Vemurafenib Plus Cobimetinib Plus PEG-interferon in Advanced Melanoma Patients Harboring the V600BRAF Mutation (VEMUPLINT)
Phase I-II Study of the Combination Vemurafenib Plus Cobimetinib Plus PEG-interferon in Advanced Melanoma Patients Harboring the V600BRAF Mutation
調査の概要
詳細な説明
Phase I A cohort of 3 consecutive patients will be treated at each dose level (first step). Patients are scheduled to receive at least two courses of therapy (cycle every 28 days) at the same dose level. Escalation of the dose to the next higher level proceeds in absence of dose-limiting toxicity (DLT). Drug-related toxicities will be evaluated during each cycle of therapy and graded according to the NCI Common Toxicity Criteria.
Adverse events (AEs) and the activity of the treatment in terms of ORR, will be assessed as primary endpoints, respectively for phase I and phase II; other variables will be compared as secondary endpoints.
The treatment scheme is Peg-Interferon 1/2/3 micrograms/Kg (lyophilized powder 296 and 444 μg vials) one time per week + Vemurafenib film-coated capsules 960 mg b.i.d. + Cobimetinib tablets 60 mg o.d. 21 days on followed by 7 days off.
Interferon treatment should start after 15 days of Vemurafenib + Cobimetinib only.
Phase I will be conducted at Istituto Nazionale per lo Studio e la Cura dei Tumori - Fondazione G. Pascale (PI Paolo Antonio Ascierto) and a minimum of 3 patients per cohort will be enrolled. Groups of 3 patients will be entered at each dose level (vemurafenib 960 mg b.i.d. + Cobimetinib 60 mg o.d. 21 days on followed by 7 days off + Peg-interferon 1/2/3 micrograms/Kg). DLT will be determined after 2 courses of therapy: if all 3 patients treated at a dose level have been observed for 2 courses of therapy without DLT, then the dose will be escalated. If at least 2/3 patients have DLT after the first 2 courses of therapy in each cohort, then the previous dose level will be considered as the MTD. If 1/3 patients have DLT, then 3 more patients will be treated at this dose level. If none of these patients has DLT, then the dose will be escalated. If at least one of the 3 additional patients has DLT, then the previous dose will be considered the MTD.
The maximum tolerated dose (MTD) is then considered the recommended dose for further evaluation (next step).
Patients experiencing toxicities that were not dose-limiting can be retreated at the same dose level upon full recovery.
Special case is represented by patients with liver metastases for whom ALT or AST increases >3xULN (i.e., Grade 2 of the CTCAE) requires a closer monitoring of the liver tests. In such cases patients with AT up to 5xULN may be allowed to participate in the trial. Therefore, a threshold level of ALT or AST >3xBaseline value (vs. the standard >3xULN threshold) is considered to prompt closer monitoring for the whole duration of the treatment. Patients with rapidly rising or high serum ALT or AST or with ALT or AST elevations accompanied by jaundice require urgent evaluation to find treatable causes of hepatocellular necrosis.
Patients will be treated until progression if the MTD is not reached.
Phase II Phase II will be conducted in approximately 10 Investigational sites located in Italy and 42 patients will be enrolled in total (including 3 patients from the phase I).
Treatment will be continued until progression or unacceptable toxicity.
研究の種類
入学 (実際)
段階
- フェーズ2
- フェーズ 1
連絡先と場所
研究場所
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Napoli、イタリア、80131
- Fondazione G.Pascale
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参加基準
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 over 18
- Untreated and pretreated (no more than 1 treatment) patients with metastatic melanoma at stage unreseactable IIIb-IV, histologically confirmed, that show V600 type BRAF mutations. Patients eligible for Phase I may have been pretreated with the investigational study treatments.
- Patient with measurable disease by RECIST v 1.1
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 - 1
- Patients who have successfully completed all the secondary side effects to previous systemic therapy
Patients with an appropriate hematologic, hepatic and renal functionality, assessed in the 7 days preceding the start of therapy, as well as:
- Absolute neutrophil count (ANC)> 1.5 X 109 / L
- Absolute platelet count > 100 X 109 / L
- Hemoglobin > 9 g/dl
- Serum creatinine < 1.5 times the normal maximum values or Creatinine Clearance > 50 mL/hr (Cockroft-Gault formula)
- Transaminase level (AST and ALT) < 2.5 times the normal maximum values
- Serum bilirubin < 1.5 times the normal maximum values
- Negative pregnancy test performed within 7 days before beginning therapy (premenopausal women)
- Patients of childbearing age (or with partners of childbearing age) must use effective contraception during therapy and for at least 6 months after the effective treatment
- Absence of any psychological, familiar or social condition that may affect compliance with study protocol and scheduled follow-up
- Dated and signed informed consent before any study procedure
Exclusion Criteria:
- Presence of symptomatic brain metastases
- Previous malignant cancer during the 2 years preceding the signing of informed consent
- Investigational study treatment within 28 days or 5 half-lives, whichever is longer, preceding the first dose of study treatments in this study
- Pregnancy and/or breast feeding;
- Nausea and vomit refractory to therapy, malabsorption, external biliary shunt, previous bowel resection, which could impair an adequate absorption
- Any of these conditions occurring in the 6 months before the start of Vemurafenib therapy: heart attack, unstable angina and/or severe degree, congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, arterial hypertension not adequately controlled
- History of atrial or ventricular arrhythmia, symptomatic> grade 2 (NCI CTCAE)
- Hystory of retinopathy
- Correct QT interval > 450msec to baseline history of congenital long QT syndrome
- Uncontrolled medical condition among which endocrine disorders (such as hypothyroidism, hyperthyroidism and diabetes mellitus)
- Other severe medical or psychiatric conditions or abnormalities of laboratory tests that may increase the risk associated with study participation or the assumption of Vemurafenib, or that may interfere with the interpretation of study results, which in the judgment of the Investigator can make the patient not eligible for the study
- Unwillingness to practice adequate contraception
- Prior systemic treatment with BRAFi or MEKi, or interferon alpha
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）
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
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実験的：Vemurafenib+Cobimetinib + Peg-interferon
Vemurafenib 960 mg b.i.d.
+ Cobimetinib 60 mg o.d.(21 days on followed by 7 days off) + Peg-interferon 1/2/3 micrograms/Kg once weekly
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Vemurafenib 960 mg b.i.d. for each course of treatment lasting 28 days
他の名前：
In the Phase I are included 3 cohorts. Cohort 1) Peg-interferon 1 µg/Kg one time per week s.c. Cohort 2) Peg-interferon 2 µg/Kg one time per week s.c. Cohort 3) Peg-interferon 3 µg/Kg one time per week s.c. Interferon treatment should start after 15 days of Vemurafenib only In the Phase II is included the cohort selected by phase I due to MTD and expanded at RD.
他の名前：
Cobimetinib 60 mg o.d.
(21 days on followed by 7 days off)
他の名前：
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Number of participants with adverse events
時間枠：up to 24 weeks
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The NCI CTC-AE (Version 4) will be used to evaluate the clinical safety of the treatment in this study. Patients will be assessed for AEs at each clinical visit up to 24 weeks and as necessary throughout the study. Hematology and biochemistry will be done as part of regular safety assessments |
up to 24 weeks
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Number of Objective tumor responses
時間枠：From date of randomization until the date of first documented progression or date of death for many cause, whichever came first, assessed up to week 32
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Objective tumor response will be measured according to the modified RECIST 1.1 criteria.
Response criteria are essentially based on a set of measurable lesions identified at baseline as target lesions, and followed until disease progression.
Durable response rate (DRR) will be identified as the percentage of patients that is still in CR and PR at week 32.
The results will be tabulated with Clopper-Pearson 95%CI for response rates
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From date of randomization until the date of first documented progression or date of death for many cause, whichever came first, assessed up to week 32
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協力者と研究者
捜査官
- スタディチェア：Paolo A Ascierto, MD、Fondazione Melanoma Onlus
出版物と役立つリンク
一般刊行物
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- Eggermont AM, Suciu S, Santinami M, Testori A, Kruit WH, Marsden J, Punt CJ, Sales F, Gore M, MacKie R, Kusic Z, Dummer R, Hauschild A, Musat E, Spatz A, Keilholz U; EORTC Melanoma Group. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet. 2008 Jul 12;372(9633):117-126. doi: 10.1016/S0140-6736(08)61033-8.
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研究記録日
主要日程の研究
研究開始 (実際)
一次修了 (実際)
研究の完了 (実際)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (見積もり)
学習記録の更新
投稿された最後の更新 (実際)
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
詳しくは
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Vemurafenibの臨床試験
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