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

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)

43 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a combination of an immune-boosting drug and chemotherapy in adults with advanced lung cancer. The treatment aims to help the immune system fight cancer while also killing cancer cells directly.

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.

What data supports the idea that Chemo-Immunotherapy for Non-Small Cell Lung Cancer is an effective treatment?

The available research does not provide specific data on the effectiveness of Chemo-Immunotherapy for Non-Small Cell Lung Cancer. The studies mentioned focus on other treatments and conditions, such as rheumatoid arthritis and a different combination of drugs for lung cancer. Therefore, there is no direct evidence from the provided information to support the effectiveness of Chemo-Immunotherapy for Non-Small Cell Lung Cancer. ^{1 2 3 4 5}

What data supports the effectiveness of the drug combination of Carboplatin, Durvalumab, and Pemetrexed for treating non-small cell lung cancer?

The research on Javanica oil emulsion injection combined with pemetrexed and platinum (similar to Carboplatin) for advanced lung cancer suggests that combining pemetrexed with platinum-based drugs can be effective in treating lung cancer. ^{1 2 3 4 5}

What safety data is available for chemo-immunotherapy in non-small cell lung cancer?

The safety data for the treatment involving Pemetrexed (Alimta) in non-small cell lung cancer (NSCLC) includes reports of scleroderma-like changes in the lower legs, myelosuppression, neutropenia, fatigue, leukopenia, nausea, dyspnea, and vomiting. Pemetrexed is used in combination with platinum compounds like cisplatin and carboplatin, and its safety profile is improved with folic acid and vitamin B12 supplementation. The FDA has approved Pemetrexed in combination with cisplatin for certain cancers, and it is also used in maintenance therapy for NSCLC. Unexpected cumulative toxicity is possible with longer durations of therapy. ^{6 7 8 9 10}

Is the chemo-immunotherapy treatment for non-small cell lung cancer safe?

Pemetrexed, a part of this treatment, can cause side effects like myelosuppression (a decrease in bone marrow activity), neutropenia (low white blood cell count), fatigue, and nausea. Taking folic acid and vitamin B12 can help reduce some of these side effects. ^{6 7 8 9 10}

Is the drug combination of Carboplatin, Durvalumab, and Pemetrexed a promising treatment for Non-Small Cell Lung Cancer?

Yes, the combination of these drugs is promising for treating Non-Small Cell Lung Cancer. Pemetrexed, when used with platinum-based drugs like Carboplatin, has shown good results in clinical trials. Adding Durvalumab, which helps the immune system fight cancer, can improve survival rates. This combination has shown potential in improving outcomes for patients. ^{7 11 12 13 14}

What makes the chemo-immunotherapy drug combination of Carboplatin, Durvalumab, and Pemetrexed unique for treating non-small cell lung cancer?

This treatment combines chemotherapy with immunotherapy, using Durvalumab to help the immune system attack cancer cells, and Pemetrexed and Carboplatin to directly kill cancer cells. This combination aims to improve survival rates by leveraging both the immune system and traditional chemotherapy, offering a novel approach compared to standard chemotherapy alone. ^{7 11 12 13 15}

Research Team

Wallace L. Akerley

Principal Investigator

Huntsman Cancer Institute

Eligibility Criteria

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

I am 18 years old or older.

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.

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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, 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]

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]

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]

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]

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]

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 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 (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]

References

1. Thailand pubmed.ncbi.nlm.nih.gov

Phase II study on Javanica oil emulsion injection (Yadanzi®) combined with chemotherapy in treating patients with advanced lung adenocarcinoma. [2022]

2. England 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. [2021]

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

Safety and efficacy of newer biologics DMARDs in the management of rheumatoid arthritis: A systematic review. [2022]

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

Subcutaneous tocilizumab versus placebo in combination with disease-modifying antirheumatic drugs in patients with rheumatoid arthritis. [2022]

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

Methotrexate in rheumatoid arthritis: optimizing therapy among different formulations. Current and emerging paradigms. [2018]

6. France pubmed.ncbi.nlm.nih.gov

[Pemetrexed-induced scleroderma-like changes in the lower legs]. [2015]

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

Review of a promising new agent--pemetrexed disodium. [2022]

8. England pubmed.ncbi.nlm.nih.gov

FDA drug approval summaries: pemetrexed (Alimta). [2022]

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

Pemetrexed and communicating hydrocephalus. [2021]

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

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

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

Combined Checkpoint Inhibition and Chemotherapy: New Era of 1st-Line Treatment for Non-Small-Cell Lung Cancer. [2020]

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

Physical and chemical stability of pemetrexed solutions in plastic syringes. [2015]

13. Switzerland 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. [2015]

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

Physical and chemical stability of pemetrexed in infusion solutions. [2022]

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

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