Study of Hydroxychloroquine and Aldesleukin in Renal Cell... | NCT01550367

NCT01550367

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

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Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

Status Module

Name	Class
Prometheus Laboratories	INDUSTRY

Label	Type	Description	Intervention Names
Hydroxychloroquine + IL-2	Experimental	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 Drug: IL-2

Name	Type	Description	Arm Group Labels	Other Names
Hydroxychloroquine	Drug	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.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Clinical Response - IL-2 Combined With Hydroxychloroquine (HCQ) at Either 1,200 mg/d or 600 mg/d) (All Patients)	Clinical Response: per RECIST v1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) with reduction in short axis to <10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease (PD):≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.	Up to 3 years
Clinical Response - IL-2 Combined With Hydroxychloroquine (HCQ) at 1,200 mg/d	Clinical Response: per RECIST v1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) with reduction in short axis to <10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease (PD):≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.	Up to 3 years
Clinical Response - IL-2 Combined With Hydroxychloroquine (HCQ) at 600 mg/d	Clinical Response: per RECIST v1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) with reduction in short axis to <10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease (PD):≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.

Secondary Outcomes

Measure	Description	Time Frame
Overall Survival (OS)	Time from date of first protocol treatment until the date of death, or censored at date of last contact.	Up to 3 years
Progression-free Survival (PFS)	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. Per RECIST 1.1, Progressive Disease (PD) is defined as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.

Eligibility Module

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.

Name	Affiliation	Role
Leonard J Appleman, MD, PhD	University of Pittsburgh	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Loyola University Chicago		Maywood	Illinois	60153	United States
Indiana University Simon Cancer Center

Arm/Group Information

ID	Title	Description
FG000	Hydroxychloroquine (HCQ) (1,200 mg/d or 600 mg/d) + 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. Hydroxychloroquine: Continuous oral administration (at 1,200 mg/d for initial (13) patients, then 600 mg/d for next (17) patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ (13 patients), but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d (17 patients).

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Hydroxychloroquine (HCQ) (1,200 mg/d or 600 mg/d) + 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. Hydroxychloroquine: Continuous oral administration (at 1,200 mg/d for initial (13) patients, then 600 mg/d for next (17) patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ, but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d.

Units	Counts
Participants	BG000

Baseline Measures

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous		Measure Analysis Population Description: Rows represent different dosage levels of HCQ.

Outcome Measures Module

Outcome Measures

Type	Title	Description	Population Description	Reporting Status	Anticipated Posting Date	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Time Frame	Units Analyzed	Denominator Units Selected	Arm/Group Information	Denominators	Classes	Analyses
Primary	Clinical Response - IL-2 Combined With Hydroxychloroquine (HCQ) at Either 1,200 mg/d or 600 mg/d) (All Patients)	Clinical Response: per RECIST v1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) with reduction in short axis to <10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease (PD):≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.	Patients with metastatic RCC treated with IL-2 combined with hydroxychloroquine (HCQ at either 1,200 mg/d or 600 mg/d) who were evaluable for clinical response. Note: Patients were initially treated at 1200 mg/d HCQ, but after several unexpected adverse events, dosing was reduced to 600 mg/d.	Posted		Count of Participants		Participants		Up to 3 years

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Hydroxychloroquine (HCQ) (1,200 mg/d ) + 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. Hydroxychloroquine: Continuous oral administration (at 1,200 mg/d (initial (13) patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ (13 patients), but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d (17 patients).

ID	Term
D000230	Adenocarcinoma
D002277	Carcinoma
D009375	Neoplasms, Glandular and Epithelial
D009370	Neoplasms by Histologic Type

ID	Term
D006886	Hydroxychloroquine
D007376	Interleukin-2
C082598	aldesleukin

ID	Term
D002738	Chloroquine
D000634	Aminoquinolines
D011804	Quinolines
D006574	Heterocyclic Compounds, 2-Ring