Description:
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.
Title
- Brief Title: CDK4/6 Tumor, Abemaciclib, Paclitaxel
- Official Title: An Open-label, Multi-center Phase IB/II Study of Abemaciclib With Paclitaxel for CDK4/6 Pathway Activated Tumors
Clinical Trial IDs
- ORG STUDY ID:
4-2020-0091
- NCT ID:
NCT04594005
Conditions
Interventions
| Drug | Synonyms | Arms |
|---|
| abemaciclib+paclitaxel | | abemaciclib+paclitaxel |
Purpose
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| abemaciclib+paclitaxel | Experimental | | |
Eligibility Criteria
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
- ≥ 19 years of age
- Subjects with measurable or evaluable disease ⑥ Subjects who meet
the following criteria: - Absolute neutrophil count (ANC) ≥ 1000
/µL (*ANC = Neutrophil segs ＋ Neutrophil bands) - Platelet count ≥
75,000/ µL - 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
⑥ 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
⑦ 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.
⑧ 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)
⑨ Active infection including hepatitis B, hepatitis C
⑩ Pregnant or lactating female
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 19 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | overall response rate |
| Time Frame: | 8 weeks |
| Safety Issue: | |
| Description: | to find the recommend phase 2 dose |
Secondary Outcome Measures
| Measure: | adverse event |
| Time Frame: | 1 week |
| Safety Issue: | |
| Description: | |
| Measure: | disease control rate |
| Time Frame: | 8 weeks |
| Safety Issue: | |
| Description: | |
| Measure: | progression free survival |
| Time Frame: | 8 weeks |
| Safety Issue: | |
| Description: | |
Details
| Phase: | Phase 1/Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Yonsei University |
Last Updated
April 22, 2021
