ALN-BCAT + Pembrolizumab for Liver Cancer

Recruiting in Palo Alto (17 mi)

+6 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Alnylam Pharmaceuticals

Must not be taking: Anti-cancer, Investigational drugs

Disqualifiers: Fibrolamellar HCC, Symptomatic extrahepatic, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

The purpose of the dose escalation part of the study is to characterize the safety and tolerability of ALN-BCAT as monotherapy and in combination with pembrolizumab; and to determine the recommended dose(s) for expansion (RDFE) of ALN-BCAT as monotherapy and in combination with pembrolizumab. The purpose of the dose expansion part of the of the study is to evaluate the antitumor activity of ALN-BCAT as monotherapy and in combination with pembrolizumab; to characterize the safety and tolerability of ALN-BCAT as monotherapy and in combination with pembrolizumab.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must not have received any anti-cancer therapy or investigational drugs within 3 weeks before starting the study.

What data supports the effectiveness of the drug ALN-BCAT + Pembrolizumab for liver cancer?

Research shows that pembrolizumab, one of the drugs in the treatment, has been effective in treating advanced liver cancer, as seen in trials where it was used alone or with other treatments. ^{1 2 3 4 5}

What safety information is available for ALN-BCAT and Pembrolizumab (Keytruda) in humans?

Pembrolizumab (Keytruda) has been studied in various cancers and is generally well tolerated, but it can cause side effects like fatigue, rash, itching, and diarrhea. Rarely, it may lead to immune-related issues such as thyroid problems, liver inflammation, and lung inflammation. There is no specific safety data available for ALN-BCAT. ^{1 6 7 8 9}

How is the drug ALN-BCAT + Pembrolizumab unique for liver cancer treatment?

The combination of ALN-BCAT and pembrolizumab is unique for liver cancer treatment because pembrolizumab is an immune checkpoint inhibitor that has shown promise in treating advanced liver cancer by helping the immune system attack cancer cells, and ALN-BCAT may offer a novel mechanism or synergy, although specific details about ALN-BCAT are not provided in the available research. ^{1 2 4 10 11}

Research Team

Medical Director

Principal Investigator

Alnylam Pharmaceuticals

Eligibility Criteria

This trial is for patients with hepatocellular carcinoma, a type of liver cancer. Participants should meet specific health criteria set by the study's guidelines to be eligible.

Inclusion Criteria

My liver cancer diagnosis is confirmed by a doctor's evaluation or tests.

My liver function is mildly to moderately impaired.

I have received treatment for cancer that cannot be surgically removed.

Exclusion Criteria

My liver cancer is of a specific type (fibrolamellar, sarcomatoid, or mixed).

I have symptoms from cancer that has spread outside my liver.

I haven't taken any cancer treatment or trial drugs in the last 3 weeks.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Characterize the safety and tolerability of ALN-BCAT as monotherapy and in combination with pembrolizumab; determine the recommended dose(s) for expansion

8-12 weeks

Dose Expansion

Evaluate the antitumor activity of ALN-BCAT as monotherapy and in combination with pembrolizumab; characterize the safety and tolerability

12-16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• ALN-BCAT (RNA-based Therapy)
• Pembrolizumab (Checkpoint Inhibitor)

Trial Overview The trial is testing ALN-BCAT alone and in combination with Pembrolizumab. It aims to find safe dosages, understand side effects, and assess how well these treatments work against liver cancer.

Participant Groups

Group I: Monotherapy: Dose Expansion Experimental Treatment 1 Intervention

Patients will be administered multiple doses of ALN-BCAT.

Group II: Monotherapy: Dose Escalation Experimental Treatment 1 Intervention

Patients will be administered multiple doses of ALN-BCAT.

Group III: Combination Therapy: Dose Expansion Experimental Treatment 2 Interventions

Patients will be administered multiple doses of ALN-BCAT in combination with pembrolizumab.

Group IV: Combination Therapy: Dose Escalation Experimental Treatment 2 Interventions

Patients will be administered multiple doses of ALN-BCAT in combination with pembrolizumab.

Who Is Running the Clinical Trial?

Alnylam Pharmaceuticals

Lead Sponsor

Trials

81

Recruited

16,100+

Dr. Yvonne Greenstreet

Alnylam Pharmaceuticals

Chief Executive Officer since 2021

MD from the University of Leeds, MBA from INSEAD

Dr. Pushkal Garg

Alnylam Pharmaceuticals

Chief Medical Officer since 2016

MD from Columbia University

Findings from Research

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 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 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]

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]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., et al.[2022]

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]

Pembrolizumab, an anti-PD-1 antibody, has shown significant efficacy in treating advanced melanoma, demonstrating superior progression-free survival compared to chemotherapy in Phase II trials and improved overall survival in Phase III trials.

The treatment is generally well tolerated with a favorable safety profile, though common side effects include fatigue and rash, while less frequent but serious immune-related adverse events can occur.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the management of metastatic melanoma. Spain, L., Younger, E., Hatipoglu, E., et al.[2020]

Pembrolizumab (Keytruda) was approved by the FDA for treating metastatic non-small cell lung cancer (mNSCLC) in patients with tumors expressing PD-L1, showing significant improvements in overall survival (OS) and progression-free survival (PFS) in two major clinical trials with thousands of participants.

In the KEYNOTE-024 trial, pembrolizumab demonstrated a 40% reduction in the risk of death compared to chemotherapy, while in the KEYNOTE-010 trial, it also showed a significant survival advantage over chemotherapy in patients who had previously progressed on treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. Pai-Scherf, L., Blumenthal, GM., Li, H., et al.[2022]

In a study of 120 patients with advanced hepatocellular carcinoma (HCC), both nivolumab and pembrolizumab showed comparable efficacy, with response rates of 8.0% for pembrolizumab and 7.4% for nivolumab, and similar median progression-free survival (PFS) of 2.7 months and 2.9 months, respectively.

The median overall survival (OS) was longer for nivolumab at 10.8 months compared to 8.1 months for pembrolizumab, but this difference was not statistically significant, indicating that both treatments are similarly effective in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world comparison of pembrolizumab and nivolumab in advanced hepatocellular carcinoma. Chen, YH., Tsai, CH., Chen, YY., et al.[2023]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]

2. England 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. [2022]

3. United States 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. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: Data from the Open-Label, Phase II KEYNOTE-224 Trial. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab with low-dose carboplatin for recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer: survival and immune correlates. [2022]

6. United States 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. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the management of metastatic melanoma. [2020]

10. England pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Real-world comparison of pembrolizumab and nivolumab in advanced hepatocellular carcinoma. [2023]