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Study of Hydroxychloroquine and Aldesleukin in Renal Cell Carcinoma Patients (RCC)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01550367
Recruitment Status : Active, not recruiting
First Posted : March 12, 2012
Last Update Posted : August 17, 2018
Prometheus Laboratories
Information provided by (Responsible Party):
Leonard Appleman, University of Pittsburgh

Brief Summary:
The main goal of the research study is to determine whether treating renal cell cancer patients with the study drug, hydroxychloroquine, along with IL-2, a standard treatment of kidney cancer that has spread to other parts of the body, can make the cancer easier to kill and eliminate. Another goal is to see how the study drug affects the body's immune cells which fight cancer cells.

Condition or disease Intervention/treatment Phase
Metastatic Renal Cell Carcinoma Drug: Hydroxychloroquine Drug: IL-2 Phase 1 Phase 2

Detailed Description:
The rationale for combining the high dose bolus aldesleukin with hydroxychloroquine includes potential positive interactions on the immune regulatory side, non-overlapping toxicities, and potential for prolongation and increased number of responses based on murine studies conducted at the University of Pittsburgh. This study is a multi-center phase II study designed to estimate the efficacy of combination therapy of standard high dose bolus IL-2 and various doses of hydroxychloroquine therapy in metastatic RCC patients.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 39 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Inhibiting the Systemic Autophagic Syndrome - A Phase I/II Study of Hydroxychloroquine and Aldesleukin in Renal Cell Carcinoma Patients (RCC). A Cytokine Working Group (CWG) Study
Study Start Date : March 2012
Actual Primary Completion Date : February 6, 2018
Estimated Study Completion Date : September 2018

Arm Intervention/treatment
Experimental: Hydroxychloroquine + IL-2
One course of treatment (84 days) will consist of high dose (600,000 IU/kg) bolus IL-2 administered intravenously every 8 hours on days 1-5 and 15-19 (maximum 14 doses/5 days of administration) and hydroxychloroquine (HCQ) orally started two weeks prior to IL-2 infusions and continued while able to take oral medication for up to 3 courses.
Drug: Hydroxychloroquine
Continuous oral administration (at 600 mg/d) will be initiated prior to the first dose (day -14) given 14 days prior to initiation of the first dose of IL-2 and then daily or twice a day throughout all three treatment courses.
Other Name: Plaquenil

Drug: IL-2
600,000 IU/kg IV bolus q 8 hrs x days 1-5 and 15-19 (maximum 28 doses - 14 per 5 day cycle) of each 84-day course
Other Name: Aldesleukin

Primary Outcome Measures :
  1. Proportion of patients with metastatic RCC treated with IL-2 + HCQ at 600mg/d who experience a clinical complete response. [ Time Frame: up to 3 years to accrue and assess outcome ]

    Evaluation of target lesions:

    -Complete Response (CR): Disappearance of all target lesions

    Evaluation of non-target lesions

    -Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level

Secondary Outcome Measures :
  1. Complete response (CR), overall survival (OS) and progression-free survival (PFS) of patients with metastatic RCC treated with IL-2 + HCQ to the historical control data. [ Time Frame: up to 3 years to accrue and assess outcome ]

    CR (target lesions): Disappearance of all target lesions CR (non-target lesions): Disappearance of all non-target lesions and normalization of tumor marker level

    Survival: date of first protocol treatment to the date of death, or censored at date of last contact.

    TTP: time from the date of first protocol treatment until the date disease progression criteria are met (in responding patients progression criteria uses the reference of the smallest measurements recorded since the treatment started) or is censored at date of last disease assessment for those who have not progressed.

  2. Safety/toxicity of IL-2 + HCQ compared to historical control data: # doses IL-2 during 1st course; toxicity after scheduled 9th dose IL-2; frequency grade III and IV or unexpected or rare toxicities [ Time Frame: up to 3 years to accrue and assess outcome ]
    Number of doses of IL-2 administered during the first course of therapy; toxicity after the scheduled 9th dose of IL-2; frequency of grade III and IV or unexpected or rare toxicities

  3. Baseline laboratory parameters outlined under "description" (to be correlated with toxicity, response, and survival). [ Time Frame: up to 3 years to accrue and assess outcome ]
    Baseline laboratory parameters include: miRNAs pre- and post-IL-2; KIR genotyping; T and NK cell enumeration and activation in the peripheral blood; circulating mDC and pDC frequency and DC function, TCR-zeta chain expression in T and NK cells, arginase or arginine levels; circulating cytokines, chemokines, growth factors and angiogenesis mediators

  4. Known prognostic criteria for RCC patients (Motzer criteria, performance status, prior nephrectomy, presence of liver and/or bone metastases categories) on clinical outcome. [ Time Frame: up to 3 years to accrue and assess outcome ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Histologically confirmed metastatic renal cell carcinoma with predominantly clear cell histology.
  • Have measurable disease by RECIST 1.1 criteria. For example, this would include tumor in the lung, liver, and retroperitoneum. Bone disease is difficult to follow and quantify and as a sole site would not be acceptable.
  • Patients must be at least 4 weeks from radiation or surgery and recovered from all ill effects.
  • Age ≥18 years.
  • Karnofsky Performance Status ≥80%.
  • Adequate end organ function:

