Trial Title:
Testing the Addition of an Anti-Cancer Drug, Abemaciclib, to the Usual Chemotherapy Treatment (5-Fluorouracil) for Metastatic, Refractory Colorectal Cancer
NCT ID:
NCT06654037
Condition:
Metastatic Microsatellite Stable Colorectal Carcinoma
Refractory Microsatellite Stable Colorectal Carcinoma
Stage IV Colorectal Cancer AJCC v8
Conditions: Official terms:
Carcinoma
Colorectal Neoplasms
Fluorouracil
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Abemaciclib
Description:
Given PO
Arm group label:
Treatment (abemaciclib, 5-FU)
Other name:
LY 2835219
Other name:
LY-2835219
Other name:
LY2835219
Other name:
Verzenio
Intervention type:
Procedure
Intervention name:
Biopsy
Description:
Undergo tissue biopsy
Arm group label:
Treatment (abemaciclib, 5-FU)
Other name:
BIOPSY_TYPE
Other name:
Bx
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood sample collection
Arm group label:
Treatment (abemaciclib, 5-FU)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Drug
Intervention name:
Fluorouracil
Description:
Given IV
Arm group label:
Treatment (abemaciclib, 5-FU)
Other name:
5 Fluorouracil
Other name:
5 Fluorouracilum
Other name:
5 FU
Other name:
5-Fluoro-2,4(1H, 3H)-pyrimidinedione
Other name:
5-Fluorouracil
Other name:
5-Fluracil
Other name:
5-Fu
Other name:
5FU
Other name:
AccuSite
Other name:
Carac
Other name:
Fluoro Uracil
Other name:
Fluouracil
Other name:
Flurablastin
Other name:
Fluracedyl
Other name:
Fluracil
Other name:
Fluril
Other name:
Fluroblastin
Other name:
Ribofluor
Other name:
Ro 2-9757
Other name:
Ro-2-9757
Summary:
This phase I trial tests the safety, side effects, and best dose of abemaciclib in
combination with 5-fluorouracil and how well it works in treating patients with
colorectal cancer that has spread from where it first started (primary site) to other
places in the body (metastatic) and that has not responded to treatment (refractory).
Abemaciclib, a type of cyclin-dependent kinase inhibitor, blocks certain proteins, which
may help keep tumor cells from growing. 5-fluorouracil, a type of antimetabolite, stops
cells from making deoxyribonucleic acid (DNA) and may kill tumor cells. Giving
abemaciclib in combination with 5-fluorouracil may be safe, tolerable, and/or effective
in treating patients with metastatic and refractory colorectal cancer.
Detailed description:
PRIMARY OBJECTIVE:
I. To determine the safety and tolerability, maximum tolerated dose (MTD) and recommended
phase 2 dose (RP2D) of abemaciclib in combination with 5-fluorouracil (5-FU) in patients
with colorectal cancer (CRC).
SECONDARY OBJECTIVES:
I. To estimate the anti-tumor activity of abemaciclib in combination with 5-FU. II. To
determine the pharmacodynamics (PD) of abemaciclib in combination with 5-FU (death
receptor 5 [DR5] dynamics and apoptosis).
III. To identify molecular subpopulations particularly sensitized to abemaciclib and
5-FU.
IV. To determine the pharmacokinetics (PK) of abemaciclib and 5-FU.
EXPLORATORY OBJECTIVES:
I. To explore exposure-response relationships for abemaciclib and 5-FU. II. To evaluate
circulating tumor DNA (ctDNA) as a predictor for treatment response to therapy.
OUTLINE: This is a dose-escalation study of abemaciclib in combination with 5-FU followed
by a dose-expansion study.
Patients receive abemaciclib orally (PO) twice daily (BID) on days 1-28 and 5-FU
intravenously (IV) over 46 hours on days 1 and 15 of each cycle. Cycles repeat every 28
days in the absence of disease progression or unacceptable toxicity. Patients also
undergo blood sample collection throughout the study and may additionally undergo a
tissue biopsy before treatment and on cycle 1 day 16.
