Olaparib + Durvalumab + Chemotherapy/Radiation for Small Cell Lung Cancer

Overseen By Marcelo V Negrao

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Other malignancy, Autoimmune disease, Immunocompromised, others

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

Compensation: Varies

Number of Visits: 4

63 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) for specific drugs. If you are taking strong or moderate CYP3A inhibitors or inducers, you will need to stop them 2 to 5 weeks before starting the study treatment. Please consult with the trial team for guidance on your specific medications.

What data supports the effectiveness of the drug combination of Olaparib, Durvalumab, and Chemotherapy/Radiation for Small Cell Lung Cancer?

Research shows that combining durvalumab with chemotherapy (platinum-etoposide) significantly improves survival in patients with extensive-stage small-cell lung cancer, as seen in the CASPIAN study. Additionally, combining olaparib with durvalumab has shown increased efficacy in preclinical studies for relapsed small cell lung cancer. ^{1 2 3 4 5}

Is the combination of Olaparib, Durvalumab, and Chemotherapy/Radiation safe for humans?

Studies have shown that Olaparib and Carboplatin can be safely combined, with common side effects including nausea, fatigue, and decreased platelet count. Durvalumab has been evaluated for safety in various solid tumors, indicating it is generally safe for use in humans. ^{1 6 7 8 9}

What makes the drug combination of Olaparib, Durvalumab, and Chemotherapy/Radiation unique for small cell lung cancer?

This treatment is unique because it combines a PARP inhibitor (Olaparib) with an immune checkpoint inhibitor (Durvalumab) and chemotherapy/radiation, aiming to enhance the body's immune response and repair DNA damage in cancer cells, which is a novel approach for small cell lung cancer. ^{1 2 7 10 11}

What is the purpose of this trial?

This phase I/II trials investigates the side effects of olaparib and durvalumab and how well it works in combination with carboplatin, etoposide, and/or radiation therapy in treating patients with extensive stage-small cell lung cancer (ES-SCLC) who have not received treatment for their disease. PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as carboplatin and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy sources to kill tumor cells and shrink tumors. Giving olaparib and durvalumab together with carboplatin, etoposide, and/or radiation therapy may help treat patients with ES-SCLC.

Research Team

Marcelo Negrao, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with extensive-stage small cell lung cancer (ES-SCLC) who haven't had treatment yet. They should have at least one lesion visible on a CT scan, be in good physical condition (ECOG 0-1), weigh over 30 kg, and agree to use two effective forms of contraception if sexually active. People can't join if they've used certain medications recently, have uncontrolled heart conditions or other serious health issues, are pregnant or breastfeeding, or have allergies to the drugs being tested.

Inclusion Criteria

Provision of signed and dated written informed consent form prior to any mandatory study specific procedures, sampling, and analyses

Your neutrophil count is at least 1.5 billion per liter.

Evidence of post-menopausal status or evidence of non-childbearing status for women of childbearing potential

Exclusion Criteria

I haven't taken immunosuppressive drugs in the last 14 days.

I have a serious health condition that is not under control.

I am not currently receiving any cancer treatments.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemo-Immunotherapy

Patients receive durvalumab, carboplatin, and etoposide. Treatment repeats every 21 days for up to 4 cycles.

12 weeks

4 cycles, each with multiple visits

Induction

Patients receive olaparib orally twice daily for 11 days.

2 weeks

Immunoradiation

Patients receive durvalumab and undergo consolidative thoracic radiotherapy.

4 weeks

Maintenance

Patients receive durvalumab and olaparib. Cycles repeat every 28 days.

Ongoing

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

30 days, then every 3 months

Treatment Details

Interventions

• Carboplatin
• Durvalumab
• Etoposide
• Olaparib
• Radiation Therapy

Trial Overview The PRIO trial is testing how well patients with ES-SCLC respond to a combination of olaparib and durvalumab along with carboplatin and etoposide chemotherapy and/or radiation therapy. Olaparib inhibits DNA repair in tumor cells while durvalumab helps the immune system attack cancer. The study aims to see if this combo can improve outcomes for these patients.

Participant Groups

Group I: Treatment (chemo-immunotherapy, radiation therapy) Experimental Treatment 5 Interventions

See detailed description.

Carboplatin is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

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

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

The KEYLYNK-012 study is a phase III clinical trial evaluating the effectiveness of pembrolizumab combined with chemoradiotherapy in patients with stage III non-small-cell lung cancer (NSCLC), involving participants aged 18 and older with unresectable disease.

This study aims to determine if the addition of pembrolizumab, with or without olaparib, improves progression-free survival and overall survival compared to standard concurrent chemoradiotherapy, with enrollment ongoing at around 190 sites.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and Design of the Phase III KEYLYNK-012 Study of Pembrolizumab and Concurrent Chemoradiotherapy Followed by Pembrolizumab With or Without Olaparib for Stage III Non-Small-Cell Lung Cancer. Jabbour, SK., Cho, BC., Bria, E., et al.[2022]

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 the phase III CASPIAN study, the combination of durvalumab with etoposide and either cisplatin or carboplatin significantly improved overall survival in patients with extensive-stage small-cell lung cancer compared to etoposide plus platinum alone.

