Trial Title:
Cetuximab Plus Dalpicilib in Patients With HPV Negative, PD-1 Resistant R/M HNSCC
NCT ID:
NCT05721443
Condition:
Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma
Conditions: Official terms:
Carcinoma
Carcinoma, Squamous Cell
Squamous Cell Carcinoma of Head and Neck
Cetuximab
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Dalpiciclib+cetuximab
Description:
The dosing regimen for cetuximab combined with dalpiciclib is: the starting dose of
cetuximab is 400 mg/m2, titrated over 120 minutes, and the titration rate should be
limited to 5 ml/min. A maintenance dose of 250 mg/m2, titrated over not less than 60
minutes, with pretreatment with H1 receptor blocker desensitization prior to dosing,
administered once weekly.
The recommended dose of dalpiciclib is 150 mg once daily for 21 days, followed by 7 days
of discontinuation (3/1 dosing regimen) for a 28-day treatment cycle. Take the drug at
approximately the same time each day. If the patient vomits or misses a dose, the dose
should not be made up that day. The next dose should be taken as usual.
Subjects will continue treatment with cetuximab in combination with dalpiciclib until
termination criteria are met.
Arm group label:
Dalpiciclib+cetuximab
Summary:
This study is the first clinical study in PD-1 resistant patients with head and neck
squamous cell carcinoma with drugs targeting EGFR signaling pathway combined with CDK4/6
inhibitors, which explores the new combination therapies urgently needed in clinical
practice and lays a foundation for subsequent studies, with important scientific research
significance and clinical value.
Detailed description:
Head and neck cancer is the sixth most common cancer in the world, with more than 550,000
incidences and 300,000 deaths per year worldwide. more than 95% of head and neck cancers
are squamous cell carcinomas, and head and neck squamous cell carcinoma (HNSCC) has a
devastating and HNSCC affects the quality of life of patients by damaging and affecting
their appearance and basic physical, sensory and speech functions. Due to the difficulty
of early detection, more than 60% of head and neck squamous cell carcinoma patients are
already at locally advanced stage when detected, and the prognosis of locally advanced
head and neck carcinoma is poor, and even after receiving aggressive treatment, it is
prone to local recurrence and distant metastasis after treatment.
About 25% of patients with squamous head and neck cancer are associated with human
papillomavirus (HPV) infection, of which the most common subtype is HPV 16, accounting
for more than 80% of all HPV-induced head and neck cancers. HPV infection suppresses the
function of oncogenes TP53 and RB, and promotes immune escape and promote the development
of head and neck cancer. In China, more than 70% of head and neck squamous carcinomas are
not associated with HPV infection, and compared with HPV-associated HNSCC, HPV-negative
HNSCC has a lower response rate to treatment and the overall prognosis of patients is
worse.
Head and neck squamous cell carcinoma has a high rate of Treg cell as well as NK cell
infiltration in the tumor microenvironment, forming an immunosuppressive tumor
microenvironment and is a group of malignancies with high immunodeficiency. Studies have
shown high levels of PD-L1 expression in tumor tissue in 46%-100% of HNSCC. Therefore,
blockade of immune checkpoint inhibitors represented by PD-L1/PD-1 is a theoretically
feasible therapeutic approach for the treatment of HNSCC. The results of previous
clinical trials of immunotherapy in patients with recurrent or metastatic head and neck
squamous carcinoma showed that anti-PD-1 antibodies led to durable remission and improved
survival in patients with either first- or second-line therapy. The KEYNOTE-048 study
confirmed that pembrolizumab in combination with chemotherapy prolonged overall survival
in patients with recurrent or metastatic head and neck squamous carcinoma and in 2021
recommended by CSCO guidelines as a first-line expert recommendation for the first-line
treatment of recurrent or metastatic head and neck squamous carcinoma (Level of Evidence
1A). However, patients with recurrent or metastatic head and neck squamous carcinoma
after failure of first-line applied anti-PD-1 therapy enter second-line therapy The
current guideline recommended second-line treatment regimens are cetuximab, afatinib or
methotrexate, but the overall prognosis of patients is poor, the drug response rate is
not high, the highest objective remission rate reported in the literature is only 13%,
and the time to tumor progression is only 2.3 months, therefore, exploring new
second-line treatment options for patients with recurrent or metastatic head and neck
squamous carcinoma after failure of anti-PD-1 therapy is a pressing clinical need.
