Abemaciclib and Nivolumab for the Treatment of Inoperable Liver Cancer

Status: Active

Description

This phase II trial studies how well abemaciclib and nivolumab work in treating liver cancer that cannot be treated by surgery (inoperable). Abemaciclib is a cancer therapy that may slow cancer growth by preventing cells from dividing. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body’s immune system attack the cancer by “removing the brakes” of the immune system, and may interfere with the ability of tumor cells to grow and spread. Giving abemaciclib and nivolumab may work better in treating liver cancer compared to nivolumab alone.

Eligibility Criteria

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
  • Ability to understand and the willingness to sign a written informed consent document
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Child-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. Female subjects of childbearing potential must use an approved contraceptive method for the duration of the study and an additional 3 weeks after the final dose of abemaciclib
  • Subjects with hepatitis B must have an hepatitis B virus (HBV) viral load < 100 IU/mL by polymerase chain reaction (PCR) during screening
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9 / L
  • Platelet count >= 75,000 x 10^9 /L
  • Hemoglobin >= 8.0 x 10^9 /L
  • Alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) =< 3 x ULN
  • Serum creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min by Cockcroft-Gault formula
  • Total bilirubin =< 2.0 x ULN
  • Serum albumin >= 2.8 g/dL
  • International normalized ratio (INR) < 1.5 (fresh frozen plasma [FFP] permitted if elevated)

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)
  • 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
  • Human immunodeficiency virus (HIV) positive by PCR

Locations & Contacts

Pennsylvania

Philadelphia
University of Pennsylvania / Abramson Cancer Center
Status: Active
Contact: Thomas Benjamin Karasic
Phone: 215-614-1858
Email: thomas.karasic@uphs.upenn.edu

Trial Objectives and Outline

PRIMARY OBJECTIVE:

I. To determine overall response rate (ORR) of abemaciclib plus nivolumab in hepatocellular carcinoma (HCC) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) version (v.) 1.1.

SECONDARY OBJECTIVES:

I. To determine progression-free survival (PFS) and duration of response (DOR) of abemaciclib plus nivolumab in HCC as measured by both RECIST v 1.1 and Immune-Modified Response Evaluation Criteria in Solid Tumors (iRECIST).

II. To measure ORR by iRECIST.

III. To summarize overall survival (OS) using Kaplan-Meier methods.

IV. To determine toxicity rates by category using Common Terminology Criteria in Adverse Events (CTCAE) v. 5.0.

EXPLORATORY OBJECTIVE:

I. To correlate outcomes with blood and tumor tissue immune markers pre- and post-therapy to explore potential biomarkers of anti-tumor response.

OUTLINE:

Patients receive abemaciclib orally (PO) twice daily (BID) on days 1-35 and nivolumab intravenously (IV) on day 8 of cycle 1 in the absence of disease progression or unacceptable toxicity. Beginning cycle 2, patients receive abemaciclib PO BID on days 1-28 and nivolumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 2 years.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
University of Pennsylvania / Abramson Cancer Center

Principal Investigator
Thomas Benjamin Karasic

Trial IDs

Primary ID UPCC 35218
Secondary IDs NCI-2019-05382
Clinicaltrials.gov ID NCT03781960