Evaluation of ABEMACICLIB Monotherapy in Patients With Locally Advanced/Metastatic Head and Neck Cancer After Failure of Platinum and Cetuximab or Anti-EGFR-based Therapy and Harboring an Homozygous Deletion of CDKN2A, and/or an Amplification of CCND1 and/or of CDK6

Study Overview
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Brief Summary
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This trial is an open-label, single arm, Phase II study using an A'Hern single stage design. The molecular prescreening step will allow to defined HPV tumor status as well as molecular status CDKN2A, CCND1 and CDK6. Following this centralized molecular screening, only patients with HPV negative status and with tumor harboring CDKN2A homozygous deletion and/or CCND1 amplification and/or CDK6 amplification could initiate abemaciclib at time of documented radiological progression. Patients will be treated with ABEMACICLIB, 400 mg/day with 2 doses of 200 mg 12 hour apart (QH12). A cycle is defined as an interval of 28 days. For each 28-day cycle, a total of 56 doses of study drug will be dispensed.

Detailed Description
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SAMPLE SIZE DETERMINATION The primary endpoint is the non-progression rate (CR, PR, SD as per RECIST 1.1) after 8 weeks of treatment. The sample size calculation was based on an A'Hern single stage phase II design, with a minimum success (non- progression) rate considered of interest of p1=40% and an uninteresting rate of p0=15%. Assuming a type I error alpha of 0.05 and 85% power, 23 patients are needed to reject the null hypothesis H0: p<=p0 vs the alternative hypothesis H1: p ≥ p1 in a unilateral situation. Based on the assumption that 10% of the patients may be non-evaluable, 25 patients will be included in the study. DATA ENTRY AND DATA MANAGEMENT All the data concerning the patients will be recorded in the eCRF throughout the study. SAE reporting will be paper-based by Fax. The sponsor will perform the study monitoring and will help the investigators to conduct the study in compliance with the clinical trial protocol, Good Clinical Practices (GCP) and local low requirements.

Official Title
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A Phase II Trial Aiming to Evaluate the Clinical Interest of ABEMACICLIB Monotherapy in Patients With Locally Advanced/Metastatic Head and Neck Cancer After Failure of Platinum and Cetuximab or Anti-EGFR-based Therapy and Harboring an Homozygous Deletion of CDKN2A, and/or an Amplification of CCND1 and/or of CDK6

Conditions
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Head and Neck Cancer, Advanced Cancer, Metastatic Cancer