In addition, the results of previous clinical trials showed that HPV-negative HNSCC had
poorer sensitivity and prognosis to immunotherapy than HPV-associated HNSCC. In
KEYNOTE-012, patients with HPV-positive HNSCC had higher objective remission (32% vs 14%)
and progression-free survival (4 months vs 2 months) with pablizumab, and similar results
were confirmed by KEYNOTE-055. Furthermore, in a meta-analysis of 11 studies,
HPV-positive HNSCC patients showed a 1.29-fold higher response rate to immunotherapy and
a twofold higher overall survival (11.5 months vs. 6.3 months) than HPV-negative HNSCC
patients.
There are a large number of ongoing clinical trials of combination targeted therapies and
immunotherapies. The basic rationale supporting these combinations is that the two
therapies combine different immunological and tumor biological mechanisms that enhance
antitumor activity; in addition, some evidence suggests that targeted therapies can
enhance certain aspects of the "cancer-immune cycle" (e.g., tumor antigenicity, T-cell
initiation/transport/infiltration, etc.) to immunotherapy. In addition, it has been shown
that targeted therapies can synergistically enhance certain aspects of the "cancer-immune
cycle" (e.g., tumor antigenicity, T cell initiation/transport/infiltration, etc.) for
immunotherapy. CDK4, one of the key cell cycle regulators, is involved in cell growth,
proliferation, dormancy or apoptosis by binding to cell cycle protein D, which regulates
the transition from G1 phase (pre-DNA synthesis) to S phase (DNA synthesis). In 2013, the
US Food and Drug Administration (FDA) approved the CDK4 inhibitor Palbociclib as a
breakthrough new drug for the treatment of advanced breast cancer, and the National
Comprehensive Cancer Network (NCCN) guidelines recommend piperacillin in combination with
an aromatase inhibitor as a first-line treatment option for HR+/HER2-advanced or
metastatic breast cancer. Recent studies have found that CDK4 gene inhibition in
combination with afatinib synergistically enhances the inhibition of the PI3k pathway in
head and neck cancer cells, which in turn reduces tumor proliferation, providing a strong
rationale for combination therapy.
P16 deletion is a hallmark event in HPV-negative HNSCC patients, and p16 inactivation
would lead to CDK4/6 hyperactivation, making CDK4/6 theoretically a potential target for
HPV-negative HNSCC. Some progress has been made with CDK4/6 inhibitors in HPV-negative
head and neck squamous carcinoma. In a multicenter, multicohort phase II clinical trial,
cohort 1 enrolled in first-line treatment of platinum-resistant HPV-negative patients
with recurrent/metastatic HNSCC, and cohort 2 enrolled in first-line treatment of
cetuximab-resistant HPV-negative cohort 3 enrolled patients with cetuximab-resistant
HPV-positive recurrent/metastatic oropharyngeal cancer, and all three groups received
Palbociclib in combination with cetuximab, showing objective remission rates of up to 39%
in cohort 1 and 19% in cohort 2, but only 4% in cohort 3, indicating that CDK4/6
inhibitors in combination with cetuximab has a promising application in the treatment of
HPV-negative HNSCC.
This clinical study involved dalpiciclib, which was developed by Jiangsu Hengrui
Pharmaceutical Co. In December 2021, the State Drug Administration approved the drug in
combination with fulvestrant for patients with recurrent or metastatic breast cancer with
hormone receptor-positive, human epidermal growth factor receptor 2-negative disease
progression after previous endocrine therapy through a priority review and approval
process. Patients. Preclinical studies have shown that dalpiciclib has comparable in vivo
efficacy and safety compared to its foreign counterparts.
This study is also the first clinical study of a drug targeting CDK4/6 in combination
with cetuximab for the treatment of HPV-negative head and neck squamous carcinoma after
progression of PD-1 therapy in China, which is of great scientific significance and
clinical value in exploring new combination therapies for HPV-negative patients, a
population with poor clinical outcome, and laying the foundation for subsequent studies.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Age 18-75 years, both sexes.
- Patients with histologically confirmed post-surgical recurrent/metastatic or locally
advanced inoperable surgically resectable squamous cell carcinoma of the head and
neck with measurable lesions (spiral CT scan ≥ 10 mm, meeting RECIST 1.1 criteria).
