Pembrolizumab + Liver-Directed/PRRT for Liver Cancer

Overseen By UCSF HDFCCC Cancer Immunotherapy Program

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Nicholas Fidelman, MD

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Immunodeficiency, Active TB, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 33

Duration: Up to 24 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of combining pembrolizumab (an immunotherapy drug) with other liver-targeted treatments for individuals with neuroendocrine tumors that have spread to the liver. These treatments may help the immune system attack cancer and inhibit its growth. The trial targets individuals with tumors that have shown symptoms or signs of progression over the past year. Those with neuroendocrine tumors exhibiting specific characteristics and signs of growth or change may be suitable candidates for this study. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it does allow concurrent somatostatin analog therapy, and you should not be on systemic steroid therapy or immunosuppressive therapy within 7 days before starting the trial treatment.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that pembrolizumab, when combined with peptide receptor radionuclide therapy (PRRT), is generally safe. One study found that patients receiving this combination experienced positive results with manageable side effects. In another study, patients treated with pembrolizumab and arterial embolization had a 17% rate of severe side effects, which is considered manageable for cancer treatments.

For those using pembrolizumab with yttrium-90 radioembolization, research indicates that this combination is safe and tolerable, even for patients with advanced liver cancer. This suggests the treatment is generally well-tolerated and has fewer side effects compared to some other cancer treatments.

Overall, these combinations with pembrolizumab have demonstrated promising safety results. However, like any treatment, there are risks of side effects. Potential trial participants should discuss the possible risks and benefits with their healthcare providers. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for liver cancer focus on chemotherapy, targeted therapy, or surgery. However, pembrolizumab, combined with different liver-directed therapies, offers a unique approach. Researchers are excited about these treatments because pembrolizumab is an immunotherapy that helps the immune system recognize and attack cancer cells. In Group I, the addition of 177Lu-DOTATATE, a peptide receptor radionuclide therapy (PRRT), targets and delivers radiation directly to cancer cells, sparing surrounding healthy tissue. This dual approach of activating the immune system and delivering targeted radiation could potentially enhance effectiveness and reduce side effects compared to traditional treatments.

What evidence suggests that this trial's treatments could be effective for liver cancer?

Research has shown that combining pembrolizumab with peptide receptor radionuclide therapy (PRRT) may help treat neuroendocrine tumors that have spread to the liver. In this trial, participants in Group I will receive pembrolizumab and PRRT. Early studies suggest that PRRT can directly target tumor cells and may boost the immune system, aiding in tumor shrinkage.

Although Groups II and III are closed, previous studies have demonstrated that using pembrolizumab with arterial embolization resulted in a median time of 9.9 months before disease progression. Similarly, pembrolizumab combined with yttrium-90 microsphere radioembolization has been found safe and manageable, with early results indicating potential effectiveness for liver cancer. These combinations aim to precisely target tumors and encourage the immune system to fight cancer cells. ^{1 6 7 8 9}

Who Is on the Research Team?

Nicholas Fidelman, MD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

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.

Inclusion Criteria

I am using two birth control methods or am not having sex to join this study.

I have a well-differentiated neuroendocrine tumor.

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

Exclusion Criteria

I have active, untreated Hepatitis B.

I have not received a live vaccine within the last 30 days.

I have had peptide receptor radionuclide therapy before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab intravenously every 21 days for up to 35 courses, with PRRT using 177Lu-DOTATATE administered every 8 weeks for up to four treatments

Up to 24 months

Visits every 3 weeks for pembrolizumab, every 8 weeks for PRRT

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Follow-up at 30 days post-treatment, then every 3-6 months

What Are the Treatments Tested in This Trial?

Interventions

• Arterial Embolization
• Pembrolizumab
• Peptide Receptor Radionuclide Therapy (PRRT) using 177Lu-DOTA0-Tyr3-Octreotate
• Yttrium-90 Microsphere Radioembolization

Trial Overview

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.

How Is the Trial Designed?

Group I: Group III [pembrolizumab, yttrium-90 microsphere RE] (CLOSED) Experimental Treatment 2 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 Treatment 2 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 Treatment 2 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.

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

Nicholas Fidelman, MD

Lead Sponsor

Trials

2

Recruited

70+

BTG International Inc.

Collaborator

Trials

43

Recruited

3,100+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

In a phase III trial involving 453 patients with advanced hepatocellular carcinoma (HCC), pembrolizumab significantly improved overall survival (14.6 months vs. 13.0 months for placebo) and progression-free survival (2.6 months vs. 2.3 months for placebo).

The objective response rate (ORR) was notably higher in the pembrolizumab group (12.7%) compared to the placebo group (1.3%), although treatment-related adverse events were more common in the pembrolizumab group (66.9% vs. 49.7% for placebo).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Versus Placebo as Second-Line Therapy in Patients From Asia With Advanced Hepatocellular Carcinoma: A Randomized, Double-Blind, Phase III Trial. Qin, S., Chen, Z., Fang, W., et al.[2023]

In a study of 104 patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib, pembrolizumab showed an objective response rate of 18.3% and a median duration of response of 21 months, indicating its effectiveness as a treatment option.