Intervention / Treatment
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* Drug: Abemaciclib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: I1. Male or female patients aged ≥ 18 years at time of inform consent signature I2. Histologically proven metastatic or locally advanced HNSCC (oropharynx, oral cavity, hypopharynx and larynx). Patients with cancer of nasopharynx (i.e. cavum cancer) are not eligible I3. Availability of a representative formalin-fixed paraffin-embedded (FFPE) primary and/or metastatic tumor tissue with an associated pathology report for molecular pre-screening: either an archival tumor block or a dedicated freshly collected tumor biopsy. I4. Documented CDKN2A homozygous deletion and/or CCND1 amplification and/or CDK6 and/or CDK4 amplification and no deletion/losses more than single copy of RB1 by copy number data before C1D1. Note: This molecular pre-screening will be centralized at at the CGH platform of Centre Léon Bérard (CLB). Note: This molecular pre-screening will be centralized at the CGH platform of Centre Léon Bérard (CLB). Note: This molecular pre-screening can be performed for patient without documented disease progression (PD) but study drug treatment cannot be initiated until confirmed radiological PD. I5. HPV negative tumor status must be documented before C1D1. Note: This analysis will be centralized and performed by translational Biopathology platform of CLB during molecular pre-screening by IHC for p16. I6. Documented radiological progression or relapse after at least platin and cetuximab or anti-EGFR-based chemotherapy (combination or sequential treatment) and other standard treatment available at time of C1D1.. I7. At least one measurable lesion by CT-scan as per RECIST 1.1. I8. At least one biopsiable tumor lesion before C1D1 i.e. at least one lesion with a diameter of at least 10 mm, visible by medical imaging and accessible to percutaneous sampling. I9. Eastern Cooperative Oncology Group (ECOG) performance status: 0 or 1. I10. Life expectancy > 12 weeks. I11. Patients must be able to swallow capsules. I12. Adequate organ and bone marrow function as defined by the following tests (to be checked using medical records and then carried out within 7 days prior C1D1): Bone marrow : Absolute neutrophil count >= 1.0 x 109/L Platelet count > 100 x 109/L Hemoglobin value >= 9 g/dL Note : Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion. Renal function Calculated creatinine clearance by MDRD or CDK-EPI > 50mL/min/1.73m2 Liver function Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN (or < 5.0 x ULN if liver metastases are present) Total serum bilirubin ≤ 1.5 x ULN (except for patients with Gilbert disease for whom a total serum bilirubin ≤ 3mg/dL is acceptable). I13. Women of childbearing potential (entering the study after a confirmed menstrual period and who have a negative pregnancy test within 7 days before C1D1) must agree to use two methods of medically acceptable forms of contraception from the date of negative pregnancy test up to 3 months after the last study drug intake. I14. Fertile males must use a highly effective contraception during dosing period and through 3 months after final dose of study drug. I15. Patient should be able and willing to comply with study visits and procedures as per protocol. I16. Patient should understand, sign, and date the written voluntary informed consent form at the screening visit prior to any protocol-specific procedures performed. I17. Patients must be covered by a medical insurance. Exclusion Criteria: NI1. Cancer disease considered curable with surgery or radiotherapy. NI2. Patient with a concurrent malignancy or has a malignancy within 3 years of study enrollment (with the exception of adequately treated basal or squamous cell carcinoma or non-melanomatous skin cancer). NI3. Patient with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of abemaciclib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection). NI4. Patient has other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment contraindicate her participation in the clinical study (for example, history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis). NI5. Persisting significant toxicities related to prior treatments i.e. ≥ Grade 2 AE according to CTCAE V5.0 except alopecia (any grade), grade 2 peripheral neuropathy and biological values as defined in inclusion criteria. NI6. Hypersensitivity to the active substance or excipient of study drug. NI7. Have received prior treatment with any CDK4/6 inhibitor (or participated in any CDK4/6 inhibitor clinical trial for which treatment assignment is still blinded). NI8. Patient has received treatment with a drug that has not received regulatory approval for any indication within : 14 days of C1D1 for non myelosuppressive agent or 21 days of C1D1 for a myelosuppressive agent. NI9. Patient has had major surgery and/or radiotherapy within 14 days prior to C1D1. NI10. Patient has received within 28 days prior to C1D1 yellow fever vaccine. NI11. Patient has a personal history within the last 12 months prior to C1D1 of any of the following conditions: syncope of cardiovascular etiology, ventricular tachycardia, ventricular fibrillation, or sudden cardiac arrest. NI12. Patient needs for the following concomitant medications/interventions not permitted during the study treatment period: Any investigational anticancer therapy other than the study drug. Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy after discussion with the Sponsor), immunotherapy, biologic or hormonal therapy for cancer treatment. Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable. Major surgery. Strong and moderate inducers and inhibitors of CYP3A (for example grapefruit or grapefruit juice, phenytoin and carbamazepine). Enzyme-Inducing Anti-Epileptic Drugs (EIAED). NI13. Patient has received an autologous or allogeneic stem-cell transplant. NI14. Patient has an active systemic fungal and/or known viral infection (for example, human immunodeficiency virus antibodies, hepatitis B surface antigen, or hepatitis C antibodies). NI15. Pregnant or breast-feeding female patients. NI16. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to C1D1and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 28 days prior to C1D1. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Abemaciclib<br> | Drug: Abemaciclib<br>* 400mg/day with 2 doses of 200mg 12-hour apart For each 28-day cycle, a total of 56 doses of study drug will be dispensed. Route of administration : oral Duration of treatment until the patient experiences an unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator after an integrated assessment of radiographic data and clinical status or withdrawal of consent.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The 8-week non-progression rate defined as the rate of patients with complete response (CR), partial response (PR) or stable disease (SD) lasting at least 8 weeks, according to RECIST v1.1 |  | 8 weeks after start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 8-week Objective response rate | Objective response rate after 8 weeks is defined as the proportion of patients with complete or partial response after 8 weeks of treatment according to RECIST 1.1. | 8 weeks after start of treatment | 
| Duration of response | The Duration of Response (DoR) will be measured from the time of first documented response (CR or PR as per RECIST 1.1) until the first documented disease progression or death due to underlying cancer, or censored at the date of the last available tumor assessment | 12 months after start of treatment | 
| Best response rate |  | 12 months after start of treatment | 
| Time to progression | The Time to Progression will be measured from the time of treatment start until the first documented disease progression | 12 months after start of treatment | 
| Time to Treatment failure | The Time to treatment failure will be measured from the time of treatment start until discontinuation of treatment for any reason, including disease progression, treatment toxicity, and death | 12 months after start of treatment | 
| Progression Free survival | Progression-Free Survival (PFS) will be measured from the date of inclusion until the date of event defined as the first documented progression or death from any cause. Patients with no event at the time of the analysis will be censored at the date of the last available tumor assessment. PFS will be estimated using the Kaplan-Meier method | 12 months after start of treatment | 
| Overall Survival | Overall survival will be measured from the date of treatment start to the date of death from any cause | 12 months after start of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clinical Trial, Phase II, Monotherapy, Abemaciclib, Homozygous deletion of CDKN2A, Amplification of CCND1, Amplification of CDK6, Multicenter Trial