Genetic Testing in Guiding Treatment for Patients With Brain Metastases

  • STATUS
    Recruiting
  • End date
    Jun 19, 2025
  • participants needed
    150
  • sponsor
    Alliance for Clinical Trials in Oncology
Updated on 19 November 2020
Investigator
Priscilla K. Brastianos
Primary Contact
Epic Care Cyberknife Center (0.7 mi away) Contact
+351 other location

Summary

This phase II trial studies how well genetic testing works in guiding treatment for patients with solid tumors that have spread to the brain. Several genes have been found to be altered or mutated in brain metastases such as NTRK, ROS1, CDK or PI3K. Medications that target these genes such as abemaciclib, GDC-0084, and entrectinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Genetic testing may help doctors tailor treatment for each mutation.

Description

PRIMARY OBJECTIVES:

I. To determine the activity of a CDK inhibitor in patients with progressive brain metastases derived from lung cancer, breast cancer, and other cancers harboring actionable genetic alterations associated with sensitivity to CDK inhibitors as measured by response rate (Response Assessment in Neuro-Oncology [RANO] criteria).

II. To determine the activity of a PI3K inhibitor in patients with progressive brain metastases derived from lung cancer, breast cancer, and other cancers harboring actionable genetic alterations in the PI3K pathway as measured by response rate (RANO criteria).

III: To determine the activity of an NTRK/ROS1 inhibitor in patients with progressive brain metastases derived from lung cancer harboring actionable NTRK/ROS1 gene fusions as measured by response rate (RANO criteria).

SECONDARY OBJECTIVES:

I. To evaluate the systemic response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria in each of the cohorts determined by treatment and primary cancer type.

II. To evaluate the clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD]) by Brain Metastases (BM)-RANO for central nervous system (CNS) in each of the cohorts determined by treatment and primary cancer type.

III. To evaluate the clinical benefit rate (CR + PR + SD) by RECIST for extracranial disease in each of the cohorts determined by treatment and primary cancer type.

IV. To evaluate the duration of response by BM-RANO in each of the cohorts determined by treatment and primary cancer type.

V. To evaluate the duration of response by RECIST in each of the cohorts determined by treatment and primary cancer type.

VI. To evaluate the progression-free survival for intracranial disease in each of the cohorts determined by treatment and primary cancer type.

VII. To evaluate the progression-free survival for extracranial disease in each of the cohorts determined by treatment and primary cancer type.

VIII. To evaluate the site of first progression (CNS versus [vs] non-CNS) in each of the cohorts determined by treatment and primary cancer type.

IX. To evaluate the overall survival in each of the cohorts determined by treatment and primary cancer type.

X. To evaluate the toxicity profile of agents in patients with brain metastases in each of the cohorts determined by treatment and primary cancer type.

OUTLINE: Patients are assigned to 1 of 3 arms.

ARM I (CDK GENE MUTATION): Patients receive abemaciclib orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II (PI3K GENE MUTATION): Patients receive PI3K inhibitor GDC-0084 PO once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM III (NTRK/ROS1 GENE MUTATION): Patients receive entrectinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 8 weeks for 2 years, then every 3 months for years 3-4, and then every 6 months thereafter for up to 5 years after registration.

Details
Treatment Abemaciclib, Entrectinib, PI3K Inhibitor GDC-0084
Clinical Study IdentifierNCT03994796
SponsorAlliance for Clinical Trials in Oncology
Last Modified on19 November 2020

Adding a note
adding personal notes guide

Select a piece of text and start making personal notes.

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have any of these conditions: CDK Gene Mutation or Metastatic Malignant Neoplasm in the Brain or NTRK Family Gene Mutation or PI3K Gene Mutation or ROS1 Gene Mutation or Metastatic...?
Do you have any of these conditions: Brain Metastases or CDK Gene Mutation or Metastatic Malignant Neoplasm in the Brain or Metastatic Solid Tumor or metastatic malignant solid tumor or M...?
Do you have any of these conditions: Metastatic Malignant Solid Neoplasm or Brain Metastasis or NTRK Family Gene Mutation or Brain Metastases or ROS1 Gene Mutation or CDK Gene Mutation or...?
PRE-REGISTRATION ELIGIBILITY CRITERIA (ALL PATIENTS) Tissue available for
biomarker testing (any brain metastasis tissue and extracranial site from any
prior resection or biopsy)
REGISTRATION ELIGIBILITY CRITERIA (ALL PATIENTS)
Participants must have histologically confirmed metastatic disease to the brain from any solid tumor. Note: this includes patients that have controlled extracranial disease with progressive intracranial metastasis, as well as patients that have progressive intracranial and extracranial disease
New or progressive brain metastases are defined as any one of the following
Untreated measurable lesions in patients who have received surgery and/or stereotactic radiosurgery (SRS) to one or more other lesions
Residual or progressive lesions after surgery if asymptomatic
Patients who have had prior whole-brain radiotherapy (WBRT) and/or SRS and then whose lesions have progressed by BM-RANO criteria or there are new lesions, are eligible. Lesions treated with SRS may be eligible if there is unequivocal evidence of progression
Patients who have not previously been treated with cranial radiation (e.g. WBRT or SRS) are eligible, but such patients must be asymptomatic or neurologically stable from their CNS metastases
Measurable CNS disease (> 10 mm)
Ability to obtain magnetic resonance imaging (MRI)s
No surgery within 2 weeks prior to or after registration
No chemotherapy within 14 days prior to registration (Note: for abemaciclib arm, a 21-day chemotherapy washout is required)
For melanoma, patients must have progressed after prior immune checkpoint blockade or for BRAF positive melanoma, BRAF/MEK inhibitors
For lung cancer, EGFR mutant patients must have failed EGFR therapies
For HER2-positive breast cancer patients, patients must have received at least one prior HER-2 directed therapy in the metastatic setting
For triple negative breast cancer (TNBC), patients must have received at least one chemotherapy in the metastatic setting
For estrogen receptor (ER)/progesterone receptor (PR)+ breast cancer, patients must have received at least one endocrine therapy in the metastatic setting
Breast cancer patients who have received ribociclib or palbociclib are eligible as long as there is documentation of CDK4 pathway alteration on a biopsy at the point of progression post-ribociclib or palbociclib
Tissue available for sequencing (any brain metastasis tissue and extracranial site from any prior resection or biopsy that was resected as part of clinical care). If the patient does not have any evidence of extracranial disease, brain metastasis tissue is sufficient for eligibility
Presence of clinically actionable alteration in NTRK, ROS1, or CDK pathway or PI3K pathway in both a brain metastasis and extracranial site
Not pregnant and not nursing, because this study involves investigational agents whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential only, a negative pregnancy test done =< 14 days prior to registration is required (Note: for abemaciclib arm, pregnancy test is required =< 7 days prior to registration)
No known leptomeningeal involvement
Eastern Cooperative Oncology Group (ECOG) performance status 0-2
Adequate organ function
Absolute neutrophil count (ANC) >= 1,500/mm^3
Platelet count >= 100,000/mm^3
Total bilirubin =< 1.5 x upper limit of normal (ULN) except in patients with Gilbert's disease
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
Creatinine =< 1.5 mg/dL OR calculated (Calc.) creatinine clearance > 45 mL/min
No uncontrolled medical comorbidities per investigator discretion (e.g. interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea)
Concurrent radiation to symptomatic non-target sites within neural axis is allowed (provided there is at least one untreated target lesion)
Concurrent systemic corticosteroids are allowed if stable dose of dexamethasone for 7 days prior to registration. Baseline doses and changes in steroid dosing will be captured
No concurrent administration of anticancer therapies (except for endocrine therapy or continuation of hormonal therapy or trastuzumab in breast cancer patients). No chemotherapy, targeted therapy or immunotherapy within 14 days prior to entering the study (Note: For abemaciclib arm, a 21-day chemotherapy washout is required)
Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug 14 days prior to registration on the study
Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment
ADDITIONAL REGISTRATION ELIGIBILITY CRITERIA FOR GDC-0084 ARM
Urine protein to creatinine (UPC) ratio < 1 or urine protein =< 1\
Recent acute myocardial infarction in the last 6 months or current angina pectoris are excluded. Patients with symptomatic bradycardia should have an electrocardiogram at baseline. If QT interval > 470 msec, the patient is excluded
Patients with uncontrolled type I or II diabetes mellitus should be excluded. Uncontrolled diabetes is defined as glycosylated hemoglobin (HbA1c) > 9% in addition to fasting glucose > 140 mg/dL on at least 2 occasions within 14 days prior to registration
ADDITIONAL REGISTRATION ELIGIBILITY CRITERIA FOR ENTRECTINIB ARM
Concurrent use of H2 receptor antagonists, receptor antagonists, proton pump
inhibitors (PPIs), and/or antacids are prohibited
ADDITIONAL REGISTRATION ELIGIBILITY CRITERIA FOR ABEMACICLIB ARM
Hemoglobin >= g/dL. Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion
Patients who received chemotherapy must have recovered (Common Terminology Criteria for Adverse Events [CTCAE] Grade 1) from the acute effects of chemotherapy except for residual alopecia or Grade 2 peripheral neuropathy prior to randomization. A washout period of at least 21 days is required between last chemotherapy dose and registration (provided the patient did not receive radiotherapy)
Patients who received adjuvant radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. A washout period of at least 14 days is required between end of radiotherapy and registration
For females of childbearing potential: A female of childbearing potential, must have a negative serum pregnancy test within 7 days prior to registration and agree to use a highly effective contraception method during the treatment period and for 3 weeks following the last dose of abemaciclib. Contraceptive methods may include an intrauterine device [IUD] or barrier method. If condoms are used as a barrier method, a spermicidal agent should be added as a double barrier protection. Cases of pregnancy that occur during maternal exposures to abemaciclib should be reported. If a patient or spouse/partner is determined to be pregnant following abemaciclib initiation, she must discontinue treatment immediately. Data on fetal outcome and breast-feeding are to be collected for regulatory reporting and drug safety evaluation
Patients with active bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive] are excluded. Screening is not required for enrollment
Patients with personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest, are excluded
Clear my responses

How to participate?

Step 1 Connect with a site
What happens next?
  • You can expect the study team to contact you via email or phone in the next few days.
  • Sign up as volunteer to help accelerate the development of new treatments and to get notified about similar trials.

You are contacting

Investigator Avatar
Name

Primary Contact

site
Name

Phone Email

0/250
Please verify that you are not a bot.
Step 2 Get screened

Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

Learn more
Step 3 Enroll in the clinical study

If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

Learn more
Step 4 Get your study results

Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

Learn more

Similar trials to consider

Loading...

Not finding what you're looking for?

Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.

Sign up as volunteer

Study

user name

Annotated by • 

 • 

Private

Reply by • Private
Loading...

Lorem ipsum dolor sit amet consectetur, adipisicing elit. Ipsa vel nobis alias. Quae eveniet velit voluptate quo doloribus maxime et dicta in sequi, corporis quod. Ea, dolor eius? Dolore, vel!

  The passcode will expire in None.
Loading...

No made yet