Pemigatinib + Durvalumab for Liver Cancer

Overseen By Allison Lipps

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Mehmet Akce

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Corneal disorders, Retinal disorders, Autoimmune disorders, 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

Compensation: Varies

Number of Visits: 1

Duration: 24 months

38 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a single arm phase II study of pemigatinib and durvalumab combination in patients with FGFR-2 fusion or rearrangement positive intrahepatic cholangiocarcinoma. Each cycle will be 3 weeks. Pemigatinib is administered at 13.5 mg orally daily 2 weeks on and 1 week off. Durvalumab is administered at 1500 mg intravenously once every 3 weeks. Subjects will require a visit with appropriate laboratory work prior to the start of each cycle. Disease assessment will occur every 9 weeks. Subjects will continue treatment until progression per RECIST 1.1, toxicity or subject/physician decision. A maximum of 24 months (about 35 cycles) of pemigatinib and durvalumab treatment from Cycle 1 Day 1 is allowed.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot use any potent CYP3A4 inhibitors or inducers within 14 days before starting the study drug, and you must have a washout period of at least 28 days after your last dose of anticancer therapy before starting the trial.

What data supports the effectiveness of the drug Durvalumab in treating liver cancer?

Durvalumab, a drug that helps the immune system fight cancer, has shown benefits in treating advanced liver cancer by prolonging survival. It has also been effective in other cancers like lung and bladder cancer, suggesting it could be helpful for liver cancer too. ^{1 2 3 4 5}

What safety data exists for the combination of Pemigatinib and Durvalumab in humans?

Durvalumab, also known as Imfinzi or MEDI4736, has been associated with an increased risk of immune-related side effects, such as pneumonitis (lung inflammation) and liver injury, which can be serious. These side effects have been observed in patients with various cancers, including lung and liver cancer, when using Durvalumab alone or in combination with other treatments. ^{1 2 5 6 7}

What makes the drug combination of Pemigatinib and Durvalumab unique for liver cancer treatment?

The combination of Pemigatinib and Durvalumab is unique for liver cancer treatment because it combines a targeted therapy (Pemigatinib) with an immunotherapy (Durvalumab). Pemigatinib targets specific genetic mutations in cancer cells, while Durvalumab helps the immune system recognize and attack cancer cells by blocking the PD-L1 protein. This dual approach may offer a novel way to treat liver cancer compared to traditional therapies. ^{1 2 5 7 8}

Research Team

Mehmet Akce, MD

Principal Investigator

Sponsor-Investigator

Eligibility Criteria

This trial is for patients who have already been treated for advanced intrahepatic cholangiocarcinoma, a type of liver cancer, and have specific genetic changes called FGFR-2 fusion or rearrangement. Participants must meet certain health standards and agree to regular visits with lab work.

Inclusion Criteria

1. Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.

3. ECOG Performance Status of 0 or 1 within 7 days prior to Cycle 1 Day 1.

4. Body weight of \> 30 kg.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pemigatinib and durvalumab combination therapy. Each cycle is 3 weeks, with pemigatinib administered orally for 2 weeks followed by 1 week off, and durvalumab administered intravenously every 3 weeks.

24 months

1 visit per cycle (in-person) with laboratory work

Follow-up

Participants are monitored for safety and effectiveness after treatment completion or discontinuation.

4 weeks

Treatment Details

Interventions

• Durvalumab
• Pemigatinib

Trial Overview The study tests a combination of two drugs: Pemigatinib taken orally in cycles (2 weeks on, 1 week off) and Durvalumab given intravenously every 3 weeks. Patients will be monitored every 9 weeks to assess the treatment's effect on their disease over up to 24 months.

Participant Groups

Group I: Pemigatinib + Durvalumab Experimental Treatment 2 Interventions

Pemigatinib 13.5 mg will be taken orally at the same time each day for 14 days (Day 1 through Day 14), followed by 7 days off treatment (Day 15 through Day 21) of each 21 day cycle. Durvalumab 1500 mg IV will be administered every 3 weeks on Day 1 of each 21-day cycle.

Durvalumab is already approved in European Union, United States, Japan for the following indications:

Approved in European Union as Imfinzi for:

• Locally advanced, unresectable non-small cell lung cancer (NSCLC)

Approved in United States as Imfinzi for:

• Extensive-stage small cell lung cancer (ES-SCLC)
• Limited-stage small cell lung cancer (LS-SCLC)
• Locally advanced or metastatic urothelial carcinoma

Approved in Japan as Imfinzi for:

• Not specified in provided sources

Who Is Running the Clinical Trial?

Mehmet Akce

Lead Sponsor

Trials

2

Recruited

70+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

University of Alabama at Birmingham

Collaborator

Trials

1,677

Recruited

2,458,000+

Findings from Research

Durvalumab, a PD-L1 inhibitor, has been shown to be safe for patients with various solid tumors, with common side effects including pruritus and fatigue, based on a meta-analysis of 17 studies involving 1,529 patients.

