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.

Study Overview

• Status: Completed
• Conditions: Unspecified Adult Solid Tumor, Protocol Specific
• Intervention / Treatment: Other: pharmacological study; Other: laboratory biomarker analysis; Other: high performance liquid chromatography; Other: mass spectrometry; Other: immunologic technique; Drug: hydroxychloroquine; Other: electron microscopy; Drug: temsirolimus; Procedure: autophagy inhibition therapy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104-4283
      • Abramson Cancer Center of the University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Maximum tolerated dose of hydroxychloroquine

Secondary Outcome Measures

Outcome Measure
Response rate
Toxicity rate as assessed by NCI CTCAE v. 3.0
Pharmacokinetic and pharmacodynamic correlative endpoints

Collaborators and Investigators

• Sponsor: Abramson Cancer Center of the University of Pennsylvania
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Ravi Amaravadi, MD, Abramson Cancer Center of the University of Pennsylvania

Study record dates

Study Major Dates

• Study Start: October 1, 2008
• Primary Completion (Actual): May 1, 2012
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: May 28, 2009
• First Submitted That Met QC Criteria: May 28, 2009
• First Posted (Estimate): May 29, 2009

Study Record Updates

• Last Update Posted (Actual): April 16, 2019
• Last Update Submitted That Met QC Criteria: April 12, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: unspecified adult solid tumor, protocol specific
• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Sirolimus; Hydroxychloroquine
• Other Study ID Numbers: CDR0000643294; UPCC-08908; 807931; WYETH-C-UPCC-03809