Patient-reported outcomes showed that the addition of durvalumab not only maintained quality of life but also delayed the worsening of key symptoms like appetite loss, cough, and fatigue, indicating a beneficial impact on patients' overall well-being.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes with first-line durvalumab plus platinum-etoposide versus platinum-etoposide in extensive-stage small-cell lung cancer (CASPIAN): a randomized, controlled, open-label, phase III study. Goldman, JW., Garassino, MC., Chen, Y., et al.[2021]

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 the CASPIAN study involving 805 patients with extensive-stage small-cell lung cancer (ES-SCLC), the combination of durvalumab and platinum-etoposide significantly improved overall survival compared to platinum-etoposide alone, with a median survival of 12.9 months versus 10.5 months.

However, adding tremelimumab to durvalumab and platinum-etoposide did not provide a significant survival benefit, indicating that durvalumab plus platinum-etoposide should be considered the new standard of care for first-line treatment of ES-SCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Goldman, JW., Dvorkin, M., Chen, Y., et al.[2021]

Olaparib (Lynparza) is approved for treating adult patients with high-risk early breast cancer that has a germline BRCA mutation, following chemotherapy treatment.

This approval highlights Olaparib's role as an adjuvant therapy, which means it is used after initial treatments to help prevent cancer recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Adjuvant Treatment for High-Risk Early Breast Cancer. Aschenbrenner, DS.[2022]

The combination of olaparib and carboplatin was found to be safe and effective in treating breast and ovarian cancer in patients with germline BRCA1 or BRCA2 mutations, with 50% of patients showing a partial response and one patient achieving a complete response.

Proteomic analysis indicated that high levels of FOXO3a expression before treatment may predict a better response to the therapy, suggesting a potential biomarker for future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. Lee, JM., Hays, JL., Annunziata, CM., et al.[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]

In a study involving 24 patients with advanced cancer, the combination of olaparib tablets (75 mg BID) and carboplatin (AUC 4 mg*min/mL) was found to be a feasible and tolerable treatment regimen, with 56% of patients showing a partial response after two cycles.

The maximum tolerable dose (MTD) was established at olaparib 75 mg BID, and significant reductions in ADP-ribose levels (98.7%) were observed, indicating effective target engagement and potential therapeutic action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I dose-escalation study of two cycles carboplatin-olaparib followed by olaparib monotherapy in patients with advanced cancer. Geenen, JJJ., Dackus, GMHE., Schouten, PC., et al.[2021]

In a study of 21 patients with extensive stage-small cell lung cancer, the combination of olaparib and pembrolizumab resulted in a median progression-free survival of 5.93 months, compared to 3.53 months for pembrolizumab alone, indicating improved efficacy.

The combination therapy also showed a higher objective response rate of 45.5% versus 10.0% for pembrolizumab alone, suggesting that olaparib enhances the effectiveness of pembrolizumab in treating this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of olaparib combined with pembrolizumab in second-line treatment for extensive-stage small cell lung cancer]. Wu, ZZ., Zhang, SJ., Hu, Y.[2020]

In a study of 120 ovarian cancer patients, the combination of olaparib with paclitaxel and carboplatin significantly improved the objective remission rate and disease control rate compared to the standard treatment with paclitaxel and carboplatin alone.

The addition of olaparib also resulted in lower levels of tumor markers and a reduced rate of tumor metastasis after one year, all without increasing the incidence of adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib and paclitaxel in combination with carboplatin in treatment of ovarian cancer: influence on disease control. Zhang, H., Zhang, Y.[2022]

References

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

Rationale and Design of the Phase III KEYLYNK-012 Study of Pembrolizumab and Concurrent Chemoradiotherapy Followed by Pembrolizumab With or Without Olaparib for Stage III Non-Small-Cell Lung Cancer. [2022]

2. 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]

3. Ireland pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes with first-line durvalumab plus platinum-etoposide versus platinum-etoposide in extensive-stage small-cell lung cancer (CASPIAN): a randomized, controlled, open-label, phase III study. [2021]

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

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

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

Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. [2021]

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

New Adjuvant Treatment for High-Risk Early Breast Cancer. [2022]

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

Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. [2022]

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

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

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

A Phase I dose-escalation study of two cycles carboplatin-olaparib followed by olaparib monotherapy in patients with advanced cancer. [2021]

10. China pubmed.ncbi.nlm.nih.gov

[Efficacy of olaparib combined with pembrolizumab in second-line treatment for extensive-stage small cell lung cancer]. [2020]

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

Olaparib and paclitaxel in combination with carboplatin in treatment of ovarian cancer: influence on disease control. [2022]