Primary objectives:* Part 1: To evaluate the safety and tolerability and determine the recommended dose(s) of INCB059872 for further study in advancedmalignancies.* Part 2: To further evaluate the safety and tolerability of INCB059872 for further…
ID
Source
Brief title
Condition
- Leukaemias
- Miscellaneous and site unspecified neoplasms malignant and unspecified
- Respiratory tract neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* 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.
Secondary outcome
* 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/MDS: ORR, defined as the proportion of subjects who achieve CR or CRi per
the International Working Group Response Criteria for Acute Myeloid Leukemia or
the International Working Group Response Criteria for MDS, as applicable.
* PK parameters of INCB059872 in plasma: Cmax, Tmax, Cmin, AUC0-t, t*, and Cl/F.
Exploratory Endpoints:
* Parts 1 and 2:
* Efficacy measured by
* Solid tumor, AML, and MDS: Duration of response, progression-free survival,
and overall survival.
* MF: Change and percentage change in spleen volume reduction (SVR) as measured
by MRI (CT scan in subjects who are not a candidate for MRI or when MRI is not
readily available) at Week 24 when compared with baseline.
* Parts 3 and 4:
* Efficacy measured by duration of response, progression-free survival, and
overall survival in SCLC and AML subjects.
* Assessment of the baseline level and changes in biomarkers and their
correlation to INCB059872 treatment, including the following:
* Peripheral blood cell population or expression profile.
* Circulating proteins associated with differentiation, inflammation, immunity,
metabolism, or tumor presence.
* Assessment of biomarkers in tumor tissues to predict the response to
INCB059872 treatment.
* MF: Symptom burden in subjects with MF as assessed using the modified
Myeloproliferative Neoplasm-Symptom Assessment Form diary and Patient Global
Impression of Change.
Background summary
INCB059872 is a covalent flaven adenine dinucleotide (FAD)-directed inhibitor
of lysinespecific demethylase 1 (LSD1) that is proposed for the treatment of
advance malignancies. LSD1 regulates gene expression epigenetically by removing
methylation marks from lysine 4 or
9 of histone H3. Target genes of LSD1 are involved in may biological processes,
including cell growth, survival, differentiation, and stem cell homeostasis.
Studies have shown that deregulated LSD1 activity is associated with human
diseases, including cancer, where overexpression of LSD1 is frequently
associated with poor clinical outcomes.
Lysine Demethylase 1 Inhibitor in Oncology
Epigenetic modifications significantly contribute to the development of various
cancers (Dawson and Kouzarides 2012). Analyses of cancer genomes have revealed
that multiple epigenetic regulatory genes are often overexpressed or mutated in
a variety of cancers (Shen and Laird 2013). One particular epigenetic enzyme
that is associated with human cancer is LSD1, the first discovered histone
demethylase and a key epigenetic regulator of chromatin architecture (Shi et al
2004). Methylated histone marks on H3K4 and H3K9 are coupled with
transcriptional activation and repression, respectively. As part of the
corepressor complex (eg, as corepressor of RE1 silencing transcription factor)
(Stavropoulos et al 2006), LSD1 has been
reported to demethylate H3K4 and represses transcription, whereas LSD1 in the
nuclear hormone receptor complex (eg, androgen receptor) may demethylate H3K9
to activate gene expression (Metzger et al 2005). This suggests that the
substrate specificity of LSD1 can be
determined by associated factors, thereby regulating alternative gene
expression in a contextdependent
manner. In addition to histone proteins, LSD1 demethylates several nonhistone
proteins critical in the regulation of cell growth, differentiation, and
survival pathways. These include p53 (Huang et al 2007), E2F (Kontaki and
Talianidis 2010), STAT3 (Yang et al 2010), Tat (Sakane et al 2011), and myosin
phosphatase target subunit 1 (Cho et al 2011). These findings suggest the
potential for additional oncogenic roles of LSD1 beyond its epigenetic role in
regulating chromatin remodeling. LSD1 also associates with other epigenetic
regulators, such as DNA methyltransferase 1 (DNMT1) (Wang et al 2009) and
histone deacetylase (HDAC) (You et al 2001). These associations augment the
