재발성 교모세포종에서의 새로운 인데노이소퀴놀론 CMYC/TOPOISOMERASE 1 억제제 (LMP744)
재발성 교모세포종을 대상으로 한 신규 인데노이소퀴놀론 C-MYC/토포이소머레이즈 1 억제제(LMP744)의 1상/2상 개방형 임상시험
Background:
Glioblastoma is a common brain cancer in adults. Treatment includes surgery, radiation, and chemotherapy. But this cancer can return after treatment and is often fatal. Researchers want to know if a study drug (LMP744) can kill glioblastoma tumor cells.
Objective:
To test LMP744 in people with glioblastoma.
Eligibility:
People aged 18 years or older with glioblastoma that returned after treatment.
Design:
Participants will be screened. They will have a surgery to remove a small sample of tumor tissue (biopsy) from the brain. This will be done under protocol 03-N-0164. They will stay in the clinic for 1 night. They will also have imaging scans and tests of their heart function.
Participants will have a central line installed: A flexible tube will be inserted into a vein in the chest. It will be attached to a "port" under the skin. This port will be used to draw blood and give medicines without having to insert new needles into a vein.
LMP744 will be given through the central line for 5 days in a row. Participants will remain in the clinic for this time.
Participants will then have a second surgery to remove as much of their tumor as possible. They will remain in the clinic until they recover from the surgery. Then they will recover at home after surgery.
Participants will return to the clinic to receive the study drug for 5 days in a row through the central line, once a month for up to 12 months. Blood tests, heart function tests, and periodic imaging scans will be repeated during these visits.
Participants will continue to have telehealth visits every 3 months after they stop taking the drug.
연구 개요
상태
정황
상세 설명
Study Description:
Patients will undergo pathological confirmation of recurrent glioblastoma via stereotactic or open biopsy (Visit 1, Day 1) to obtain baseline reference tissue. Following confirmation of recurrent glioblastoma by histopathological tissue analysis by a pathologist, study participants with confirmed histopathologically recurrent glioblastoma will be readmitted (Visit 2, Day 1). Patients will receive an initial cycle of 190 mg/m^2/day LMP744 infused over 1 hour for 5 consecutive days (Visit 2, Days 1-5). Participants will then undergo surgical intervention for brain biopsy and/or resection, as clinically appropriate based on neurosurgical assessment within 7 calendar days of the 5th dose of LMP744, but no earlier than 24 hours after the 5th dose of LMP744 (Visit 2, between Days 6 and 12 inclusive). Tissue, CSF, and plasma will be collected during the post-treatment surgical intervention for molecular analysis. Patients will then be discharged from the hospital. Following a 3-8-week period of recuperation, study participants will then resume LMP744 (5 days on; 23 days off; up to 12 cycles) and be followed until death.
A comparative pharmacodynamic analysis will be conducted on the pre- and post-treatment tissue to evaluate the biological response to LMP744 and correlate pharmacodynamic changes with clinical outcomes.
Objectives:
Primary Objective:
-To evaluate objective response rate (ORR) in patients with recurrent glioblastoma treated with up to 12 cycles of LMP744.
Secondary Objectives:
- To evaluate progression-free survival in patients with recurrent glioblastoma treated with up to 12 cycles of LMP744 compared to historical controls.
- To evaluate overall survival (OS) in patients with recurrent glioblastoma treated with up to 12 cycles of LMP744 compared to historical controls.
- To assess the pharmacologic (PK/PD) response by exploring molecular and metabolic changes in pre- versus posttreatment glioblastoma tissue following administration of LMP744.
- To assess the impact of LMP744 treatment on self-reported quality of life (QOL) as measured by the validated SF-36 instrument.
Exploratory Objective:
- To explore the molecular changes observed in post-treatment tissue with clinical outcomes, aiming to identify potential predictive markers of response to LMP744.
- To explore changes in the molecular and metabolic profiles in matched tissue, CSF, and plasma from patients treated with LMP744 compared to their pre-treatment baseline.
Safety Outcomes:
To descriptively monitor, document, and report adverse events (AEs) and serious adverse events (SAEs) in participants with recurrent glioblastoma treated with LMP744.
