Chemo-Immunotherapy for Non-Small Cell Lung Cancer

(STAGGER Trial)

Overseen By Kaitlin Stephens

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Utah

Must not be taking: Immunosuppressants, Anti-PD-1, Anti-PD-L1, Anti-CTLA-4

Disqualifiers: ALK, EGFR, Autoimmune disorders, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 4 cycles (first 2 cycles are 28 days each, next 2 cycles are 21 days each)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of chemotherapy and immunotherapy to evaluate its effectiveness for treating non-small cell lung cancer that has spread or is not easily removable. Researchers aim to determine which of two dosing schedules is most effective. The trial includes two groups: one receives chemotherapy (including drugs like Carboplatin and Pemetrexed) first, followed by immunotherapy (such as Durvalumab); the other group receives them in reverse order. Individuals with non-squamous type non-small cell lung cancer, who have not previously undergone chemo-immunotherapy and have measurable disease, might be suitable candidates. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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

The trial protocol does not specify if you must stop taking your current medications. However, if you are taking any prohibited medications, a washout period of at least 5 half-lives or as clinically indicated is required before starting the treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot use immunosuppressive medications within 14 days of starting the trial, except for certain permitted steroids. Additionally, any prohibited medications must be stopped for at least 5 half-lives before starting the trial.

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

Research shows that combining carboplatin, durvalumab, and pemetrexed is generally well-tolerated by patients with non-small cell lung cancer. Studies have found that these treatments work well together, with manageable side effects.

Carboplatin, a chemotherapy drug used for many years in cancer treatment, can cause side effects like nausea and tiredness, but medication and care usually control these.

Durvalumab, an immunotherapy drug, helps the immune system fight cancer. It has been used in treating other cancer types and can cause side effects like cough and fatigue, which are mostly mild to moderate.

Pemetrexed, another chemotherapy drug for lung cancer, may cause side effects such as low blood cell counts and skin rash, but proper monitoring can manage these effectively.

Previous studies have shown that this combination is safe, indicating that while side effects can occur, they are often not severe and can be managed with the right care. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this chemo-immunotherapy combination for non-small cell lung cancer because it integrates both chemotherapy and immunotherapy in a unique sequence. Carboplatin and pemetrexed are standard chemotherapy drugs, but the addition of durvalumab, an immunotherapy, aims to enhance the body's immune response against cancer cells. Unlike traditional treatments that often rely solely on chemotherapy, this approach uses the immune system to potentially improve outcomes and extend survival. By alternating the timing of chemotherapy and immunotherapy, researchers believe they can optimize treatment effectiveness while minimizing side effects.

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

This trial will compare two treatment approaches for advanced non-small cell lung cancer (NSCLC) using a combination of carboplatin, durvalumab, and pemetrexed. Research has shown that these drugs together may help treat NSCLC. Participants in Arm A will receive chemotherapy first, followed by immunotherapy, while those in Arm B will receive immunotherapy first, followed by chemotherapy. Studies have found that durvalumab, when combined with chemotherapy drugs like carboplatin, can help the immune system fight cancer more effectively. Specifically, durvalumab is already approved for use with other drugs to treat widespread lung cancer. Early results suggest that adding pemetrexed might improve patient outcomes. This combination is being tested in this trial to evaluate its effectiveness and patient tolerance. Overall, this treatment approach appears promising for those with advanced lung cancer. ^{2 4 6 7 8}

Who Is on the Research Team?

Matthew Gumbleton, MD

Principal Investigator

Huntsman Cancer Institute

Are You a Good Fit for This Trial?

Adults with metastatic non-squamous non-small cell lung cancer who haven't had chemoimmunotherapy can join this trial. They must be willing to use effective birth control and follow the study's protocol, including visits and exams. People with certain health conditions or those on immunosuppressive medications (except some steroids) are excluded.

Inclusion Criteria

Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol

I have recovered from side effects of previous treatments, with only mild symptoms remaining.

You have a disease that can be measured using CT or MRI scans according to specific guidelines.

Exclusion Criteria

You have had an organ transplant from someone else.

I haven't taken immunosuppressive drugs, except allowed steroids, in the last 14 days.

