Open-Label Study of the CDK4/6 Inhibitor SPH4336 in Subjects With Locally Advanced or Metastatic Liposarcomas

Study SPH4336-US-01 is an open-label (no placebo), multicenter clinical trial to evaluate the safety, blood levels (pharmacokinetics) and preliminary anti-tumor effects of SPH4336, a selective enzyme blocker, in patients with specific types of liposarcomas (tumors expressing the target of the study drug).

Study SPH4336-US-01 is a multicenter, non-randomized, open-label Phase 2 study of SPH4336 with a safety lead-in in subjects with CDK4-positive liposarcomas (dedifferentiated or well-differentiated/dedifferentiated liposarcomas). SPH4336 is an orally administered, molecularly targeted chemotherapy drug called a cyclin-dependent kinase inhibitor (CDK4/6 inhibitor), which acts to block the ability of cancer cells to divide and thus prevents tumors from growing. SPH4336 (tablets) will be administered orally once each day in successive 28-day cycles until demonstration of progressive disease or the development of unacceptable toxicity.

The study will incorporate a safety lead-in for the initial 10 subjects. Safety will be evaluated after 10 subjects (minimum 1 cycle completed) by a Safety Review Committee (SRC). The study will be stopped if unacceptable toxicity is observed in more than 2 subjects.

Tumor assessments according to RECIST v1.1 will be performed at baseline and every 6 weeks (from Cycle 1, Day 1 (C1D1)) for 36 weeks, then every 12 weeks thereafter. Plasma samples for pharmacokinetics will be collected in all subjects. Baseline (pretreatment) tumor tissue (archival or fresh) will be collected from all subjects to confirm histologically a liposarcoma with a dedifferentiated component and CDK4 positivity. Tumor tissue biomarkers (e.g., phospho-Rb, Ki-67) will be analyzed in the first 10 study subjects in baseline (pretreatment) and C1D15 tumor tissue samples.

Eligibility Criteria:
Inclusion Criteria:

* Informed consent
* ≥ 18 years of age
* ECOG performance status 0 or 1
* Histologically confirmed, locally advanced or metastatic sarcoma

  * Dedifferentiated or well-differentiated/dedifferentiated liposarcomas
* No more than 3 prior lines of treatment
* Evidence of progression as evidenced by at least one of the following within the past 3 months:

  * An increase of at least 20% in measurable tumors
  * The appearance of new lesions
  * Unequivocal progression of non-measurable lesions
* Measurable disease per RECIST v1.1
* If residual treatment-related toxicity from prior therapy:

  * All treatment-related toxicity resolved to Grade 1 or baseline (alopecia excepted)
* ANC ≥ 1,500/μL
* Platelets ≥ 100,000/μL
* Hgb ≥ 9.0 g/dL (in the absence of pRBC transfusion over the prior 4 weeks)
* Estimated glomerular filtration rate of ≥ 60 mL/min (based on the Cockcroft and Gault formula for individualized estimates of GFR)
* Total bilirubin ≤ 1.5 x the Upper Limit of Normal (ULN) or ≤ 3 x ULN if known Gilbert's disease
* AST and ALT ≤ 3 x ULN or ≤ 5 x ULN if malignant involvement of the liver
* Sterile or willing to use effective contraception (approved hormonal contraceptive such as oral contraceptives, patches, implants, injections, rings or hormonally-impregnated intrauterine device (IUD), or an IUD in women of childbearing potential and a condom in men) during the study and for 3 months following the last dose of study drug
* Availability of archived tumor tissue or willingness to undergo a baseline tumor biopsy, and in the first 10 study subjects, to determine baseline tumor biomarker levels and a willingness to undergo a second tumor biopsy at C1D15 to assess treatment-induced changes in tumor biomarker levels

Exclusion Criteria:

* Prior treatment with a CDK4/6-targeted agent
* Patient's tumor known to be CDK4 negative
* Anticancer therapy (e.g., chemotherapy, biologics, irradiation) within 14 days or 5 half-lives (whichever is greater) of screening
* Major surgery within 28 days of screening
* Requirement for systemic treatment with strong CYP3A4 inhibitors or inducers of CYP3A4 at study entry
* Central nervous system metastases or leptomeningeal disease, unless appropriately treated and neurologically stable without steroids for ≥ 28 days
* Other malignancy unless disease-free for ≥ 2 years and not expected to relapse or require treatment during study participation
* Active systemic infection or severe localized infection
* Known HIV-positive with CD4+ cell counts \< 350 cells/uL or a history of an AIDS-defining opportunistic infection
* Known hepatitis B virus (HBV) or hepatitis C virus (HCV) infection with viral load above the limit of quantification
* Active COVID-19 infection
* Major cardiac abnormalities (e.g., uncontrolled angina, unstable arrhythmias, myocardial infarction, NYHA Class ≥ 3 CHF) ≤ 6 months of C1D1
* Persistent (3 ECGs ≥ 5 mins apart) prolongation of the QTcF (Fridericia) \> 470 msec
* \[Females\] Pregnant or nursing
* Any other medical or psychiatric condition, or laboratory abnormality that would result in an unacceptable risk with study participation
* Presence of active gastrointestinal disease or other condition expected to interfere significantly with absorption, distribution, metabolism or excretion of oral therapy (e.g., ulcerative disease, uncontrolled nausea, vomiting, chronic diarrhea, malabsorption syndrome)