A Randomized Phase III Trial of Checkpoint Blockade in Lung Cancer Patients in the Adjuvant Setting Based on Pathologic Response Following Neoadjuvant Therapy (CLEAR)

Plain English Summary

Testing the Addition of AZD6738 (Ceralasertib) to Immunotherapy to Increase Time Without Cancer for Patients With Non-Small Cell Lung Cancer is a Phase 3 clinical trial sponsored by National Cancer Institute (NCI) studying Lung Non-Small Cell Carcinoma, Stage II Lung Cancer AJCC v8, Stage IIIA Lung Cancer AJCC v8, Stage IIIB Lung Cancer AJCC v8. This trial tests if adding a drug called AZD6738 to standard immunotherapy can help prevent lung cancer from returning after initial treatment. It is for patients with non-small cell lung cancer (NSCLC) who have had chemotherapy, surgery, and are not showing a complete response to that treatment. Participation involves receiving either AZD6738 plus immunotherapy or immunotherapy alone, with regular check-ups and tests. An alternative for patients with a complete response to initial treatment is to join a different study (SWOG S2414 INSIGHT). The trial aims to enroll 630 participants.

Official Summary

This phase III trial compares the effect of adding AZD6738 to durvalumab versus durvalumab alone to increase time without cancer in patients with non-small cell lung cancer, following treatment with chemotherapy and surgery. AZD6738 may stop the growth of tumor cells and may kill them by blocking some of the enzymes needed for cell growth. Durvalumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Adding AZD6738 to durvalumab may increase time without cancer in patients with non-small cell lung cancer, following treatment with chemotherapy and surgery.

Who Can Participate

Here is what you need to know about eligibility for this trial. Adults aged 18 and older with stage II to select stage IIIB non-small cell lung cancer. Patients must have undergone initial treatment with chemotherapy and immunotherapy before surgery, and not have a complete response after surgery. Individuals with known EGFR or ALK genetic alterations, or those who have had certain lung conditions or organ transplants, cannot participate. Patients must be able to undergo regular CT scans and blood tests, and not be pregnant or breastfeeding. This trial is studying Lung Non-Small Cell Carcinoma, Stage II Lung Cancer AJCC v8, Stage IIIA Lung Cancer AJCC v8, Stage IIIB Lung Cancer AJCC v8, so participants generally need a confirmed diagnosis.

What They're Measuring

The main goal is to see if patients stay free of cancer for a longer time after treatment, meaning the therapy might be more effective at preventing recurrence. The specific primary outcome measures are: Disease free survival (DFS) (From randomization to the earliest event defined as the first recurrence of non-small cell lung cancer (NSCLC), any new lung cancer or death, up to 10 years). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 3, the final and most rigorous stage before seeking FDA approval. Phase 3 trials involve 300-3,000+ patients across multiple sites and compare the new treatment directly against the current standard of care. These pivotal trials generate the evidence needed for regulatory review. About 58% of Phase 3 drugs receive FDA approval. Successful Phase 3 results typically lead to a New Drug Application submission.

Why This Trial Matters

This trial aims to fill a gap in treating lung cancer by exploring a new combination therapy to reduce the chance of cancer coming back after surgery. As a Phase 3 trial, positive results could directly lead to FDA approval, making this treatment available to the broader patient population. This research targets Lung Non-Small Cell Carcinoma, Stage II Lung Cancer AJCC v8, Stage IIIA Lung Cancer AJCC v8, Stage IIIB Lung Cancer AJCC v8, where improved treatment options are needed.

Investor Insight

This Phase III trial, sponsored by the NCI, targets a significant market for advanced lung cancer treatments, with a focus on adjuvant therapy, suggesting a high potential for impact if successful. Phase 3 trials have approximately a 50-60% chance of gaining FDA approval if they reach this stage. The large enrollment target of 630 participants suggests significant investment in this program.

Is This Trial Right for Me?

Ask your doctor about the specific chemotherapy and immunotherapy you received before surgery and your current cancer stage. Understand the difference between a complete pathological response and a non-pathological complete response, and how it affects your eligibility. Be prepared for regular visits for drug administration, CT scans, blood draws, and potential side effect monitoring. The trial is being conducted at 20 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 630 participants

Interventions

• PROCEDURE: Biospecimen Collection — Undergo blood sample collection
• DRUG: Ceralasertib — Given PO
• PROCEDURE: Computed Tomography — Undergo CT scan
• BIOLOGICAL: Durvalumab — Given IV
• PROCEDURE: Echocardiography Test — Undergo echocardiography

Primary Outcomes

• Disease free survival (DFS) (From randomization to the earliest event defined as the first recurrence of non-small cell lung cancer (NSCLC), any new lung cancer or death, up to 10 years)

Secondary Outcomes

• Overall survival (OS) (From randomization to death from any cause, up to 10 years)
• Incidence of adverse events (Up to 10 years)

Full Eligibility Criteria

Inclusion Criteria:

