Monalizumab or Oleclumab with Durvalumab and Radiation for Lung Cancer

Recruiting at 63 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressive medications

Disqualifiers: Metastatic disease, Autoimmune disease, others

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

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

Compensation: Varies

Number of Visits: 17

Duration: 52 weeks

26 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial information does not specify whether you need to stop taking your current medications. However, it mentions that you cannot use immunosuppressive medication within 14 days before starting the trial. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment Monalizumab or Oleclumab with Durvalumab and Radiation for Lung Cancer?

Research shows that Durvalumab, when used after chemoradiotherapy, significantly improves survival in patients with unresectable stage III non-small-cell lung cancer. Combining Durvalumab with other drugs like Oleclumab or Monalizumab may enhance this benefit, as seen in the COAST study. ^{1 2 3 4 5}

Is the combination of Monalizumab or Oleclumab with Durvalumab and Radiation safe for humans?

Durvalumab, when used for lung cancer, has been associated with an increased risk of pneumonitis (inflammation of the lung tissue), which is a serious and potentially life-threatening side effect. This highlights the importance of monitoring for lung-related side effects when using this treatment. ^{1 3 4 6 7}

How is the treatment with Monalizumab or Oleclumab and Durvalumab with Radiation for Lung Cancer different from other treatments?

This treatment is unique because it combines durvalumab, an immune therapy drug, with either monalizumab or oleclumab, which are antibodies targeting specific proteins on cancer cells, alongside radiation therapy. This combination aims to enhance the immune system's ability to fight cancer, potentially offering better outcomes for patients who cannot undergo standard chemotherapy. ^{1 2 3 8 9}

What is the purpose of this trial?

This phase I trial studies the safety of adding durvalumab to accelerated hypofractionated radiation therapy (ACRT) or conventionally fractionated radiation therapy, as well as the safety of adding either monalizumab or oleclumab to durvalumab plus conventionally fractionated radiation therapy in treating patients with non-small cell lung cancer that has spread to nearby tissue or lymph nodes (locally advanced). Accelerated hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Immunotherapy with monoclonal antibodies, such as durvalumab and monalizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Oleclumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD73, which is found on some types of tumor cells. Oleclumab may block CD73 and help the immune system kill tumor cells. It is not yet known whether adding durvalumab to ACRT or adding monalizumab or oleclumab to durvalumab plus conventionally fractionated radiation therapy will work better in treating patients with non-small cell lung cancer.

Research Team

Steven H Lin

Principal Investigator

NRG Oncology

Eligibility Criteria

This trial is for adults with stage II-III non-small cell lung cancer (NSCLC) that can't be removed by surgery. They must have a specific level of tumor protein called PD-L1, good organ function, and no liver or kidney damage. Participants need to be physically able to undergo the treatments (ECOG 0-2), have sufficient lung function, and weigh over 30 kg.

Inclusion Criteria

You had a medical check-up within the month before signing up for the study.

Your white blood cell count is at least 1500 cells per cubic millimeter.

I need extra oxygen due to my tumor but the amount has been stable.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2 weeks

1 visit (in-person)

Treatment

Participants receive durvalumab and either monalizumab or oleclumab with radiation therapy

52 weeks

13 cycles, each 4 weeks long

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Every 3 months for year 1, every 4 months for year 2

Treatment Details

Interventions

• Durvalumab
• Fractionated Stereotactic Radiation Therapy
• Hypofractionated Radiation Therapy
• Radiation Therapy

Trial Overview The ARCHON-1 trial is testing if adding durvalumab to standard radiation therapy improves outcomes in NSCLC patients. It's also comparing the effects when either monalizumab or oleclumab are added into this treatment mix. The study will look at different doses of radiation and how well these combinations work together.

Participant Groups

Group I: Arm IV (durvalumab, oleclumab, standard RT) Experimental Treatment 6 Interventions

Starting 2 weeks prior to radiation therapy, patients receive durvalumab IV over 60 minutes on day 1 of each cycle. Patients also receive oleclumab IV over 60 minutes on days 1 and 15 of cycles 1-2, then on day 1 of cycles thereafter. Treatment repeats every 4 weeks for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo conventionally fractionated radiation therapy 1 fraction per day, 5 days per week for 30 fractions. Patients also undergo brain MRI or CT scan during screening and as clinically indicated, chest CT scans on study and during follow up, and collection of blood samples during screening and on study.

Group II: Arm III (durvalumab, monalizumab, standard RT) Experimental Treatment 6 Interventions

Starting 2 weeks prior to radiation therapy, patients receive durvalumab IV over 60 minutes and monalizumab IV over 60 minutes on day 1 of each cycle. Treatment repeats every 4 weeks for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo conventionally fractionated radiation therapy 1 fraction per day, 5 days per week for 30 fractions. Patients also undergo brain MRI or CT scan during screening and as clinically indicated, chest CT scans on study and during follow up, and collection of blood samples during screening and on study.

