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Protocol Details

Phase II Study of Nivolumab (anti-PD1), Tadalafil and Oral Vancomycin in Patients with Refractory Primary Hepatocellular Carcinoma or Liver Dominant Metastatic Cancer from Colorectal or Pancreatic Cancers

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

19-C-0033

Sponsoring Institute

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 18
Max Age: N/A

Referral Letter Required

No

Population Exclusion(s)

Pregnant Women and Fetuses;
Children

Special Instructions

Currently Not Provided

Keywords

Anticancer Activities;
Altering Gut Commensual Bacteria;
Immunodulatory Effect;
Checkpoint Inhibition

Recruitment Keyword(s)

None

Condition(s)

Heptocellular Carcinoma;
Heptocellular Cancer;
Metastatic pancreatic cancer;
Metastatic colorectal cancer;
Liver Metastasis

Investigational Drug(s)

Nivolumab

Investigational Device(s)

None

Intervention(s)

Drug: nivolumab
Drug: tadalafil
Drug: oral vancomycin

Supporting Site

National Cancer Institute

Background:

A most common liver cancer in adults is hepatocellular carcinoma. Other kinds of liver cancer happen when colorectal or pancreatic cancer spreads to the liver. Researchers want to study if a combination of drugs helps people with these cancers. The drugs are nivolumab, tadalafil, and vancomycin.

Objective:

To investigate if nivolumab given with tadalafil and vancomycin causes liver cancer to shrink.

Eligibility:

Adults ages 18 years and older with hepatocellular carcinoma or metastases to the liver from colorectal or pancreatic cancer for which standard treatment has not worked

Design:

Participants will be screened with:

Medical and cancer history

Review of symptoms and ability to perform normal activities

Physical exam

Heart test. Some participants may meet with a cardiologist and/or have another heart test.

Scan of the chest, abdomen, and pelvis

Blood and urine tests

Tumor sample review. This can be from a previous procedure.

Participants will receive the study drugs in 4-week cycles. In each cycle participants will:

Get nivolumab through a small plastic tube in the arm on Day 1.

Take tadalafil by mouth 1 time every day.

Take vancomycin by mouth 4 times a day. They will take it every day for weeks 1 3, then not take it for week 4.

Complete a medicine diary of dates, times, missed doses and symptoms.

Throughout the study, participants will repeat screening tests and will give stool samples or rectal swabs.

After their last cycle, participants will have 3 follow-up visits over 3 months. Then they will be contacted every 6 months by phone or email and asked about their general well-being.

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Eligibility

INCLUSION CRITERIA:

-Patients must have

--histopathological confirmation of HCC (Cohort 1) OR

--histopathological confirmation of carcinoma by in the setting of clinical and radiological characteristics which, together with the pathology, are highly suggestive of a diagnosis of HCC (Cohort 1) OR

--histopathological confirmation of advanced colorectal or pancreatic malignancy with liver involvement as dominant site of metastasis (Per multidiscipline tumor board review and approval) (Cohort 2).

-Patients must have disease that is not amenable to potentially curative resection, transplantation or ablation.

-Patients must have progressed on, been intolerant to, or refused prior sorafenib/lenvatinib and/or atezolizumab/bevacizumab therapy (Cohort 1 only).

-Subjects must have progressed on or after standard systemic chemotherapy (at least one line of chemotherapy for patients with liver metastasis from PDAC, at least two lines of chemotherapy for patients with liver metastasis from CRC) (Cohort 2 only).

-Patients must have evaluable or measurable disease per RECIST 1.1

-Patients must have lesion accessible for biopsy and be willing to undergo pre- and posttreatment biopsies.

-ECOG performance status of 0 to 1

-If liver cirrhosis is present, patient must have a Child-Pugh score less than or equal to 7

-Active chronic HBV infected subjects must be on antivirals and have HBV DNA <100IU/mL. HCV infected subjects can be enrolled with close HCV RNA level monitoring.

-Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of nivolumab in combination with tadalafil and vancomycin in patients less than 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials

-Adequate hematological function defined by:

--white blood cell (WBC) count greater than or equal to 3 (SqrRoot) 10^9/L

--absolute neutrophil count (ANC) greater than or equal to 1.5 (SqrRoot) 10^9/L,

--lymphocyte count greater than or equal to 0.5 (SqrRoot) 10^9/L,

--platelet count greater than or equal to 60 (SqrRoot) 10^9/L, and

--Hgb greater than or equal to 9 g/ dL (more than 48 hours post-completion of blood transfusion)

-Adequate hepatic function defined by:

--a total bilirubin level less than or equal to 1.5 (SqrRoot) ULN,

--an AST level <5(SqrRoot) ULN,

--an ALT level <5 (SqrRoot) ULN.

-Adequate renal function defined by:

--Creatinine clearance (CrCl) greater than or equal to 50 mL/min/1.73 m^2 by 24 hours urine collection or as predicted by the Cockcroft-Gault formula:

--CrCl = (140 age (y)) x (weight in kg) x (0.85, if female) x1.73 m^2/72 x Serum Creatinine (mg/dL) x pt. s BSA (m^2) Or

-The effects of nivolumab on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and up to 5 months (women) and 7 months (men) after the last dose of the drug. 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.

-Patients with a history of cardiovascular disease may be enrolled per cardiology consultation and approval with echocardiogram and troponin level in normal range at the time of enrollment.

-Patient must be able to understand and willing to sign a written informed consent document.

EXCLUSION CRITERIA:

-Patients who have had standard-of-care anti-cancer therapy or therapy with investigational agents (e.g. chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies or other investigation agents), large field radiotherapy, or major surgery within 4 weeks prior to enrollment.

-Therapy with antibiotics within 30 days prior to enrollment.

-Therapy with nitrates, alpha-blockers, or cytochrome P450 (CYP3A4) inhibitors within 7- days prior to enrollment and for whom stopping is unsafe and/or a safe substitute is not medically recommended. Use of PDE5 inhibitors such as vardenafil (Levitra ), tadalafil (Cialis ), and sildenafil citrate (Viagra ) less than or equal to 15-days prior to enrollment.

-The patient must not be currently on a corticosteroid dose greater than physiologic replacement dosing defined as 10 mg of cortisone per day or its equivalent.

-For PDAC patients with liver metastases, primary PDAC has not been resected (unless the primary is in the tail of the pancreas).

-Patients with known brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.

-Have signs of liver failure, e.g. clinical significant ascites, encephalopathy, or variceal bleeding within 6 months prior to enrollment.

-Prior major liver resection: remnant liver <50% of the initial liver volume. Patients with a biliary stent can be included.

-Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids. These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome or CIDP, myasthenia gravis; systemic autoimmune disease such as SLE, connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn s, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome. Such diseases should be excluded because of the risk of recurrence or exacerbation of disease.

Of note, patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible. Patients with rheumatoid arthritis and other arthropathies, Sjogren s syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible.

-Have history of idiopathic pulmonary fibrosis (including bronchiolitis obliterans with organizing pneumonia) or evidence of active pneumonitis on screening chest CT scan.

-Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

-Patients with myocardial infarction or myocarditis within 12 months prior to enrollment.

-History of severe or unstable cerebrovascular disease.

-Sustained hypotension (<90/50 mmHg) or uncontrolled hypertension (>160/100 mmHg)

-Stroke within 6 months prior to enrollment.

-HIV-positive patients are excluded because HIV causes complicated immune deficiency and study treatment can possess more risks for these patients.

-Have had prior transplant of any kind.

-Have ascites.

-History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab, tadalafil or vancomycin.

-History of severe hypersensitivity reaction to any monoclonal antibody.

-Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years prior to enrollment.

-Pregnant women are excluded from this study because nivolumab s potential for teratogenic or abortifacient effects is unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with nivolumab, breastfeeding should be discontinued if the mother is treated with nivolumab


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Citations:

Not Provided

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Contacts:

Principal Investigator

Referral Contact

For more information:

Tim F. Greten, M.D.
National Cancer Institute (NCI)



Donna M. Hrones, C.R.N.P.
National Cancer Institute (NCI)
BG 10 RM 5B40
10 CENTER DR
BETHESDA MD 20814
(240) 858-3155
donna.mabry@nih.gov

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
1-888-NCI-1937

Clinical Trials Number:

NCT03785210

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