Phase II study of MK-3475 in conjunction with lymphodepletion, TIL, and high or low dose IL-2 in patients with metastatic melanoma
Rodabe N. Amaria
The goal of this clinical research study is to learn if pembrolizumab, an infusion of T-cells, chemotherapy (cyclophosphamide and fludarabine), and either high or low dose interleukin-2 (IL-2) can help to control metastatic melanoma. The safety of this drug combination will also be studied. T-cells are white blood cells in your body that are important to the immune system. The T-cells used in this study will be collected and grown in a separate study (MD Anderson Protocol 2004-0069) Screening Tests Signing this consent form does not mean that you will be able to take part in this study. You will have screening tests to help the doctor decide if you are eligible. You will have a physical exam. You will have an electrocardiogram (EKG) to check your heart function. Blood (about 4 tablespoons) and urine will be collected for routine tests and to check for hepatitis B and C, HIV (the AIDS virus), and other types of infections. This routine urine or blood collection will also include a pregnancy test, if you can become pregnant. To take part in this study, you must not be pregnant. Blood (about 2 teaspoons) will be drawn to test for an infection called cytomegalovirus (CMV). You will have tests to check your lung function. You will have a cardiac stress test to check your heart function. For this test, you will either exercise on a treadmill or receive a drug that makes your heart beat faster (such as dopamine hydrochloride) while the study staff checks your heart rate with a heart monitor. The doctor will describe the cardiac stress test to you in more detail. You will fill out 2 questionnaires about your quality of life. This should take about 10 minutes total to complete. You will have either an excisional or core tumor biopsy to check the status of the disease. To perform an excisional biopsy, the affected area is completely removed by cutting it out. To perform a core biopsy, a sample of tissue is removed using a hollow core needle that has a cutting edge. The study doctor will tell you which type of biopsy you will have and you will sign a separate consent form explaining the procedure and its risks in more detail. Blood (about 3 tablespoons) will be drawn to study your immune system. Within 30 days before your first dose of study drugs, you will have a computed tomography (CT) or positron emission tomography (PET)/CT scan of the chest, abdomen, and pelvis to check the status of the disease. You will also have a CT of the neck, if the doctor thinks it is needed. If you have not had 1 in the last 30 days, you will have magnetic resonance imaging (MRI) or a CT scan of the brain to check the status of the disease. If you the doctor thinks it is needed, you will have photographs taken of any skin lesions by a medical photographer. Your private areas will be covered (as much as possible), and a picture of your face will not be taken unless there are lesions on your face. The study doctor will discuss the screening test results with you. If the screening tests show that you are not eligible to take part in the study, you will not be enrolled. Other options will be discussed with you..
Disease Group: Melanoma
Treatment Agent: Interleukin-2,MK-3475
Treatment Location: Only at MDACC
Primary Objectives Evaluate the overall response rates of MK-3475 combined with lymphodepletion, TIL and high or low dose interleukin-2 therapy in patients with metastatic melanoma. Secondary Objectives: Comparison of progression free survival between the treatment arms Comparison of overall survival between the treatment arms Comparison of deep tumor responses (defined as over 60% reduction in tumor burden) between the treatment arms as per RECIST criteria Number of complete responses in both treatment arms Safety evaluations by CTCAE v 4 Exploratory Objective Identification of biomarkers predictive of treatment response or failure through immunohistochemistry, flow cytometry, gene expression changes as assessed by NanoString codeset, neo-antigen identification and CDR3 sequencing from blood and tumor samples acquired from baseline and on-treatment samples.
IRB Review and Approval Date: 08/07/2015
Recruitment Status: Open
Projected Accrual: N/A
1) Turnstile I - Screening: Patients must have metastatic melanoma or
stage III in-transit, subcutaneous, or regional nodal disease.
2) Patients must have a lesion amenable to resection for the generation of TIL on MD Anderson Protocol 2004-0069.
3) Patients must receive an MRI/CT/PET of the brain within 6 months of signing informed consent. If new CNS lesions are present, patient must have definitive treatment (including surgery or radiation). PI or his designee should make final determination regarding enrollment.
4) Age greater than or equal to 18 years.
5) Clinical performance status of ECOG 0 - 1 within 30 days of signing informed consent.
6) Patients previously treated with immunotherapy, targeted therapy, or no therapy (treatment naïve) will be eligible.
7) Patients receiving cytotoxic agents will be evaluated by the PI or his designee for eligibility suitability.
8) Patients with a negative pregnancy test (urine or serum) must be documented within 14 days of screening for women of childbearing potential (WOCBP). A WOCBP has not undergone a hysterectomy or who has not been naturally postmenopausal for at least 12 consecutive months (i.e. who has not had menses at any time in the preceding 12 consecutive months).