Group III: Arm II (CLOSED) (Durvalumab and standard RT) Experimental Treatment 5 Interventions

Starting 2 weeks prior to radiation therapy, patients receive durvalumab IV over 60 minutes on day 1 of each cycle. Treatment repeats every 4 weeks for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo conventionally fractionated radiation therapy 1 fraction per day, 5 days per week for 30 fractions. Patients also undergo brain MRI or CT scan during screening and as clinically indicated, chest CT scans on study and during follow up, and collection of blood samples during screening and on study.

Group IV: Arm I (CLOSED) (Durvalumab and ACRT) Experimental Treatment 5 Interventions

Starting 2 weeks prior to radiation therapy, patients receive durvalumab IV over 60 minutes on day 1 of each cycle. Treatment repeats every 4 weeks for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ACRT 1 fraction per day, 5 days per week for 15 fractions. Patients also undergo brain MRI or CT scan during screening and as clinically indicated, chest CT scans on study and during follow up, and collection of blood samples during screening and on study.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

NRG Oncology

Collaborator

Trials

242

Recruited

105,000+

Findings from Research

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]

The DUART trial is a Phase II study investigating the safety and tolerability of durvalumab in patients with unresectable, stage III non-small-cell lung cancer (NSCLC) who cannot undergo chemotherapy due to poor performance status or other health issues.

This study aims to evaluate whether durvalumab can improve survival outcomes for these patients compared to the current standard of care, which is radiotherapy alone, based on promising results from the PACIFIC trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DUART: durvalumab after radiotherapy in patients with unresectable, stage III NSCLC who are ineligible for chemotherapy. Filippi, AR., Dziadziuszko, R., García Campelo, MR., et al.[2022]

In a study of 68 patients with locally advanced non-small cell lung cancer treated with intensity-modulated radiotherapy (IMRT), the administration of durvalumab significantly improved distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS), with hazard ratios of 0.31, 0.33, and 0.32 respectively.

The study also found that while grade 2 or higher radiation pneumonitis (RP) was associated with worse DMFS, reducing the incidence of RP could enhance patient outcomes, highlighting the importance of managing treatment-related side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab after chemoradiotherapy for locally advanced non-small cell lung cancer prolonged distant metastasis-free survival, progression-free survival and overall survival in clinical practice. Yamamoto, T., Tsukita, Y., Katagiri, Y., et al.[2022]

In a study of 107 patients with stage III non-small cell lung cancer (NSCLC) treated with concurrent chemoradiotherapy (CCRT) and intensity-modulated radiotherapy (IMRT), the median progression-free survival (PFS) was 20.7 months, indicating effective treatment outcomes.

Factors associated with longer PFS included a favorable response to CCRT, a radiation dose of 62 Gy or more, and having stage IIIA NSCLC, while shorter durations of durvalumab treatment and lower radiation doses were linked to increased mortality risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy profiles of concurrent chemoradiotherapy with intensity-modulated radiotherapy followed by durvalumab in patients with unresectable stage III non-small cell lung cancer: A multicenter retrospective cohort study. Takeda, Y., Kusaba, Y., Tsukita, Y., 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 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 a study of 14 patients with stage III NSCLC receiving Atezolizumab after chemoradiotherapy, 57% developed pneumonitis, indicating a significant risk associated with this treatment approach.

The onset of pneumonitis occurred on average 2.45 months after starting Atezolizumab, suggesting that monitoring for this side effect is crucial in patients undergoing this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pneumonitis in Non-Small Cell Lung Cancer Patients Receiving Atezolizumab Post Chemo-Radiation. Saade, LJ., Tfayli, A.[2023]

References

1. United States 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. [2022]

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

Complete pathological response in locally advanced non-small-cell lung cancer patient: A case report. [2021]

3. England pubmed.ncbi.nlm.nih.gov

DUART: durvalumab after radiotherapy in patients with unresectable, stage III NSCLC who are ineligible for chemotherapy. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Durvalumab after chemoradiotherapy for locally advanced non-small cell lung cancer prolonged distant metastasis-free survival, progression-free survival and overall survival in clinical practice. [2022]

5. Ireland pubmed.ncbi.nlm.nih.gov

The efficacy profiles of concurrent chemoradiotherapy with intensity-modulated radiotherapy followed by durvalumab in patients with unresectable stage III non-small cell lung cancer: A multicenter retrospective cohort study. [2022]

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

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

7. China 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. [2022]

8. Thailand pubmed.ncbi.nlm.nih.gov

Pneumonitis in Non-Small Cell Lung Cancer Patients Receiving Atezolizumab Post Chemo-Radiation. [2023]

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

A phase 2 trial of durvalumab treatment following radiation monotherapy in patients with non-small cell lung cancer ineligible for stage III chemoradiotherapy: The SPIRAL-RT study. [2023]