Phase III Trial of Stereotactic Radiosurgery (SRS) Versus Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) for Brain Metastases From Small Cell Lung Cancer

Plain English Summary

Testing if High Dose Radiation Only to the Sites of Brain Cancer Compared to Whole Brain Radiation That Avoids the Hippocampus is Better at Preventing Loss of Memory and Thinking Ability is a Phase 3 clinical trial sponsored by NRG Oncology studying Metastatic Lung Small Cell Carcinoma, Metastatic Malignant Neoplasm in the Brain, Recurrent Lung Small Cell Carcinoma, Stage IV Lung Cancer AJCC v8. Compares stereotactic radiosurgery (SRS) to whole brain radiation therapy (WBRT) that avoids the hippocampus to prevent memory loss. For patients with small cell lung cancer that has spread to the brain, with up to 4 brain metastases ≤ 4 cm. Participation involves MRI, blood tests, and neurocognitive assessments. Alternative treatments include standard WBRT with memantine. The trial aims to enroll 200 participants.

Official Summary

This phase III trial compares the effect of stereotactic radiosurgery to standard of care memantine and whole brain radiation therapy that avoids the hippocampus (the memory zone of the brain) for the treatment of small cell lung cancer that has spread to the brain. Stereotactic radiosurgery is a specialized radiation therapy that delivers a single, high dose of radiation directly to the tumor and may cause less damage to normal tissue. Whole brain radiation therapy delivers a low dose of radiation to the entire brain including the normal brain tissue. Hippocampal avoidance during whole-brain radiation therapy (HA-WBRT) decreases the amount of radiation that is delivered to the hippocampus which is a brain structure that is important for memory. The drug, memantine, is also often given with whole brain radiotherapy because it may decrease the risk of side effects related to thinking and memory. Stereotactic radiosurgery may decrease side effects related to memory and thinking compared to standard of care HA-WBRT plus memantine.

Who Can Participate

Here is what you need to know about eligibility for this trial. Eligible if diagnosed with small cell lung cancer within 5 years, up to 4 brain metastases ≤ 4 cm, Karnofsky performance status ≥ 70, and proficient in English or French Canadian. Not eligible if brain metastases are symptomatic or in eloquent locations, or if there is impaired decision-making capacity. Age ≥ 18, creatinine clearance ≥ 30 ml/min, and negative pregnancy test for women of childbearing potential. Prior intracranial surgical resection is allowed. This trial is studying Metastatic Lung Small Cell Carcinoma, Metastatic Malignant Neoplasm in the Brain, Recurrent Lung Small Cell Carcinoma, Stage IV Lung Cancer AJCC v8, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The primary outcome measures the time to neurocognitive failure, which means how long it takes for patients to experience memory or thinking problems. The specific primary outcome measures are: Time to neurocognitive failure (Up to 1 year). 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 the gap in treatment options for preventing cognitive decline in patients with brain metastases from small cell lung cancer. 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 Metastatic Lung Small Cell Carcinoma, Metastatic Malignant Neoplasm in the Brain, Recurrent Lung Small Cell Carcinoma, Stage IV Lung Cancer AJCC v8, where improved treatment options are needed.

Investor Insight

The market size for treating brain metastases is significant, with a competitive landscape that includes various radiation therapies. Approval probability is moderate given the phase and sponsor's rep Phase 3 trials have approximately a 50-60% chance of gaining FDA approval if they reach this stage.

Is This Trial Right for Me?

Ask your doctor about your eligibility and the potential risks and benefits of participating. Participation involves regular MRI scans, blood tests, and neurocognitive assessments. This trial is currently recruiting participants. 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: 200 participants

Interventions

• PROCEDURE: Biospecimen Collection — Undergo blood sample collection
• PROCEDURE: Magnetic Resonance Imaging — Undergo MRI
• DRUG: Memantine Hydrochloride — Given PO
• OTHER: Neurocognitive Assessment — Ancillary studies
• RADIATION: Stereotactic Radiosurgery — Undergo SRS

Primary Outcomes

• Time to neurocognitive failure (Up to 1 year)

Secondary Outcomes

• Preservation of neurocognitive function (1 year)
• Perceived difficulties in cognition (Up to 1 year)
• Symptom burden (Up to 1 year)
• Time to intracranial disease progression (From the date of randomization to the date of intracranial disease progression, assessed up to 10 years)
• Overall survival (From the date of randomization to the date of death, or otherwise, the last follow-up date on which the patient was reported alive, assessed up to 10 years)

Full Eligibility Criteria

Inclusion Criteria:

* Pathologically (histologically or cytologically) proven diagnosis of small cell lung cancer within 5 years of registration. If the original histologic proof of malignancy is greater than 5 years, then pathological (i.e., more recent) confirmation is required (e.g., from a systemic or brain metastasis);

  * Patients with de novo or recurrent small cell lung cancer are permitted.
* Brain metastases =\< 4 cm in largest diameter and outside a 5-mm margin around either hippocampus must be visible on contrast-enhanced magnetic resonance imaging (MRI) performed =\< 21 days prior to study entry.