* STEP 0: Patient must be \>= 18 years of age
* STEP 0: Patient must have stage II to select stage IIIB (N2 but excluding N3) non-small cell lung cancer (NSCLC) of any histology using International Association for the Study of Lung Cancer (IASLC) 8th edition. Stage is assessed at time of initiating pre-operative chemo-immunotherapy
* STEP 0: Patient must fall into one of the following categories:

  * Planning to undergo, be currently undergoing, or recently completed any standard of care neoadjuvant chemo-immunotherapy with plans to undergo surgical resection
  * Recently completed any standard of care neoadjuvant chemo-immunotherapy AND completed surgical resection and are awaiting pCR status.
  * Recently completed any standard of care neoadjuvant chemo-immunotherapy AND completed surgical resection with confirmed non-path complete response (CR) status.

NOTES:

* Patient must have completed at least 3 cycles of neoadjuvant chemo-immunotherapy before surgery in order to be eligible for Step 1 randomization.
* Patients who have completed their surgical resection prior to enrollment in step 0 registration must have their surgery date within a window that will allow initiation of EA5231 treatment (cycle 1 day 1) to commence within 4-12 weeks following surgery

  * STEP 1: EA5231 CLEAR randomization for patients without a pCR post-surgery. Patient's with pCR after surgery will be offered to enroll in the SWOG study S2414 INSIGHT instead
  * STEP 1: Patient must have completed R0 resection after standard of care neoadjuvant chemo-immunotherapy (minimum three cycles completed) for stage II to select stage IIIB (N2 but excluding N3) non-small cell lung cancer (NSCLC) of any histology using IASLC 8th Edition
  * STEP 1: Patient must have non-pathological CR status post-surgery. The pathological CR/non-pathological CR status will be determined by local pathology using IASLC criteria and using the surgical sample tissue
  * STEP 1: Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 - ≤ 2 (or Karnofsky ≥ 60%)
  * STEP 1: Patient must not have any known EGFR or ALK genetic alterations. Mutation negative status will be determined per local institutional practices and consistent with National Comprehensive Cancer Network (NCCN) guidelines
  * STEP 1: Patient must have undergone a chest CT after surgery and within 28 days prior to step 1 randomization
  * STEP 1: Patient must have recovered from clinically significant adverse events of their most recent therapy/intervention prior to step 1 randomization
  * STEP 1: Patient must not have experienced a toxicity that led to the permanent discontinuation of prior immunotherapy
  * STEP 1: Patient must not be receiving ongoing steroids at a dose of prednisone 10 mg or higher (or equivalent) at the time of step 1 randomization. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) are allowed. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) are allowed
  * STEP 1: Patient must not have received or have a plan to receive post-operative radiation therapy (PORT)
  * STEP 1: Patient must not have a history of treatment-related pneumonitis requiring ongoing steroids or supplemental oxygen use
  * STEP 1: Patient must not have a history of interstitial lung disease (ILD)
  * STEP 1: Patient must not have diagnosis of ataxia telangiectasia
  * STEP 1: Patient must not have history of active primary immunodeficiency
  * STEP 1: Patient must not have history of allogenic organ transplantation
  * STEP 1: Patient must have body weight \> 30 kg
  * STEP 1: Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. All patients of childbearing potential must have a blood test or urine study within 14 days prior to Step 1 randomization to rule out pregnancy. A patient of childbearing potential is defined as anyone, regardless of whether they have undergone tubal ligation, who meets the following criteria:
* Has achieved menarche at some point
* Has not undergone a hysterectomy or bilateral oophorectomy
* Has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

  * STEP 1: Patient must not expect to conceive or father children by using highly accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study. Patients of childbearing potential must use at least 1 highly effective method of contraception in addition to a condom and continue to use it throughout their time on protocol treatment. Male patients must use a condom plus spermicide throughout their time on while on proto

Trial Locations

• NEA Baptist Memorial Hospital and Fowler Family Cancer Center - Jonesboro, Jonesboro, Arkansas, United States
• Tower Cancer Research Foundation, Beverly Hills, California, United States
• Cedars Sinai Medical Center, Los Angeles, California, United States
• Cedars-Sinai Cancer - Tarzana, Tarzana, California, United States
• Torrance Memorial Physician Network - Cancer Care, Torrance, California, United States
• Hartford Hospital, Hartford, Connecticut, United States
• Midstate Medical Center, Meriden, Connecticut, United States
• The Hospital of Central Connecticut, New Britain, Connecticut, United States
• Beebe South Coastal Health Campus, Millville, Delaware, United States
• Helen F Graham Cancer Center, Newark, Delaware, United States
• ...and 10 more locations

Frequently Asked Questions

Related Conditions

• Lung Cancer
• Non-Small Cell Lung Cancer
• Adjuvant Therapy
• Neoadjuvant Therapy
• Immunotherapy
• Checkpoint Inhibitors
• Targeted Therapy
• Oncology
• Thoracic Oncology
• Cancer Research

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