Triple Drug Therapy for Non-Small Cell Lung Cancer

Overseen By Don Gibbons

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Immunosuppressants, MEK inhibitors

Disqualifiers: Autoimmune disorders, Active infection, Cardiac conditions, 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: 38

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of three drugs—durvalumab and tremelimumab (both immunotherapy drugs), and selumetinib (a targeted therapy drug)—to treat advanced or returning non-small cell lung cancer (NSCLC). The researchers aim to determine how well this trio can help the immune system fight cancer and block tumor growth. Participants will receive these drugs on different schedules to identify the best approach. Suitable candidates have stage IV NSCLC or cancer that has returned after treatment, and they must know their KRAS mutation status. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on any other cancer treatments or investigational drugs, and you should not have used immunosuppressive medications recently. It's best to discuss your specific medications with the trial team.

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

Research is examining the effectiveness and safety of a combination of three drugs—durvalumab, tremelimumab, and selumetinib—for treating non-small cell lung cancer. Previous studies have shown that durvalumab and tremelimumab, when combined with chemotherapy, are generally well-tolerated. Health Canada has approved these two drugs for certain cancer treatments, indicating their safety.

Selumetinib has been tested with other drugs in various studies and is generally safe in smaller doses. Common side effects include tiredness, skin rash, and diarrhea, but these are usually manageable.

As this trial is in its early stages, it aims to determine the best dose and assess the safety of the drug combination. Early-phase trials involve some uncertainty about safety but help researchers understand how patients handle the treatment. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this triple drug therapy for non-small cell lung cancer because it combines three powerful agents: durvalumab, selumetinib, and tremelimumab, each bringing something unique to the table. Unlike standard treatments that often focus on single pathways, this combination targets multiple fronts. Durvalumab and tremelimumab are immune checkpoint inhibitors, enhancing the body's immune response against cancer cells by targeting PD-L1 and CTLA-4 pathways, respectively. Selumetinib, on the other hand, is a MEK inhibitor, which blocks a key protein in the MAPK/ERK pathway that cancer cells use to grow. This multi-pronged approach could potentially offer more comprehensive cancer control and improve patient outcomes compared to existing therapies.

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

Research has shown that using durvalumab, tremelimumab, and selumetinib together might help treat non-small cell lung cancer. These drugs boost the immune system to fight cancer and block enzymes that aid tumor growth. In this trial, participants will receive either an intermittent or continuous regimen of these three drugs. One study found that adding tremelimumab to durvalumab and chemotherapy helped patients live longer without their cancer worsening and improved overall survival for those with advanced lung cancer. Another study demonstrated that this combination is effective and generally well-tolerated. While these results are promising, more research is needed to confirm the effectiveness of this specific drug combination. ^{2 6 7 8 9}

Who Is on the Research Team?

Don L. Gibbons

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with stage IV non-small cell lung cancer or recurrent disease not suitable for curative therapy. Participants must have adequate organ function, measurable disease, no prior treatment with certain inhibitors, and agree to use contraception. Those with stable brain metastases treated without steroids may qualify.

Inclusion Criteria

You have a disease that can be measured using a specific set of guidelines called RECIST 1.1.

I weigh more than 30 kilograms.

You must have at least 100,000 platelets per microliter of blood.

Exclusion Criteria

I haven't had major surgery in the last 4 weeks, except for a procedure to get a vascular access port.

I haven't taken strong immune system suppressing drugs in the last 14 days, except for low-dose or inhaled steroids.

I have an autoimmune or inflammatory condition but it's controlled or I've been stable for the last 5 years.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-escalation

Participants receive selumetinib in a dose-escalation study to determine the maximum tolerated dose

28 days per course

4 visits (in-person) per course

Dose expansion

Participants receive selumetinib, durvalumab, and tremelimumab in either an intermittent or continuous schedule

28 days per course, repeated in the absence of disease progression or unacceptable toxicity

4 visits (in-person) per course

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Follow-up at 30 and 90 days, then every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Durvalumab
• Selumetinib
• Tremelimumab

Trial Overview The study tests the combination of selumetinib (blocks tumor growth enzymes) with durvalumab and tremelimumab (monoclonal antibodies that boost the immune system against cancer). It aims to determine the best dose of selumetinib and assess how well this trio works together in advanced lung cancer.

How Is the Trial Designed?

Group I: Arm II (continuous selumetinib, durvalumab, tremelimumab) Experimental Treatment 3 Interventions

Participants receive selumetinib PO BID on days 1-28 and durvalumab IV over 60 minutes on day 1. Participants also receive tremelimumab IV over 60 minutes on day 1 for courses 1-4. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (intermittent selumetinib, durvalumab, tremelimumab) Experimental Treatment 3 Interventions

Participants receive selumetinib PO BID on days 1-7 and 15-21 and durvalumab intravenously (IV) over 60 minutes on day 1. Participants also receive tremelimumab IV over 60 minutes on day 1 for courses 1-4. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a phase 1b study involving 78 patients with advanced non-small cell lung cancer (NSCLC) who had previously failed PD-(L)1 therapy, the combination of durvalumab and tremelimumab showed a manageable safety profile, with common side effects including fatigue and diarrhea.