  * The total tumor volume must be 30 cm\^3 or less. Lesion volume will be approximated by measuring the lesion's three perpendicular diameters on contrast enhanced, T1-weighted MRI and the product of those diameters will be divided by 2 to estimate the lesion volume (e.g. xyz/2). Alternatively, direct volumetric measurements via slice by slice contouring on a treatment planning software package can be used to calculate the total tumor volume.
  * Brain metastases can be diagnosed synchronous to the initial diagnosis of small cell lung cancer or metachronous to the initial diagnosis and management of small cell lung cancer.
  * Brain metastases must be diagnosed on MRI, which will include the following elements:

    * REQUIRED MRI ELEMENTS

      * Post gadolinium contrast-enhanced T1-weighted three-dimensional (3D) spoiled gradient (SPGR). Acceptable 3D SPGR sequences include magnetization prepared 3D gradient recalled echo (GRE) rapid gradient echo (MP-RAGE), turbo field echo (TFE) MRI, BRAVO (Brain Volume Imaging) or 3D Fast FE (field echo). The T1-weighted 3D scan should use the smallest possible axial slice thickness, not to exceed 1.5 mm.
      * Pre-contrast T1 weighted imaging (3D imaging sequence strongly encouraged).
      * A minimum of one axial T2 FLAIR (preferred) or T2 sequence is required. This can be acquired as a two dimensional (2D) or 3D image. If 2D, the images should be obtained in the axial plane.
    * ADDITIONAL RECOMMENDATIONS

      * Recommendation is that an axial T2 FLAIR (preferred) sequence be performed instead of a T2 sequence.
      * Recommendation is that that pre-contrast 3D T1 be performed with the same parameters as the post-contrast 3D T1.
      * Recommendation is that imaging be performed on a 3 Tesla (3T) MRI.
      * Recommendation is that the study participants be scanned on the same MRI instrument at each time point.
      * Recommendation is that if additional sequences are obtained, these should meet the criteria outlined in Kaufmann et al., 2020.
      * If additional sequences are obtained, total imaging time should not exceed 60 minutes.
      * If additional metastases not known at the time of registration/randomization or seen in the MRI used for eligibility are subsequently found on the radiation therapy (RT) planning MRI such that the total intacranial volume exceeds 30 cm\^3, the patient is still considered eligible.
* History/physical examination
* Age \>= 18
* Karnofsky performance status of \>= 70
* Creatinine clearance \>= 30 ml/min
* Following the diagnosis of brain metastases, patients can initiate and treat with systemic (chemotherapy and/or immunotherapy) before enrollment only if their brain metastases are asymptomatic and not located in eloquent locations (e.g., brainstem, pre-/post-central gyrus, visual cortex). However, within 21 days prior to enrollment, brain MRI must be repeated to confirm eligibility.

  * Patients with symptomatic brain metastases and/or brain metastases in eloquent locations (e.g., brainstem, pre-/post central gyrus, visual cortex) are eligible for enrollment on the trial; however, the specific treatment approach of starting with systemic therapy alone and delaying brain radiation is not recommended for these patients.
* Concurrent immunotherapy with brain radiation (SRS or HA-WBRT) is permitted.
* Negative urine or serum pregnancy test (in women of childbearing potential) within 14 days prior to registration. Women of childbearing potential and men who are sexually active must use contraception while on study.
* Patients may have had prior intracranial surgical resection.
* Because neurocognitive testing is the primary goal of this study, patients must be proficient in English or French Canadian.
* The patient must provide study-specific informed consent prior to study entry.

  * Patients with impaired decision-making capacity are not permitted on study.
* ELIGIBILITY CRITERIA PRIOR TO STEP 2 REGISTRATION
* The following baseline neurocognitive tests must be completed within 21 days prior to Step 2 registration: HVLT-R, TMT, and COWA. The neurocognitive test will be uploaded into RAVE for evaluation by Dr. Wefel. Once the upload is complete, within 3 business days a notification will be sent via email to the RA to proceed to Step 2.

  * NOTE: Completed baseline neurocognitive tests can be uploaded at the t

Trial Locations

• Mayo Clinic Hospital in Arizona, Phoenix, Arizona, United States
• Kaiser Permanente-Anaheim, Anaheim, California, United States
• Kaiser Permanente-Bellflower, Bellflower, California, United States
• Kaiser Permanente Los Angeles Medical Center, Los Angeles, California, United States
• Los Angeles General Medical Center, Los Angeles, California, United States
• USC / Norris Comprehensive Cancer Center, Los Angeles, California, United States
• Kaiser Permanente-Ontario, Ontario, California, United States
• UCHealth University of Colorado Hospital, Aurora, Colorado, United States
• UCHealth Memorial Hospital Central, Colorado Springs, Colorado, United States
• Memorial Hospital North, Colorado Springs, Colorado, United States
• ...and 10 more locations

Frequently Asked Questions

Related Conditions

• Small cell lung cancer, brain metastases, recurrent lung cancer, stage IV lung cancer, and metastatic malignant neoplasm in the brain.

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