Aldesleukin, Hypofractionated Radiation Therapy, and Pembrolizumab in Treating Patients with Advanced, Refractory Solid Tumors or Lymphoma
This phase I / II trial studies how well aldesleukin, hypofractionated radiation therapy, and pembrolizumab work in treating patients with solid tumors or lymphoma that have spread to other places in the body (advanced) and or do not respond to treatment (refractory). Aldesleukin is an immunotherapy drug that increases the activity and growth of white blood cells called T lymphocytes and B lymphocytes. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving aldesleukin, hypofractionated radiation therapy, and pembrolizumab may offer significant clinical benefit to patients who fail to respond to pembrolizumab alone.
- Adults with histologically proven, advanced solid malignancy or lymphoma.
- Failure to respond to checkpoint blockade therapy or previously responding patients who progress on PD-1/PD-L1 checkpoint blockade therapy.
- ECOG (Eastern Cooperative Oncology Group) performance status score of 0-1.
- Presence of a candidate treatment lesion (subcutaneous or nodal lesions are preferable but visceral lesions will be considered) accessible and safe for radiotherapy and serial intralesional injections.
- Presence of at least one target lesion (distinct from treatment lesion and outside of treatment lesion radiation field) evaluable for response by irRECIST.
- Life expectancy >= 6 months.
- Absolute neutrophil count (ANC) >= 1,500/mcL (performed within 10 days of treatment initiation).
- Platelets >= 100,000/mcL (performed within 10 days of treatment initiation).
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment).
- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (performed within 10 days of treatment initiation). (Glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) * Creatinine clearance should be calculated per institutional standard.
- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (performed within 10 days of treatment initiation).
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases (performed within 10 days of treatment initiation).
- Albumin >= 2.5 mg/dL (performed within 10 days of treatment initiation).
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (performed within 10 days of treatment initiation).
- Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (performed within 10 days of treatment initiation).
- No other active malignancy.
- Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
- Female subjects of childbearing potential must be willing to use an adequate method of contraception as outlined for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
- Male subjects of childbearing potential must agree to use an adequate method of contraception as outlined starting with the first dose of study therapy through 120 days after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
- Signed informed consent.
- Ability to comply with the protocol.
- Systolic >= 80.
- No active auto-immune disease and not on therapy for auto-immune disease.
- Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are eligible.
- Uncontrolled concomitant disease.
- Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Use of inhaled or topical steroids or systemic corticosteroids < 10 mg/ day is permitted.
- Has a known history of active TB (Bacillus tuberculosis).
- Hypersensitivity to pembrolizumab or any of its excipients.
- Has had a prior anti-cancer monoclonal antibody (mAb) (excluding PD-1/PD-L1 inhibitor) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent. Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
- Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
- Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
- Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
- History of severe autoimmune disease.
- Treatment with systemic immunostimulatory agents within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrollment (with the exception of checkpoint blockade therapy).
- Treatment with systemic corticosteroids or other systemic immunosuppressive medications within past 4 weeks or 5 half-lives whichever is shorter. Use of inhaled or topical steroids or systemic corticosteroids < 10 mg/ day is permitted.
- Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
- Has an active infection requiring systemic therapy.
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
- Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid (RNA) [qualitative] is detected).
- Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed.
- Patients unable to tolerate checkpoint inhibitor therapy.
- Unresolved grade 3 or any grade 4 non-hematological, treatment-related adverse events (AEs) attributed to prior PD-1/ PD-L1 checkpoint blockade. A minimum of 2 weeks from prior PD-1/PD-L1 checkpoint blockade to initiating study treatment.
Locations & Contacts
Contact: Arta Monir Monjazeb
Trial Objectives and Outline
I. To determine if this regimen converts patients with resistance to PD-1/PD-L1 checkpoint blockade into responders as determined by abscopal response rate (defined as response rate at lesions not treated with radiotherapy [RT] + aldesleukin [IL-2]) using immune related RECIST (irRECIST).
II. To determine the objective response rate (ORR), disease control rate (DCR), and progression free survival (PFS) using RECIST 1.1 (Response Evaluation Criteria for Solid Tumors).
I. To determine the maximum tolerated dose (MTD) of intralesional IL-2 that can be administered with hypofractionated radiotherapy (RT) and pembrolizumab. (Phase I)
II. To characterize the safety profile and toxicity of intralesional IL-2, RT, and pembrolizumab using CTCAE v4.03 (Common Toxicity Criteria for Adverse Events version 4.03). (Phase II)
I. To analyze serial blood samples for systemic cytokine / chemokine levels, and to quantify the number, function, T-cell diversity, and gene expression of circulating immune cell subsets.
II. To evaluate serial tumor tissue biopsies for tumor infiltrating immune cell subsets, T-cell diversity, expression of immune proteins including IDO and PD-L1, gene expression signatures, and mutational load.
III. To correlate immune parameters from translational objectives 1 and 2 with clinical outcomes to discover mechanisms of resistance and biomarkers of response.
OUTLINE: This is a phase I, dose-escalation study of aldesleukin followed by a phase II study.
Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. During week 1 of cycle 2, patients undergo 3 fractions of hypofractionated radiation therapy delivered 12-96 hours apart on consecutive days or every-other-day. Beginning 24-96 hours after the completion of radiotherapy, patients also receive aldesleukin via intralesional injection biweekly (at least 48 hours apart) for up to 4 doses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 12 weeks.
Trial Phase & Type
University of California Davis Comprehensive Cancer Center
Arta Monir Monjazeb
Secondary IDs NCI-2019-03831
Clinicaltrials.gov ID NCT03474497