재발성 또는 진행성 고등급 신경교종 성인 환자를 대상으로 한 GLIX1의 1상 안전성 및 용량 탐색 연구
재발성 또는 진행성 고등급 신경교종 성인 환자에서 경구 투여되는 GLIX1의 1상 안전성 및 용량 탐색 연구
This is an open-label, multicenter dose-escalation study to be followed by a dose expansion to define the optimal dose of GLIX1 as monotherapy by reviewing safety and tolerability, disease characteristics and pharmacokinetic profiles and preliminary clinical activity in participants with a high grade diffuse glioma that progressed during or recurred after prior standard of care therapies or investigational therapies as clinically indicated.
Patients will be treated daily with GLIX1 capsules until disease progression or unacceptable safety.
연구 개요
상태
상태
정황
정황
개입 / 치료
개입 / 치료
상세 설명
Glioblastomas (GBMs) are the most common and aggressive primary malignant tumors in adult central nervous system. High-grade glioma almost always recur and/or progress, and upon progression treatment options are very limited with no universal standard therapy established.
GLIX1 is a small molecule administered PO (per os, i.e., orally), that targets the deoxyribonucleic acid (DNA) damage repair mechanism by enhancing Tet methylcytosine dioxygenase 2 (TET2) activity. Increasing the activity of the TET2 enzyme increases DNA oxidation at 5-methylcytosine residues. Such oxidation is normally processed by base excision repair. During base excision repair, a single stranded DNA break is formed. These single strand DNA breaks are well tolerated in normal cells. In cancer, alterations in DNA methylation are common and TET2 activity is inhibited, giving rise to increased DNA methylation in close genomic proximity. When GLIX1 agonizes TET2 activity in cancer cells, excessive base excision repair results in numerous single strand DNA breaks in close proximity, which ultimately converge to form double strand DNA breaks that overwhelm the repair capacity of these cancer cells, resulting in apoptotic cell death.
High-grade glioma have some of the lowest levels of genomic 5-hydroxymethylcytosine. Thus, enhancing the activity of the TET2 enzyme in these cells is likely to have the greatest effect in terms of treating cancers.
Indeed, GLIX1 has been shown to cross the blood brain barrier in rodents and has shown significant activity in various in vitro and in vivo GBM and glioma tumor models.
연구 유형
연구 유형
등록 (추정된)
등록
단계
단계
- 1단계
연락처 및 위치
연구 장소
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California
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Palo Alto, California, 미국, 94304
- 모병
- Stanford University
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연락하다:
- Lewis Naya
- 전화번호: (650) 725-0379
- 이메일: secure-sci-cto-neuro-crcs@lists.stanford.edu
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Florida
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Tampa, Florida, 미국, 33612
- 모병
- Moffitt Cancer Center
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수석 연구원:
- Patrick Grogan, MD
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연락하다:
- Patrick Grogan, MD
- 전화번호: 813-745-8000
- 이메일: Patrick.grogan@moffitt.org
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Illinois
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Chicago, Illinois, 미국, 60611
- 모병
- Northwestern Medicine
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연락하다:
- Ditte Primdahl, MD
- 전화번호: 312-695-1202
- 이메일: cancer@northwestern.edu
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New York
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New York, New York, 미국, 10016
- 모병
- NYU Langone Health
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수석 연구원:
- Alexandra Miller, MD, PhD
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연락하다:
- Alexandra Miller, MD
- 전화번호: (212) 731-6267
- 이메일: cancertrials@nyulangone.org
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참여기준
자격 기준
자격 기준
공부할 수 있는 나이
건강한 자원 봉사자를 받아들입니다
연구 대상 성별
설명
Main Inclusion Criteria:
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Adult patients aged ≥18 years at the time of informed consent
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Participants must have histologically confirmed Grade 3 or Grade 4 glioma
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Recurrent or progressive disease
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A maximum of two prior treatment lines
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Interval of at least 3 months since the last day off of radiotherapy, unless tumor progression and index lesion is outside the prior radiation field.
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Interval since last dose of systemic therapy and Baseline MRI of ≥28 days, except:
- for nitrosoureas (e.g., lomustine, carmustine, fotemustine): 42 days (6 weeks)
- for monoclonal antibodies: 42 days (6 weeks)
- for small molecules, 4 weeks or at least 5 half-lives (whatever is longer)
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Recovered from all toxicities from prior treatments to Grade 1 or less by NCI CTCAE v6.0:
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Participants receiving corticosteroids must be on a stable or decreasing dose of ≤6 mg daily dexamethasone (or ≤40 mg prednisone) for the 7 days prior to the start of study treatment.
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Participants with seizures must be adequately controlled on a stable regimen of anti-epileptic drugs.
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Adequate performance status: Eastern Cooperative Oncology Group (ECOG) 0 or 1.
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Ability to swallow tablets or capsules.
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Adequate hematological, liver and renal function.
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Women of childbearing potential must have a negative serum pregnancy test result within 7 days prior to first dosing. Women must use a highly effective form of contraception (with Pearl Index <1%) for the duration of the study and for at least 3 months after the last dose of study medication.
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Men with partners of childbearing potential must be willing to use condoms in combination with a second effective method of contraception by the partner during the study and for at least 3 months after the last dose of study medication.
Main Exclusion Criteria:
- Known contraindication for gadolinium (Gd) based, contrast-enhanced MRI
- Prior history of another invasive malignancy unless a complete remission was achieved at least 3 years prior to enrolment AND no additional therapy is required during the study period, except for anti-estrogen or androgen therapy and/or bisphosphonates or denosumab.
- Participants with known active or uncontrolled infection, and/or unexplained fever >38°C in the 3 days prior to the start of study treatment.
- Major non-tumor related surgical procedure or significant traumatic injury within 28 days prior to signing of consent.
- Receiving any investigational products (defined as treatment for which there is currently no regulatory authority-approved indication) within 4 weeks or 5 half-lives (whichever is the longest) prior to Baseline MRI.
공부 계획
연구는 어떻게 설계됩니까?
디자인 세부사항
- 주 목적: 치료
- 할당: 해당 없음
- 중재 모델: 순차적 할당
- 마스킹: 없음(오픈 라벨)
팔의 수
무기와 개입
참가자 그룹 / 팔참가자 그룹 / 팔 |
개입 / 치료개입 / 치료 |
|---|---|
|
실험적: GLIX1
Escalating doses of GLIX1, starting at a dose of 1000 mg/day |
Administered orally, once daily, in cycles of 28 days |
연구는 무엇을 측정합니까?
주요 결과 측정
주요 결과 측정
결과 측정 |
측정값 설명 |
기간 |
|---|---|---|
|
Safety Profile of GLIX1 (%Participants with Treatment-emergent Adverse Events)
기간: From first administration of GLIX1 (Cycle 1 Day 1) until 30 days following last dose administration
|
%Participants with treatment-emergent adverse events (TEAEs) based on CTCAE v6.0 |
From first administration of GLIX1 (Cycle 1 Day 1) until 30 days following last dose administration
|
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Maximal Tolerated Dose and/or Recommended Dose
기간: From first administration of GLIX1 (Cycle 1 Day 1) until one cycle of 28 days is complete
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Maximal Tolerated Dose (MTD) is selected as the dose for which the isotonic estimate of the Dose Limiting Toxicity (DLT) rate is closest to the target rate of 0.3 |
From first administration of GLIX1 (Cycle 1 Day 1) until one cycle of 28 days is complete
|
공동 작업자 및 조사자
연구 기록 날짜
연구 주요 날짜
연구 시작 (실제)
연구 시작
기본 완료 (추정된)
기본 완료
연구 완료 (추정된)
연구 완료
연구 등록 날짜
최초 제출
최초 제출
QC 기준을 충족하는 최초 제출
QC 기준을 충족하는 최초 제출
처음 게시됨 (실제)
처음 게시됨
연구 기록 업데이트
마지막 업데이트 게시됨 (실제)
마지막 업데이트 게시됨
QC 기준을 충족하는 마지막 업데이트 제출
QC 기준을 충족하는 마지막 업데이트 제출
마지막으로 확인됨
마지막으로 확인됨
추가 정보
이 연구와 관련된 용어
추가 관련 MeSH 약관
기타 연구 ID 번호
기타 연구 ID 번호
- GLIX1-C101
개별 참가자 데이터(IPD) 계획
개별 참가자 데이터(IPD)를 공유할 계획입니까?
약물 및 장치 정보, 연구 문서
미국 FDA 규제 의약품 연구
미국 FDA 규제 기기 제품 연구
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