After approximately 2.5 years of follow-up, pembrolizumab demonstrated durable anti-tumor activity with manageable safety, as most treatment-related adverse events were low grade, and no new safety concerns were identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated efficacy and safety of KEYNOTE-224: a phase II study of pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. Kudo, M., Finn, RS., Edeline, J., et al.[2022]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

In a phase II trial involving 51 patients with advanced hepatocellular carcinoma (HCC) who had not received prior systemic therapy, pembrolizumab demonstrated a 16% objective response rate, indicating its potential effectiveness in this patient population.

The treatment showed a median overall survival of 17 months and a median duration of response of 16 months, with a safety profile that included grade ≥3 treatment-related adverse events in 16% of patients, suggesting it is tolerable for use in advanced HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: Data from the Open-Label, Phase II KEYNOTE-224 Trial. Verset, G., Borbath, I., Karwal, M., et al.[2023]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

In a study of 491 oncology patients treated with pembrolizumab, 14.3% developed liver injury, with a median onset of 62 days, and those with liver injury had significantly poorer outcomes, including lower rates of tumor remission and higher mortality.

Only 28.6% of liver injury cases were confirmed as drug-induced hepatotoxicity, indicating that careful evaluation is necessary before administering corticosteroids, as these patients had better outcomes compared to those with unconfirmed liver injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liver injury is most commonly due to hepatic metastases rather than drug hepatotoxicity during pembrolizumab immunotherapy. Tsung, I., Dolan, R., Lao, CD., et al.[2020]

In a phase 2 trial involving 104 patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib, pembrolizumab demonstrated an objective response rate of 17%, indicating its potential efficacy as a treatment option for this patient population.

While 73% of patients experienced treatment-related adverse events, most were manageable, with serious events occurring in 15% of patients, suggesting that pembrolizumab is generally tolerable for patients with advanced liver cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Zhu, AX., Finn, RS., Edeline, J., et al.[2022]

In a phase III study involving 413 patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib, pembrolizumab showed a median overall survival of 13.9 months compared to 10.6 months for placebo, indicating its potential effectiveness as a treatment option.

While pembrolizumab demonstrated improved overall survival and progression-free survival compared to placebo, the study noted a higher incidence of grade 3 or higher adverse events, suggesting a need to weigh the benefits against the risks when considering this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. Finn, RS., Ryoo, BY., Merle, P., et al.[2020]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12057501/

Efficacy and challenges of combining transarterial ...

Another study also reported better outcomes including a median PFS of 9.9 months and median OS of 22.6 months in the combination therapy (15).

2.

merck.com

merck.com/news/mercks-keytruda-pembrolizumab-significantly-improved-overall-survival-os-versus-placebo-in-certain-patients-with-advanced-hepatocellular-carcinoma-hcc-previously-treated-with-sora/

Merck's KEYTRUDA® (pembrolizumab) Significantly ...

Additional efficacy endpoint results of the trial showed KEYTRUDA plus BSC reduced the risk of disease progression or death by 26% (HR=0.74 [95 ...

3.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11145164/

Safety and Preliminary Efficacy of Pembrolizumab Following ...

Patients with liver-confined hepatocellular carcinoma (HCC) were planned to receive up to two rounds of TACE followed by pembrolizumab 200 mg every 21 days ...

4.

tandfonline.com

tandfonline.com/doi/full/10.2217/fon-2022-0916

PETAL protocol: a phase Ib study of pembrolizumab after ...

Median OS achieved with atezolizumab plus bevacizumab was as high as 19.2 months, almost as high as the survival reported in TACE trials [Citation14]. Recently, ...

5.

eisai.com

eisai.com/news/2024/news202466.html

LENVIMA® (lenvatinib) Plus KEYTRUDA® ...

LENVIMA plus KEYTRUDA in combination with TACE reduced the risk of disease progression or death by 34% compared to TACE alone.

6.

merck.com

merck.com/news/merck-and-eisai-provide-update-on-phase-3-leap-012-trial-in-unresectable-non-metastatic-hepatocellular-carcinoma/

Merck and Eisai Provide Update on Phase 3 LEAP-012 ...

The five-year relative survival rate for liver cancer in the U.S. is 22% based on Surveillance, Epidemiology, and End Results (SEER) data from ...

7.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03062358

NCT03062358 | Study of Pembrolizumab (MK-3475) or ...

The primary hypothesis of this study is that overall survival is prolonged in participants who receive pembrolizumab compared to those who receive placebo.

8.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/38578610/

Safety and Preliminary Efficacy of Pembrolizumab ...

Median duration of response was 7.3 months (95% CI: 6.3-8.3). Median overall survival was 33.5 months (95% CI: 11.6-NE). Dynamic changes in ...

9.

researchgate.net

researchgate.net/publication/293641599_525_Safety_and_efficacy_of_pembrolizumab_MK-3475_in_patients_pts_with_advanced_biliary_tract_cancer_Interim_results_of_KEYNOTE-028

525 Safety and efficacy of pembrolizumab (MK-3475) in ...

The overall response rate (ORR) was 13.0% with 17% of patients experiencing grade 3 − 4 treatment-related AEs [14] . The duration of response ...