I have not had radiation therapy in the last 2 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive staggered chemo-immunotherapy with durvalumab, pemetrexed, and carboplatin. Arm A receives chemotherapy first, followed by immunotherapy, while Arm B receives immunotherapy first, followed by chemotherapy. This is followed by maintenance therapy with durvalumab and pemetrexed.

4 cycles (first 2 cycles are 28 days each, next 2 cycles are 21 days each)

Maintenance Therapy

Participants receive maintenance therapy with durvalumab and pemetrexed until treatment discontinuation.

Until treatment discontinuation

Follow-up

Participants are monitored for safety and effectiveness after treatment, with outcome measures assessed up to 5 years.

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Carboplatin
• Durvalumab
• Pemetrexed

Trial Overview The trial is testing two staggered dosing regimens of Durvalumab combined with Pemetrexed and Carboplatin in patients. It aims to determine which regimen is more effective for treating advanced lung cancer in a Phase II open label, randomized setting.

How Is the Trial Designed?

Group I: Arm B: Immuno-Chemo Experimental Treatment 3 Interventions

ArmB receives immunotherapy on D1 and chemotherapy on D8 of a 28-day cycle for the first 2cycles. After the first 2cycles, patients on Arm A and Arm B will be administered chemotherapy and immunotherapy on D1 of a 21day cycle for cycles 3 and 4. After 4cycles of chemo-immunotherapy, patients receive maintenance therapy with durvalumab and pemetrexed until treatment discontinuation. Maintenance therapy is administered on D1 of a 21day cycle.

Group II: Arm A: Chemo-Immuno Experimental Treatment 3 Interventions

ArmA receives chemotherapy on D1 and immunotherapy on D8 of a 28-day cycle for the first 2cycles. After the first 2cycles, patients on Arm A and Arm B will be administered chemotherapy and immunotherapy on D1 of a 21day cycle for cycles 3 and 4. After 4cycles of chemo-immunotherapy, patients receive maintenance therapy with durvalumab and pemetrexed until treatment discontinuation. Maintenance therapy is administered on D1 of a 21day cycle.

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?

University of Utah

Lead Sponsor

Trials

1,169

Recruited

1,623,000+

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

Published Research Related to This Trial

Pemetrexed remains chemically stable for up to 2 days at room temperature and 31 days when refrigerated, indicating it can be safely stored for these durations in dextrose 5% injection and NaCl 0.9% injection.

However, significant microparticulate formation occurs in pemetrexed solutions stored in PVC bags beyond 24 hours in refrigeration, suggesting that to ensure safety and efficacy, storage should be limited to the manufacturer's recommended 24-hour period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Physical and chemical stability of pemetrexed in infusion solutions. Zhang, Y., Trissel, LA.[2022]

Pemetrexed, when combined with carboplatin, has shown promising antitumor activity with mild toxicity in phase II clinical trials, but it can lead to serious adverse reactions such as toxic epidermal necrolysis, as seen in a reported case.

Supplementation with folic acid and vitamin B12 is recommended during pemetrexed treatment to help reduce the risk of hematological and gastrointestinal side effects, although severe skin reactions can still occur.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxic epidermal necrolysis related to pemetrexed and carboplatin with vitamin B12 and folic acid supplementation for advanced non-small cell lung cancer. Bosch-Barrera, J., Gaztañaga, M., Ceballos, J., et al.[2015]

Pemetrexed, when combined with cisplatin, significantly improves median survival in patients with malignant pleural mesothelioma, with a median survival of 12.1 months compared to 9.3 months for cisplatin alone, based on a phase III trial involving 448 patients.

The drug works by inhibiting key enzymes involved in DNA synthesis, but it can cause side effects like myelosuppression, neutropenia, and fatigue, necessitating supportive care with folic acid, vitamin B12, and corticosteroids during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA drug approval summaries: pemetrexed (Alimta). Hazarika, M., White, RM., Johnson, JR., et al.[2022]

Pemetrexed, commonly used for treating mesothelioma and lung adenocarcinoma, has been associated with a rare case of communicating hydrocephalus in a patient undergoing maintenance therapy, highlighting a potential unexpected toxicity.

