Temsirolimus and Valproic Acid in Treating Young Patients With Relapsed Neuroblastoma, Bone Sarcoma, or Soft Tissue Sarcoma
A Multi-center Phase I Trial of Temsirolimus in Combination With Valproic Acid in Children and Adolescents With Multiply Relapsed Pediatric Solid Tumors
RATIONALE: Drugs such as temsirolimus and valproic acid may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Valproic acid may also stop the growth of solid tumors by blocking blood flow to the tumor.
PURPOSE: This phase I trial is studying the side effects and the best dose of temsirolimus when given together with valproic acid in treating young patients with relapsed neuroblastoma, bone sarcoma, or soft tissue sarcoma.
調査の概要
詳細な説明
OBJECTIVES:
Primary
- To identify the maximum-tolerated dose of temsirolimus in combination with valproic acid in highly pretreated pediatric patients with refractory solid tumors.
Secondary
- To estimate the objective response rate in patients treated with this regimen.
- To estimate the progression-free survival of patients treated with this regimen.
- To explore the association between tumor IGF-IR, mTOR expression, HDAC, autophagy biomarkers, and sera levels of temsirolimus, valproate, and VEGF-A with toxicity and disease response.
- To evaluate the ability of selected member divisions of a newly developed North Carolina-based pediatric oncology consortium to cooperate in clinical trials.
OUTLINE: This a multicenter, dose-escalation study of temsirolimus.
Patients receive temsirolimus IV over 30-60 minutes on days 1, 8, 15, and 22 and oral valproic acid* 3 times daily on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Blood samples are collected at baseline and periodically during study for pharmacokinetic and VEGF-A studies. Tumor tissue samples from archived biopsy are also analyzed for IGF-IR, mTOR expression, HDAC, and autophagy biomarkers.
After completion of study therapy, patients are followed every 3 months for 1 year, every 4 months for 2 years, and then every 6 months for 2 years.
NOTE: * Doses of valproic acid are titrated beginning 3-7 days prior to starting temsirolimus to achieve plasma levels of 75-100 µg/mL.
研究の種類
入学 (実際)
段階
- フェーズ 1
連絡先と場所
研究場所
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North Carolina
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Chapel Hill、North Carolina、アメリカ、27599-7295
- Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
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Charlotte、North Carolina、アメリカ
- Carolina Healthcare System
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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
DISEASE CHARACTERISTICS:
Histologically confirmed malignant solid tumor at original diagnosis, including the following:
- Neuroblastoma
- Bone sarcomas (primary neuroectodermal tumors/ Ewing sarcoma (PNET/ES), osteosarcoma)
- Soft tissue sarcomas (rhabdosarcoma and related tumors)
- Histologically confirmed of relapsed disease is highly recommended but not mandatory
- Measurable disease according to RECIST
Refractory or progressive disease after ≥ 1 and ≤ 4 prior chemotherapy regimens
- Patients with neuroblastoma, PNET/ES, or rhabdosarcoma must have failed a cyclophosphamide/topotecan-containing regimen
- Stem cell transplantation, including preparative regimen and post-transplant immunotherapy, is considered to be 1 regimen
PATIENT CHARACTERISTICS:
- Karnofsky performance status (PS) 50-100% (or Lansky PS 50-100%)
- Life expectancy ≥ 8 weeks
- ANC ≥ 750/mm^3
- Platelet count ≥ 75,000/mm^3 (transfusion independent)
Hemoglobin 8.0 g/dL (may receive RBC transfusions)
- Patients with tumor metastatic to bone marrow are allowed to receive transfusions to maintain hemoglobin and platelet counts
- Serum creatinine normal
- Total bilirubin ≤ 1.5 times upper limit of normal (ULN) OR direct bilirubin < 1.0 mg/dL (if total bilirubin > 2.0 mg/dL)
- ALT < 5 times ULN
- Negative pregnancy test
- Not pregnant or nursing
- Fertile patients must use effective contraception
- Families must be able to give consent in English or Spanish
- No allergy to H1 antihistamines
PRIOR CONCURRENT THERAPY:
- See Disease Characteristics
- More than 2 weeks since prior chemotherapy, immunotherapy, or radiotherapy and recovered
- No concurrent anticonvulsants, including valproic acid
- No concurrent strong inducers or inhibitors of CYP3A4, including grapefruit juice
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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他の：Single Arm Temsirolimus + Valproic Acid
Drug: temsirolimus 60-230mg/m2 weekly during each 28 day course, for up to 12 courses Drug: valproic acid (VPA) All patients will be given oral VPA (5 mg/kg, 3 times a day for each 28 day course, up to 12 courses |
60-230mg/m2 weekly during each 28 day course, for up to 12 courses
他の名前：
All patients will be given oral VPA (5 mg/kg, 3 times a day for each 28 day course, up to 12 courses
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
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Maximum tolerated dose (MTD) of temsirolimus in combination with valproic acid
時間枠：4 weeks
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The planned starting dose of Temsirolimus is 60mg/M2.
The traditional 3+3 design will be used, where the MTD is defined as the dose with the probability of a DLT of 0.20
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4 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 |
|---|---|---|
|
Objective response rate
時間枠：every 12 weeks
|
Each patient will be classified according to their "best response".
Best response is determined from the sequence of the objective statuses as described in RECIST 1.1
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every 12 weeks
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Progression-free survival
時間枠：3 years
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If the patient's disease has not progressed at the time protocol-directed therapy is complete, any tumor assessments available during the follow-up period (up to 3 years) will be evaluated using RECSIT 1.1
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3 years
|
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Temsirolimus pharmakokinetic parameters (Maximum plasma concentration)
時間枠：doses 1 and 5
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Blood will be drawn prior to, 30 minutes, 1hr, 2hr, 5hr, 24hr after completion of doses 1 and 5. Levels of Temsirolimus will be measured using validated liquid chromatography and tandem mass spectroscopic methods
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doses 1 and 5
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協力者と研究者
捜査官
- 主任研究者：Julie Blatt, MD、UNC Lineberger Comprehensive Cancer Center
研究記録日
主要日程の研究
研究開始
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 (見積もり)
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
本研究に関する用語
キーワード
追加の関連 MeSH 用語
その他の研究ID番号
- LCCC 0901
- P30CA016086 (米国 NIH グラント/契約)
- CDR0000665319 (その他の識別子：PDQ)
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