A Phase 1, Multi-center, Open-label, Dose Escalation Study to Evaluate Safety, Tolerability,
Pharmacokinetics, and Clinical Activity of Orally Administered LP-108 in Subjects with
Relapsed or Refractory Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia
(CMML), or Acute Myeloid Leukemia (AML)
The primary objectives are to assess the safety and tolerability profile, determine the
maximum tolerated dose (MTD), and/or the recommended Phase 2 dose (RP2D) of LP-108
administered daily as a single agent dosed orally in adult subjects with relapsed/refractory
MDS/CMML/AML; to characterize the pharmacokinetics (PK) profile of LP-108 in adult subjects
with relapsed/refractory MDS/CMML/AML.
Secondary objectives are to evaluate preliminary efficacy regarding the effect of LP-108
(monotherapy or combination therapy) on objective response rate (ORR) for AML (including rate
of complete remission [CR]with or without minimal residual disease [MRD], CR with incomplete
platelet recovery [CRp], CR with incomplete blood count recovery [CRi], morphologic
leukemia-free state (MLFS), and partial remission [PR]), and ORR for MDS (CR with or without
persistent dysplasia, PR, and marrow CR), and ORR for CMML (including CR, complete
cytogenetic remission, PR, marrow response, and clinical benefit), progression-free survival
(PFS), duration of response (DOR) (for all subjects achieving an objective response),
event-free survival (EFS), and overall survival (OS) for AML, MDS and CMML.
Exploratory objectives are to explore blood borne biomarkers that may influence development
of hematological malignancy and/or response to treatment (where response is defined broadly
to include efficacy, tolerability, or safety); to study genes/genetic variation that may
influence PK or response (ie, absorption, distribution, metabolism, excretion, safety,
tolerability, and efficacy) to treatment, and/or genetic drivers of hematological malignancy
such as AML, MDS, and CMML; to explore the relationship between PK and selected endpoints
(ie, blood borne biomarkers), where deemed appropriate.
Once the MTD is declared and the RP2D is established, additional subjects will be enrolled in
a cohort expansion phase (Phase 1b) that might adapt combination therapies with other agents
such as hypomethylating agents (HMA), and in the United States and ex-US sites.
A subject will be eligible for study participation if he/she meets the following criteria:
1. Male or female subjects, ≥ 18 years of age at the time of Screening.
2. Eligible subject must have an advanced hematologic malignancy including:
- MDS with refractory anemia with excess blasts (RAEB; subtype RAEB-1 or RAEB-2) as
defined by World Health Organization (WHO) 2016 and/or MDS with high- or very
high-risk per the Revised International Prognostic Scoring System (IPSS-R)
(Greenberg et al. 2012) (Appendix 8) that is relapsed or refractory to prior
therapy for MDS, or the subject is intolerant to established therapy known to
provide clinical benefit for their condition (ie, subjects must not be candidates
for regimens known to provide clinical benefit), according to the treating
physician and with approval of the Medical Monitor;
- Relapsed and/or primary refractory AML as defined by WHO 2016 revised criteria;
- CMML (with ≥ 5% blasts in bone marrow) as defined by WHO that is relapsed and/or
refractory and that, in the opinion of the Investigator, requires treatment or
that has exhausted treatment options that would be considered standard of care.
3. White blood cell (WBC) count ≤ 25 × 109 cells/L at the time of enrollment (hydroxyurea
is allowed to control white count prior to and during therapy).
4. Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2.
5. Predicted life expectancy of ≥ 3 months.
6. Subject must have adequate coagulation, renal, and hepatic function, per laboratory
reference ranges at Screening as follows:
- Activated partial thromboplastin time and prothrombin time not to exceed 1.5 ×
the upper limit of normal (ULN);
- Calculated creatinine clearance (Cr Cl) ≥ 60 mL/min using 24-hour CrCl OR
modified Cockcroft-Gault formula (using ideal body mass [IBM] instead of mass):
CrCl = (140-Age) x IBM (kg) x [1.0 if Male, 0.85 if Female] 72 x Serum Creatinine
Or, if serum creatinine is in μmol/L:
CrCl = (140-Age) x IBM (kg) x [1.23 if Male, 1.04 if Female] Serum Creatinine (μmol/L)
IBM should be calculated:
IBM = [(height cm - 154) x 0.9] + (50 if Male, 45.5 if Female)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 ×ULN;
bilirubin ≤ 1.5 × ULN (except subjects with Gilbert's Syndrome, who may have a
bilirubin > 1.5 × ULN, per discussion between the Investigator and the Medical
7. Adequate cardiac function defined as: shortening fraction of ≥ 27% by echocardiogram,
or ejection fraction of ≥ 50% by echocardiogram or radionuclide angiogram (nuclear
8. Females of childbearing potential and non-sterile males must practice at least 1 of
the following methods of birth control with their partner(s) throughout the study and
for 90 days after discontinuing study drug:
- Total abstinence from sexual intercourse as the preferred lifestyle of the
subject; periodic abstinence is not acceptable;
- Surgically sterile partner(s) by vasectomy, bilateral orchiectomy, bilateral
tubal ligation, bilateral oophorectomy or hysterectomy
- Intrauterine device
- Double-barrier method including contraceptive sponge, diaphragm or cervical cap
with spermicidal jellies or cream and a condom
- Hormonal contraceptives (oral, parenteral, vaginal ring or transdermal) for at
least 1 month prior to study drug administration.
