liposarcoma

Phase Ib: To determine the MTD and/or RP2D of HDM201 in combination with LEE011 in patients with liposarcoma using two different HDM201 dosing schedules. Phase II: To assess anti-tumor activity HDM201 in combination with LEE011 in patients with liposarcoma

HDM201/Ribociclib (LEE011)

HDM201
LEE011

capsule

1mg, 2.5mg, 10mg, 100mg/Capsule
50, 200mg/Capsule

Efficacy assessments
Tumor assessment per RECIST v1.1.

Safety assessments
Incidence and severity of AEs and SAEs, including changes in laboratory
values, vital signs and ECGs.

Other assessments
HDM201 and LEE011 pharmacokinetics assessments. Pharmacodynamics markers in blood and tumor.
Genetic alterations in cancer related genes found in tumor to evaluate their relationship with clinical outcomes.

Patients eligible for inclusion in this study have to meet all of the following
criteria:
1. Written informed consent obtained prior to any screening procedures
(unless an assessment was done as part of the standard of care).
2. Patients (male or female) ≥ 20 years of age.
3. Patients with histologically documented, locally advanced or metastatic
WD/DD LPS who have received at least one prior systemic therapy.
4. Patients with radiologic progression, defined by RECIST v.1.1, occurring
while on/or within 6 months after last systemic treatment, prior to
enrollment.
5. Patients must have disease that can be evaluated by RECIST v1.1;
measurable disease is required for patients enrolled in the Phase II.
6. ECOG performance status of 0-1.
7. Patients must be suitable and willing to undergo baseline biopsy
according to treating institution’s own guidelines and requirements for
such procedure, unless inaccessible disease and approved by Novartis.

