Patient
Inclusion Criteria:
1. ≥18 years of age at the time of consent. 2. Provided signed written ICF and voluntary consent prior to any mandatory
study-specific procedures, sampling, and analyses.
3. Have a histologically or cytologically documented advanced solid tumor that has
relapsed from or is refractory to standard treatment, or for which no standard
treatment is available.
Note: patients with certain tumor types such as those with relatively high
prevalence of DDR gene alterations and/or PTGR1 over expression (e.g., triple
negative breast cancer, lung, prostate, ovarian, pancreatic, bladder, and GBM) may
be preferentially enrolled in Phase 1a.
4. ECOG performance status 0-1 or Karnofsky performance scale >60 for GBM patients.
5. Patients must have measurable disease per RECIST 1.1 or RANO 2.0 criteria as
applicable.
Note: patients without measurable disease may be eligible, following discussion with
the investigator and the sponsor, if the patient presents with non-measurable but
evaluable disease of any size unequivocally attributable to advanced solid tumor.
6. Patients must have life expectancy >3 months.
7. Adequate organ function at screening defined as:
Liver Function.
- - AST, ALT ≤3 x ULN or <5 x ULN in cases of documented liver metastases or
involvement of liver in the disease process.
- - Total serum bilirubin ≤1.5 x ULN or <5 x ULN if secondary to Gilbert's syndrome
or documented liver metastases or involvement of liver in the disease process.
Renal Function.
- - Serum creatinine clearance ≥60 mL/min either measured or calculated using
standard Cockcroft-Gault formula.
- - Serum electrolyte (potassium, calcium, and magnesium) levels within the normal
reference range (may be supplemented according to institutional standard).
Bone Marrow Function:
- - Hemoglobin ≥8 g/dL (The use of transfusion or other intervention to achieve
hemoglobin ≥8 g/dL is acceptable.
For those patients undergoing RBC
transfusion, hemoglobin must be evaluated at least 14 days after the last RBC
transfusion).
- - Platelet count ≥100,000/μL (assessed ≥7 days following last platelet
transfusion in patients with thrombocytopenia requiring platelets).
Blood clotting function:
- - INR and aPTT ≤1.5 x ULN.
Study patients on therapeutic doses of anticoagulation
medication must have INR and/or aPTT ≤ the upper limit of the therapeutic range
for intended use.
8. Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test within 3 days of first dose of LP-184. A woman is of child-bearing
potential unless she:
- - has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy;
- is age ≥60 years and is amenorrhoeic; or.
- - is age <60 years and has been amenorrhoeic for ≥12 months (including no
irregular menses or spotting) in the absence of any medication which induces a
menopausal state and has documented ovarian failure by serum estradiol and
follicle-stimulating hormone levels within the institutional laboratory
postmenopausal range).
9. WOCBP or must agree to use highly effective contraceptive methods and avoid egg
donation during the study treatment and for 6 months after the last dose of LP-184.
10. Men of reproductive potential agree to use highly effective contraceptive methods
and avoid sperm donation during the study treatment and for 3 months after the last
dose of LP-184. A man is of child-producing potential unless he has had a bilateral
vasectomy with documented aspermia or a bilateral orchiectomy.
11. Is willing to provide archived samples (blocks and/or slides) for comprehensive DDR
genomic analyses and/or PTGR1 expression profiling and/or other genomic alterations
if the patient has a PR/CR.
12. Regarding brain metastases, based on screening contrast brain MRI, patients must
have 1of the following:
- - No evidence of brain metastases.
- - Untreated brain metastases not requiring immediate local therapy.
For patients
with untreated CNS lesions >2.0 cm on screening contrast brain MRI, discussion
with and approval from the Medical Monitor is required prior to enrollment.
- - Previously treated brain metastases that are either stable for at least 4 weeks
since last treatment or progressed since prior local CNS therapy and not
requiring immediate re-treatment with local therapy in the opinion of the
investigator.
Patient
Exclusion Criteria:
1. Exposure to anti-cancer therapy within 2 weeks or within at least 5 half-lives of
the anticancer agent whichever is shorter; or 4 weeks from any
biologics/immunotherapies or any investigational therapy prior to the first dose of
LP-184.