Endpoints:
Primary Endpoint:
-Stable disease or Partial response (>=50% disease reduction) or complete response (100% disease reduction) based on RANO 2.0 criteria
Secondary Endpoints:
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PFS will be assessed based on the RANO 2.0 criteria for glioblastoma assessment as follows:
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Imaging Criteria:
- >=25% or more increase in enhancing lesions despite stable or increasing steroid dose
- >=25% increase in non-enhancing FLAIR/T2W lesions, not attributable to other non-tumor causes
- Occurrence of any new lesions
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Clinical Features:
- Clinical deterioration not attributable to other non-tumor causes or steroid decrease
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Overall survival in patients treated with LMP744
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Pharmacologic (PK/PD) response measured by molecular (transcriptomic, proteomic and/or metabolomic) tissue level changes and Differential molecular changes in tissues pre-versus post-LMP744 treatment
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Self-reported quality of life (QOL) as measured by the SF-36 survey at baseline, after each treatment cycle, and at study completion.
연구 유형
등록 (추정된)
단계
- 2 단계
- 1단계
연락처 및 위치
연구 연락처
- 이름: Sadhana Jackson, M.D.
- 전화번호: (301) 594-7037
- 이메일: sadhana.jackson@nih.gov
연구 장소
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Maryland
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Bethesda, Maryland, 미국, 20892
- 모병
- National Institutes of Health Clinical Center
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연락하다:
- Surgical Neurology Branch
- 전화번호: (301) 496-2921
- 이메일: snbrecruiting@nih.gov
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연락하다:
- NIH Clinical Center Office of Patient Recruitment (OPR)
- 전화번호: TTY dial 711 800-411-1222
- 이메일: ccopr@nih.gov
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-
참여기준
자격 기준
공부할 수 있는 나이
건강한 자원 봉사자를 받아들입니다
연구 대상 성별
설명
- INCLUSION CRITERIA:
Participant must meet all the following inclusion criteria to be deemed eligible for this study:
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Participants >= 18 years of age
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Tissue-based diagnosis of recurrent glioblastoma, IDH-wildtype by a neuropathologist
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Karnofsky Performance Status (KPS) >60
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Willing to use effective birth control method
--The effects of LMP744 on developing human fetuses are unknown. Therefore, females of childbearing potential and their male partners must be willing to use an effective method of contraception during the clinical study (hormonal, barrier, surgical, or abstinence) before study enrollment and for 6 months after the last dose of the study drug. If the female becomes pregnant or suspects she is pregnant while participating in this study, she must inform her treating physician immediately.
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Agreeable to undergo surgical intervention for brain biopsy and/or resection.
- Initial diagnostic biopsy under 03-N-0164 will be performed to confirm recurrent disease and obtain pre-treatment tissue.
- The surgical intervention may include stereotactic/needle biopsy, open biopsy, and/or resection, as determined by neurosurgical assessment. Only participants for whom gross total resection of tumor is not expected to be achievable will be included in the study.
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Willing and able to appoint a durable power of attorney
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Able to provide informed consent or have a legally authorized representative (LAR) to provide consent, if incapacitated.
EXCLUSION CRITERIA:
An individual who meets any of the following criteria will be excluded from participation in this study:
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Pregnant and/or nursing females
--As LMP744 is a novel agent with the potential for teratogenic or abortifacient effects, pregnant and/or nursing females will be excluded from receiving drug
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Significant medical co-morbidities that would compromise the participant s ability to tolerate LMP744 and which cannot reasonably be controlled (per the investigator s judgment, such as poorly controlled chronic kidney disease and/or poorly controlled congestive heart failure)
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Social situations that would limit compliance with study requirements, such as chronic homelessness
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Prior chemotherapy or biologic therapy completed within 4 weeks (6 weeks for nitrosoureas and mitomycin C) or a duration of 5 half-lives (whichever is shorter)
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Additional malignancy diagnosed or requiring active treatment within 1 year of screening
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Unable to undergo an MRI scan of the brain
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Active autoimmune disease that requires systemic treatment within 2 years of screening
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Cardiac disease
- >=2 MIs
- >=2 coronary revascularization procedures
- Cardiac Troponin T or I >= 2x the institutional upper limit of normal at screening
- Ejection fraction <45% on screening echocardiogram
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Chronic hypokalemia (K<2.5 mmol/L)
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Human Immunodeficiency Virus (HIV)
- Known history of HIV
- Positive HIV 1/2 at screening.
