What side effects are associated with this type of intervention?

Common treatments for Neuroendocrine Tumors (NETs) include immunotherapy with monoclonal antibodies such as Pembrolizumab. Known side effects of Pembrolizumab and similar immunotherapies include fatigue, rash, diarrhea, and pruritus. More severe immune-related adverse events can occur, such as pneumonitis, colitis, hepatitis, endocrinopathies (including thyroid dysfunction and diabetes), and nephritis. These side effects result from the immune system attacking normal organs and tissues in addition to the tumor cells.

What prior FDA approvals exist?

Pembrolizumab, an immunotherapy with monoclonal antibodies, has been studied for its efficacy in treating well-differentiated neuroendocrine tumors (NETs) with liver metastases. While the context does not provide specific FDA approvals for pembrolizumab in NETs, it highlights its potential when combined with liver-directed therapies or peptide receptor radionuclide therapy. Other FDA-approved treatments for NETs include everolimus, which has shown efficacy in advanced, non-functional, well-differentiated NETs of gastrointestinal or lung origin, as demonstrated in the RADIANT-4 study. These treatments aim to enhance the immune response against cancer cells and control tumor growth.

What other types of research exist?

Promising novel alternatives to Pembrolizumab for Neuroendocrine Tumors patients include Atezolizumab, Nivolumab, and Peptide Receptor Radionuclide Therapy (PRRT). Atezolizumab has shown safety and efficacy in advanced cancers, including those with brain metastases. Nivolumab has demonstrated exceptional responses in various cancers, including mesothelioma and melanoma. PRRT, which involves targeting tumor cells with a radioactive component attached to a peptide, has shown potential in treating receptor-positive tumors and may work synergistically with immunotherapy.

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Monoclonal Antibodies

Pembrolizumab + Liver-Directed/PRRT for Liver Cancer

Q: What is the mechanism of action of this treatment?

Neuroendocrine Tumors (NETs) are commonly treated with somatostatin analogs like lanreotide, which inhibit hormone secretion and tumor growth, and peptide receptor radionuclide therapy (PRRT), which delivers targeted radiation to tumor cells. Immunotherapy, such as pembrolizumab, uses monoclonal antibodies to enhance the body's immune response against cancer cells by blocking the PD-1/PD-L1 pathway, allowing T-cells to attack tumors more effectively. This is particularly important for NET patients as it offers a targeted approach that can potentially improve outcomes in cases where traditional therapies are less effective.

Phase 2

Waitlist Available

Research Sponsored by Nicholas Fidelman, MD

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Be >= 18 years of age on day of signing informed consent

Have a histologically proven well-differentiated neuroendocrine tumor (WHO grade 1, grade 2, or morphologically and/or clinically well-differentiated grade 3) of any primary site, including unknown primary site

Must not have

Has known active untreated Hepatitis B

Has had prior peptide receptor radionuclide therapy (group 1 only)

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 3 years

Awards & highlights

No Placebo-Only Group

Summary

This trial tests a combination of pembrolizumab and liver-targeted treatments or PRRT for patients with specific liver-spread neuroendocrine tumors. The treatments aim to boost the immune system and directly attack tumors. It focuses on patients whose tumors are difficult to treat with standard methods. Everolimus has demonstrated effectiveness in neuroendocrine neoplasms and has shown a synergistic effect with radiation therapy.

Who is the study for?

This trial is for adults with well-differentiated neuroendocrine tumors that have spread to the liver. Participants must show tumor progression, have a life expectancy over 3 months, and adequate organ function. They should not be pregnant or breastfeeding and agree to use contraception. Exclusions include severe liver involvement by the tumor, active infections, certain medical treatments within specific timeframes before the trial starts, and known allergies to pembrolizumab.

What is being tested?

The effectiveness of combining pembrolizumab (an immunotherapy drug) with either liver-directed therapies (like arterial embolization or radioembolization using Yttrium-90) or peptide receptor radionuclide therapy using 177Lu-DOTA0-Tyr3-Octreotate is being tested in patients with neuroendocrine tumors and liver metastases. The goal is to see if this combination works better than pembrolizumab alone.

What are the potential side effects?

Potential side effects may include immune-related reactions affecting organs, infusion-related symptoms like fever or chills, fatigue, changes in blood counts leading to increased infection risk or bleeding problems. Liver-directed therapies can cause abdominal pain or changes in liver function tests.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am 18 years old or older.

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I have a well-differentiated neuroendocrine tumor.

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My tumor is grade 2 or 3, has a Ki-67 index over 10%, and shows somatostatin receptor expression.

Select...

My cancer has grown or spread in the last year.

Select...

I am fully active or restricted in physically strenuous activity but can do light work.

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My blood counts and organ functions are within the required ranges.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

Select...

I have active, untreated Hepatitis B.

Select...

I have had peptide receptor radionuclide therapy before.

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I've had a procedure on my bile duct that affected the Ampulla of Vater or required a connection between my bile duct and intestines.

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More than 75% of my liver is affected by cancer.

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I have an immune system disorder or have been on steroids or other immune-weakening medicines in the last week.

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I have an active Tuberculosis infection.

Select...

I am currently being treated for an infection.

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I haven't had any cancer treatment with monoclonal antibodies in the last 4 weeks or have recovered from their side effects.

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I have cancer that has spread to my brain or spinal cord.

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I have liver fibrosis confirmed by tests or scans.

Select...

I have been treated with drugs targeting PD-1, PD-L1, or PD-L2.

Select...

I have been diagnosed with HIV.

Select...

I have been treated for an autoimmune disease in the last 2 years.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 3 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 3 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 3 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Number of treatment-related adverse events (Group 1)

Proportion of participants with an overall response

Secondary study objectives

Duration of response (DOR)

Immune-related progression free survival (irPFS)

Median Progression free survival (PFS)

+1 more

Side effects data

From 2024 Phase 3 trial • 804 Patients • NCT03040999

64%

Radiation skin injury

63%

Stomatitis

58%

Anaemia

56%

Nausea

48%

Dry mouth

45%

Constipation

45%

Weight decreased

44%

Dysphagia

42%

Neutrophil count decreased

33%

Dysgeusia

33%

Vomiting

32%

Fatigue

31%

White blood cell count decreased

28%

Hypomagnesaemia

26%

Decreased appetite

25%

Hypothyroidism

25%

Hypokalaemia

24%

Lymphocyte count decreased

24%

Platelet count decreased

23%

Oropharyngeal pain

23%

Blood creatinine increased

22%

Diarrhoea

22%

Odynophagia

20%

Hypoacusis

20%

Alanine aminotransferase increased

20%

Hyponatraemia

19%

Tinnitus

19%

Oral candidiasis

19%

Asthenia

16%

Pyrexia

16%

Cough

15%

Aspartate aminotransferase increased

15%

Rash

14%

Insomnia

13%

Acute kidney injury

13%

Pharyngeal inflammation

13%

Pruritus

12%

Dysphonia

12%

Gamma-glutamyltransferase increased

11%

Pneumonia

11%

Dehydration

10%

Hyperthyroidism

10%

Hypoalbuminaemia

10%

Hypocalcaemia

10%

Headache

10%

Productive cough

Neck pain

Peripheral sensory neuropathy

Gastrooesophageal reflux disease

Hiccups

Hyperglycaemia

Hyperuricaemia

Dizziness

Hypophosphataemia

Urinary tract infection

Ear pain

Localised oedema

Hyperkalaemia

Erythema

Oral pain

Abdominal pain upper

Arthralgia

Anxiety

Febrile neutropenia

Dyspepsia

Saliva altered

Back pain

Oedema peripheral

Hypertension

Dyspnoea

Nasopharyngitis

Alopecia

Dry skin

Sepsis

Pneumonia aspiration

Trismus

Pneumonitis

Laryngeal oedema

Malnutrition

Pharyngeal haemorrhage

Cellulitis

Septic shock

Systemic infection

Clostridium difficile colitis

Cardiac arrest

Death

Bronchitis

Hepatitis

Immune-mediated hepatitis

Oesophagitis

General physical health deterioration

Hypophagia

Tumour haemorrhage

Cerebrovascular accident

Syncope

Acute respiratory failure

Aspiration

Colitis

Mouth haemorrhage

Hypersensitivity

Acute myocardial infarction

Abscess neck

Device related infection

Stoma site infection

Vascular device infection

Wound infection

Hypercalcaemia

Pulmonary embolism

Respiratory failure

100%

80%

60%

40%

20%

Study treatment Arm

Pembrolizumab + CRT Followed by Pembrolizumab

Placebo + CRT Followed by Placebo

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

3Treatment groups

Experimental Treatment

Group I: Group III [pembrolizumab, yttrium-90 microsphere RE] (CLOSED)Experimental Treatment2 Interventions

Patients receive pembrolizumab as in Group I. Patients with any number of liver lesions, largest measuring more than 5 cm, who have \< 75% liver parenchyma replacement by tumors, undergo yttrium-90 microsphere Radio Embolization (RE) 3-15 days following the first dose of pembrolizumab.

Group II: Group II [pembrolizumab, TAE] (CLOSED)Experimental Treatment2 Interventions

Patients receive pembrolizumab as in Group I. Patients with any number of liver lesions, largest being no larger than 5 cm, who have \< 75% liver parenchyma replacement by tumors, undergo Arterial Embolization (TAE) over 2-3 hours, 3-7 days following the first dose of pembrolizumab.

Group III: Group I [pembrolizumab, 177Lu DOTATATE]Experimental Treatment2 Interventions

Patients will be treated with pembrolizumab and intravenous peptide receptor radionuclide therapy (PRRT) using 177Lu-DOTA0-Tyr3-Octreotate (177Lu-DOTATATE, Lutathera®) for up to four (4) sessions. Patients with somatostatin receptor positive (SSTR+) tumors with Ki-67 index \> 20% (well-differentiated grade 3) and any number of liver and/or extrahepatic lesions with liver parenchyma replacement by tumor \< 75%. Patients who achieve progressive or stable disease response after cycle 4 may receive an additional 4 cycles of pembrolizumab and lutetium Lu-177 DOTATATE in the absence of disease progression or unacceptable toxicity and pembrolizumab for up to 35 cycles.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Arterial Embolization

2016

Completed Phase 2

~10

Pembrolizumab

2017

Completed Phase 3

~3130

0 / 19Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Neuroendocrine Tumors (NETs) are commonly treated with somatostatin analogs like lanreotide, which inhibit hormone secretion and tumor growth, and peptide receptor radionuclide therapy (PRRT), which delivers targeted radiation to tumor cells. Immunotherapy, such as pembrolizumab, uses monoclonal antibodies to enhance the body's immune response against cancer cells by blocking the PD-1/PD-L1 pathway, allowing T-cells to attack tumors more effectively. This is particularly important for NET patients as it offers a targeted approach that can potentially improve outcomes in cases where traditional therapies are less effective.

Inclusion body myositis: update.