart failure (CHF) or documented ejection fraction (EF) ≤ 50%
Pulmonary disease with DLCO ≤ 65% or FEVI ≤ 65%, or dyspnea at rest or requiring oxygen
Any other comorbidity that the physician judges to be incompatible with intensive chemotherapy
− TG E/E1: The subjects in TG E must have previously received platinum-based therapy, but additional lines of therapies are allowed. The subjects in TG E1 must not have received more than 1 previous line of therapy for locally advanced or metastatic SCLC. The previous line of therapy must be a platinum-based therapy, and the subjects must have progressed on or after this treatment.
5. Willingness to undergo a pretreatment bone marrow biopsy or aspirate (AML/MDS/MF) during screening (may be waived with medical monitor approval). For subjects with solid malignancies, must have baseline archival tumor specimen available: a tumor block or approximately 15 slides from biopsy or resection of primary tumor or metastasis that are < 2 years old (specimens > 2 years old may be accepted with medical monitor approval).
Please refer to study protocol for further inclusion criteria |
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| E.4 | Principal exclusion criteria |
1. Receipt of anticancer medications, anticancer therapies, or investigational drugs within the following interval before the first administration of study drug (requirement may be waived with medical monitor approval):
a. < 5 half-lives or 14 days, whichever is longer, for any investigational agent
b. < 5 half-lives for all other anticancer medications
c. < 6 weeks for mitomycin-C or nitrosoureas
2. Any unresolved toxicity ≥ Grade 2 from previous anticancer therapy except for stable chronic toxicities (≤ Grade 2) not expected to resolve.
3. All treatment groups: prior receipt of an LSD1 inhibitor therapy. Parts 3 and 4 TG E/E1: prior receipt of anti–programmed cell death-1, anti–programmed death ligand 1, or anti–PD-L2 antibody.
4. Any of the following laboratory results at screening without transfusions and hematopoietic growth factor support in solid tumors (no lower limits in AML and MDS, or in MF with medical monitor approval):
Absolute neutrophil count (× 109/L): < 1.5
Hemoglobin (g/dL): < 9.0
Platelet count (× 109/L): < 100
5. Laboratory and medical history parameters outside Protocol-defined range unless associated with primary malignancy or metastatic disease and with medical monitor approval:
a. Total bilirubin > 1.5 × institutional upper limit of normal (ULN) if no liver metastases or > 3 × ULN in the presence of liver metastases or presence of documented Gilbert syndrome (unconjugated hyperbilirubinemia).
b. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.0 × institutional ULN.
c. Creatinine clearance < 60 mL/min based on the institutional formula.
Please refers to study protocol for further exclusion criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Parts 1 and 2: Safety and tolerability as assessed by monitoring frequency, duration, and severity of adverse events (AEs) through physical examinations, by evaluating changes in vital signs and electrocardiograms (ECGs), and through clinical laboratory blood and urine sample evaluations.
• Parts 3 and 4: Safety and tolerability as assessed by monitoring frequency, duration, and severity of AEs through physical examinations, by evaluating changes in vital signs and ECGs, and through clinical laboratory blood and urine sample evaluations in combinations therapies. |
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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 ECG is performed at the screening, EOT, and safety follow-up visits.
Triplicate ECGs are performed on Cycle 1 Day 1 and Cycle 1 Day 15 at predose and 1, 2, and 6 hours postdose. A triplicate ECG is performed on Cycle 1 Day 8 approximately 24 hours after the last dose on Day 7.
Urine will be collected from each subject at Cycle 1 Day 15 predose and then after administration of INCB059872.
All study and laboratory assessments will be performed as indicated in the schedule of assessments. |
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| E.5.2 | Secondary end point(s) |
• Parts 1 and 2: Tumor response rates in those subjects with measurable disease or spleen volume changes as determined by investigator assessment of response per disease-specific guidelines.
− Solid tumors: Objective response rate (ORR), defined as the percentage of subjects having complete response (CR) or partial response (PR) will be determined by the investigator assessment of radiographic disease assessments per RECIST v1.1.
− Acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS): ORR, defined as the proportion of subjects who achieve CR or complete remission with incomplete hematologic recovery (CRi) per the International Working Group Response Criteria for Acute Myeloid Leukemia or the International Working Group Response Criteria for MDS, as applicable.
− MF: Change and percentage change in spleen volume reduction (SVR) as measured by magnetic resonance imaging (MRI; computed tomography [CT] scan in subjects who are not a candidate for MRI or when MRI is not readily available) at Week 12 when compared with baseline.
• Parts 3 and 4: Tumor response rates in those subjects with measurable disease as determined by investigator assessment of response per disease-specific guidelines.
− Small cell lung cancer (SCLC): ORR, defined as the percentage of subjects having CR or PR will be determined by the investigator assessment of radiographic disease assessments per RECIST v1.1.
− AML: ORR, defined as the proportion of subjects who achieve CR or CRi per the International Working Group Response Criteria for Acute Myeloid Leukemia.
• PK parameters of INCB059872 in plasma: Cmax, Tmax, Cmin, AUC0-t, t½, and Cl/F. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The schedule for disease assessments will be at screening (this will be considered the baseline assessment) for all subjects and then once every 8 weeks throughout the study for solid tumor and once every 4 weeks for AML/MDS/MF.
PK assessments will be performed as indicated in the schedule of assessments. |
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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 | Yes |
| 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 | 4 |
| 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 |
| Netherlands |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| 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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