As the use of pemetrexed increases, especially in maintenance settings, healthcare providers should be vigilant for unusual side effects, including neurological complications, during long-term treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed and communicating hydrocephalus. Son, CO., Mott, FE.[2021]

In a study of 58 patients with advanced lung cancer, the combination of Javanica oil emulsion injection (Yadanzi®) with standard chemotherapy (pemetrexed and platinum) showed a higher rate of life improvement (82.8%) compared to chemotherapy alone (51.7%), indicating enhanced quality of life for patients receiving the combination treatment.

The combined treatment group experienced fewer instances of leukopenia (a drop in white blood cells) compared to the control group, suggesting that Yadanzi® may help reduce side effects associated with chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study on Javanica oil emulsion injection (Yadanzi®) combined with chemotherapy in treating patients with advanced lung adenocarcinoma. Lu, YY., Huang, XE., Cao, J., et al.[2022]

Methotrexate (MTX) is the preferred treatment for rheumatoid arthritis due to its favorable safety profile and cost-effectiveness, with an optimal starting dose of 15 mg/week that can be increased to 25-30 mg/week based on patient tolerance.

While oral MTX is commonly used, subcutaneous administration may offer better efficacy and patient compliance, as it has been associated with fewer disease exacerbations and improved quality of life for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methotrexate in rheumatoid arthritis: optimizing therapy among different formulations. Current and emerging paradigms. Cipriani, P., Ruscitti, P., Carubbi, F., et al.[2018]

Pemetrexed (Alimta) shows a response rate of 16%-23% as a single agent for non-small-cell lung cancer (NSCLC) and a higher response rate of 38.9%-44.8% when combined with cisplatin, leading to a median survival of 8.9-10.9 months.

The main side effect of pemetrexed is neutropenia, but this can be mitigated with vitamin B12 and folate supplements, highlighting the importance of supportive care in enhancing treatment safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed (Alimta): a new antifolate for non-small-cell lung cancer. Ettinger, DS.[2017]

Pemetrexed, a treatment for malignant pleural mesothelioma and non-small cell lung cancer, has been associated with a new toxicity resembling scleroderma, as seen in two cases involving painful induration and edema of the lower extremities.

This adverse effect can be mistaken for erysipelas due to similar symptoms, but it lacks fever; recognizing this toxicity is crucial for timely diagnosis and management, and folate and vitamin B12 supplementation may help reduce its incidence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pemetrexed-induced scleroderma-like changes in the lower legs]. Corbaux, C., Marie, J., Meraud, JP., et al.[2015]

A systematic review of phase 3 clinical trials involving biologic DMARDs (Adalimumab, Baricitinib, Pefacitinib, and Sirukumab) showed significant improvements in the ACR 20 response rate for these newer agents, with rates of 72.4% for SB5, 70% for Baricitinib, and up to 74.5% for Pefacitinib at various time points.

The study indicates that these newer biologics not only improve rheumatoid arthritis symptoms effectively but also maintain an acceptable safety profile compared to existing therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of newer biologics DMARDs in the management of rheumatoid arthritis: A systematic review. Zago, BA., Priyadharshini, A., Vijayakumar, TM.[2022]

Pemetrexed is a multitargeted antifolate that effectively inhibits key enzymes in the folate pathway, showing clinical activity in non-small-cell lung cancer (NSCLC) and various other solid tumors.

The addition of low-level folic acid and vitamin B12 supplements enhances the safety of pemetrexed treatment without reducing its effectiveness against tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of Pemetrexed (Alimta , LY231514) in lung cancer therapy. Molina, JR., Adjei, AA.[2015]

Tofacitinib 10 mg combined with methotrexate (MTX) and peficitinib 150 mg with MTX were found to be among the most effective treatments for rheumatoid arthritis (RA) patients who did not respond adequately to disease-modifying antirheumatic drugs (DMARDs), based on a meta-analysis of 9 randomized controlled trials involving 3836 patients.

Both tofacitinib and peficitinib did not show a significant increase in the risk of serious adverse events compared to other treatments, indicating they are safe options for RA management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the efficacy and safety of tofacitinib and peficitinib in patients with active rheumatoid arthritis: A Bayesian network meta-analysis of randomized controlled trials. Lee, YH., Song, GG.[2021]

In the BREVACTA study involving 656 patients with rheumatoid arthritis, subcutaneous tocilizumab (TCZ-SC) demonstrated significantly greater efficacy than placebo, achieving an ACR20 response in 60.9% of patients compared to 31.5% for placebo after 24 weeks.

