Abemaciclib and Nivolumab for Subjects With Hepatocellular Carcinoma

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate the effectiveness of the combination of nivolumab and abemaciclib for the treatment of hepatocellular carcinoma. Other goals of this study are to learn about the side effects that this combination of drugs may cause and to learn more about how these drugs work by studying blood and tissue.

Official Title
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Phase II Trial of Abemaciclib and Nivolumab for Subjects With Hepatocellular Carcinoma

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Abemaciclib
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have hepatocellular carcinoma (HCC) that is inoperable (where surgery is not indicated due to disease extent, co-morbidities, or other technical reasons) Histologic confirmation of HCC is not required for screening but is required prior to initiation of study treatment. Subjects with hepatocholangiocarcinoma or cholangiocarcinoma are not eligible. Tumor must be positive for retinoblastoma (RB) expression by immunohistochemistry Age > 18 years and ability to understand and the willingness to sign a written informed consent document. ECOG performance status of 0 or 1 Childs-Pugh score of <7 Life expectancy of at least 12 weeks Must be able to swallow tablets Must be willing to comply with protocol procedures (including completion of diaries and outcome measures) Local or loco-regional therapy to the liver (i.e. surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation) must have been completed > 4 weeks prior to enrollment Must be willing to undergo a pretreatment and on-treatment biopsy and have a tumor site that is accessible for core needle biopsy Measurable or evaluable disease as defined by RECIST v. 1.1 Women of childbearing potential must have a negative serum pregnancy test performed within 7 days of the first dose of abemaciclib (see Appendix A for definition of childbearing potential). Female subjects of childbearing potential must use an approved contraceptive method (detailed in Appendix A) for the duration of the study and an additional 3 weeks after the final dose of abemaciclib. Subjects with hepatitis B must have an HBV viral load < 100 IU/mL by PCR during screening Must have adequate organ and hematopoietic function as defined below: Exclusion Criteria: Any history of a serious medical or psychiatric condition that would prevent the subject from signing the informed consent form Pregnant or breastfeeding Use of any chemotherapy within 3 weeks prior to the first study treatment date Use of any experimental therapy within 4 weeks or 5 half-lives, whichever is longer, prior to the first study treatment date Use of radiation within 2 weeks prior to the first study treatment date (4 weeks if radiation to liver as per section 4.1) Prior treatment with a CDK 4/6 inhibitor Prior treatment with a PD-1 or PD-L1 inhibitor Those who have not recovered from adverse events < Grade 1 from prior therapy, with the exceptions of alopecia of any grade or stable peripheral neuropathy < Grade 2 Subjects may not receive concomitant anticancer agents or radiation. Antiviral agents aimed at treating infectious hepatitis are permitted History of or suspected hypersensitivity to nivolumab or abemaciclib Uncontrolled ascites Esophageal varices requiring treatment within the past 6 months (banding or medication) Subjects with uncontrolled brain metastases. Subjects with brain metastases must have stable neurological status following local therapy (surgery or radiation) for at least 4 weeks prior to first study treatment and must be off of steroids related to the brain metastases. Any concurrent condition requiring the continued or anticipated use of systemic steroids beyond physiologic replacement dosing (excluding non-systemic inhaled, topical skin, nasal, and/or ophthalmic corticosteroids). All other systemic corticosteroids above physiologic replacement dosing must be discontinued at least 4 weeks prior to first study treatment Active drug or alcohol use or dependence as documented in the chart that, in the opinion of the investigator, would interfere with adherence to study requirements Active bacterial or fungal infection requiring IV therapy at the start of protocol treatment A second primary malignancy that, in the judgment of the investigator, may affect the interpretation of results Any illness or condition that in the opinion of the investigator may affect the safety of the subject or the evaluation of any study endpoint (e.g. interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, 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) Personal history of ventricular tachycardia, ventricular fibrillation, or sudden cardiac arrest Prior organ allograft or allogeneic bone marrow transplantation Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range with medication Active autoimmune disease, except for vitiligo, type 1 diabetes mellitus, asthma, atopic dermatitis, or endocrinopathies manageable by hormone replacement; other autoimmune conditions may be allowable at the discretion of the Principal Investigator Any other conditions judged by the investigator that would limit the evaluation of the subject HIV positive by PCR

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 & Nivolumab<br>Subjects will receive abemaciclib monotherapy 150mg twice daily for seven days then will initiate nivolumab 480mg IV every 28 days while continuing twice daily abemaciclib. | Drug: Abemaciclib<br>* Abemaciclib will be given at a dose of 150mg by mouth twice daily continuously for the duration of trial therapy.<br>* Other names: Verzenio;Drug: Nivolumab<br>* Nivolumab will be administered at a dose of 480mg IV every 28 days. Treatment with nivolumab will begin after an initial 7-day treatment period with abemaciclib monotherapy.<br>* Other names: Opdivo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | The objective response rate is determined by the percentage of participants on study attaining a partial or complete response as noted per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival | Progression-Free survival is determined from the start of study treatment until the time of documented disease progression or death per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) and iRECIST criteria (guidelines for response criteria for use in trials testing immunotherapies) | From the start of study treatment until disease progression, death, whichever came first up to 2 years | 
| Duration of Response | Time from the first recorded partial response or complete response (whichever comes first) defined Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; until disease progression or death | up to 2 years | 
| Overall Survival |  | From the start of treatment to death, due to any cause or last patient contact alive, assessed up to 2 years |