Dato-DXd + Durvalumab + Carboplatin for Advanced Non-Small Cell Lung Cancer

(AVANZAR Trial)

Not currently recruiting at 295 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Disqualifiers: Small-cell lung cancer, Brain metastases, Hepatitis B/C, 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

Compensation: Varies

Number of Visits: Unknown

Duration: Approximately 3 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for advanced non-small cell lung cancer (NSCLC) that surgery cannot treat. It compares the effectiveness and safety of a new drug combo—datopotamab deruxtecan (a TROP2-directed antibody-drug conjugate), durvalumab (an immunotherapy drug), and carboplatin (a chemotherapy drug)—against a standard treatment using pembrolizumab and chemotherapy. The study targets individuals with stage IIIB, IIIC, or IV NSCLC who lack specific genetic changes, such as EGFR mutations, that other treatments address. Those with advanced NSCLC without these genetic changes, especially if it affects daily life, might find this trial suitable. As a Phase 3 trial, it represents the final step before FDA approval, offering participants a chance to be part of a potentially groundbreaking treatment.

Do I need to stop my current medications for this trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research shows that the combination of datopotamab deruxtecan (Dato-DXd), durvalumab, and carboplatin is generally well-tolerated by patients with advanced non-small cell lung cancer (NSCLC). Studies have found that these treatments together have manageable side effects.

In earlier studies, many patients continued treatment without major problems. Common side effects included nausea, tiredness, and low blood cell counts, often mild or moderate. Serious side effects were less common.

Dato-DXd is being studied in various trials and shows promising results in treating cancer. Durvalumab and carboplatin are widely used in cancer treatments and have known safety records.

This combination aims to target cancer cells more effectively while controlling side effects. Prospective trial participants should consult their doctor to understand these treatments and their potential effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Dato-DXd, Durvalumab, and Carboplatin for treating advanced non-small cell lung cancer (NSCLC) because it brings a fresh approach to tackling this challenging disease. Unlike the standard of care, which often involves chemotherapy and immune checkpoint inhibitors separately, this combination utilizes Datopotamab deruxtecan (Dato-DXd), an innovative antibody-drug conjugate. Dato-DXd specifically targets and delivers chemotherapy directly into cancer cells, potentially reducing side effects and increasing effectiveness. Additionally, Durvalumab, an immune checkpoint inhibitor, helps the immune system attack cancer more effectively. This dual action—targeted chemotherapy delivery combined with immune system engagement—offers a promising new strategy against NSCLC.

What evidence suggests that this trial's treatments could be effective for advanced non-small cell lung cancer?

Studies have shown promising results for the combination of Datopotamab Deruxtecan (Dato-DXd), Durvalumab, and Carboplatin in treating advanced non-small cell lung cancer (NSCLC). Participants in this trial will receive this combination, which previous studies have shown results in a median survival of 14.6 months. Another study demonstrated high response rates in patients using this treatment. These findings suggest that Dato-DXd with Durvalumab and Carboplatin could effectively treat those with advanced NSCLC. Research indicates this combination might offer a new treatment option for patients whose cancer lacks certain genetic changes. ^{1 2 4 5 6}

Who Is on the Research Team?

Charu Aggarwal

Principal Investigator

Perelman Center for Advanced Medicine

Are You a Good Fit for This Trial?

Adults over 18 with advanced non-small cell lung cancer (NSCLC) stages IIIB, IIIC, or IV without certain genetic changes can join. They should be in good physical condition (ECOG PS of 0 or 1), have not had previous systemic therapy for their cancer stage, and must have proper organ function and bone marrow reserve.

Inclusion Criteria

My lung cancer is at an advanced stage and cannot be removed by surgery.

My cancer does not have certain genetic changes that can be treated with specific drugs.

I am fully active or can carry out light work.

Exclusion Criteria

My lung cancer is a mix of small-cell and non-small cell or is a sarcomatoid variant.

I have a serious eye condition affecting my cornea.

I do not have an infection needing IV drugs.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Dato-DXd in combination with durvalumab and carboplatin or pembrolizumab in combination with histology-specific platinum-based chemotherapy

Approximately 3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 1 year

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Carboplatin
• Datopotamab deruxtecan
• Durvalumab

Trial Overview

The trial is testing a new combination of drugs: Datopotamab Deruxtecan (Dato-DXd) with Durvalumab and Carboplatin against the standard treatment Pembrolizumab with platinum-based chemotherapy. It's to see which is better as a first-line treatment for NSCLC.

How Is the Trial Designed?

Group I: Dato-DXd + Durvalumab + Carboplatin Experimental Treatment 3 Interventions

Participants will be randomized to receive 6.0mg/kg Dato-DXd plus 1120 mg durvalumab plus carboplatin area under the curve \[AUC\] 5 mg/mL/minute.

Group II: Histologic-specific therapy Active Control 5 Interventions

Non-squamous NSCLC participants will be randomized to receive 200 mg pembrolizumab plus 500 mg/m2 pemetrexed plus either AUC 5 mg/mL/minute carboplatin or 75 mg/m2 cisplatin. Squamous NSCLC participants will be randomized to receive 200 mg of pembrolizumab plus 200 mg/m2 paclitaxel plus AUC 5 or 6 mg/mL/minute carboplatin.

