結腸直腸がんに対する通常の化学療法であるセツキシマブとエンコラフェニブへの抗がん剤ZEN003694の追加試験
難治性BRAF V600E転移性結腸直腸がん患者を対象としたセツキシマブおよびエンコラフェニブとの併用によるZEN003694（ZEN-3694）の第1相試験
This phase I trial tests the safety, best dose, and effectiveness of ZEN003694 in combination with cetuximab and encorafenib in treating patients with colorectal cancer that has not responded to previous treatment (refractory), that has come back after a period of improvement (relapsed), and that has spread from where it first started (primary site) to other places in the body (metastatic). ZEN003694 is a protein inhibitor that binds to BET proteins. When ZEN003694 binds to BET proteins, it disrupts gene expression. Preventing the expression of certain growth-promoting genes may inhibit proliferation of tumor cells that over-express BET proteins. Immunotherapy with monoclonal antibodies, such as cetuximab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Encorafenib is an enzyme inhibitor. It inhibits pathways that are responsible for controlling cell proliferation and survival, which may lead to a decrease in tumor cell proliferation. Both cetuximab and encorafenib have been approved to treat cancer. Adding ZEN003694 to cetuximab and encorafenib may be more effective at treating patients with refractory metastatic colorectal cancer than giving the usual treatment (cetuximab and encorafenib) alone.
調査の概要
状態
状態
条件
条件
介入・治療
介入・治療
詳細な説明
PRIMARY OBJECTIVES:
I. To define the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of BET bromodomain inhibitor ZEN-3694 (ZEN003694) when used in combination with cetuximab and encorafenib.
II. To define the safety profile of combination of ZEN003694, encorafenib, and cetuximab.
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity. II. To evaluate clinical response signals of the combination. III. To assess the pharmacodynamic (PD) profile of the combination as defined by MAPK inhibition.
IV. To assess the pharmacokinetics (PK) of ZEN003694 in combination with encorafenib.
EXPLORATORY OBJECTIVE:
I. To characterize pharmacodynamics and potential mechanisms of resistance to therapy via whole exome sequencing (WES), ribonucleic acid sequencing (RNAseq), and assay for transposase-accessible chromatin with sequencing (ATACseq)/HiSeq 4000 or NovaSeq following progression on treatment.
OUTLINE: This is a dose-escalation study of ZEN003694 followed by a dose-expansion study.
Patients receive ZEN003694 orally (PO) once daily (QD) on days 1-28 of each cycle, cetuximab intravenously (IV) over 120 minutes on days 1 and 15 of each cycle, and encorafenib PO QD on days 1-28 of each cycle. NOTE: In the dose-expansion study, patients receive encorafenib on days 2-28 of cycle 1 and then on days 1-28 of cycles thereafter. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo echocardiography (ECHO) or multi-gated acquisition scan (MUGA), computed tomography (CT) or magnetic resonance imaging (MRI), and collection of blood samples throughout the trial. Patients may also undergo biopsy at screening and on study.
After completion of study treatment, patients are followed up every 2 months.
