Radiotherapy + Immunotherapy/PARP Inhibitor for Small Cell Lung Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Corticosteroids, Immunosuppressants, PARP inhibitors

Disqualifiers: Pregnancy, Autoimmune disorders, ILD, 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: 4

Duration: 13 weeks

25 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a randomized multi-arm trial evaluating the safety and efficacy of thoracic radiation therapy followed by either durvalumab as monotherapy or in combination with tremelimumab or olaparib in participants with Extensive-Stage Disease Small Cell Lung Cancer (ES-SCLC) who have completed a first-line platinum-based chemotherapy regimen and achieved ongoing complete response (CR), partial response (PR) or stable disease (SD).

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

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on a checkpoint inhibitor (a type of cancer treatment), you must stop it before starting the trial's thoracic radiotherapy.

What data supports the effectiveness of the drug combination of Durvalumab and Olaparib for small cell lung cancer?

Research shows that combining Olaparib and Durvalumab can be more effective than using either alone for small cell lung cancer. Additionally, Durvalumab has been shown to improve survival rates in extensive-stage small cell lung cancer when combined with chemotherapy. ^{1 2 3 4 5}

Is the combination of radiotherapy and durvalumab safe for humans?

Durvalumab, when used with radiotherapy, has been studied for safety in various cancers. Some patients experience adverse events (unwanted side effects), with lung toxicity being a common issue that can lead to stopping the treatment. ^{2 6 7 8 9}

How is the treatment of radiotherapy combined with immunotherapy and PARP inhibitor unique for small cell lung cancer?

This treatment is unique because it combines radiotherapy with a PARP inhibitor and an immune checkpoint inhibitor, which together enhance the immune system's ability to fight cancer by reshaping the tumor environment and increasing immune cell activity, offering a novel approach for small cell lung cancer that has limited treatment options. ^{1 3 10 11 12}

Research Team

Alberto A Chiappori, MD

Principal Investigator

H. Lee Moffitt Cancer Center and Research Institute

Eligibility Criteria

This trial is for adults with Small Cell Lung Cancer who've had a positive response to first-line platinum-based chemotherapy. They must be willing to use effective contraception, have no severe allergies to the study drugs, and not have received certain prior treatments that could affect results. Participants should be in good enough health with proper organ function and an expected lifespan of at least 16 weeks.

Inclusion Criteria

You have tested positive for HIV or have a history of AIDS.

I will start the study treatment within 60 days after my last platinum-based chemotherapy.

I agree not to donate sperm during and up to 6 months after the study if I receive combination therapy, or 3 months after if on monotherapy.

Exclusion Criteria

I have never been treated with PARP inhibitors like olaparib.

I am not allergic to any of the drugs or their components used in this study.

I do not have severe autoimmune or inflammatory disorders that need constant treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Participants receive thoracic radiotherapy (30 Gray units total, 3 Gray units X 10 fractions)

3-4 weeks

Treatment

Participants receive Durvalumab monotherapy or in combination with Tremelimumab or Olaparib

13 weeks

Every 4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Durvalumab
• Olaparib
• Thoracic Radiotherapy
• Tremelimumab

Trial Overview The trial tests thoracic radiation followed by durvalumab alone or combined with tremelimumab or olaparib in patients who responded well to initial chemo. It's randomized, meaning participants are put into groups by chance, and it compares the safety and effectiveness of these treatment combinations.

Participant Groups

Group I: Thoracic Radiotherapy plus Durvalumab and Olaparib Experimental Treatment 3 Interventions

Patients will receive thoracic radiotherapy (30 Gray units total, 3 Gray units X 10 fractions), then in 2-3 weeks begin 1500 mg intravenously of Durvalumab every 4 weeks and 300 mg orally of Olaparib twice a day

Group II: Thoracic Radiotherapy plus Durvalumab and 75mg Tremelimumab Experimental Treatment 3 Interventions

Patients will receive thoracic radiotherapy (30 Gray units total, 3 Gray units X 10 fractions), then in 2-3 weeks begin 1500 mg intravenously of Durvalumab every 4 weeks for up to 4 doses and 75mg intravenously of Tremelimumab every 4 weeks for up to 4 doses

Group III: Thoracic Radiotherapy plus Durvalumab and 300mg Tremelimumab Experimental Treatment 3 Interventions

Patients will receive thoracic radiotherapy (30 Gray units total, 3 Gray units X 10 fractions), then in 2-3 weeks begin 1500 mg intravenously of Durvalumab every 4 weeks and 300 mg Tremelimumab IV x 1 (single dose)

Group IV: Thoracic Radiotherapy plus Durvalumab Active Control 1 Intervention

This Arm is a standard of care Arm. Patients will receive thoracic radiotherapy (30 Gray units total, 3 Gray units X 10 fractions), then in 2-3 weeks begin 1500 mg intravenously of Durvalumab every 4 weeks for up to 13 doses

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?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

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

Findings from Research

In a study of 40 patients with relapsed small cell lung cancer, the combination of olaparib and durvalumab showed a 12-week disease control rate of 28.9%, indicating some effectiveness, although it fell short of the target of 60%.

The treatment was generally well-tolerated, with adverse events like anemia, nausea, and fatigue being common, and 80% of patients experienced grade 3 or higher adverse events, suggesting that while the combination is safe, careful monitoring is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib and durvalumab in patients with relapsed small cell lung cancer (MEDIOLA): An open-label, multicenter, phase 1/2, basket study. Krebs, MG., Delord, JP., Jeffry Evans, TR., et al.[2023]

In a study involving 10 patients receiving palliative radiotherapy (RT) combined with durvalumab, the treatment was well tolerated, with only 50% experiencing mild to moderate adverse events, primarily G2 mucositis, and no severe adverse events reported.

The treatment showed promising efficacy, with a 60% objective response rate in evaluable lesions and a significant decrease in tumor growth rate after RT, indicating that durvalumab combined with RT may effectively reduce tumor size in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent irradiation with the anti-programmed cell death ligand-1 immune checkpoint blocker durvalumab: Single centre subset analysis from a phase 1/2 trial. Levy, A., Massard, C., Soria, JC., et al.[2022]

In the phase III CASPIAN trial involving previously untreated adults with extensive-stage small cell lung cancer (ES-SCLC), the addition of durvalumab to chemotherapy significantly improved overall survival and progression-free survival compared to chemotherapy alone.

Durvalumab combined with etoposide and either carboplatin or cisplatin demonstrated a manageable safety profile, making it a valuable first-line treatment option and an accepted standard of care for patients with ES-SCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab: A Review in Extensive-Stage SCLC. Al-Salama, ZT.[2022]

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 the Phase 3 PACIFIC study involving 713 patients with unresectable stage III non-small-cell lung cancer (NSCLC), the anti-PD-L1 agent durvalumab significantly improved median progression-free survival (17.2 months vs. 5.6 months for placebo) and overall survival (not reached vs. 28.7 months for placebo).

While durvalumab showed a slight increase in grade 3 or 4 toxicity (30.5% vs. 26.1% for placebo), its efficacy in prolonging survival justifies its use, leading to its licensing for this treatment setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beyond chemoradiotherapy: improving treatment outcomes for patients with stage III unresectable non-small-cell lung cancer through immuno-oncology and durvalumab (Imfinzi®▼, AstraZeneca UK Limited). Patel, P., Alrifai, D., McDonald, F., et al.[2023]

In a Phase II trial involving 74 patients with unresectable, locally advanced non-small cell lung cancer (NSCLC), durvalumab immunotherapy combined with radiotherapy resulted in a promising 12-month progression-free survival (PFS) rate of 72.1%, indicating its efficacy as a treatment option.