After completion of study treatment, patients are followed up every 3 months for 6
months.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Patients must have histologically or cytologically confirmed microsatellite
stability (MSS) metastatic colorectal cancer where patients have progressed on
standard therapies which would have included 5-FU or capecitabine, oxaliplatin, and
irinotecan. Patients must have had progression of disease (PD) or intolerance to
bevacizumab and anti-EGFR antibodies (cetuximab or panitumumab) in patients who have
left-sided and RAS-wildtype colorectal cancer (CRC)
- Patients must have measurable disease
- Age ≥ 18 years. Because no dosing or adverse event data are currently available on
the use of abemaciclib in combination with 5-FU in patients < 18 years of age,
children are excluded from this study
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
- Hemoglobin ≥ 8 g/dL
- Absolute neutrophil count ≥ 1,500/mcL
- Platelets ≥ 100,000/mcL
- Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/
alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x
institutional ULN for patients who do not have liver metastases, and ≤ 5 x
institutional ULN for patients with liver metastases
- Glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m^2
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV
viral load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load
- Patients with treated brain metastases are eligible if follow-up brain imaging after
central nervous system (CNS)-directed therapy shows no evidence of progression
- Patients with a prior or concurrent malignancy whose natural history or treatment
does not have the potential to interfere with the safety or efficacy assessment of
the investigational regimen are eligible for this trial
- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification. To be
eligible for this trial, patients should be class II or better
- Patients must have available archival tumor tissue at the time of patient enrollment
for molecular profiling studies. A biopsy may be done if archival tissue is not
available
- Palliative radiation for symptom management to a metastatic site will be permitted
during the course of the study. Please discuss specific cases with the national
principal investigator (PI)
- Patients must have completed previous systemic therapy for at least five half-lives
or 2 weeks, whichever is shorter, prior to study dosing
- Patients who received chemotherapy must have recovered (Common Terminology Criteria
for Adverse Events [CTCAE] grade ≤ 1) from the acute effects of chemotherapy except
for residual alopecia or grade 2 peripheral neuropathy prior to randomization
- Patients who have not had major surgery within 14 days prior to randomization
- Patients who do not have serious and/or uncontrolled preexisting medical
condition(s) that, in the judgment of the investigator, would preclude participation
in this study (for example, interstitial lung disease, severe dyspnea at rest or
requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine
clearance < 30ml/min], history of major surgical resection involving the stomach or
small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting
chronic condition resulting in baseline grade 2 or higher diarrhea)
- Patients who received radiotherapy must have completed and fully recovered from the
acute effects of radiotherapy. A washout period of at least 14 days is required
between end of radiotherapy and randomization
- Patients who are able to swallow oral medications
- Patients who do not have a personal history of any of the following conditions:
syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin
(including, but not limited to, ventricular tachycardia and ventricular
fibrillation), or sudden cardiac arrest
- Patients who do not have an active systemic bacterial infection (requiring
intravenous [IV] antibiotics at time of initiating study treatment) or fungal
infection
- The effects of abemaciclib on the developing human fetus are unknown. For this
reason and because cyclin-dependent kinases (CDK) inhibiting agents as well as other
therapeutic agents used in this trial are known to be teratogenic, men and women
treated or enrolled on this protocol must also agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to the study, for
the duration of study participation, and 3 months after completion of abemaciclib
and fluorouracil. Should a woman become pregnant or suspect she is pregnant while
she or her partner is participating in this study, she should inform her treating
physician immediately
- Ability to understand and the willingness to sign a written informed consent
document. Legally authorized representatives may sign and give informed consent on
behalf of study participants
Exclusion Criteria:
- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1) with the exception of alopecia
- Patients who are receiving any other investigational agents. There is to be a
washout period of two weeks or five half-lives, whichever is shorter, for all
investigational agents prior to treatment initiation on this study. Individual cases
can be discussed with the national PI
- History of allergic reactions attributed to compounds of similar chemical or
biologic composition to abemaciclib or other agents (5-FU) used in study such as a
previous intolerance to 5-FU or capecitabine, including patients with known or
suspected dihydropyrimidine dehydrogenase deficiency
- Patients who have received previous treatment with a CDK4/6 inhibitor
- Patients with a gastrointestinal pathology or history that adversely impacts the
ability to take or absorb oral medication
- Patients with peritoneal metastases complicated by ascites which are refractory to
diuretic therapy and requires therapeutic paracenteses more than once every 2 weeks
- Patients receiving any medications or substances that are strong inhibitors or
inducers of CYP3A enzymes before enrollment or while on protocol therapy are
ineligible. Patients receiving moderate CYP3A inhibitors or inducers will be
monitored. Because the lists of these agents are constantly changing, it is
important to regularly consult a frequently-updated medical reference. As part of
the enrollment/informed consent procedures, the patient will be counseled on the
risk of interactions with other agents, and what to do if new medications need to be
prescribed or if the patient is considering a new over-the-counter medicine or
herbal product
- Patients with uncontrolled intercurrent illness or any other significant
condition(s) that would make participation in this protocol unreasonably hazardous
- Pregnant women are excluded from this study because abemaciclib is a CDK-inhibiting
agent with the potential for teratogenic or abortifacient effects. Because there is
an unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with abemaciclib, breastfeeding should be discontinued if
the mother is treated with abemaciclib. These potential risks may also apply to
other agents used in this study
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Start date:
November 22, 2024
Completion date:
December 1, 2026
Lead sponsor:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
National Cancer Institute (NCI)
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06654037
