Chloroquine

Property	Information
Drug Name	Chloroquine and Hydroxychloroquine
FDA Approval	No (for glioblastoma treatment)
Used for	Glioblastoma, in combination with traditional chemotherapy agents
Clinical Trial Phase	Reviewed in recent meta-analyses and studies
Clinical Trial Explanation	Not specified
Common Side Effects	Generally well-tolerated; specific studies noted minimal impact on adverse event incidence
OS without	BCNU alone: median survival of 11 months
OS with	Chloroquine with BCNU: median survival significantly improved to 25-33 months; recent meta-analysis supports decreased mortality and improved survival time in glioblastoma patients
PFS without	Not specified in the recent analysis
PFS with	Not directly specified; chloroquine shown to induce remission rates without increasing adverse events significantly
Usefulness Rating	4
Usefulness Explanation	Not specified
Toxicity Level	1 or 2
Toxicity Explanation	Not specified

Notes: Recent studies highlight Chloroquine's potential in glioblastoma treatment, significantly improving survival rates when combined with chemotherapy. Chloroquine acts as an autophagy inhibitor, potentially enhancing chemotherapy's effectiveness by inhibiting a survival mechanism in cancer cells. Hydroxychloroquine's efficacy at the maximum tolerated dose has not shown improvement in survival, suggesting Chloroquine as the more promising agent for future clinical trials, especially considering tumor genetic profiles such as EGFR status.

Links: * [Chloroquine Supplementation for the Treatment of Glioblastoma: A Meta-analysis of Randomized Controlled Studies - PubMed](https://pubmed.ncbi.nlm.nih.gov/36409625)

• [Chloroquine in Cancer Therapy: A Double-Edged Sword of Autophagy - AACR Journals](https://aacrjournals.org/cancerres/article/73/1/3/584147/Chloroquine-in-Cancer-Therapy-A-Double-Edged-Sword)

From Ben Williams Book: Chloroquine and Hydroxychloroquine

In a series of studies conducted in Mexico City (23, 24, 25) patients received the traditional chemotherapy agent BCNU, with or without a 150 mg daily dose of chloroquine (the equivalent of 250 mg chloroquine phosphate). The results were that patients receiving chloroquine had a median survival time of 25-33 months, while those receiving BCNU alone had a median survival time of 11 months. Chloroquine at the dose used had no detectable toxicity. Because the cytotoxic mechanism of BCNU is similar to that of Temodar, it seems likely that chloroquine should increase the efficacy of Temodar, although this has yet to be demonstrated. One of several mechanisms by which chloroquine makes chemotherapy more effective is that it inhibits autophagy, an intracellular process that involves the cell digesting some of its internal parts to allow repair of the damage caused by the chemotherapy.

Disappointingly, a multi-center phase I/II trial testing the addition of7hydroxychloroquine (which differs from chloroquine only by a single hydroxyl group) to standard radiochemotherapy for newly diagnosed glioblastoma failed to show any improvement in survival over historical averages. In the phase I safety and toxicity study, all 3 subjects given 800 mg/d hydroxychloroquine along with chemoradiation experienced grade 3 or 4 neutropenia or thrombocytopenia, and 600 mg/d was determined to be the maximum tolerated dose. 76 patients were then treated at this dose in the phase 2 cohort. Autophagy inhibition (the proposed mechanism of action) was not consistently achieved at that dose, and patient survival (median OS 15.6 months, 2-year survival of 25%) was not improved relative to historical control groups. The study concluded that hydroxychloroquine was ineffective in this context at the maximum tolerated dose (304).

Recent preclinical work (305) has shown increased reliance on autophagy and sensitivity

to chloroquine treatment in EGFR-overexpressing glioma cells, and any future trials with chloroquine for high-grade gliomas may benefit from a subgroup analysis based on EGFR status.Property "Has original text" (as page type) with input value "Chloroquine and Hydroxychloroquine</br></br>In a series of studies conducted in Mexico City (23, 24, 25) patients received the</br>traditional chemotherapy agent BCNU, with or without a 150 mg daily dose of</br>chloroquine (the equivalent of 250 mg chloroquine phosphate). The results were that</br>patients receiving chloroquine had a median survival time of 25-33 months, while those</br>receiving BCNU alone had a median survival time of 11 months. Chloroquine at the dose</br>used had no detectable toxicity. Because the cytotoxic mechanism of BCNU is similar to</br>that of Temodar, it seems likely that chloroquine should increase the efficacy of Temodar,</br>although this has yet to be demonstrated. One of several mechanisms by which</br>chloroquine makes chemotherapy more effective is that it inhibits autophagy, an</br>intracellular process that involves the cell digesting some of its internal parts to allow</br>repair of the damage caused by the chemotherapy.</br></br>Disappointingly, a multi-center phase I/II trial testing the addition</br>of7hydroxychloroquine (which differs from chloroquine only by a single hydroxyl group)</br>to standard radiochemotherapy for newly diagnosed glioblastoma failed to show any</br>improvement in survival over historical averages. In the phase I safety and toxicity study,</br>all 3 subjects given 800 mg/d hydroxychloroquine along with chemoradiation</br>experienced grade 3 or 4 neutropenia or thrombocytopenia, and 600 mg/d was</br>determined to be the maximum tolerated dose. 76 patients were then treated at this dose</br>in the phase 2 cohort. Autophagy inhibition (the proposed mechanism of action) was not</br>consistently achieved at that dose, and patient survival (median OS 15.6 months, 2-year</br>survival of 25%) was not improved relative to historical control groups. The study</br>concluded that hydroxychloroquine was ineffective in this context at the maximum</br>tolerated dose (304).</br></br>Recent preclinical work (305) has shown increased reliance on autophagy and sensitivity</br></br>to chloroquine treatment in EGFR-overexpressing glioma cells, and any future trials with</br>chloroquine for high-grade gliomas may benefit from a subgroup analysis based on EGFR</br>status." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.

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