Durvalumab + Oleclumab/Monalizumab for Lung Cancer

(PACIFIC-9 Trial)

Not currently recruiting at 229 trial locations

Overseen By AstraZeneca Lung Cancer Study Locator Service

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must not be taking: Immunosuppressants

Disqualifiers: Other malignancy, Pneumonitis, Autoimmune disorders, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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: Unknown

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness and safety of combining durvalumab, a cancer-fighting drug, with either oleclumab or monalizumab to treat a specific type of lung cancer that cannot be removed by surgery. It targets individuals with non-small cell lung cancer (NSCLC) who have undergone chemotherapy and radiation without cancer progression. Participants will receive one of three treatments: durvalumab with oleclumab, durvalumab with monalizumab, or durvalumab with a placebo (a substance with no therapeutic effect). Eligible individuals must have completed chemotherapy and radiation treatment without further disease progression. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial requires that you stop using immunosuppressive medications (drugs that lower the body's ability to fight infections) within 14 days before starting the study treatment. Other medications are not specifically mentioned, so it's best to discuss your current medications with the trial team.

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

Research has shown that durvalumab is generally safe for patients with various solid cancers. When combined with tremelimumab, it is well-tolerated and can improve patient outcomes. Oleclumab, sometimes used with durvalumab, has been tested in patients with advanced colorectal cancer and is considered safe.

Studies suggest that monalizumab is safe when used with durvalumab and chemotherapy for treating small cell lung cancer. This combination has been tested in clinical settings with a focus on safety.

Both combinations—durvalumab with oleclumab and durvalumab with monalizumab—have been part of several studies to ensure they do not cause severe side effects in most patients. These findings support the safety of these treatments for further testing in clinical trials like the one under consideration. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments involving Durvalumab combined with Oleclumab and Monalizumab for lung cancer because they offer novel approaches to enhancing the body's immune response against cancer cells. Most treatments for lung cancer, like chemotherapy and radiotherapy, directly attack cancer cells, but these can also damage healthy cells. Durvalumab works differently by blocking a protein called PD-L1, which helps immune cells recognize and attack cancer cells more effectively. Oleclumab targets another protein, CD73, potentially increasing the anti-tumor activity by reducing immune suppression in the tumor environment. Meanwhile, Monalizumab blocks NKG2A, a receptor that can inhibit immune cells, thus unleashing a more robust immune attack on cancer cells. These mechanisms offer a promising new approach to treating lung cancer by harnessing and directing the body's natural defenses.

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

In this trial, participants will receive different treatment combinations to assess their effectiveness for non-small cell lung cancer (NSCLC). Previous studies have shown promising results when combining durvalumab with either oleclumab or monalizumab. Specifically, the combination of durvalumab and oleclumab achieved a progression-free survival (PFS) rate of 64.8% after 10 months, indicating patients lived longer without cancer worsening. Meanwhile, the combination of durvalumab and monalizumab achieved an even higher PFS rate of 72.7%. These combinations proved more effective than durvalumab alone, which had a PFS rate of 39.2%. Durvalumab is known to help stop cancer from growing or spreading after chemotherapy and radiation. These findings suggest that adding oleclumab or monalizumab to durvalumab may improve outcomes for patients with this type of lung cancer. ^{1 6 7 8 9}

Who Is on the Research Team?

Fabrice Barlesi, MD

Principal Investigator

Gustave Roussy, Cancer Campus, Grand Paris

Are You a Good Fit for This Trial?

Adults over 18 with Stage III unresectable Non-Small Cell Lung Cancer (NSCLC) who haven't worsened after platinum-based chemoradiation. They must have normal organ function, no history of certain autoimmune diseases or other cancers within the last 5 years, and not be on immunosuppressants.

Inclusion Criteria

I have provided a tumor tissue sample before starting CRT.

My organs and bone marrow are working well.

Your tumor has been tested for PD-L1 status by a central laboratory.

Exclusion Criteria

My lung cancer is a mix of small cell and non-small cell types.

My Stage III NSCLC has worsened despite platinum-based treatments.

