AZD9291 Combinations for Non-Small Cell Lung Cancer

Recruiting at 33 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: AstraZeneca

Must be taking: EGFR TKIs

Must not be taking: CYP3A4 inducers, CYP1A2 inhibitors

Disqualifiers: Cardiac diseases, Active hepatitis, Others

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

Compensation: Varies

Number of Visits: 6

344 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires stopping certain medications before starting the study. You must stop taking EGFR TKIs (like erlotinib or gefitinib) about 8 days before the first dose and avoid certain other medications and supplements that affect liver enzymes at least 3 weeks prior.

What data supports the effectiveness of the drug combination AZD9291, AZD6094, Selumetinib, Koselugo, Selumetinib, AZD6244, ARRY-142886 for non-small cell lung cancer?

Research shows that Selumetinib, one of the drugs in the combination, significantly improves survival and response rates in patients with a specific type of non-small cell lung cancer when used with another drug, docetaxel. ^{1 2 3 4 5}

What safety data exists for Selumetinib (AZD6244, ARRY-142886) in humans?

Selumetinib has been studied in healthy volunteers and patients with non-small-cell lung cancer (NSCLC). It has been evaluated for its pharmacokinetics (how the drug moves through the body) and tolerability (how well people can handle the drug without severe side effects). ^{1 3 4 6 7}

What makes the drug combination of AZD9291, AZD6094, and Selumetinib unique for non-small cell lung cancer?

This drug combination is unique because it targets specific resistance mechanisms in non-small cell lung cancer, using AZD9291 to inhibit EGFR mutations and Selumetinib to block MEK pathways, potentially delaying or preventing resistance to treatment. ^{1 5 8 9 10}

What is the purpose of this trial?

The purpose of this study is to determine the safety, tolerability and preliminary anti-tumour activity of AZD9291 when given together with AZD6094 or selumetinib in patients with EGFR mutation positive advanced lung cancer

Research Team

Pasi A Jänne, MD, PhD

Principal Investigator

Dana-Faber Cancer Institute

Eligibility Criteria

Adults with advanced lung cancer and specific EGFR mutations who've seen their disease progress on previous EGFR TKI treatments like gefitinib or erlotinib. They must have at least one measurable lesion, be able to take oral meds, and have good organ function. Pregnant women, those with certain heart conditions or active infections, and patients recently on other cancer therapies are excluded.

Inclusion Criteria

My lung cancer has a specific EGFR mutation.

Signed informed consent

My cancer progressed despite treatment with drugs like gefitinib or erlotinib.

Exclusion Criteria

I do not have stomach or intestine problems affecting medication absorption.

I am not taking any strong CYP3A4 inducers for the last 3 weeks.

I have previously been treated with a specific type of lung cancer medication.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Combination Dose Finding

Participants receive AZD9291 in combination with novel therapeutics to determine optimal dosing and schedule

6-12 weeks

Regular visits for safety monitoring and dose adjustments

Dose Expansion

Further evaluation of safety and tolerability of the determined combination dose

Ongoing

Visits every 6 weeks for tumor response evaluation

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• AZD6094
• AZD9291
• Selumetinib

Trial Overview The trial is testing the safety and effectiveness of AZD9291 in combination with other drugs (AZD6094 or selumetinib) for treating advanced lung cancer. It's exploring different combinations to see which works best against tumors that have a particular mutation making them resistant to standard treatments.

Participant Groups

Group I: Selumetinib Experimental Treatment 4 Interventions

AZD9291 in combination with selumetinib

Group II: MEDI4736 Experimental Treatment 2 Interventions

AZD9291 in combination with MEDI4736. Enrolment into the patient cohort that evaluated AZD9291 treatment in combination with MEDI4736 as 1st line treatment has been terminated due to an increased incidence of ILD-like events (interstitial lung disease/pneumonitis), and is no longer being evaluated in this study.

Group III: AZD6094 (monotherapy) Experimental Treatment 1 Intervention

AZD6094 in monotherapy (for Japan only)

Group IV: AZD6094 Experimental Treatment 4 Interventions

AZD9291 in combination with AZD6094

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

Findings from Research

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]

AZD2171, a potent inhibitor of vascular endothelial growth factor receptors, can be safely combined with standard chemotherapy (carboplatin and paclitaxel) in patients with advanced non-small-cell lung cancer, showing no dose-limiting toxicities at doses of 30 mg or 45 mg per day.

The combination treatment resulted in a 45% response rate, with tumor shrinkage observed in nearly all patients, indicating promising antitumor activity despite some manageable side effects like fatigue and diarrhea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I and pharmacokinetic study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with carboplatin and paclitaxel in patients with advanced non-small-cell lung cancer: the National Cancer Institute of Canada clinical trials group. Laurie, SA., Gauthier, I., Arnold, A., et al.[2015]

AZD9291 is effective for treating patients with T790M mutant non-small-cell lung cancer after failure of first-generation EGFR TKIs, but resistance to AZD9291 eventually develops, as seen in a case study of a female patient whose disease progressed after 6 months of treatment.

The patient's re-biopsy revealed a transformation of her lung adenocarcinoma to small cell lung cancer, indicating that this transformation may be a potential resistance mechanism to AZD9291, suggesting that treatments for small cell carcinoma could be considered in such cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transformation to small-cell carcinoma as an acquired resistance mechanism to AZD9291: A case report. Li, L., Wang, H., Li, C., et al.[2022]

References

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

Metabolism, Excretion, and Pharmacokinetics of Selumetinib, an MEK1/2 inhibitor, in Healthy Adult Male Subjects. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Impact of KRAS codon subtypes from a randomised phase II trial of selumetinib plus docetaxel in KRAS mutant advanced non-small-cell lung cancer. [2018]

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

Selumetinib in the treatment of non-small-cell lung cancer. [2018]

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

Comparison of the Pharmacokinetics of the Phase II and Phase III Capsule Formulations of Selumetinib and the Effects of Food on Exposure: Results From Two Randomized Crossover Trials in Healthy Male Subjects. [2022]

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

Identification of common predictive markers of in vitro response to the Mek inhibitor selumetinib (AZD6244; ARRY-142886) in human breast cancer and non-small cell lung cancer cell lines. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Population pharmacokinetics of the MEK inhibitor selumetinib and its active N-desmethyl metabolite: data from 10 phase I trials. [2021]

7. United States 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. [2021]

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

Acquired Resistance to the Mutant-Selective EGFR Inhibitor AZD9291 Is Associated with Increased Dependence on RAS Signaling in Preclinical Models. [2022]

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

Phase I and pharmacokinetic study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with carboplatin and paclitaxel in patients with advanced non-small-cell lung cancer: the National Cancer Institute of Canada clinical trials group. [2015]

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

Transformation to small-cell carcinoma as an acquired resistance mechanism to AZD9291: A case report. [2022]