Clinical trial NCT01550367: Study of Hydroxychloroquine and Aldesleukin in Renal Cell Carcinoma Patients (RCC)
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Metastatic Renal Cell Carcinoma
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: Prometheus Laboratories
First posted: 2012-03-12
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Clinical Response - IL-2 Combined With Hydroxychloroquine (HCQ) at Either 1,200 mg/d or 600 mg/d) (All Patients)
timeFrame: Up to 3 years
measure: Clinical Response - IL-2 Combined With Hydroxychloroquine (HCQ) at 1,200 mg/d
timeFrame: Up to 3 years
measure: Clinical Response - IL-2 Combined With Hydroxychloroquine (HCQ) at 600 mg/d
timeFrame: Up to 3 years
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Up to 3 years
measure: Progression-free Survival (PFS)
timeFrame: Up to 3 years
measure: Number of Doses of IL-2 + HCQ
timeFrame: Up to 3 years
measure: Frequency of Grade III and Grade IV Toxicities
timeFrame: Up to 3 years
measure: Worst Grade of Adverse Event Experienced
timeFrame: Up to 3 years
measure: Worst Grade of Adverse Event At Least Possibly Related to Treatment Experienced
timeFrame: Up to 3 years
measure: Worst Grade of Adverse Event At Least Probably Related to Treatment Experienced
timeFrame: Up to 3 years
measure: Serum Lactate Dehydrogenase
timeFrame: Up to 2 years
measure: Hemoglobin Levels
timeFrame: Up to 3 years
measure: Serum Calcium Levels (Corrected)
timeFrame: Up to 3 years
measure: Prior Nephrectomy
timeFrame: Up to 3 years
measure: Number of Participants With Low Karnofsky Performance Status
timeFrame: Up to 3 years
measure: Natural Killer (NK) Cells
timeFrame: Up to 3 years
measure: Myeloid Derived Suppressor Cell (MDSC)
timeFrame: Up to 3 years
measure: Regulatory T Cells (Treg)
timeFrame: Up to 3 years
measure: Plasmacytoid Dendritic Cells (pDC)
timeFrame: Up to 3 years
measure: T-cell Lymphocytes
timeFrame: Up to 3 years
measure: Conventional Dendritic Cells (cDC)
timeFrame: Up to 3 years
Other outcomes:
Locations:
city: Maywood
country: United States
facility: Loyola University Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Simon Cancer Center
state: Indiana
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Hanover
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
city: Columbus
country: United States
facility: The Ohio State University Comprehensive Cancer Center
state: Ohio
city: Portland
country: United States
facility: Providence Health & Services
state: Oregon
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute / UPMC CancerCenter
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Leonard J Appleman, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: