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Abemaciclib Neuropharmacokinetics of Diffuse Midline Glioma Using Intratumoral Microdialysis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05413304
Recruitment Status : Not yet recruiting
First Posted : June 10, 2022
Last Update Posted : August 12, 2022
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

Diffuse midline gliomas are the most aggressive brain tumors of childhood and young adults. Most people with these tumors survive less than 2 years. Researchers want to see if an anticancer drug (abemaciclib) can help.

Objective:

To see if researchers can measure how much abemaciclib is in a person's brain tumor and brain fluid after they take the drug for a few days.

Eligibility:

People aged 18 to 39 with recurrent high-grade glioma or diffuse midline glioma.

Design:

Participants will be screened with:

Medical history

Physical exam

Blood and urine tests

Tests of heart function

Imaging scans of the brain, with a contrast agent

Screening tests will be repeated during the study. Participants will also have chest X-rays.

Participants will take abemaciclib by mouth twice a day for 4 and a half days.

Participants will undergo surgery. They will have either a tumor biopsy (a needle will be inserted to remove a small piece of tissue) or a surgical resection (part or all of the tumor will be removed). A small tube (catheter) will be placed in their brain for 48 hours to collect fluid samples. They will have a neurological exam every few hours while the tube is in place. Two days later, the tube will be removed without surgery. Participants will stay in the hospital for about 4 days for treatment.

Based on the results of abemaciclib levels in the brain, participants may keep taking abemaciclib and another drug (temozolomide) by mouth until their cancer gets worse or they have bad side effects. While taking these two drugs, participants will come back to the clinic for follow-up routinely. They will be followed by the study for life.


Condition or disease Intervention/treatment Phase
Glioma Drug: pre-operative abemaciclib Device: Device for Cerebral Fluid Dialysate Collection Device: Ashion Analytics GEM ExTra Drug: abemaciclib + temozolomide Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 7 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Feasibility of Evaluating Abemaciclib Neuropharmacokinetics of Diffuse Midline Glioma Using Intratumoral Microdialysis
Estimated Study Start Date : August 17, 2022
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : August 31, 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Abemaciclib

Arm Intervention/treatment
Experimental: 1/Abemaciclib and microdialysis monitoring
Abemaciclib orally BID for 4.5 days followed by resection or biopsy and microdialysis catheter placement with continuous monitoring for 48 hours post-operative and genomic sampling of tissue/blood; followed by abemaciclib+temozolomide maintenance therapy
Drug: pre-operative abemaciclib
pre-operatively for 4.5 days; 200mg twice daily (9 total doses)

Device: Device for Cerebral Fluid Dialysate Collection
post-resection or post-biopsy continuous intracerebral microdialysis sampling for 48-hours to assess CNS drug entry and targeted inhibition with abemaciclib

Device: Ashion Analytics GEM ExTra
resection/biopsy genomic sampling of tumor tissue and blood to identify therapeutic targets

Drug: abemaciclib + temozolomide
abemaciclib 150mg po BID and temozolomide 200mg/m2 po daily x 5 days in 28 day cycles (temozolomide 150mg/m2 po daily x 5 days for cycle 1)




Primary Outcome Measures :
  1. intra-tumoral sampling adequacy [ Time Frame: surgery/biopsy and multiple timed retrievals 2 - 48 hours post catheter insertion ]
    fraction of participants who have adequate intra-tumoral sampling

  2. concentration of abemaciclib [ Time Frame: intratumoral: surgery/biopsy and multiple timed retrievals 2 - 48 hours post catheter insertion; blood/systemic: surgery/biopsy, multiple timed retrievals 1-72 hours post catheter insertion, and Day 5 of every other maintenance therapy cycle ]
    intratumoral vs. systemic concentrations of abemaciclib post abemaciclib administration.

  3. adverse events [ Time Frame: Study Day 1 through 30 days after the last intervention ]
    fraction of participants who experience any adverse event/complication, including adverse events grades and types


Secondary Outcome Measures :
  1. relationship between abemaciclib PK and PD studies on subsequent treatment and participant outcome [ Time Frame: 10 years post-enrollment ]
    Descriptive results from abemaciclib PK and PD studies on subsequent treatment and participant outcomes



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 39 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

    • Participants must have recurrent high grade glioma or midline glioma based on clinical and/or radiologic findings
    • Participants with cortical high grade gliomas must have previous intra-operative pathology confirming disease
    • Participants must be > 18 and < 39 years old at the time of enrollment
    • Ability to swallow tablets/pills

Prior Therapies:

At least 4 weeks must have elapsed since any major surgeries, with no evidence of infections. Minimally invasive biopsies (outside of the brainstem) and central line placements are not considered major surgeries

Participants who have received prior treatment with abemaciclib or another specific CDK4/6 inhibitor are not eligible for enrollment (ex., Ribociclib, Palbociclib - list is not all inclusive)

Participants 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 randomization (provided the participant did not receive radiotherapy).