TCZ-SC was well tolerated, with a safety profile comparable to previous studies, showing similar rates of adverse events and serious adverse events between TCZ-SC and placebo, although injection site reactions were more common with TCZ-SC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subcutaneous tocilizumab versus placebo in combination with disease-modifying antirheumatic drugs in patients with rheumatoid arthritis. Kivitz, A., Olech, E., Borofsky, M., et al.[2022]

Pemetrexed disodium is a promising new antifolate drug that targets multiple enzymes involved in the synthesis of DNA and RNA, showing potential in treating cancers like mesothelioma, non-small cell lung carcinoma, and pancreatic cancer.

Combining pemetrexed with platinum-based drugs and gemcitabine has shown encouraging results, and taking daily oral folate can help reduce side effects like blood-related toxicities while maintaining its effectiveness against tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of a promising new agent--pemetrexed disodium. Paz-Ares, L., Bezares, S., Tabernero, JM., et al.[2022]

In patients with metastatic non-small-cell lung cancer (NSCLC) expressing PD-L1 in ≥50% of tumor cells, pembrolizumab significantly improves progression-free and overall survival compared to traditional platinum-based chemotherapy.

Combining pembrolizumab with standard chemotherapy (pemetrexed and a platinum drug) enhances survival outcomes regardless of PD-L1 expression, indicating a broader efficacy of this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined Checkpoint Inhibition and Chemotherapy: New Era of 1st-Line Treatment for Non-Small-Cell Lung Cancer. Wang, C., Kulkarni, P., Salgia, R.[2020]

Pemetrexed solutions reconstituted with NaCl 0.9% to a concentration of 25 mg/mL are physically and chemically stable for up to 31 days when stored at 4 degrees Celsius, making it safe for longer-term use in clinical settings.

The study confirmed that there were no significant changes in the solution's appearance or composition, indicating that pemetrexed can be reliably stored and used without loss of efficacy during this time frame.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Physical and chemical stability of pemetrexed solutions in plastic syringes. Zhang, Y., Trissel, LA.[2015]

Citations

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NCT04163432 | Staggered, Chemo-Immunotherapy With ... This is a Phase II, open label, randomized study of durvalumab in combination with pemetrexed and carboplatin in eligible adult patients with locally ...

2. imfinzihcp.com imfinzihcp.com/nsclc/metastatic.html

Immunotherapy for Metastatic NSCLC IMFINZI, in combination with etoposide and either carboplatin or cisplatin, is indicated for the first-line treatment of adult patients with extensive-stage ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1470204516304983

Articles Carboplatin and pemetrexed with or without ... Combination of pembrolizumab, carboplatin, and pemetrexed could be an effective and tolerable first-line treatment option for patients with advanced non- ...

4. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2020-02644

Staggered Chemo-Immunotherapy (Pemetrexed and ... This phase II trial studies how well staggered chemo-immunotherapy (pemetrexed and carboplatin with durvalumab) works in treating patients with non-squamous ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa1709937

Durvalumab after Chemoradiotherapy in Stage III Non– ... This phase 3 study compared the anti–programmed death ligand 1 antibody durvalumab as consolidation therapy with placebo in patients with stage III NSCLC

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12206876/

Real-world safety of carboplatin in non-small cell lung cancer This study aims to systematically assess carboplatin-related AEs and explore demographic factors that may influence risk.

7. thelancet.com thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00494-7/fulltext

A phase II clinical trial evaluating the safety and efficacy of ... A phase II clinical trial evaluating the safety and efficacy of durvalumab as first line therapy in advanced and metastatic non-small cell lung cancer patients ...

8. astrazenecaclinicaltrials.com astrazenecaclinicaltrials.com/study/D419AC00002

Study of Durvalumab alone or Chemotherapy for patients ... This is a randomized, open-label, multi-center Phase III study to determine the efficacy and safety of durvalumab versus platinum-based SoC chemotherapy