activities of DNMT or HDACs. LSD1 inhibitors may therefore potentiate the
effects of HDAC or DNMT inhibitors (Han et al 2013, Singh et al 2011). LSD1
contributes to a variety of biological processes, including the regulation of
cell proliferation, the epithelial-mesenchymal transition, cellular
transformation of somatic cells, and self-renewal and differentiation, the
latter impacting stem cell biology both in embryonic stem cells and in cancer
stem cells (Chen et al 2012 , Adamo et al 2011). These cancer stem cells may
render cancer cells resistant to conventional therapies, such as chemotherapy
or radiotherapy, and promote tumor recurrence after treatment (Beck and
Blanpain 2013). In this regard, LSD1 functions in maintaining an
undifferentiated tumor initiating or cancer stem cell phenotype in a spectrum
of cancers (Wang et al 2011, Zhang et al 2013). Notably, acute myeloid leukemia
(AML) cells retain a less differentiated stem cell*like phenotype or leukemia
stem cell (LSC) potential. Genome-wide gene expression analyses have revealed
that LSD1 regulates a subset of genes involved in multiple oncogenic programs
to maintain the LSC phenotype in AML, and inhibition of LSD1 has demonstrated
therapeutic benefit in preclinical models of murine and human AML (Harris et al
2012, Schenk et al 2012). A variety of additional hematologic cancers also
overexpress LSD1, including significant subsets of high-grade B-cell and T-cell
non- Hodgkin's lymphomas and Hodgkin's lymphomas (Niebel et al 2014), although
the therapeutic benefit of LSD1 inhibition in these cancers has not yet been
evaluated.
In addition to hematologic malignancies, overexpression of LSD1 is frequently
observed in many types of solid tumors, and its expression is associated with a
more clinically aggressive phenotype and poor prognostic outcome. Cancers in
which overexpression of LSD1 has been documented include bladder cancer (Hayami
et al 2011), small cell lung cancer (SCLC) (Mohammad et al 2015), non-SCLC (Lv
et al 2012), breast cancer (Lim et al 2010), ovarian cancer (Konovalov and
Garcia-Bassets 2013), glioma (Sareddy et al 2013), colorectal cancer (Hayami et
al 2011, Ding et al 2013), a variety of sarcomas (Bennani-Baiti et al 2012),
neuroblastoma (Schulte et al 2009), prostate cancer (Suikki et al 2010),
esophageal squamous cell cancer (Yu et al 2013), papillary thyroid cancer (Kong
et al 2013), and Ewing sarcoma (Sankar et al 2014). In these studies, either
genetic knockdown of LSD1 expression or treatment with small-molecule
inhibitors of LSD1 resulted in decreased cancer cell proliferation and/or
induction of apoptosis both in vitro and in vivo. These findings suggest a
potential therapeutic benefit of LSD1 inhibitors in a broad range of cancers
beyond AML.
Study Rationale
Cancer has several common characteristic that can be observed across numerous
tumor types.
One common characteristic is the uncontrolled growth and survival of cells and
their ability to become invasive throughout the body. LSD1 contributes to tumor
development by altering epigenetic marks on histones and nonhistone proteins.
Accumulating data have validated that either genetic depletion or
pharmacological inhibition of LSD1 normalizes oncogenic and cancer stem
cell*like patterns of gene expression, thereby inducing differentiation
programs, decreasing cell proliferation, and promoting apoptosis in cancer
cells (Harris et al 2012, Schenk et al 2012). Therefore, LSD1 inhibitors have
the potential to be effective treatments for human cancers with aberrant LSD1
activation.
Study objective
Primary objectives:
* 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.
Secondary objectives:
* 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.
Exploratory Objectives:
* Parts 1 and 2: To further evaluate the efficacy of INCB059872 as a
monotherapy in subjects with advanced malignancies.
* Parts 3 and 4: To further evaluate the efficacy of INCB059872 in combination
with other therapies in subjects with advanced malignancies.
* To assess the pharmacodynamics (PD) of INCB059872 and characterize the impact
on biomarkers in peripheral blood and tumor tissue.
* To explore potential predictive biomarkers to identify subgroups that would
benefit most from INCB059872.
* To evaluate preliminary efficacy of INCB059872 with respect to myelofibrosis
(MF) symptoms.