  • Participants who received 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 randomization.
  • Adequate performance scale as defined below:
  • Karnofsky >=50% within 14 days prior to enrollment.
  • Adequate organ function within 14 days prior to enrollment as defined below:

Hematologic Function: Participants must have an absolute neutrophil count >=1500/microliters, hemoglobin >=9 g/dL (transfusion independent, defined as not receiving blood transfusion unless related to trauma or surgeries), and platelets >=100,000/microliters (transfusion independent, defined as not receiving platelet transfusions unless related to trauma or surgeries)

Hepatic Function: Participants must have bilirubin within 1.5 x the upper limit of normal for age, with the exception of those with Gilbert syndrome, and AST/ALT within < 3 x upper limit of normal.

Renal Function: Participants must have a creatinine clearance or radioisotope GFR >60ml/min/1.73 m2 or a normal serum creatinine.

Cardiac Function: Normal ejection fraction (ECHO or cardiac MRI) >= 53% (or the institutional normal); QTC or QTcF < 450 msec.

  • Willingness to avoid grapefruit or grapefruit juice during abemaciclib administration
  • Informed Consent: Ability of participant or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document.
  • Willingness of participant or LAR to sign a written informed consent document and co-enroll in study 03-N-0164
  • The effects of abemaciclib on the developing human fetus are unknown, however CDK-inhibiting agents are known to be teratogenic. Temozolomide is a cytotoxic chemotherapeutic agent which is known to be teratogenic. For these reasons, women of child-bearing potential must agree to use a highly effective method of contraception prior to study entry, for the duration of study participation, and for 3 weeks after the last dose of abemaciclib and 6 months after temozolomide. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation.

A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (>= 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).

Woman participants of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 7 days of the first dose of abemaciclib.

Highly effective contraception include intrauterine devices (IUD), hormonal (birth control pills, injections, implants), tubal ligation, or partner s vasectomy .

Cases of pregnancy that occur during maternal exposures to abemaciclib should be reported. If a participant or spouse/partner is determined to be pregnant following abemaciclib initiation she must discontinue treatment immediately. Data on fetal outcomes and breastfeeding are to be collected for regulatory reporting and drug safety evaluation.

-Abemaciclib administration must be able to begin no later than 14 days after the date of radiographic diagnosis (by T2 or FLAIR imaging)

EXCLUSION CRITERIA:

  • Participants who cannot safely undergo a biopsy due to contraindications
  • Pregnant women, or women who intent to become pregnant during the study, are excluded from this study because of the teratogenic effects of abemaciclib. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued if the mother is treated on study.
  • Serious preexisting medical condition(s) that would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance <30ml/min], history of major surgical resection involving the stomach or small bowel that would preclude adequate absorption, or preexisting Crohn s disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).
  • Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, active bleeding diatheses or renal transplant, or psychiatric illness/social situations that would limit compliance with study requirements.
  • 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.
  • Active systemic 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]. Participants with HIV who have adequate CD4 counts and who have no requirement for antiviral therapy will be eligible. NOTE: Screening is not required for enrollment.
  • Requires treatment with strong/moderate CYP3A inhibitors or inducers. Participants receiving any medications or substances that are inducers or strong/moderate inhibitors of CYP3A4 are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product.
  • Inability to undergo MRI and/or contraindication for MRI examinations following the MRI protocol (see Study Procedure Manual). Prosthesis or orthopedic or dental braces that would interfere with MRI.
  • Refractory nausea and vomiting that would limit drug administration in the opinion of the Principal Investigator
  • Known severe hypersensitivity to abemaciclib, temozolomide or any excipient of abemaciclib or temozolomide or history of allergic reactions attributed to compounds of similar chemical or biologic composition to abemaciclib and temozolomide.
  • Clinical judgment by the investigator that the participant should not participate in the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05413304


Contacts
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Contact: Sadhana Jackson, M.D. (240) 760-6018 sadhana.jackson@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Sadhana Jackson, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT05413304    
Other Study ID Numbers: 220003
22-C-0003
First Posted: June 10, 2022    Key Record Dates
Last Update Posted: August 12, 2022
Last Verified: August 5, 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition all large scale genomic sequencing data will be shared with subscribers to dbGaP.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Clinical data available during the study and indefinitely.@@@@@@Genomic data will be shared from the time of upload to dbGaP.
Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. Requests for all collected IPD data from clinical trials, conducted under a binding collaborative agreement between NCI/DCTD and a pharmaceutical/biotechnology company, that are not under DSMB monitoring must be in compliance with the terms of the binding collaborative agreement and must be approved by NCI/DCTD and the Pharmaceutical Collaborator (i.e., the NCI ETCTN Director in conjunction with the NCI/DCTD Regulatory Affairs Branch). @@@@@@Genomic IPD will be shared through dbGaP, per rules of the database, for purposes of genomic analysis.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Central Nervous System
Cdk4/6
Brain Cancer
Surgical Resection
Additional relevant MeSH terms:
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Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Dialysis Solutions
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Pharmaceutical Solutions