9. Females of childbearing potential (ie, non-postmenopausal for at least 2 years or
surgically sterile) must have a negative pregnancy result as follows:
- At Screening on a serum sample obtained within 14 days prior to the first study
drug administration, and
- Prior to dosing on a urine or serum sample obtained on the first day of study
drug administration if it has been > 7 days since obtaining the serum pregnancy
test results in Screening.
10. Male subjects must refrain from sperm donation, from initial study drug administration
until 90 days after the last dose of study drug.
11. Subject must be able to understand and voluntarily sign and date an informed consent,
approved by an IEC/IRB, prior to any protocol-related procedures.
A subject will not be eligible for study participation if he/she meets any of the following
1. Subjects with known hypersensitivity to any of the components of LP-108.
2. Subjects with a diagnosis of promyelocytic leukemia/retinoic acid receptor alpha
(PML-RARA) or non-PML-RARA rearranged acute promyelocytic leukemia (APL).
3. Subjects who have undergone hematopoietic stem cell transplantation (HSCT) within 60
days of the first dose of LP-108, or subjects on immunosuppressive therapy post-HSCT
at the time of Screening, or with clinically significant graft-versus-host disease
(GVHD). (Subjects in relapse after allogeneic transplantation must be off calcineurin
inhibitors for at least 4 weeks. The use of topical steroids and/or up to 20 mg/day
prednisone or equivalent systemic steroids for ongoing GVHD is permitted).
4. Subject has received any of the following therapies within 28 days or 5 half-lives
(whichever is longer) prior to the first dose of study drug, or has not recovered to
less than Grade 1 clinically significant adverse effect(s)/toxicity(s) of the previous
- Any anti-cancer therapy including chemotherapy, hormonal therapy, biologic or
immunotherapy, targeted small molecule agents, etc. (corticosteroid therapy < 20
mg/day prednisone equivalent for < 14 days at time of study treatment and
hydroxyurea cytoreduction therapy according to institutional guidelines to treat
disease associated symptoms are permitted).
- Any investigational therapy.
5. Subject has received the following medications or therapies within 7 days prior to the
first dose of study drug:
- Cytochrome P450, family 3, subfamily A (CYP3A) and CYP2D6, CYP1A2, CYP2C19 strong
inhibitors (see Appendix 10 for strong inhibitors). In Phase 1b of this trial,
the criterion regarding CYP3A4 strong inhibitors will be removed at time of
amendment of the trial when Phase 1b is to be initiated. The amendment will
include recommendations on concomitant dosing of LP-108 and strong CYP3A4
inhibitors such as azole antifungal agents, PK monitoring for the initial weeks
on study, as well as closer safety monitoring for subjects.
- Strong CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St. John's
- Inhibitors of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP)
(see Appendix 11 for P gp and BCRP inhibitors).
- Sensitive CYP2C8 substrates (such as montelukast, pioglitazone, repaglinide,
rosiglitazone) or CYP2C8 substrates with a narrow therapeutic index (eg,
amiodarone, fosphenytoin, paclitaxel, penprocoumon, phenytoin).
- Systemic acid reducing agents, including antacids, H-2-receptor antagonists, and
proton pump inhibitors.
6. Subject has consumed grapefruit, grapefruit products, Seville oranges (including
marmalade containing Seville oranges) or Star fruit within 3 days prior to the first
dose of study drug.
7. Subject has a significant history of renal, neurologic, psychiatric, pulmonary,
endocrinologic, metabolic, immunologic, cardiovascular, or hepatic disease that, in
the opinion of the Investigator, would adversely affect his/her participation in this
study. For subjects who have required a surgical intervention for any above diseases
within the past 6 months, a discussion with the Investigator and the Medical Monitor
8. Subject has a cardiovascular disability status of New York Heart Association Class ≥
9. Subject has QTc > 480 ms.
10. Subject has a history of other malignancies other than the eligible hematologic
malignancy within the past 1 year prior to study entry, with the exception of:
- Adequately treated in situ carcinoma of the cervix uteri;
- Basal cell carcinoma of the skin or localized squamous cell carcinoma of the
- Previous malignancy confined and surgically resected (or treated with other
modalities) with curative intent.
11. Subject exhibits evidence of other clinically significant uncontrolled condition(s)
including, but not limited to:
- Uncontrolled systemic infection (bacterial, fungal)
- Known active or poorly controlled of human immunodeficiency virus or active
hepatitis B or C
- Unexplained fever > 38.5°C during the Screening period or on their first day of
study drug administration (at the discretion of the Investigator, if the fever is
considered related to the subject's malignancy may be enrolled).
12. A female subject is pregnant or breast-feeding.
13. Subjects with known dysphagia, short-gut syndrome, gastroparesis, or other conditions
that, in the opinion of the Investigator, may limit the ingestion or gastrointestinal
absorption of drugs administered orally.
14. Subjects who are not amenable to serial bone marrow aspiration/biopsy, peripheral
blood sampling, and urine sampling during the study (the diagnosis and evaluation of
hematologic malignancy can be made by bone marrow core biopsy when an aspiration is
unobtainable and/or is not a part of the standard of care; bone marrow biopsy is
required in case of "dry tap" or unevaluable aspiration usually due to diluted
15. Subjects with known and active central nervous system (CNS) involvement (radiographic
or cytologic) at Screening; subjects with history of CNS involvement who have no
symptoms suggestive of CNS disease and have had at least 2 success lumbar punctures
without cytologic evidence of leukemia may be included after discussion and approval
of Medical Monitor. (Evaluation of cerebrospinal fluid is only required if there is a
clinical suspicion of CNS involvement by leukemia during screening in subjects without
a history of CNS involvement).
16. Subjects with immediate life-threatening, severe complications of leukemia such as
uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated