Autophagy Inhibition to Augment Mammilian Target of Rapamycin (mTOR) Inhibition: A Phase I/II Trial of RAD001 and Hydroxychloroquine (HCQ) in Patients With Previously Treated Renal Cell Carcinoma

NCT01510119 | Completed Phase 1 DMC

• 1 other identifier: UPCC 07811
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 3

Brief Summary

This is an open labeled phase I dose escalation study of hydroxychloroquine (HCQ) and RAD001 in patients with advanced renal cell carcinoma followed by a Phase II trial of RAD001 with HCQ. The target population are patients with one to three prior treatments for advanced renal cell carcinoma. In the phase I portion a traditional 3+3 design will be used to determine the maximal tolerated dose and/or recommended phase II dose for HCQ in combination with RAD001 po 10 mg/day.

Conditions

Metastatic Clear Cell Renal Cell Carcinoma

Outcome Measures

Primary Outcomes (1)

• PFS

  6 months

Study Arms (2)

Intervention - Dose Level 1

EXPERIMENTAL

RAD001 given 10mg/daily by mouth and 400mg hydroxychloroquine twice daily by mouth. Cycle 1 will include 1 week run-in of RAD001. Following this, both RAD001 and hydroxychloroquine given without interruption. Cycle 1 duration is 35 days; all subsequent cycles are 28 days. RAD001 and hydroxychloroquine continuously administered until progression of disease or unacceptable toxicity.

Drug: Hydroxychloroquine; Drug: RAD001

Intervention - Dose Level 2 Phase 2

EXPERIMENTAL

RAD001 given 10mg/daily by mouth and 600mg hydroxychloroquine twice daily by mouth. Cycle 1 will include 1 week run-in of RAD001. Following this, both RAD001 and hydroxychloroquine given without interruption. Cycle 1 duration is 35 days; all subsequent cycles are 28 days. RAD001 and hydroxychloroquine continuously administered until progression of disease or unacceptable toxicity.

Drug: Hydroxychloroquine; Drug: RAD001

Interventions

Hydroxychloroquine DRUG

Also known as: HCQ

Intervention - Dose Level 1; Intervention - Dose Level 2 Phase 2

RAD001 DRUG

Also known as: Everolimus, Afinitor

Intervention - Dose Level 1; Intervention - Dose Level 2 Phase 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histological evidence of metastatic renal cell carcinoma that has been previously treated with 1-3 prior regimens
• Phase I only, any number of prior regimens with evidence of progressive disease
• Patients must have at least one measurable site of disease according to RECIST criteria that has not been previously irradiated. If the patient has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation
• Age 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status £
• Adequate bone marrow function as shown by: absolute neutrophil count (ANC) 1.5 x 109/L, Platelets 100 x 109/L, Hb 9 g/dL
• Adequate liver function as shown by:
• Serum bilirubin 1.5 x upper limit of normal
• ALT and aspartate aminotransferase (AST) 2.5x upper limit of normal ( 5x upper limit of normal in patients with liver metastases)
• international normalized ratio (INR) and PTT 1.5. (Anticoagulation is allowed if target INR 1.5 on a stable dose of warfarin or on a stable dose of anticoagulant for 2 weeks at time of randomization.) Adequate renal function: serum creatinine 2.0 x upper limit of normal or Creatinine Clearance 60 .11 Fasting serum cholesterol 300 mg/dL OR 7.75 mmol/L AND fasting triglycerides 2.5 x upper limit of normal . NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication.
• Signed informed consent

You may not qualify if:

• Patients currently receiving anticancer therapy or who have received anticancer therapy within 4 weeks of the start of study drug (including chemotherapy, radiation therapy, antibody based therapy, etc.). To prevent explosive disease progression associated with angiogenic rebound from impacting the results of this study, patients who have received prior antiangiogenic therapy in the form of a small molecule multikinase inhibitor or bevacizumab must be off prior therapy for 1 week and have antiangiogenic therapy-associated adverse events (AEs) resolve to grade 2 before starting study treatment.
• Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery or patients that may require major surgery during the course of the study
• Prior treatment with any investigational drug within the preceding 4 weeks .4 Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent. Topical or inhaled corticosteroids are allowed.
• Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period
• Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases
• Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin, Stage I resected melanoma, ductal carcinoma in situ, squamous cell carcinoma of the skin, resected, basal cell carcinoma, indolent prostate cancer
• Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
• Symptomatic congestive heart failure of New York heart Association Class III or IV
• Unstable angina pectoris, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
• Severely impaired lung function with a previously documented spirometry and diffusing capacity of lung for carbon monoxide that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air
• Uncontrolled diabetes as defined by fasting serum glucose 1.5 x ULN
• Active (acute or chronic) or uncontrolled severe infections
• Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis
• A known history of HIV seropositivity as reported by the patient
• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)

Sponsors & Collaborators

• Abramson Cancer Center at Penn Medicine: lead
• University of Pittsburgh: collaborator
• Rutgers Cancer Institute of New Jersey: collaborator

Study Sites (3)

University of Medicine and Dentistry of New Jersey

New Brunswick, New Jersey, United States

Location

Abramson Cancer Center of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pittsburgh, Hillman Cancer Center

Pittsburgh, Pennsylvania, United States

Location

MeSH Terms

Conditions

Clear-cell metastatic renal cell carcinoma

Interventions

Hydroxychloroquine; Everolimus

Intervention Hierarchy (Ancestors)

Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Sirolimus; Macrolides; Lactones; Organic Chemicals

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 11, 2012
• First Posted: January 13, 2012
• Study Start: September 1, 2011
• Primary Completion: April 4, 2016
• Study Completion: January 5, 2017
• Last Updated: April 24, 2020

Record last verified: 2020-04

Locations

US (3)