The treatment was generally well-tolerated, with a high objective response rate of 90.9%, although 52.9% of patients experienced severe adverse events (grade 3 or 4), highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab Plus Concurrent Radiotherapy for Treatment of Locally Advanced Non-Small Cell Lung Cancer: The DOLPHIN Phase 2 Nonrandomized Controlled Trial. Tachihara, M., Tsujino, K., Ishihara, T., et al.[2023]

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]

Patients with locally advanced non-small cell lung cancer (LA-NSCLC) who received concurrent chemoradiotherapy (CCRT) and durvalumab had a significantly higher 1-year local control rate (89%) compared to those who received CCRT alone (47%), indicating that adding durvalumab may enhance local tumor control.

While the addition of durvalumab improved local control, it was associated with a slightly higher incidence of grade 2 pneumonitis (50% in the durvalumab cohort vs. 41% in the CCRT-alone cohort), highlighting the importance of monitoring for respiratory side effects in patients undergoing this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the Efficacy and Toxicity of Concurrent Chemoradiotherapy and Durvalumab and Concurrent Chemoradiotherapy Alone for Locally Advanced Non-small Cell Lung Cancer With N3 Lymph Node Metastasis. Abe, T., Iino, M., Saito, S., et al.[2023]

Durvalumab, a PD-L1 inhibitor, has been shown to provide a survival benefit as a maintenance therapy for patients with unresectable stage III non-small-cell lung cancer (NSCLC) after chemoradiotherapy, and it is approved by major regulatory agencies.

While durvalumab can cause immune-mediated adverse events, its safety profile is comparable to other PD-1/PD-L1 inhibitors, with most side effects being manageable and mild, although combination therapies may increase the risk of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation of durvalumab for the treatment of non-small-cell lung cancer. Shibata, Y., Murakami, S.[2022]

References

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

Olaparib and durvalumab in patients with relapsed small cell lung cancer (MEDIOLA): An open-label, multicenter, phase 1/2, basket study. [2023]

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

Concurrent irradiation with the anti-programmed cell death ligand-1 immune checkpoint blocker durvalumab: Single centre subset analysis from a phase 1/2 trial. [2022]

3. France pubmed.ncbi.nlm.nih.gov

Durvalumab: A Review in Extensive-Stage SCLC. [2022]

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

Five-Year Survival Outcomes From the PACIFIC Trial: Durvalumab After Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. [2022]

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

Beyond chemoradiotherapy: improving treatment outcomes for patients with stage III unresectable non-small-cell lung cancer through immuno-oncology and durvalumab (Imfinzi®▼, AstraZeneca UK Limited). [2023]

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

Durvalumab Plus Concurrent Radiotherapy for Treatment of Locally Advanced Non-Small Cell Lung Cancer: The DOLPHIN Phase 2 Nonrandomized Controlled Trial. [2023]

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

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

8. Greece pubmed.ncbi.nlm.nih.gov

Evaluation of Durvalumab-induced Lung Toxicity Using a Spontaneous Reporting Database. [2022]

9. Greece pubmed.ncbi.nlm.nih.gov

Comparison of the Efficacy and Toxicity of Concurrent Chemoradiotherapy and Durvalumab and Concurrent Chemoradiotherapy Alone for Locally Advanced Non-small Cell Lung Cancer With N3 Lymph Node Metastasis. [2023]

10. Ireland pubmed.ncbi.nlm.nih.gov

PARP inhibitor plus radiotherapy reshapes an inflamed tumor microenvironment that sensitizes small cell lung cancer to the anti-PD-1 immunotherapy. [2022]

11. China pubmed.ncbi.nlm.nih.gov

Tolerability, safety, and preliminary antitumor activity of fuzuloparib in combination with SHR-1316 in patients with relapsed small cell lung cancer: a multicenter, open-label, two-stage, phase Ib trial. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Safety evaluation of durvalumab for the treatment of non-small-cell lung cancer. [2022]