研究の種類
研究の種類
入学 (推定)
入学
段階
段階
- フェーズ 1
連絡先と場所
研究場所
-
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California
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Costa Mesa、California、アメリカ、92627
- 募集
- UC Irvine Health Cancer Center-Newport
-
主任研究者：
- Farshid Dayyani
-
コンタクト：
- Site Public Contact
- 電話番号：877-827-8839
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Irvine、California、アメリカ、92612
- 募集
- UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
-
コンタクト：
- Site Public Contact
- 電話番号：877-827-8839
- メール：ucstudy@uci.edu
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主任研究者：
- Farshid Dayyani
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Los Angeles、California、アメリカ、90033
- 募集
- USC / Norris Comprehensive Cancer Center
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主任研究者：
- Heinz-Josef Lenz
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コンタクト：
- Site Public Contact
- 電話番号：323-865-0451
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Los Angeles、California、アメリカ、90033
- 一時停止
- Los Angeles General Medical Center
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Orange、California、アメリカ、92868
- 募集
- UC Irvine Health/Chao Family Comprehensive Cancer Center
-
コンタクト：
- Site Public Contact
- 電話番号：877-827-8839
- メール：ucstudy@uci.edu
-
主任研究者：
- Farshid Dayyani
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Colorado
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Aurora、Colorado、アメリカ、80045
- 募集
- UCHealth University of Colorado Hospital
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コンタクト：
- Site Public Contact
- 電話番号：720-848-0650
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主任研究者：
- Alexis D. Leal
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Kansas
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Fairway、Kansas、アメリカ、66205
- 積極的、募集していない
- University of Kansas Clinical Research Center
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Kansas City、Kansas、アメリカ、66160
- 積極的、募集していない
- University of Kansas Cancer Center
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Overland Park、Kansas、アメリカ、66211
- 積極的、募集していない
- University of Kansas Hospital-Indian Creek Campus
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Westwood、Kansas、アメリカ、66205
- 積極的、募集していない
- University of Kansas Hospital-Westwood Cancer Center
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Louisiana
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New Orleans、Louisiana、アメリカ、70121
- 積極的、募集していない
- Ochsner Medical Center Jefferson
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Ohio
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Columbus、Ohio、アメリカ、43210
- 募集
- Ohio State University Comprehensive Cancer Center
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主任研究者：
- Shafia Rahman
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コンタクト：
- Site Public Contact
- 電話番号：800-293-5066
- メール：Jamesline@osumc.edu
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Oklahoma
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Oklahoma City、Oklahoma、アメリカ、73104
- 募集
- University of Oklahoma Health Sciences Center
-
コンタクト：
- Site Public Contact
- 電話番号：405-271-8777
- メール：ou-clinical-trials@ouhsc.edu
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主任研究者：
- Susanna V. Ulahannan
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Texas
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Houston、Texas、アメリカ、77030
- 募集
- UT MD Anderson Cancer Center
-
コンタクト：
- Site Public Contact
- 電話番号：866-632-6789
- メール：askmdanderson@mdanderson.org
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主任研究者：
- Salvador Alonso Martinez
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Virginia
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Charlottesville、Virginia、アメリカ、22908
- 募集
- University of Virginia Cancer Center
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主任研究者：
- Paul Kunk
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コンタクト：
- Site Public Contact
- 電話番号：434-243-6303
- メール：uvacancertrials@hscmail.mcc.virginia.edu
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Richmond、Virginia、アメリカ、23298
- 募集
- VCU Massey Comprehensive Cancer Center
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主任研究者：
- Khalid Matin
-
コンタクト：
- Site Public Contact
- 電話番号：804-628-6430
- メール：CTOclinops@vcu.edu
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参加基準
適格基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
Inclusion Criteria:
- Patients must have histologically confirmed and radiographically measurable metastatic colorectal adenocarcinoma with known BRAF V600E mutation, confirmed in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory with at least one tumor measurable as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and for which standard curative or palliative measures do not exist or are no longer effective
- Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of ZEN003694 in combination with cetuximab and encorafenib in patients < 18 years of age, children are excluded from this study
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
- Absolute neutrophil count ≥ 1,500/mcL
- Platelets ≥ 100,000/mcL
- Hemoglobin (Hb) ≥ 9 mg/dl
- Total bilirubin ≤ 1.5 mg/dl (excluding Gilbert's disease)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 3 x institutional upper limit of normal (ULN)
- Creatinine clearance (CrCL) glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m^2
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
- Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression
- Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy
- Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
- Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. Patients should be New York Heart Association Functional Classification of class II or better
- Patients must have progressed after at least 1 prior systemic treatment for incurable advanced or metastatic disease
- Patients must have received prior treatment with the combination of encorafenib and cetuximab. They must have tolerated the combination at doses planned for the study
- For the dose expansion phase, patients must have discontinued encorafenib at least 2 weeks prior to starting study treatment
- The effects of ZEN003694 on the developing human fetus are unknown. For this reason and because BRD and BET inhibitor agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for at least 4 months following the last dose of study drug. Women must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 72 hours prior to the start of investigational product. 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
- Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants
Exclusion Criteria:
- Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia
- Patients who are receiving any other investigational agents
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to ZEN003694 or other agents used in study
- Patients with uncontrolled intercurrent illness including, but not limited to, active bleeding diatheses, poorly controlled infection/disorders, or nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy
- Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 or substrates of CYP1A2 with narrow therapeutic windows are ineligible. Strong inhibitors or inducers of CYP3A4 must be discontinued at least 7 days prior to the first dose of ZEN003694. As proton pump inhibitors (PPIs), H2 receptor antagonists, and antacids may alter the pharmacokinetics of ZEN003694 by reducing ZEN003694 exposure, patients receiving proton pump inhibitors are ineligible. If H2 blockers or other acid reducing agents are used concomitantly with ZEN003694, a staggered dosing schedule should be used, either dose ZEN003694 2 hours before the H2 blocker or 10-12 hours after an H2 blocker. 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 patient 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 patient is considering a new over-the-counter medicine or herbal product
- Pregnant women are excluded from this study because ZEN003694 is BRD and BET inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ZEN003694, breastfeeding should be discontinued if the mother is treated with ZEN003694. These potential risks may also apply to other agents used in this study
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：なし
- 介入モデル：単一グループの割り当て
- マスキング：なし（オープンラベル）
アーム数
武器と介入
参加者グループ / アーム参加者グループ / アーム |
介入・治療介入・治療 |
|---|---|
|
実験的：Treatment (ZEN003694, cetuximab, encorafenib)
Patients receive ZEN003694 PO QD on days 1-28 of each cycle, cetuximab IV over 120 minutes on days 1 and 15 of each cycle, and encorafenib PO QD on days 1-28 of each cycle. NOTE: In the dose-expansion study, patients receive encorafenib on days 2-28 of cycle 1 and then on days 1-28 of cycles thereafter. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA, CT or MRI, and collection of blood samples throughout the trial. Patients may also undergo biopsy at screening and on study. |
Undergo CT
他の名前：
Undergo MRI
他の名前：
Undergo ECHO
他の名前：
Undergo MUGA
他の名前：
Undergo biopsy
他の名前：
Undergo collection of blood samples
他の名前：
Given IV
他の名前：
Given PO
他の名前：
Given PO
他の名前：
|
この研究は何を測定していますか？
主要な結果の測定
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Maximum tolerated dose (dose escalation cohort)
時間枠：Up to completion of dose escalation phase
|
Will be determined based on the number of grade 3 or 4 adverse events in patients who participate on the study. Toxicities will be graded according to Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v 5.0). |
Up to completion of dose escalation phase
|
|
Recommended phase 2 dose (dose escalation cohort)
時間枠：Up to completion of dose escalation phase
|
Will be determined based on the number of grade 3 or 4 adverse events in patients who participate on the study. Toxicities will be graded according to CTCAE v 5.0. |
Up to completion of dose escalation phase
|
二次結果の測定
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Time to progression
時間枠：Time between consent onto study and progression, withdraw, or death, assessed up to 3 years
|
Will be estimated according to Kaplan-Meier analysis. |
Time between consent onto study and progression, withdraw, or death, assessed up to 3 years
|
|
Time to death
時間枠：Time between consent onto study and death, assessed up to 3 years
|
Will be estimated according to Kaplan-Meier analysis. |
Time between consent onto study and death, assessed up to 3 years
|
|
Overall survival (OS)
時間枠：Up to 3 years
|
Median OS will be estimated according to Kaplan-Meier analysis. |
Up to 3 years
|
|
Progression-free survival (PFS)
時間枠：From start of treatment to time of progression or death, whichever occurs first, assessed up to 3 years
|
Median PFS will be estimated according to Kaplan-Meier analysis. |
From start of treatment to time of progression or death, whichever occurs first, assessed up to 3 years
|
|
MAPK inhibition
時間枠：Baseline and cycle 1 day 14 (C1D14)
|
MAPK inhibition, measured by phosphorylated ERK pharmacodynamic profiling, will be evaluated to determine efficacy of the combination. |
Baseline and cycle 1 day 14 (C1D14)
|
|
Pharmacokinetic profile of ZEN003694 when combined with encorafenib
時間枠：Prior to ZEN003694 administration on C1D1, C1D2 and C1D15, as well as 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours post ZEN003694 administration on C1D1 and C1D15
|
Plasma concentration-time curves will be analyzed by noncompartmental methods using routines supplied. |
Prior to ZEN003694 administration on C1D1, C1D2 and C1D15, as well as 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours post ZEN003694 administration on C1D1 and C1D15
|
その他の成果指標
その他の成果指標
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Presence or absence of a given gene mutation
時間枠：At pre-treatment and post-progression
|
The presence or absence of a given gene mutation will be evaluated by next-generation sequencing. |
At pre-treatment and post-progression
|
協力者と研究者
捜査官
捜査官
- 主任研究者：Salvador Alonso Martinez、University of Texas MD Anderson Cancer Center LAO
出版物と役立つリンク
一般刊行物
- Lee HM, Zheng Z, Sorokin A, Wong CW, Napolitano S, Chowdhury S, Kanikarla PM, Singh AK, Kochat V, Bristow CA, Srinivasan S, Peoples M, Arslan E, Alshenaifi JY, Villarreal OE, Morris VK, Shen JP, Meric-Bernstam F, Jain AK, Fowlkes NW, Anderson A, Menter DG, Saw AK, Rai K, Kopetz S. Reprogramming of Cellular Plasticity via ETS and MYC Core-regulatory Circuits During Response to MAPK Inhibition in BRAF-mutant Colorectal Cancer. bioRxiv [Preprint]. 2025 Jun 20:2025.06.15.659716. doi: 10.1101/2025.06.15.659716.
- Lee HM, Zheng Z, Sorokin A, Wong CW, Napolitano S, Chowdhury S, Kanikarla Marie P, Singh AK, Kochat V, Bristow CA, Srinivasan S, Peoples M, Arslan E, Alshenaifi JY, Villarreal OE, Morris VK, Shen JP, Meric-Bernstam F, Jain AK, Fowlkes NW, Anderson A, Menter DG, Saw AK, Rai K, Kopetz S. Reprogramming of Cellular Plasticity via ETS and MYC Core-Regulatory Circuits during Response to MAPK Inhibition in BRAF-Mutant Colorectal Cancer. Clin Cancer Res. 2026 Aug 3;32(15):3309-3324. doi: 10.1158/1078-0432.CCR-25-4370.
研究記録日
主要日程の研究
研究開始 (実際)
研究開始
一次修了 (推定)
一次修了
研究の完了 (推定)
研究の完了
試験登録日
最初に提出
最初に提出
QC基準を満たした最初の提出物
QC基準を満たした最初の提出物
最初の投稿 (実際)
最初の投稿
学習記録の更新
投稿された最後の更新 (実際)
投稿された最後の更新
QC基準を満たした最後の更新が送信されました
QC基準を満たした最後の更新が送信されました
最終確認日
最終確認日
詳しくは
本研究に関する用語
追加の関連 MeSH 用語
その他の研究ID番号
その他の研究ID番号
- NCI-2023-08787
- UM1CA186688 (米国 NIH グラント/契約)
- 10605 (その他の識別子：CTEP)
- NCI-2023-08787 (レジストリ識別子：CTRP (Clinical Trial Reporting Program))
- 2024-0120
- 10605 (その他の識別子：University of Texas MD Anderson Cancer Center LAO)
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
IPD プランの説明
NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
米国で製造され、米国から輸出された製品。
この情報は、Web サイト clinicaltrials.gov から変更なしで直接取得したものです。研究の詳細を変更、削除、または更新するリクエストがある場合は、register@clinicaltrials.gov。 までご連絡ください。 clinicaltrials.gov に変更が加えられるとすぐに、ウェブサイトでも自動的に更新されます。