Higher levels of PD-L1 expression in tumors are linked to better treatment responses to durvalumab, indicating that PD-L1 could serve as a useful biomarker for predicting the drug's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. Yang, H., Shen, K., Zhu, C., et al.[2022]

Durvalumab, a PD-L1 blocking antibody, has shown clinical efficacy and a manageable safety profile in treating advanced non-small-cell lung cancer, especially in patients with ≥25% PD-L1 expression.

The drug is being evaluated in various treatment settings, including as a monotherapy and in combination with other therapies, showing promising results particularly after chemoradiation, although lower response rates were noted in patients with EGFR and ALK mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab in non-small-cell lung cancer patients: current developments. Mezquita, L., Planchard, D.[2018]

Durvalumab is an FDA-approved monoclonal antibody that enhances T-cell responses against cancer by blocking the PD-L1 pathway, specifically for patients with advanced urothelial carcinoma who have progressed after platinum-based chemotherapy.

The drug is currently being tested in phase III trials for various cancers, including lung and head and neck cancers, indicating its potential broad application in oncology beyond urothelial carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. Syed, YY.[2022]

Immune checkpoint inhibitors (ICIs) like anti-PD-1 and anti-CTLA-4 antibodies are effective treatments for metastatic melanoma and other advanced cancers, with biomarkers such as PD-L1 expression and tumor mutational load helping to predict patient response.

Current clinical practice uses biomarkers like pre-treatment tumor burden and serum lactate dehydrogenase levels to estimate the effectiveness of ICIs, while emerging research on the gut microbiome and imaging biomarkers may further enhance prediction of treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomarkers for Clinical Benefit of Immune Checkpoint Inhibitor Treatment-A Review From the Melanoma Perspective and Beyond. Buder-Bakhaya, K., Hassel, JC.[2022]

The DEDUCTIVE trial is a phase Ib study evaluating the safety and tolerability of combining durvalumab, a PD-L1 inhibitor, with tivozanib, a VEGFR tyrosine kinase inhibitor, in patients with advanced hepatocellular carcinoma (HCC).

Both durvalumab and tivozanib have shown effectiveness as single agents in HCC, but this trial aims to explore their concurrent use, particularly in treatment-naive patients and those who have progressed on other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter, phase Ib/II, open-label study of tivozanib with durvalumab in advanced hepatocellular carcinoma (DEDUCTIVE). Mahmood, S., Li, D., Lee, A., et al.[2023]

In a study of 83 patients with unresectable stage III non-small cell lung cancer (NSCLC) receiving durvalumab, 25.3% experienced pneumonitis, confirming the risk associated with this treatment.

The incidence of pneumonitis observed in this real-world setting aligns with findings from the PACIFIC trial, indicating that the safety profile of durvalumab is consistent in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Incidence of Pneumonitis in Patients Receiving Durvalumab. LeClair, JN., Merl, MY., Cohenuram, M., et al.[2022]

In a study of 112 patients receiving durvalumab for cancer treatment, 19% experienced liver injury, which was linked to higher rates of tumor progression and mortality, indicating that liver injury may be a significant concern in this patient population.

Among the liver injury cases, 29% were classified as probable drug-induced liver injury (DILI) related to durvalumab, but these cases were generally mild and self-limited, suggesting that while monitoring for liver injury is important, severe complications are rare.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liver injury during durvalumab-based immunotherapy is associated with poorer patient survival: A retrospective analysis. Swanson, LA., Kassab, I., Tsung, I., et al.[2023]

Durvalumab, an immunotherapy drug for non-small cell lung cancer (NSCLC), has shown significant activity and acceptable tolerability, especially in patients with at least 25% PD-L1 tumor expression, and has been established as a standard treatment following chemoradiation based on the PACIFIC study results.

While durvalumab is effective in wild-type EGFR and ALK patients, its efficacy is lower in those with EGFR mutations or ALK-positive status, highlighting the need for ongoing research into combination therapies and the management of treatment-related toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab for the treatment of non-small cell lung cancer. Mezquita, L., Planchard, D.[2019]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Durvalumab in non-small-cell lung cancer patients: current developments. [2018]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Biomarkers for Clinical Benefit of Immune Checkpoint Inhibitor Treatment-A Review From the Melanoma Perspective and Beyond. [2022]

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

A multicenter, phase Ib/II, open-label study of tivozanib with durvalumab in advanced hepatocellular carcinoma (DEDUCTIVE). [2023]

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

Real-World Incidence of Pneumonitis in Patients Receiving Durvalumab. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Liver injury during durvalumab-based immunotherapy is associated with poorer patient survival: A retrospective analysis. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Durvalumab for the treatment of non-small cell lung cancer. [2019]