However, the treatment demonstrated limited efficacy, with an objective response rate of only 5.3% in PD-(L)1-refractory patients and 0% in PD-(L)1-relapsed patients, indicating that this combination may not be effective after PD-(L)1 treatment failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brief Report: Safety and Antitumor Activity of Durvalumab Plus Tremelimumab in Programmed Cell Death-(Ligand)1-Monotherapy Pretreated, Advanced NSCLC: Results From a Phase 1b Clinical Trial. Garon, EB., Spira, AI., Goldberg, SB., et al.[2023]

In a study involving 58 patients with advanced squamous non-small-cell lung cancer (sqNSCLC) who had previously progressed on anti-PD-(L)1 therapy, the combination of durvalumab and tremelimumab showed minimal efficacy, with only a 7% response rate in those with primary resistance and no responses in the acquired resistance cohort.

The treatment resulted in a median progression-free survival of about 2 months and an overall survival of approximately 7.6 to 7.7 months, indicating limited effectiveness in overcoming resistance to prior therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of durvalumab plus tremelimumab as therapy for patients with previously treated anti-PD-1/PD-L1 resistant stage IV squamous cell lung cancer (Lung-MAP substudy S1400F, NCT03373760). Leighl, NB., Redman, MW., Rizvi, N., et al.[2023]

The phase III POSEIDON trial demonstrated that a three-drug regimen combining the CTLA4 inhibitor tremelimumab, the PD-L1 inhibitor durvalumab, and chemotherapy significantly improves progression-free survival and overall survival in patients with metastatic non-small cell lung cancer compared to chemotherapy alone.

This study suggests that targeting multiple immune pathways with this combination therapy may enhance treatment effectiveness for lung cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Three-Drug Regimen Bests Chemo in NSCLC. [2022]

The combination of durvalumab and tremelimumab in cancer treatment is associated with a higher incidence of severe adverse events (32.6%) compared to durvalumab alone (23.8%), indicating increased safety concerns with the combination therapy.

Patients receiving the combination therapy also experienced higher rates of specific side effects such as diarrhea (15.6% vs. 8.1%), rash (11.1% vs. 6.5%), and treatment discontinuation (18% vs. 3%), highlighting the need for careful monitoring and patient counseling regarding these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. Fahmy, O., Ahmed, OAA., Khairul-Asri, MG., et al.[2023]

In a phase 1b study involving 102 patients with advanced non-small cell lung cancer, the combination of durvalumab and tremelimumab demonstrated manageable safety, although 36% of patients experienced serious treatment-related adverse events, including three treatment-related deaths.

The treatment showed evidence of antitumor activity in both PD-L1-positive and PD-L1-negative tumors, with a confirmed objective response rate of 23% in the cohort receiving tremelimumab 1 mg/kg, indicating potential effectiveness regardless of PD-L1 status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Antonia, S., Goldberg, SB., Balmanoukian, A., 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]

Durvalumab, an immunotherapy drug for non-small cell lung cancer (NSCLC), has shown significant activity and acceptable tolerability, especially in patients with at least 25% PD-L1 tumor expression, and has been established as a standard treatment following chemoradiation based on the PACIFIC study results.

While durvalumab is effective in wild-type EGFR and ALK patients, its efficacy is lower in those with EGFR mutations or ALK-positive status, highlighting the need for ongoing research into combination therapies and the management of treatment-related toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab for the treatment of non-small cell lung cancer. Mezquita, L., Planchard, D.[2019]

This phase I/II clinical trial is investigating the safety and efficacy of a combination treatment involving selumetinib, tremelimumab, and durvalumab in 40 patients with previously treated, unresectable non-small-cell lung cancer (NSCLC).

The study aims to determine the maximum tolerated dose and progression-free survival, while also exploring biomarkers of response and resistance, which could help tailor future treatments for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II Trial of Immunotherapy With Durvalumab and Tremelimumab With Continuous or Intermittent MEK Inhibitor Selumetinib in NSCLC: Early Trial Report. Gaudreau, PO., Lee, JJ., Heymach, JV., et al.[2021]

The combination of durvalumab and tremelimumab showed improved disease control rates in patients with head and neck squamous cell carcinoma compared to tremelimumab alone, indicating its potential efficacy in this cancer type.

The combination therapy had a tolerable safety profile, with no significant increase in treatment-related adverse events compared to monotherapy, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab and tremelimumab combination therapy versus durvalumab or tremelimumab monotherapy for patients with solid tumors: A systematic review and meta-analysis. Wang, BC., Li, PC., Fan, JQ., et al.[2022]

In the phase 3 POSEIDON study involving 1013 treatment-naïve patients with metastatic non-small-cell lung cancer (NSCLC), the combination of tremelimumab, durvalumab, and chemotherapy significantly improved overall survival and progression-free survival compared to chemotherapy alone.

Patients receiving the combination treatment also experienced a longer time to deterioration in quality of life and various symptoms, indicating better overall health status compared to those on chemotherapy, supporting its use as a first-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes with durvalumab, with or without tremelimumab, plus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer (POSEIDON). Garon, EB., Cho, BC., Luft, A., et al.[2023]

In a safety run-in phase of the DURIGAST PRODIGE 59 study involving 11 patients with advanced gastric or gastro-oesophageal junction adenocarcinoma, 63.6% experienced significant adverse events, primarily neutropenia, indicating a notable safety concern with the treatment combination.

The combination of FOLFIRI with Durvalumab and/or Tremelimumab showed an expected safety profile, allowing progression to the randomized phase II study, although careful monitoring for serious adverse events is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of FOLFIRI + Durvalumab +/- Tremelimumab in Second Line of Patients with Advanced Gastric Cancer: A Safety Run-In from the Randomized Phase II Study DURIGAST PRODIGE 59. Evrard, C., Aparicio, T., Soularue, E., et al.[2022]

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