    1. Hematologic: ANC ≥ 1000cells/uL, platelets ≥ 100,000/uL, hemoglobin ≥ 9g/dl (pre transfusion values used for prognostic factor, can be transfused or use recombinant erythropoietin growth factors but must not have active bleeding).
    2. Liver: AST ≤ 2 x ULN (upper limit of normal), serum total bilirubin ≤ 2 x ULN (except for patients with Gilbert's Syndrome).
    3. Renal: serum creatinine ≤ 1.5 mg/dL or estimated creatinine clearance ≥ 60ml/min using Cockcroft-Gault estimation using the formula per protocol.
    4. Pulmonary: FEV1 ≥ 2.0 liters or ≥ 75% of predicted for height and age. (PFTs are required for patients over 50 or with significant pulmonary or smoking history defined as >20 pack years or history of COPD/emphysema).
    5. Cardiac: No evidence of congestive heart failure, symptoms of coronary artery disease, myocardial infarction less than one year prior to entry, serious cardiac arrhythmias, or unstable angina. Patients who are over 40 or have had previous cardiac disease will be required to have a negative or low probability cardiac stress test for cardiac ischemia.
  • Women should not be lactating and, if of childbearing age, have a negative pregnancy test within two weeks of entry to the study.
  • Appropriate contraception in both genders.
  • The patient must be competent and have signed informed consent.
  • CNS: No history of cerebrovascular accident, transient ischemic attacks, central nervous system or brain metastases.

Exclusion Criteria:

  • Patients who have previously received IL-2 are NOT eligible. Patients on HCQ in neoadjuvant protocols or in the past for clinical indications ARE eligible, as are patients who have previously received CTLA-4 and/or PD-1/PD-L1 antibodies.
  • Concomitant second malignancy except for non-melanoma skin cancer, and non-invasive cancer such as cervical CIS, superficial bladder cancer without local recurrence or breast CIS.
  • In patients with a prior history of invasive malignancy, less than five years in complete remission.
  • Positive serology for HIV, hepatitis B or hepatitis C.
  • Significant co-morbid illness such as uncontrolled diabetes or active infection that would preclude treatment on this regimen.
  • Use of corticosteroids or other immunosuppression (if patient had been taking steroids, at least 2 weeks must have passed since the last dose).
  • History of inflammatory bowel disease or other serious autoimmune disease. (Not including thyroiditis and rheumatoid arthritis). Patients already on hydroxychloroquine for such disorders are not eligible.
  • Patients with organ allografts.
  • Uncontrolled hypertension (BP >150/100 mmHg).
  • Proteinuria dipstick > 3+ or ≥ 2gm/24 hours.
  • Urine protein:creatinine ratio ≥ 1.0 at screening.
  • Major surgery, open biopsy, significant traumatic injury within 28 days of starting treatment or anticipation of need for major surgical procedure during the course of the study.
  • Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to starting treatment. Central venous catheter placements are permitted.
  • History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to starting treatment.
  • Serious, non-healing wound, ulcer, or bone fracture.
  • History of tumor-related or other serious hemorrhage, bleeding diathesis, or underlying coagulopathy.
  • History of deep venous thrombosis, clinically significant peripheral vascular disease, or other thrombotic event.
  • Inability to comply with study and/or follow-up procedures.
  • Individuals with known history of glucose 6 phosphate deficiency are excluded from the trial (possible issue with HCQ tolerance).
  • Patients with previously documented macular degeneration or diabetic retinopathy are excluded from the trial.
  • Baseline EKG with QTc > 470 msec (including subjects on medication). Subjects with ventricular pacemaker for whom QT interval is not measurable will be eligible on a case-by-case basis.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01550367

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United States, Illinois
Loyola University Chicago
Maywood, Illinois, United States, 60153
United States, Indiana
Indiana University Simon Cancer Center
Indianapolis, Indiana, United States, 46202
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, New Hampshire
Dartmouth-Hitchcock Medical Center
Hanover, New Hampshire, United States, 03755
United States, Ohio
The Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States, 43210
United States, Oregon
Providence Health & Services
Portland, Oregon, United States, 97213
United States, Pennsylvania
University of Pittsburgh Cancer Institute / UPMC CancerCenter
Pittsburgh, Pennsylvania, United States, 15232
Sponsors and Collaborators
Leonard Appleman
Prometheus Laboratories
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Principal Investigator: Leonard J Appleman, MD, PhD University of Pittsburgh

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Responsible Party: Leonard Appleman, MD, University of Pittsburgh Identifier: NCT01550367     History of Changes
Other Study ID Numbers: UPCI 11-080
First Posted: March 12, 2012    Key Record Dates
Last Update Posted: August 17, 2018
Last Verified: August 2018

Additional relevant MeSH terms:
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Carcinoma, Renal Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antirheumatic Agents
Antineoplastic Agents
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Analgesics, Non-Narcotic
Sensory System Agents
Peripheral Nervous System Agents