Patients eligible for this study must not meet any of the following criteria:
1. Prior treatment with compounds with the same mode of action, i.e.
p53:HDM2 inhibitors or CDK4/6 inhibitors.
2. Patients with TP53 mutated tumors, if the TP53 molecular status is
known as a result of previous testing.
3. Patients with symptomatic central nervous system (CNS) metastases who
are neurologically unstable or require increasing doses of steroids or
local CNS-directed therapy (such as radiotherapy, surgery or intrathecal
chemotherapy) to control their CNS disease.
Note: Patients with controlled CNS metastases, or asymptomatic CNS
metastases that do not require local antineoplastic therapy, such as
radiotherapy, surgery or intrathecal chemotherapy, may be permitted to
participate in this trial after discussion with the sponsor.
4. Concurrent other malignancy. Exceptions to this exclusion criteria
include: adequately treated basal cell or squamous cell skin cancer; in
situ carcinoma of the cervix, treated curatively and without evidence of
recurrence for at least one year prior to signing the main ICF; or other
solid tumor treated curatively, and without evidence of recurrence for at
least one year prior to study entry.
5. Impaired cardiac function or any clinically significant cardiac disease,
including any of the following:
• Clinically significant heart disease such as cardiac heart failure
(CHF) requiring treatment (NYHA grade ≥ 2), unstable angina
pectoris or myocardial infarction within the past 3 months, or left
ventricular ejection fraction (LVEF) < 50% or less than the
institution lower limit of normal as determined by multiple gated
acquisition scan (MUGA) or echocardiogram (ECHO).
• QT corrected with Fridericia’s (QTcF) >450 ms screening ECG or
congenital long QT syndrome or family history of unexpected sudden
cardiac death.
• Any other clinically significant heart disease such as angina
pectoris, unstable arrhythmia, symptomatic resting bradycardia,
right bundle branch block, bifascicular block, or any heart
disease that requires the use of a cardiac pacemaker ≤ 3 months
prior to starting study drug.
6. Symptomatic history of thromboembolic or cerebrovascular events
within the last 3 months, including transient ischemic attack,
cerebrovascular accident, deep vein thrombosis, or pulmonary embolism.
7. Current diagnosis of acute or chronic pancreatitis.
8. Impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of study drugs (e.g., ulcerative diseases,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small
bowel resection that requires nutritional support).
9. Presence of ≥ CTCAE grade 2 toxicity (except alopecia of any grade)
due to prior cancer therapy, according to the National Cancer Institute
Common Terminology Criteria for Adverse Events (NCI-CTCAE,
version 4.03).
10. Previous therapy that precludes enrollment:
• Prior radiation therapy that included > 30% of the bone marrow
reserve within 2 weeks of treatment start, (i.e. limited local radiation
therapy for palliative purposes is permissible in the 6 week window).
• Chemotherapy, or any continuous or intermittent small molecule
therapeutics within ≤ 2 weeks (6 weeks for nitrosourea, mitomycinC) prior to starting study treatment or absence of recovery from
clinically significant side effects of such therapy.
• Biological therapy (e.g. antibodies) within 2 weeks or absence of
recovery from side effects of such therapy or 5 half-lives, whichever
is shorter, prior to start of study treatment.
• Treatment in a prior investigational study within 2 weeks prior to
start of study treatment.
• Major surgery within 2 weeks of the first dose of study drug
(insertion of a central venous access device, and insertion of a
feeding tube are not considered major surgery).
11. Patients who are currently receiving treatment with herbal or drug
medications that meet one of the following criteria and cannot be
discontinued at least 5 days prior to the start of treatment with HDM201
and LEE011 and for the duration of the study (unless specified
otherwise):
All regimens:
 Moderate or strong inhibitors or inducers of CYP3A4/5.
 Substrates of CYP3A4/5 with a narrow therapeutic index (NTI).
 Medications with a known risk of prolonging the QT interval or
inducing Torsades de Pointes.
In addition, for regimen 4 and 5 (HDM201 administered once every 3 or
4 weeks):
 Substrates of CYP2C19 with NTI (24 hr prior to and 1 week after
each dosing of HDM201).
 Substrates of OATP1B1 (24 hr prior to and 1 week after each dosing
of HDM201).
• P-gp substrates (4 hr pre and post HDM201 administration)
12. Patients with the following laboratory values during screening:
Hematology (transfusion before the study start to reach inclusion criteria
is not acceptable)
• Absolute neutrophil count (ANC) < 1.5 x 109
/L
• Platelet count < 100 x 109
/L
• Hemoglobin (Hb) < 9 g/dL
Biochemistry
• Serum creatinine > 1.5 x ULN
• Total bilirubin > 1.5 x ULN, except for patients with known Gilbert
syndrome, who are excluded if total bilirubin > 3.0 x ULN or direct
bilirubin > 1.5 x ULN.
• Alanine aminotransferase (ALT) > 3 x ULN, except for patients
that have tumor involvement of the liver, who are excluded if >
5 x ULN
• Aspartate aminotransferase (AST) > 3 x ULN, except for patients that
have tumor involvement of the liver, who are excluded if > 5 x ULN
• Potassium, magnesium or calcium abnormality > CTCAE grade 1
(despite oral supplementation)
13. Known Human Immunodeficiency Virus (HIV) infection and/or active
Hepatitis B or Hepatitis C infection (NB: testing for any of the infections
is not mandatory).
14. Any severe, acute, or chronic medical or psychiatric condition or
laboratory abnormality that would increase the risk associated with study
participation or study treatment administration or that may interfere with
the interpretation of study results and, in the judgment of the investigator,
would make the patient inappropriate for the study.
15. Patients treated with growth factors targeting the myeloid lineage (e.g. GCSF, GM-CSF, M-CSF) within 2 weeks of starting study treatment.
Growth factors targeting the erythroid lineage (e.g. Erythropoietin,
darbepoetin and Erythropoietin-biosimilar) are allowed as long as they
have been initiated at least 2 weeks prior to study treatment.
16. Pregnant or nursing (lactating) women, where pregnancy is defined as
the state of a female after conception and until the termination of
gestation, confirmed by a positive hCG laboratory test.
17. Women of child-bearing potential, defined as all women physiologically
capable of becoming pregnant, unless they are using highly effective
methods of contraception during dosing and for up to 21 days after study
treatment discontinuation. Highly effective contraception methods
include:
• Total abstinence (when this is in line with the preferred and usual
lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are not
acceptable methods of contraception.
• Female sterilization (have had surgical bilateral oophorectomy with
or without hysterectomy) or tubal ligation at least six weeks before
taking study treatment. In case of oophorectomy alone, only when the
reproductive status of the woman has been confirmed by follow-up
hormone level assessment.
• Male sterilization (at least 6 months prior to screening). For female
subjects on the study the vasectomized male partner should be the
sole partner for that subject.
• Combination of any two of the following (a+b or a+c, or b+c):
a. Use of oral, injected or implanted hormonal methods of
contraception or other forms of hormonal contraception that have
comparable efficacy (failure rate <1%), for example hormone
vaginal ring or transdermal hormone contraception.
b. Placement of an intrauterine device (IUD) or intrauterine system
(IUS).
c. Barrier methods of contraception: Condom or Occlusive cap
(diaphragm or cervical/vault caps) with spermicidal
foam/gel/film/cream/vaginal suppository.
In case of use of oral contraception women should have been stable on
the same pill for a minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing
potential if they have had 12 months of natural (spontaneous)
amenorrhea with an appropriate clinical profile (e.g. age appropriate,
history of vasomotor symptoms) or have had surgical bilateral
oophorectomy (with or without hysterectomy) or tubal ligation at least
six weeks ago. In the case of follow-up hormone level assessment is she
considered not of child bearing potential.
18. Sexually active males unless they use a condom during intercourse while
taking drug and for 21 days after stopping study medication and should
not father a child in this period. A condom is required to be used also by
vasectomized men in order to prevent delivery of the drug via seminal
fluid.