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 ORR for AML, MDS, CMML, PFS, DOR, and OS
A subject will be eligible for study participation if the subject meets the following
- 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 revised criteria and/or MDS with
high- or very high-risk (risk score > 4.5) per the Revised International
Prognostic Scoring System (IPSS-R) (Greenberg et al. 2012) 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 2016 revised criteria
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.
- Blast count ≤ 30 × 10^9 cells/L at the time of initiating investigational therapy
(hydroxyurea is allowed to control blast count prior to and during therapy).
- Subject must have adequate coagulation, renal, and hepatic function.
- 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
Cockcroft-Gault formula (using actual body weight)
- 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
- Adequate cardiac function defined as: shortening fraction of ≥ 27% by echocardiogram,
or ejection fraction of ≥ 50% by echocardiogram.
A subject will not be eligible for study participation if he/she meets any of the following
- Subjects with a diagnosis of promyelocytic leukemia/retinoic acid receptor alpha
(PML-RARA) or non-PML-RARA rearranged acute promyelocytic leukemia (APL).
- 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).
- Subject has received any of the following therapies within 14 days or 5 half-lives
(whichever is shorter) prior to the first dose of study drug, or has not recovered to
≤ Grade 1 clinically significant adverse effect(s) of the previous therapy:
- 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.
- Subject has received the following medications or therapies within 7 days or 5
half-lives (whichever is shorter) prior to the first dose of study drug:
- Cytochrome P450, family 3, subfamily A (CYP3A4) strong inhibitors (see Appendix
10 for strong CYP3A4 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 CYP3A4 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).
- Subject has baseline prolongation of the corrected QTc > 480 ms (calculated per
Fridericia's formula [QTc = QT/RR (1/3)].
- 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:
- Subject with breast cancer or prostrate cancer on endocrine therapy with stable
- 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
- Subject exhibits evidence of other clinically significant uncontrolled condition(s)
including, but not limited to:
- Uncontrolled systemic infection (bacterial, fungal, viral)
- Known active or poorly controlled human immunodeficiency virus or active
hepatitis B or C infection
- 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).
- 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 successful lumbar punctures
without cytologic evidence of leukemia may be included after discussion and approval
of the 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).
- Subjects with immediate life-threatening, severe complications of leukemia such as
uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated
- Requires ongoing treatment with
- Systemic acid-reducing agents including H-2-receptor antagonists and proton pump
- Sensitive CYP2C8 substrates (such as montelukast, pioglitazone, repaglinide,
rosiglitazone) or CYP2C8 substrates with a narrow therapeutic index (eg,
amiodarone, fosphenytoin, paclitaxel, penprocoumon, phenytoin)