High Dose Aldesleukin with or without Entinostat in Treating Patients with Metastatic or Unresectable Renal Cell Cancer
This phase II trial studies how well high dose aldesleukin with or without entinostat work in treating patients with renal cell cancer that has spread to other areas of the body (metastatic) or cannot be removed by surgery (unresectable). Interleukins are proteins made by white blood cells and other cells in the body that may help regulate immune response. Entinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not known if high dose aldesleukin with or without entinostat may work better in treating patients with renal cell cancer.
- Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information prior to registration. * NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 within 7 days prior to registration.
- Life expectancy of greater than 6 months.
- Patients must have pathological diagnosis of renal cell carcinoma that is metastatic or surgically unresectable. The histology must be clear cell carcinoma or predominant clear cell carcinoma.
- Patients must have measurable or evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
- Up to 2 prior therapies for renal cell cancer (RCC) are allowed. Prior palliative radiation to metastatic lesion(s) is permitted, provided there is at least one measurable and/or evaluable lesion(s) that has not been irradiated.
- Forced expiratory volume in one second (FEV1) > 2.0 liters or > 75% of predicted for height and age.
- No evidence of congestive heart failure, symptoms of coronary artery disease, myocardial infarction less than 6 months prior to entry, serious cardiac arrhythmias, or unstable angina. * NOTE: Patients who are over 40 or have had previous myocardial infarction greater than 6 months prior to entry will be required to have a negative or low probability cardiac stress test for cardiac ischemia.
- White blood cell (WBC) >= 3,000 K/mm^3 within 28 days prior to registration.
- Absolute Neutrophil Count (ANC) >= 1,500/mm^3 within 28 days prior to registration.
- Leukocytes >= 3,000/mm^3 within 28 days prior to registration.
- Platelets >= 100,000/mm^3 within 28 days prior to registration.
- Hemoglobin (Hgb) >= 12 g/dL within 28 days prior to registration.
- Serum creatinine =< 1.5 x upper limit of normal (ULN) within 28 days prior to registration.
- Calculated creatinine clearance >= 50 mL/min within 28 days prior to registration (per Cockcroft-Gault formula).
- Corrected calcium =< 10 mg/dL within 28 days prior to registration.
- Urine protein < 1 +; if >= 1+, a 24 hour urine protein should be obtained and be < 1,000 mg within 28 days prior to registration.
- Total Bilirubin =< 1.5 × upper limit of normal (ULN) within 28 days prior to registration.
- Aspartate aminotransferase (AST) =< 2.5 × ULN within 28 days prior to registration.
- Alanine aminotransferase (ALT) =< 2.5 × ULN within 28 days prior to registration.
- Lactate dehydrogenase within normal limits within 28 days prior to registration.
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 × ULN; activated partial thromboplastin time (aPTT) within 28 days prior to registration.
- Females of childbearing potential must have a negative serum pregnancy test during screening and within 3 days prior to receiving first dose of study medication. * NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.
- Females of childbearing potential and males must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 90 days after treatment discontinuation. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method.
- No history of cerebrovascular accident, transient ischemic attacks, central nervous system or brain metastases. * NOTE: Patients with central nervous system (CNS) metastases should have a head computed tomography (CT)/magnetic resonance imaging (MRI) within 21 days prior to treatment initiation. Any imaging abnormality indicative of CNS metastases will exclude the patient from the study. Patients with previously excised/gamma knifed solitary or oligometastases and no evidence of recurrent disease for 6 months are eligible.
- Concurrent use of valproic acid use is not allowed.
- Receiving medications that can affect clotting ability: warfarin, aspirin (once-daily aspirin use- maximum dose 325 mg/day is permitted), nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar agents.
- Patients may not be receiving other investigational agents.
- Active infection requiring systemic therapy.
- Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
- Any prior history of other cancer within the prior 5 years with the exception of: adequately treated basal cell carcinoma, cervical intraepithelial neoplasia (CIN)/cervical carcinoma in situ, melanoma in situ or ductal carcinoma in situ (DCIS)], localized Gleason 6 prostate cancer, papillary thyroid cancer or other non-melanoma skin cancers.
- Any medical condition that would preclude adequate evaluation of the safety and toxicity of the study combination.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (New York Association class II, III, or IV), angina pectoris requiring nitrate therapy, recent myocardial infarction (< the last 6 months), cardiac arrhythmia, history of cerebrovascular accident (CVA) within 6 months, hypertension (defined as blood pressure of > 160 mmHg systolic and/or > 90 mmHg diastolic on medication), corrected QT interval (QTc) interval > 470 msec, history of peripheral vascular disease, uncontrolled diabetes mellitus, or psychiatric illness/social situations that would limit compliance with study.
- Human immunodeficiency virus (HIV)-positive patients are eligible if their HIV is well-controlled (undetectable viral load [VL] and CD4 count > 350) and they are on anti-retrovirals unlikely to interact with entinostat. * NOTE: HIV testing is not required prior to registration.
- Known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C (e.g., hepatitis C virus ribonucleic acid [qualitative]). Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBc Ab] and absence of hepatitis B surface antigen [HBsAg]) are eligible. * NOTE: hepatitis B virus (HBV) deoxyribonucleic acid (DNA) test must be performed prior to study treatment. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for hepatitis C virus (HCV) ribonucleic acid (RNA).
- Serious or non-healing wound, ulcer or bone fracture.
- Left ventricular ejection function < 45%.
- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to day 1 therapy.
- Anticipation of need for major surgical procedures during the course of the study.
Locations & Contacts
Contact: Roberto Pili
Contact: Roberto Pili
Contact: Roberto Pili
Contact: Gerald Patrick Miletello
Contact: Ralph J. Hauke
Status: In review
Contact: Roberto Pili
Trial Objectives and Outline
I. Estimate and compare progression free survival (PFS) in patients receiving high dose aldesleukin (interleukin 2) or high dose interleukin 2 plus entinostat, stratified by no prior therapies versus (vs) prior therapies.
I. Estimate and compare the objective response rate (ORR) in patients receiving high dose interleukin 2 or high dose interleukin 2 plus entinostat, stratified by no prior therapies vs prior therapies.
II. Assess the safety and tolerability of high dose interleukin 2 plus entinostat.
III. Assess duration of response in patients receiving high dose interleukin 2 or high dose interleukin 2 plus entinostat.
IV. Assess overall survival in patients receiving high dose interleukin 2 or high dose interleukin 2 plus entinostat.
I. Determine whether modulation of specific immune cell subsets is associated with response to high dose interleukin 2 plus entinostat.
II. Assess PD L1 expression levels in archival tumor samples and correlate with response to
high dose interleukin 2 plus entinostat.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive entinostat orally (PO) every 2 weeks beginning on day -14 and high dose aldesleukin intravenously (IV) over 1 hour every 8 hours on days 1-5 and 15-19. Treatment repeats every 84 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue to receive entinostat PO every 2 weeks for up to 1 year at the discretion of treating physician.
ARM II: Patients receive high dose aldesleukin IV as in Arm I.
After completion of study treatment, patients are followed up at 30 days then every 6 months thereafter.
Trial Phase & Type
Indiana University / Melvin and Bren Simon Cancer Center
Secondary IDs NCI-2018-01621
Clinicaltrials.gov ID NCT03501381