- Have received at least 1 cycle of prior PD-1 immunotherapy with imaging confirmation
of progression or clinician determination of no continued benefit from treatment;
provided that this is completed at least 4 weeks prior to the first dose of study
drug and all associated toxic events have returned to normal or grade I or less as
defined by CTCAE 4.03 classification.
- HPV viral testing determined to be negative, using the IHC method.
- Availability of tumor tissue (paraffin specimens less than 2 years old or fresh
tumor tissue) for detection of PD-L1 and CDK4-related genes.
- ECOG score of 0 or 1.
- Expected survival of ≥ 12 weeks.
- Normal major organ function within 2 weeks prior to treatment, i.e., meeting the
following criteria：Bone marrow function: hemoglobin ≥ 100 g/L without transfusion or
colony-stimulating factor support therapy, white blood cell count ≥ 4.0*10^9/L or
neutrophil count ≥ 2.0*10^9/L, and platelet count ≥ 100*10^9/L; Liver: serum total
bilirubin level ≤ 1.5 times the upper limit of normal, aspartate aminotransferase
(AST) and alanine aminotransferase (ALT) ≤ 1.5 times the upper limit of normal;
Renal: blood creatinine level below 1.5 times the upper limit of normal or
creatinine clearance ≥ 60 ml/min and urea nitrogen ≤ 200 mg/L; Urine protein <+, or
if urine protein + then total 24-hour protein must be <500mg; Blood glucose: within
normal range and/or with diabetes in treatment but under stable glycemic control;
Pulmonary function: baseline FEV1 of at least 2L; if baseline FEV1 <2L then FEV1
>800ml expected post-surgery as assessed by a surgical specialist; Cardiac function:
no myocardial infarction within 1 year; no unstable angina; no symptomatic severe
arrhythmias; no cardiac insufficiency.
Exclusion Criteria:
- Patients previously treated with cetuximab or other anti-EGFR monoclonal antibodies
or small molecule tyrosine kinase inhibitors.
- Patients who are currently receiving antineoplastic therapy.
- Patients who have participated or are participating in a clinical trial of another
drug/therapy within 4 weeks prior to the first dose of the study drug.
- Patients who have received hematopoietic stimulating factors, such as granulocyte
colony-stimulating factor (G-CSF), erythropoietin, etc., within 1 week prior to the
first dose of the study drug.
- Positive HIV antibody or syphilis spirochete antibody test results.
- Patients with active hepatitis B or C: If positive for HBsAg or HBcAb, additional
HBV DNA testing (results above the upper limit of the normal range). If HCV antibody
test result is positive, add HCV RNA test (result above the upper limit of the
normal range).
- Known hypersensitivity to recombinant humanized EGFR monoclonal antibody drugs and
their components.
- Massive pleural or ascites fluid with clinical symptoms and requiring symptomatic
management.
- Active lung disease (interstitial pneumonia, pneumonia, obstructive lung disease,
asthma) or a history of active tuberculosis.
- Has any uncontrollable clinical problem, including but not limited to: Persistent or
active (severe) infection; Poorly controlled diabetes mellitus; Cardiac disease
(Class III/IV congestive heart failure or heart block as defined by the New York
Heart Association); Deep vein thrombosis or pulmonary embolism; myocardial
infarction; severe or unstable arrhythmia or angina; percutaneous coronary
intervention, acute coronary syndrome, coronary artery bypass grafting;
cerebrovascular accident, transient ischemic attack, cerebral embolism within 6
months prior to first dose.
- Previous stem cell transplantation or organ transplantation.
- Those with a history of psychotropic substance abuse and unable to abstain or a
history of psychiatric disorders.
- Other serious, acute or chronic medical conditions or abnormalities in laboratory
tests that, in the judgment of the investigator, may increase the risk associated
with study participation or may interfere with the interpretation of study results.
- Patients who, in the judgment of the investigator, have poor compliance or other
conditions that make them unsuitable for participation in this trial.
- Patients with a history of other malignancies within five years.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
the Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Address:
City:
Shanghai
Zip:
200011
Country:
China
Status:
Recruiting
Contact:
Last name:
Guoxin Ren, M.D
Phone:
13916948812
Email:
renguoxincn@sina.com
Start date:
April 1, 2023
Completion date:
January 1, 2026
Lead sponsor:
Agency:
Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University
Agency class:
Other
Source:
Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05721443
