Hydroxychloroquine and Temsirolimus in Treating Patients With Metastatic Solid Tumors That Have Not Responded to Treatment
A Phase I Trial of Hydroxychloroquine in Combination With Temsirolimus in Patients With Refractory Solid Tumors
RATIONALE: Drugs used in chemotherapy, such as hydroxychloroquine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving hydroxychloroquine together with temsirolimus may kill more tumor cells.
PURPOSE: This phase I trial is studying the side effects and best dose of hydroxychloroquine when given together with temsirolimus in treating patients with metastatic solid tumors that have not responded to treatment.
調査の概要
状態
詳細な説明
OBJECTIVES:
Primary
- Determine the maximum tolerated dose of hydroxychloroquine (HCQ) in combination with temsirolimus (TEM) in patients with metastatic refractory solid tumors.
Secondary
- Describe the toxicity of this regimen in these patients.
- Measure the response rate in patients treated with this regimen.
Tertiary
- Establish a population pharmacokinetic (PK) model for HCQ and its metabolites in combination with TEM.
- Use the population PK model to estimate the exposure of HCQ in individual patients.
- Compare PK parameters for this regimen to data from published single agent studies.
- Measure the change in median number of autophagic vesicles/cell in peripheral blood mononuclear cells with TEM alone and with TEM and HCQ and correlate these changes with HCQ exposure.
OUTLINE: This is a dose-escalation study of hydroxychloroquine.
Patients receive temsirolimus IV over 30 minutes once a week beginning in week 1 and oral hydroxychloroquine twice daily beginning in week 2. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.
Blood samples are collected at baseline and periodically during study for pharmacokinetic and pharmacodynamic studies and measurement of autophagy inhibition. Samples are analyzed via HPLC and tandem mass spectrometry, immunoblotting assays, and electron microscopy.
研究の種類
入学 (予想される)
段階
- フェーズ 1
連絡先と場所
研究場所
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Pennsylvania
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Philadelphia、Pennsylvania、アメリカ、19104-4283
- Abramson Cancer Center of the University of Pennsylvania
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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 refractory solid tumor for which no curative standard therapy exists
- Metastatic disease
Treated brain metastases that have been stable ≥ 3 months allowed
- At least 1 week since prior steroids
PATIENT CHARACTERISTICS:
- ECOG performance status of 0-1
- ANC ≥ 1,500/mm^3
- Platelet count ≥ 100,000/mm^3
- Creatinine ≤ 2 times upper limit of normal (ULN)
- ALT and AST ≤ 5 times ULN
- Total bilirubin ≤ 1.5 mg/dL
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- No serious concurrent infection or medical illness that would jeopardize the ability of the patient to receive the treatment outlined in this protocol with reasonable safety
No prior or other concurrent malignancy except for curatively treated carcinoma-in-situ at any site or basal cell carcinoma or squamous cell carcinoma of the skin
- Patients who have been free of disease (any prior malignancy) for ≥ 5 years are eligible
- No porphyria
- No psoriasis, except well controlled psoriasis under the care of a specialist
- No previously documented macular degeneration or diabetic retinopathy
- No HIV positivity
PRIOR CONCURRENT THERAPY:
- See Disease Characteristics
- Any number and type of prior anticancer therapies allowed
- No prior mTOR inhibitors
- At least 4 weeks since prior immunotherapy (i.e., aldesleukin, interferon, CTLA-4) or chemotherapy and recovered
- At least 2 weeks since prior oral targeted therapy and recovered
- At least 4 weeks since prior and no other concurrent investigational anticancer therapy (except for vaccines)
- No other concurrent therapy
- No concurrent combination antiretroviral therapy for HIV-positive patients
- No concurrent cytochrome P450 enzyme-inducing anticonvulsant drugs (i.e., phenytoin, carbamazepine, phenobarbital, primidone, or oxcarbazepine)
- Concurrent non-enzyme inducing anticonvulsants, including felbamate, valproic acid, gabapentin, lamotrigine, tiagabine, topiramate, zonisamide, or levetiracetam allowed
- Concurrent hematologic growth factors (filgrastim [G-CSF], pegfilgrastim, epoetin alfa) allowed in patients with severe myelosuppression
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
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 |
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Maximum tolerated dose of hydroxychloroquine
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二次結果の測定
結果測定 |
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回答率
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Toxicity rate as assessed by NCI CTCAE v. 3.0
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Pharmacokinetic and pharmacodynamic correlative endpoints
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協力者と研究者
捜査官
- 主任研究者:Ravi Amaravadi, MD、Abramson Cancer Center of the University of Pennsylvania
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 (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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