9) Turnstile II - Treatment: Patients must sign the treatment consent document before Turnstile II screening procedures. Before the treatment starts and at each visit, the patient will be asked to complete two quality of life questionnaires. It should take about 15 minutes to complete the questionnaires (FACT-G, FACT-Melanoma). Patients must fulfill all of the following criteria to be eligible for Turnstile II of the study.
10) Patients must have adequate TIL that were previously harvested and then cryopreserved on MDACC protocol 2004-0069.
11) Patients who have had prior therapy (BRAF inhibitors, ipilimumab, anti PD-1 antibody or anti PD-L1 antibody) or treatment naïve patients are eligible as long as toxicity from therapy is grade </= 1 or at baseline.
12) Patients must have at least one biopsiable measurable metastatic melanoma, lesion > 1cm and must be amenable to undergoing serial biopsies through the course of therapy. This lesion must not be documented as one of the target lesions
13) Patients may have CNS metastases which have been treated and are radiographically stable for at least 4 weeks
14) Patients of both genders must practice birth control for four months after receiving the preparative regimen (lymphodepletion) and continue to practice birth control throughout the study. Patients must have a documented negative pregnancy test (urine or serum) for women who have menstruated in the past 12 months and without sterilization surgery.
15) Unless surgically sterile by bilateral tubal ligation or vasectomy of partner(s), or if the patient is post-menopausal, the patient agrees to continue to use a barrier method of contraception throughout the study such as: condom, diaphragm, hormonal, IUD, or sponge plus spermicide. Abstinence is an acceptable form of birth control.
16) Pregnancy testing will be performed within 14 days of screening for women of childbearing potential (WOCBP). A WOCBP has not undergone a hysterectomy or who has not been naturally postmenopausal for at least 12 consecutive months (i.e. who has not had menses at any time in the preceding 12 consecutive months).
17) Clinical performance status of ECOG 0-1 within 30 days of signing consent
18) A stress cardiac test (stress thallium, stress MUGA, dobutamine echocardiogram or other stress test that will rule out cardiac ischemia) within 1 month of lymphodepletion.
19) 12-lead EKG showing no active ischemia and QTc interval less than 480 msec
20) Pulmonary function tests (FEV1>65% or FVC>65% of predicted) within 1 month of lymphodepletion.
21) Have measurable disease based on RECIST 1.1 and irRC criteria
22) Demonstrate adequate organ function as defined below, all screening labs should be performed within 10 days of treatment initiation.
23) System Hematological Absolute neutrophil count (ANC) >/= 1,500 /mcL; Platelets >/= 100,000 / mcL; Hemoglobin >/= 9 g/dL or >/= 5.6 mmol/L Renal Serum creatinine OR Measured or calculated a creatinine clearance (GFR can also be used in place of creatinine or CrCl) </= 1.5 X upper limit of normal (ULN) OR >/= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN Hepatic Serum total bilirubin </= 1.5 X ULN OR Direct bilirubin </= ULN for subjects with total bilirubin levels > 1.5 ULN; AST (SGOT) and ALT (SGPT) </= 2.5 X ULN OR </= 5 X ULN for subjects with liver metastases.
24) Contd #23: Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) 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 </= 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.
1) Turnstile I - Screening: Active systemic infections requiring
intravenous antibiotics, coagulation disorders or other major medical
illnesses of the cardiovascular, respiratory or immune system. PI or his
designee shall make the final determination regarding appropriateness of enrollment
2) Primary immunodeficiency and need for chronic steroid therapy, Exception: Patients on chronic physiologic dose of steroid equivalent to prednisone < 10 mg/day is allowed.
3) Patients who are pregnant or nursing.
4) Presence of a significant psychiatric disease, which in the opinion of the principal investigator or his designee, would prevent adequate informed consent.
5) Turnstile II - Treatment: Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
6) Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to initiation of lymphodepletion. Exception: Patients on chronic physiologic dose of steroid equivalent to predinsone < 10 mg/day is allowed.
7) Has not recovered (i.e., </= Grade 1 or at baseline) from adverse events due to investigational or standard agents administered more than 4 weeks earlier.
8) Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to lymphodepletion 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, alopecia, hypophysitis stable on physiologic dose of steroid equivalent to prednisone < 10 mg/day, hypothyoidism stable on hormone replacement 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.
9) Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
10) 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 initiation of lymphodepletion.
11) Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen’s syndrome will not be excluded from the study. Subjects with hypophysitis stable on physiologic dose of steroid will not be excluded from the study.
12) Has evidence of interstitial lung disease or has a history of non-infectious pneumonitis that required steroids or current pneumonitis.
13) Has an active infection requiring systemic therapy.
14) Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
15) 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.
16) Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
17) Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
18) Has received a live vaccine within 30 days prior to the first dose of trial treatment.
19) Any active systemic infections requiring intravenous antibiotics, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, such as abnormal stress thallium or comparable test, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease. PI or his designee shall make the final determination regarding appropriateness of enrollment.
Information and next steps
Rodabe N. Amaria
Melanoma Medical Oncology
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