Study design
This is an open-label, dose-escalation/dose-expansion study of the
lysine-specific demethylase 1 (LSD1) inhibitor INCB059872 as a monotherapy and
combination therapy in subjects with advanced malignancies. Subjects will
receive INCB059872 doses once every other day (QOD) on a 28-day continuous
therapy schedule; if QOD is well-tolerated, the next dose may be administered
at a different dosing regimen (ie, once daily [QD]) but will not exceed the
100% dose escalation for a total daily dose. The study will be conducted in 4
parts: Parts 1 and 2 will evaluate INCB059872 as monotherapy, with Part 1 for
dose escalation and Part 2 for dose expansion, and Parts 3 and 4 will evaluate
INCB059872 in combination with select therapies, with Part 3 for combination
dose escalation and Part 4 for combination dose expansion. Part 1 (monotherapy
dose escalation) will determine the starting dose(s) of INCB059872 for dose
expansion, based on maximum tolerated dose (MTD). The recommended dose(s) will
be taken forward into Part 2 (monotherapy dose expansion). It is important to
note that there may be a different MTD in different treatment groups. The
initiation of Part 2 will be based on further review of the ongoing clinical
study and preclinical data of INCB059872 and information from literature. Part
3 (dose escalation of INCB059872 in combination therapy) will be initiated
after the MTD in Part 1 is determined. Part 4 (dose expansion of INCB059872 in
combination therapy) will explore the dose(s) confirmed in Part 3 and the
dose(s) may be different based on combination therapy and/or tumor type.
Intervention
INCB059872 will be self-administered orally QOD on a 28-day cycle. In each
cycle of the QOD dosing schedule, subjects should receive 14 doses of
INCB059872. Tablets will be available in 1 mg strength. The initial starting
dose for Part 1 will be 2 mg. For QOD administration, if a dose is missed by
more than 24 hours, the subject should skip the dose and take the next
scheduled dose at the usual time. INCB059872 tablet should be taken on an empty
stomach if possible (refrain from food consumption during the period 2 hours
before and 1 hour after taking INCB059872). For subjects participating in the
food-effect portion of the study in Part 2, Expansion Cohort B1, a high-fat,
high-calorie meal will be consumed within 30 minutes before taking INCB059872
on Cycle 2 Day 1. Alternative dosing regimens (ie, once daily) may be explored
based on emerging PK/PD and safety
data.
Study burden and risks
Additional visits to the hospital, having additional physical tests including
hepatitis blood test. Additional imaging and biopsies.
Possible side effects from blood draws or biopsies are fainting, bruising,
soreness, and tenderness at the needle site and on rare occasions, infection.
Rash or minor irritation of the skin from ECG pads. Risks of bone marrow
biopsy include pain, redness, swelling, bruising, excessive bleeding,
particularly in people with low platelets, infection, especially in people with
weakened immune systems, long-lasting discomfort at the biopsy site and, if
breastbone is chosen as the biopsy site, penetration of the breastbone
(sternum) during sternal aspirations, which may cause heart or lung problems
and possible need for anesthesia.
Riverbridge House Guildford Road
KT22 9AD KT22 9AD
GB
Riverbridge House Guildford Road
KT22 9AD KT22 9AD
GB
Listed location countries
Age
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: Newly diagnosed, treatment-naive AML, or MDS who are
unfit to tolerate standard intensive chemotherapy at study entry and who are
eligible to receive azacitidine as first-line therapy for the disease under
study.
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 diffusing capacity of the lungs for carbon monoxide*
65% or FEVI * 65%, or dyspnea at rest or requiring oxygen
* Any other comorbidity that the physician judges to be incompatible with
intensive chemotherapy
OR
Subjects with newly diagnosed, treatment-naïve, IPSS-R intermediate or higher
risk disease MDS who have at least 5% bone marrow blasts, who are unfit to
tolerate standard intensive chemotherapy at study entry and who are eligible to
receive azacitidine as first-line therapy for the disease under study.
The following treatments for prior lower risk MDS are acceptable:
Revlimid®, low-dose cytarabine, and growth factors.
* 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
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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR201700171028-NL |
| CCMO | NL62333.056.17 |
| Other | Unknown for now |