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?

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 has been approved for use in patients with locally advanced PD-L1-positive non-small cell lung cancer (NSCLC) after chemoradiotherapy, based on its efficacy demonstrated in the PACIFIC trial and subsequent analysis of 211 patients in the Expanded Access Program (EAP).

In the EAP, 126 patients who received durvalumab were included, some of whom had oligometastatic disease and a history of autoimmune conditions, indicating that durvalumab may be effective and safe for a broader patient population than previously studied.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab after definitive chemoradiotherapy in locally advanced NSCLC: Data of the German EAP. Faehling, M., Schumann, C., Christopoulos, P., et al.[2020]

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 a phase Ib study involving 136 patients, durvalumab (Du) combined with tremelimumab (Tr) and standard platinum-doublet chemotherapy was found to be safe, with most drug-related adverse events being mild (≤ grade 2) and primarily due to chemotherapy.

Among 73 patients with non-small cell lung cancer (NSCLC), the treatment achieved a 51% objective response rate, with a median progression-free survival of 6.5 months and overall survival of 19.8 months, indicating promising efficacy comparable to other immunotherapy and chemotherapy combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase IB study of durvalumab with or without tremelimumab and platinum-doublet chemotherapy in advanced solid tumours: Canadian Cancer Trials Group Study IND226. Juergens, RA., Hao, D., Ellis, PM., et al.[2021]

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]

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 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, an anti-PD-L1 monoclonal antibody, is being tested in a Phase II study for its feasibility and effectiveness in patients with early-stage non-small cell lung cancer (NSCLC) by administering three infusions before surgery.

The study aims to achieve a complete surgical resection rate of at least 85% and assess major pathological response, with a total of 81 patients required to determine if neoadjuvant immunotherapy can improve survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[IoNESCO trial: Immune neoajuvant therapy in early stage non-small cell lung cancer]. Mignard, X., Antoine, M., Moro-Sibilot, D., et al.[2019]

The AEGEAN trial is a phase III study involving approximately 800 patients with resectable, early-stage non-small-cell lung cancer (NSCLC) that aims to evaluate the effectiveness of durvalumab combined with chemotherapy before surgery and as a monotherapy after surgery.

This study will assess key outcomes such as pathological complete response and event-free survival, potentially improving treatment strategies for patients with Stage II-III NSCLC, where current survival rates remain low despite standard postoperative chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design and Rationale for a Phase III, Double-Blind, Placebo-Controlled Study of Neoadjuvant Durvalumab + Chemotherapy Followed by Adjuvant Durvalumab for the Treatment of Patients With Resectable Stages II and III non-small-cell Lung Cancer: The AEGEAN Trial. Heymach, JV., Mitsudomi, T., Harpole, D., et al.[2022]

In a study of 314 patients with early rheumatoid arthritis, achieving an optimal methotrexate (MTX) dose (≥10 mg/week initially, escalating to ≥20 mg/week) significantly improved the chances of reaching remission and normal functioning after one year, with odds ratios of 4.28 and 4.36, respectively.

Despite the benefits in symptoms and function, the optimal MTX dose did not affect radiological progression of the disease over the two-year study period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimal methotrexate dose is associated with better clinical outcomes than non-optimal dose in daily practice: results from the ESPOIR early arthritis cohort. Gaujoux-Viala, C., Rincheval, N., Dougados, M., et al.[2022]

Methotrexate (MTX) shows a delayed therapeutic response in rheumatoid arthritis (RA), with maximum improvement in disability scores occurring around 30 months after starting treatment, indicating that patients may need to be on MTX for a longer period to see full benefits.

Despite initial improvements, disability scores began to re-progress after 42 months, suggesting that treatment strategies should be adjusted sooner to prevent return to baseline disability, highlighting the need for more proactive management of RA with potential dosage adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The methotrexate therapeutic response in rheumatoid arthritis. Ortendahl, M., Holmes, T., Schettler, JD., et al.[2013]

Methotrexate (MTX) is the most commonly used drug in combination therapies for rheumatoid arthritis, showing the best results when paired with leflunomide, cyclosporine, or in a triple combination with sulphasalazine and hydroxychloroquine.

Combining MTX with biologics, especially TNF inhibitors, abatacept, rituximab, or tocilizumab, enhances treatment efficacy and helps prevent disease progression, with safety profiles similar to individual medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Combination therapy using methotrexate with DMARDs or biologics--current status]. Krüger, K.[2021]

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This is a Phase III, randomized, open-label, multicenter, global study to compare the efficacy and safety of Datopotamab Deruxtecan (Dato-DXd) in combination ...

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The first neoadjuvant trial examining an ADC plus chemo-immunotherapy in resectable NSCLC, pCR rates were highest in the datopotamab-deruxtecan-containing arm.

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Three Phase 3 Trials of Datopotamab Deruxtecan-Based ...

The first patients have been dosed in three global, randomized phase 3 trials evaluating the efficacy and safety of datopotamab deruxtecan (Dato- DXd)-based ...