I don't have lasting side effects from previous cancer treatments, except for hair loss.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Durvalumab in combination with Oleclumab or Monalizumab, or Durvalumab with placebo, administered in 28-day cycles for up to 12 months

12 months

Monthly visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, including progression-free survival and overall survival assessments

Up to 9 years

What Are the Treatments Tested in This Trial?

Interventions

• Durvalumab
• Monalizumab
• Oleclumab

Trial Overview The study is testing Durvalumab in combination with either Oleclumab or Monalizumab against a placebo to see if they improve outcomes for NSCLC patients post-chemoradiation. It's randomized and double-blind, meaning neither doctors nor patients know who gets which treatment.

How Is the Trial Designed?

Group I: Arm B: Durvalumab and Monalizumab Experimental Treatment 3 Interventions

Durvalumab + Monalizumab on Day 1 of each 28-day cycle for up to 12 months. Placebo infusion will be administered on Day 15 of cycles 1 and 2 only

Group II: Arm A: Durvalumab and Oleclumab Experimental Treatment 2 Interventions

Durvalumab on Day 1 of each 28-day cycle + Oleclumab on Days 1 and 15 of cycles 1 and 2, then on Day 1 of each subsequent 28-day cycle for up to 12 months

Group III: Arm C: Durvalumab and Placebo Active Control 2 Interventions

Durvalumab on Day 1 of each 28-day cycle + Placebo on Days 1 and 15 of cycles 1 and 2, then on Day 1 of each subsequent 28-day cycle for up to 12 months

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?

AstraZeneca

Lead 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

Published Research Related to This Trial

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]

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]

The combination of durvalumab and tremelimumab in cancer treatment is associated with a higher incidence of severe adverse events (32.6%) compared to durvalumab alone (23.8%), indicating increased safety concerns with the combination therapy.

Patients receiving the combination therapy also experienced higher rates of specific side effects such as diarrhea (15.6% vs. 8.1%), rash (11.1% vs. 6.5%), and treatment discontinuation (18% vs. 3%), highlighting the need for careful monitoring and patient counseling regarding these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. Fahmy, O., Ahmed, OAA., Khairul-Asri, MG., et al.[2023]

In the phase III PACIFIC trial, durvalumab significantly improved overall survival (OS) and progression-free survival (PFS) in patients with unresectable stage III non-small-cell lung cancer after chemoradiotherapy, with a 5-year OS rate of 42.9% compared to 33.4% for placebo.

The updated analyses, with a median follow-up of 34.2 months, showed that durvalumab continues to provide durable benefits, establishing a new standard of care for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Five-Year Survival Outcomes From the PACIFIC Trial: Durvalumab After Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. Spigel, DR., Faivre-Finn, C., Gray, JE., et al.[2022]

In a phase II study involving 189 patients with unresectable stage III non-small-cell lung cancer, combining durvalumab with either oleclumab or monalizumab significantly improved the overall response rate (ORR) and progression-free survival (PFS) compared to durvalumab alone.

The safety profile of the combination therapies was similar to durvalumab alone, with no new significant safety concerns, indicating that these combinations could be promising options for further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

COAST: An Open-Label, Phase II, Multidrug Platform Study of Durvalumab Alone or in Combination With Oleclumab or Monalizumab in Patients With Unresectable, Stage III Non-Small-Cell Lung Cancer. Herbst, RS., Majem, M., Barlesi, F., et al.[2022]

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 the phase III PACIFIC trial, durvalumab treatment led to a low incidence of immune-mediated adverse events (imAEs), with any-grade immune-mediated pneumonitis occurring in 9.4% of patients and grade 3/4 imAEs in only 3.4%.

Despite the occurrence of imAEs being more common with durvalumab compared to placebo, these events were generally manageable with treatments like corticosteroids, indicating that the benefits of the PACIFIC regimen outweigh the risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterizing immune-mediated adverse events with durvalumab in patients with unresectable stage III NSCLC: A post-hoc analysis of the PACIFIC trial. Naidoo, J., Vansteenkiste, JF., Faivre-Finn, C., et al.[2022]

In a study of 121 patients with stage III non-small cell lung cancer treated with durvalumab, those with over 50% PD-L1 expression had significantly better outcomes, with a 1-year survival rate of 97% compared to 73% and 78% for lower expression groups.