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Active Hepatitis B or Hepatitis C infection at screening
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Active infection requiring systemic antibacterial, antiviral or antifungal therapy <7 days prior to initiation of study drug
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Recipient of autologous or allogeneic T cells
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Solid organ or tissue transplant recipients
공부 계획
연구는 어떻게 설계됩니까?
디자인 세부사항
- 주 목적: 치료
- 할당: 해당 없음
- 중재 모델: 단일 그룹 할당
- 마스킹: 없음(오픈 라벨)
무기와 개입
참가자 그룹 / 팔 |
개입 / 치료 |
|---|---|
|
실험적: Arm A
All patients will receive LMP744 as the interventional drug along with surgery for a biopsy and a second surgery for either resection or an additional biopsy to compare the tissue pre vs. post-drug treatment. |
Indenoisoquinolone C-MYC/TOPOISOMERASE 1 Inhibitor Conventional Surgery or Biopsy |
연구는 무엇을 측정합니까?
주요 결과 측정
결과 측정 |
측정값 설명 |
기간 |
|---|---|---|
|
Partial response (>=50% disease reduction) or complete response (100% disease reduction) based on RANO 2.0 criteria
기간: 5 years
|
As ORR is associated with survival experience, this endpoint allows for objective evaluation of efficacy of LMP744 in this proof-of-concept phase 2 trial |
5 years
|
2차 결과 측정
결과 측정 |
측정값 설명 |
기간 |
|---|---|---|
|
Progression-Free Survival (PFS): Time from the start of treatment with LMP744 until disease progression based on RANO 2.0 criteria
기간: 5 years
|
PFS provides a measure of treatment efficacy in delaying tumor progression. While the study is not powered to demonstrate superiority of LMP744 to concurrent controls, the study will compare LMP744 to historical controls to generate information for planning of a future phase 3 trial. |
5 years
|
|
Overall Survival (OS): Time from the start of treatment with LMP744 until death from any cause
기간: 5 years
|
OS is the gold standard for assessing the ultimate benefit of a therapy on survival. We will compare OS between LMP744 and historical controls to provide information for planning of a future phase 3 trial |
5 years
|
|
Changes in transcriptomic and proteomic profiles before and after LMP744 treatment
기간: 5 years
|
Evaluating changes in these markers will provide insight into the pharmacodynamic effects of LMP744 at the molecular level. The selected markers are involved in DNA damage response, cell cycle regulation, and survival pathways, which are critical in understanding the tumor's response to the drug. |
5 years
|
|
Change in self-reported quality of life (QOL) as measured by the SF-36 survey at baseline, after each treatment cycle, and at study completion.
기간: 5 years
|
The SF-36 is a validated tool for assessing the quality of life in cancer patients and captures the broad impact of treatment on physical, emotional, and social well-being. Tracking changes in QOL over time will provide insight into the patient-reported outcomes related to LMP744 treatment. This endpoint is essential for understanding the broader implications of treatment beyond clinical and molecular measures, giving a more comprehensive assessment of treatment benefit or burden. |
5 years
|
공동 작업자 및 조사자
수사관
- 수석 연구원: Sadhana Jackson, M.D., National Institute of Neurological Disorders and Stroke (NINDS)
간행물 및 유용한 링크
연구 기록 날짜
연구 주요 날짜
연구 시작 (실제)
기본 완료 (추정된)
연구 완료 (추정된)
연구 등록 날짜
최초 제출
QC 기준을 충족하는 최초 제출
처음 게시됨 (실제)
연구 기록 업데이트
마지막 업데이트 게시됨 (실제)
QC 기준을 충족하는 마지막 업데이트 제출
마지막으로 확인됨
추가 정보
이 연구와 관련된 용어
추가 관련 MeSH 약관
기타 연구 ID 번호
- 10002185
- 002185-N
개별 참가자 데이터(IPD) 계획
개별 참가자 데이터(IPD)를 공유할 계획입니까?
IPD 계획 설명
We plan to share IPD as requested by publications and CRADA partner.
IPD 공유 기간
Study protocol will be shared as requested. CSR will be shared at the time the CSR is due.
IPD 공유 액세스 기준
De-identified IPD will be shared with the CRADA partner through the EDC.
IPD 공유 지원 정보 유형
- 연구_프로토콜
- CSR
약물 및 장치 정보, 연구 문서
미국 FDA 규제 의약품 연구
미국 FDA 규제 기기 제품 연구
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