CDK4/6 Tumor Abemaciclib Paclitaxel

  • STATUS
    Recruiting
  • End date
    Aug 10, 2022
  • participants needed
    36
  • sponsor
    Yonsei University
Updated on 1 May 2021

Summary

Cyclin D-dependent kinases (CDKs) are often activated in human cancer owing to various genetic and epigenetic events. This affects regulatory pathways, and it results in uncontrolled proliferation due to loss of checkpoint integrity. Most tumors show increased activity of CDKs, and this permits escape from senescence during the evolution of malignancy.

Among them, cyclin D-CDK4/6-INK4 pathway alterations accelerate G1 progression which provides proliferative and survival advantage to cancer. Therefore, preclinical data demonstrated inhibition of cyclin D-dependent kinase activity have therapeutic benefit. CDK4/6 controls entry into cell cycle progression by regulating Retinoblastoma protein (Rb). The majority of human cancers are known to retain wild-type Rb. In addition, CDK4 amplification and mutations also noted in several tumors. In Rb retained tumors, CDK 4/6 inhibitors reduced Rb phosphorylation and induced G1 arrest. In previous study, CDK4/6 inhibitor showed antitumor activities in Rb-positive breast and colon cancer cell lines. Rapid tumor regression was also noticed in mouse xenograft model. In CDK4 amplified sarcoma cell lines, knockdown of CDK4 inhibited cancer cell proliferation.

Cyclin D1 acts with CDK4 and CDK6 to phosphorylate Rb and promote cell-cycle progression, and CDK4/6 inhibitor might be effective for the patients with CCND1/2/3 amplification/mutation or CDK 4/6 amplification. Therefore, basket trial (NCT03310879) is ongoing for the patients with genomic alterations in CCND1, CDKN2A, or CDK4. Amplification/mutation of CCND1/2/3 and CDK4/6 occurs in approximately 15-30% of various solid tumors; sarcoma, GBM, melanoma, gem cell tumor, and gynecologic tumors Regarding the more potent synergistic effect, paclitaxel demonstrated a rationale for promising combination partner with CDK 4/6 inhibitors. In non-small cell lung cancer cell lines, synergistic anti-tumor activities were reported with paclitaxel combination. Corollary, we planned to conduct the phase Ib/II trial of abemaciclib and paclitaxel combination in CDK4/6 pathway activated tumors as one subgroup of multi-arms in ongoing basket trial.

Details
Condition Cancer, Cancer/Tumors, Ewing's Family Tumors, Cancer (Pediatric), Neoplasms
Treatment abemaciclib+paclitaxel
Clinical Study IdentifierNCT04594005
SponsorYonsei University
Last Modified on1 May 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Histologically or cytologically confirmed locally advanced or metastatic solid tumors, for which standard therapy proven to provide clinical benefit no longer
CDK4/6 activated tumors on next-generation sequencing or FISH (fluorescence in situ hybridization) analyses
CCND1, 2, or 3 high-level amplification, CCND1 mutation, or a CCND1 splice variant expected to lead to nuclear retention of cyclin D1 protein
CDK4 or CDK6 high-level amplification
ECOG performance status of 0 to 1
years of age
Subjects with measurable or evaluable disease Subjects who meet the following criteria: - Absolute neutrophil count (ANC) 1000 /L (ANC = Neutrophil segs Neutrophil bands) - Platelet count 75,000/ L - Serum creatinine < 1.5 x upper limit of normal (ULN)
AST (SGOT) and ALT (SGPT) < 3 x upper limit of normal (ULN) (If there is Liver Metastasis < 5 x upper limit of normal (ULN))
Total bilirubin < 1.5 x upper limit of normal (ULN)
Provision of written informed consent prior to any study procedure

Exclusion Criteria

Any unresolved chronic toxicity greater than CTC grade 2 from previous anticancer therapy
Any previous chemotherapy or immunotherapy within 2 weeks or at least 3-5 half-lives for previous chemo/immunotherapy whichever is longer
Any major operation or irradiation within 2 weeks of baseline disease assessment
Any clinically significant gastrointestinal abnormalities which may impair intake or absorption of the study drug
Previously abemaciclib-exposed patients
Subjects with symptomatic central nervous system (CNS) metastases who are
neurologically unstable or have required increasing doses of steroids within
the 2 weeks prior to study entry to manage CNS symptoms
Other co-existing malignancies or malignancies diagnosed within the last 3
years with the exception of basal cell carcinoma, thyroid cancer or cervical
cancer in situ
Subjects with an uncontrolled major cardiovascular disease (including AMI
within 12 months, unstable angina within 6 months, over NYHA class III
congestive heart failure, congenital long QT syndrome, 2 or more AV Block and
uncontrolled hypertension)
Active infection including hepatitis B, hepatitis C
Pregnant or lactating female
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