Higher PD-L1 expression (>50%) was strongly associated with improved progression-free survival and overall survival, indicating that PD-L1 levels could be a key factor in predicting the effectiveness of durvalumab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor PD-L1 expression is associated with outcomes in stage III non-small cell lung cancer (NSCLC) patients treated with consolidation durvalumab. Jazieh, K., Gad, M., Saad, A., et al.[2022]

In the NeoCOAST trial involving 83 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant chemoimmunotherapy using combinations of durvalumab with oleclumab or monalizumab significantly improved major pathologic response (MPR) rates compared to durvalumab alone.

The safety profiles of the combination therapies were comparable to durvalumab alone, and enhanced immune responses were observed in patients receiving the combinations, indicating a promising approach for improving treatment outcomes in NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant Durvalumab Alone or Combined with Novel Immuno-Oncology Agents in Resectable Lung Cancer: The Phase II NeoCOAST Platform Trial. Cascone, T., Kar, G., Spicer, JD., et al.[2023]

Immune checkpoint inhibitors (ICIs), particularly durvalumab, have significantly improved treatment outcomes for patients with advanced non-small cell lung cancer (NSCLC), establishing them as the standard of care either alone or with chemotherapy.

Durvalumab is specifically approved as a consolidation treatment after chemo-radiotherapy for stage III NSCLC, highlighting its role in enhancing patient prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on Targeted Therapies for Advanced Non-Small Cell Lung Cancer: Durvalumab in Context. Gullapalli, S., Remon, J., Hendriks, LEL., et al.[2020]

Durvalumab, an immune checkpoint inhibitor, has shown promising efficacy in treating advanced non-small cell lung cancer (NSCLC) in early phase trials, demonstrating a good safety profile.

The PACIFIC trial has successfully met its primary endpoint, indicating that durvalumab may be an important part of future treatment strategies for NSCLC, with ongoing studies potentially confirming its superiority over current therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MEDI 4736 (durvalumab) in non-small cell lung cancer. Jeanson, A., Barlesi, F.[2021]

Citations

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Adaptive NSCLC Trial Misses Target Efficacy, Reaches ... The PIONeeR trial, evaluating combinations of immunotherapy drugs for advanced NSCLC, identified durvalumab plus ceralasertib as a promising treatment option.

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Lung Cancer Trial Falls Short of Goal, But Presents Clinical ... The mean estimated 12-week DCR was 24.1% in arm A (95% CI, 10.7%-41.0%), 50.0% in arm C (95% CI, 33.1%-66.9%), 13.6% in arm E (95% CI, 3.0%-30.4 ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.22.00227

COAST: An Open-Label, Phase II, Multidrug Platform Study ... Durvalumab significantly improves overall survival for patients with unresectable stage III non–small-cell lung cancer and no progression ...

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NCT05221840 | A Global Study to Assess the Effects of ... This is a Phase III, randomised, double-blind, multicentre, international study assessing the efficacy and safety of durvalumab (MEDI4736) in combination ...

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Imfinzi combined with novel immunotherapies improved ... The 10-month PFS rate was 64.8% for the durvalumab plus oleclumab combination and 72.7% for durvalumab plus monalizumab, versus 39.2% with ...

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A phase II trial of monalizumab in combination with ... A phase II trial of monalizumab in combination with durvalumab (MEDI4736) plus platinum-based chemotherapy for first-line treatment of extensive stage small ...

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NCT03801902 | Testing the Safety of Adding Either ... This phase I trial studies the safety of adding durvalumab to accelerated hypofractionated radiation therapy (ACRT) or conventionally fractionated radiation ...

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Testing the Safety of Adding Either Monalizumab (IPH2201) or ... This phase I trial studies the safety of adding durvalumab to accelerated hypofractionated radiation therapy (ACRT) or conventionally fractionated radiation ...