Note: Low dose steroids (oral prednisone or equivalent ≤20 mg/day, except patients
with GBM), localized non-CNS radiotherapy, previous hormonal therapy with
luteinizing hormone-releasing hormone agonists for prostate cancer and treatment
with bisphosphonates and RANKL inhibitors are not criteria for exclusion if such
therapy has not been changed within 4 weeks before LP-184 treatment.
2. Any history of retinopathy and/or macular degeneration (without specifications or
grades).
3. Has received radiation within 4 weeks of Cycle 1 Day 1. Unless the tumor at the site
of treatment continues to increase in size after the patient has completed
radiotherapy treatment.
4. Infection requiring antibiotics, antivirals, or antifungals within 1 week prior to
first dose of study drug, unless such infection is adequately controlled (defined as
exhibiting no ongoing signs/symptoms related to the infection and with clinical
improvement). In the case of prophylactic use of these agents, discussion with the
Medical Monitor is required prior to enrollment.
5. Hepatitis B and/or hepatitis C infection (as detected by positive testing for
hepatitis B surface antigen [HbsAg] or antibody to hepatitis C virus with
confirmatory testing) or known seropositivity for or history of active viral
infection with human immunodeficiency virus (HIV).
6. Are pregnant or breastfeeding. (NOTE: breast milk cannot be stored for future use
while the mother is being treated on study).
7. Have clinically significant cardiac disease including:
- - New York Heart Association Class IV heart failure.
- - Myocardial infarction or stroke ≤3 months prior to the first dose of LP-184.
- - Unstable angina within ≤12 weeks prior to the first dose of LP-184 unless the
underlying disease has been corrected by procedural intervention e.g., stent,
bypass.
- - Severe aortic stenosis.
- - Uncontrolled arrhythmia.
Sponsor approval of patients with arrhythmia is
required.
- - QTc >470 ms by Fredericia criteria.
- - Congenital long QT syndrome, or a QT interval corrected by Fridericia's formula
(QTcF) >470 ms (average of triplicate ECGs) at Screening and/or on Cycle 1 Day
1 (pre-dose) except for a documented bundle branch block or unless secondary to
pacemaker.
In the case of a documented bundle branch block or a pacemaker,
discussion with the medical monitor is required prior to enrollment.
8. Have clinically significant AEs that have not returned to baseline or ≤Grade 1 based
on NCI-CTCAE prior to first dose of study drug, unless approved by the sponsor.
Patients with chronic Grade 2 toxicities may be eligible per the discretion of the
investigator and sponsor (e.g., Grade 2 chemotherapy-induced neuropathy, alopecia,
or hypothyroidism from prior immunotherapy treatment).
9. Have had major surgery (requiring general anesthesia) within ≤4 weeks of first dose
of LP-184.
10. Have any other serious medical condition which, in the opinion of the investigator,
would preclude the patient from study participation.
11. Have clinically active brain metastases, defined as untreated and symptomatic, or
requiring therapy with steroids at a dose > 2 mg of dexamethasone or equivalent or
anticonvulsants to control associated symptoms. Patients with treated brain
metastases that are no longer symptomatic and who require no treatment with steroids
may be included in the study if they have recovered from the acute toxic effect of
radiotherapy. A minimum of 4 weeks must have elapsed between the end of whole brain
radiotherapy and study enrollment (1 week for stereotactic radiotherapy).
12. For patients with suspected or known CNS metastatic disease, based on screening
brain MRI, patients must not have:
Any untreated brain lesions >2.0 cm in size unless Medical Monitor approved
enrollment.
Ongoing use of systemic corticosteroids for control of symptoms of brain metastases
at a total daily dose of >2 mg of dexamethasone (or equivalent).
Patients on a chronic stable dose of ≤2 mg total daily of dexamethasone (or
equivalent) are eligible with discussion and approval by the medical monitor. (Note:
this is not applicable to patients with GBM).
Any brain lesion thought to require immediate local therapy, including (but not
limited to) a lesion in an anatomic site where an increase in size or possible
treatment-related edema may pose a risk to the patient (e.g., brain stem lesions).
Patients who underwent local treatment for such lesions identified by screening
contrast brain MRI may still be eligible based on criteria described under CNS
inclusion criteria described above.
• Known or suspected leptomeningeal disease as documented by the investigator.
13. Male patients with partners currently pregnant, or male patients able to father
children, and female patients of childbearing potential who are unwilling or unable
to use highly effective methods of contraception as outlined in this protocol for
the duration of the study and for at least 3 months (male) or 6 months (female)
after last dose of study drug
