Nivolumab and Ipilimumab followed by Isolated Limb Infusion with Melphalan in Treating Patients with Stage IIIB-IV In-Transit Extremity Melanoma
This phase II trial studies the side effects of nivolumab and ipilimumab followed by isolated limb infusion with melphalan in treating patients with stage IIIB-IV melanoma on the arm or leg (extremity) that has begun to spread to other parts of the body (In transit). Monoclonal antibodies, such as nivolumab and ipilimumab, may find tumor cells and help kill them. Drugs used in chemotherapy, such as melphalan, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Isolated limb infusion is a procedure used to deliver anticancer drugs directly to an arm or leg but not to the rest of the body. Giving nivolumab and ipilimumab followed by isolated limb infusion with melphalan may be a better treatment for melanoma.
Inclusion Criteria
- Patient must have histologically proven primary or recurrent extremity melanoma, stage IIIB, IIIC, or stage IV (American Joint Committee on Cancer [AJCC] staging must be documented in patient’s medical record, as determined by computed tomography [CT] of the chest, abdomen and pelvis, and/or whole body positron emission tomography [PET] scan, and magnetic resonance imaging [MRI] of the brain within 4 weeks prior to administration of study drug)
- Patients with stage IV disease with no more than five metastases in no more than two visceral organ sites will be eligible; if a multidisciplinary tumor board determines trial entry for an individual patient with stage IV exceeding this number of metastases is appropriate, that patient can be enrolled
- Patient must have an Eastern Cooperative Oncology Group (ECOG)/Zubrod status of 0-1
- Patient’s disease must be bi-dimensionally measurable by caliper or radiological method as defined in the Response Evaluation Criteria in Solid Tumors (RECIST) criteria; for subjects with a single lesion, archived tissue must be available for research analysis; multiple superficial melanoma lesions must have an aggregate total diameter of >=10 mm
- Disease to be treated by ILI must be distal to the planned site of tourniquet placement (which for the leg is generally the apex of the femoral triangle, or for the arm is distal to the deltoid insertion); if provider feels ILI appropriate with disease in these areas, patients may be enrolled with principal investigator (PI) approval
- Hemoglobin > 9.0 g/dl
- White blood count (WBC) of > 2000 ul 3
- Absolute neutrophil count (ANC) > 1,000/ ul 3
- Platelet count > 75,000/ ul 3
- Total bilirubin < 2.0 x upper limit of normal (ULN)
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN
- Serum creatinine < 2.0 x ULN
- Patient must have a palpable femoral/radial pulse in the affected extremity
- Patients must have a life expectancy of > 6 months
- Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 5 months after the last dose of investigational product; WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy or bilateral oophorectomy) or is not post-menopausal; post-menopause is defined as: * Amenorrhea > 12 consecutive months without another cause, or * For women with irregular menstrual periods and taking hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL * Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, have had tubal ligation or are practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be of childbearing potential * WOCBP must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 48 hours before the start of nivolumab and ipilimumab * Men of fathering potential must be using an adequate method of contraception to avoid conception throughout the study (and for up to 7 months after the last dose of investigational product)
- Patient must provide a signed and dated written informed consent prior to registration and any study-related procedures
- Patient must provide written authorization to allow the use and disclosure of their protected health information at any institution subject to United States (US) Health Insurance Portability and Accountability Act (HIPAA) regulations
- Ability to read and understand English and the ability to complete paper +/- electronic survey assessments
Exclusion Criteria
- Cardiac disease: congestive heart failure > class II New York Heart Association (NYHA); patients must not have unstable angina (angina symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months
- Autoimmune disease: history of or current active autoimmune diseases, (e.g. including but not limited to inflammatory bowel diseases [IBD], rheumatoid arthritis, autoimmune thyroiditis, autoimmune hepatitis, systemic sclerosis [scleroderma and variants], systemic lupus erythematosus, autoimmune vasculitis, autoimmune neuropathies [such as Guillain-Barre syndrome; vitiligo and adequately controlled endocrine deficiencies such as hypothyroidism are not exclusionary)
- Prior allogeneic stem cell transplantation
- Patients who have intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation
- History of or current immunodeficiency disease (e.g. splenectomy or splenic irradiation)
- Psychiatric conditions or diminished capacity that could compromise the giving of informed consent, or interfere with study compliance; any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of nivolumab and ipilimumab hazardous or obscure the interpretation of adverse events (AEs)
- Concomitant therapy with any of the following: interleukin (IL) 2, interferon, or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids (used in the management of cancer or non-cancer-related illnesses); however, during the course of the study, use of corticosteroids is allowed if used for treating immune-related adverse events (irAEs), adrenal insufficiencies, or if administered at doses of prednisone =< 10 mg daily or equivalent
- Prior therapy with single agent nivolumab, pembrolizumab or other PD-1/PD-L1 antibody or prior therapy with ipilimumab/CTLA-4 antibody for metastatic/unresectable disease is allowed unless they have received it as combination immunotherapy. Patients who received these agents in the adjuvant setting may be enrolled, provided it has been at least 3 months since receiving therapy
- Women of childbearing potential (WOCBP) who: * Are unwilling or unable to use acceptable methods of contraception to avoid pregnancy for their entire study period and for at least 5 months after cessation of study drug, or * Have a positive pregnancy test at baseline, or * Are pregnant or breastfeeding
- Persons of reproductive potential must agree to use an adequate method of contraception throughout treatment and for at least 5 months after ipilimumab/nivolumab is stopped (7 months for men) * Sexually active WOCBP must use an effective method of birth control during the course of the study, in a manner such that risk of failure is minimized; before study enrollment, WOCBP must be advised of the importance of avoiding pregnancy during study participation and the potential risk factors for an unintentional pregnancy; all WOCBP MUST have a negative pregnancy test before first receiving ipilimumab/nivolumab; if the pregnancy test is positive, the patient must not receive ipilimumab/nivolumab and must not be enrolled in the study
- Known brain metastasis
- Known human immunodeficiency virus (HIV) infection or chronic hepatitis B or C; must test during screening if history is not known
- Active clinically serious infection > Common Terminology Criteria for Adverse Events (CTCAE) grade 2
- Thrombotic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months
- Pulmonary hemorrhage/bleeding event > CTCAE grade 2 within 4 weeks of study entry
- Any other hemorrhage/bleeding event > CTCAE grade 3 within 4 weeks of study entry
- Evidence or history of any bleeding or coagulation disorder
- Patients with known heparin induced thrombocytopenia
- Antineoplastic therapy, radiotherapy, or any other investigational drug within 30 days prior to first study drug administration
- Current treatment, or treatment in the previous 24 months, for another non-melanoma malignancy, with the exception of adequately treated basal cell or squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ of the cervix; patients treated with curative intent for other malignancies within 24 months may be enrolled on a case by case basis after discussion/approval with the study PI
- Unable to return at the regular required intervals for reassessment, or study drug administration
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT02115243.
PRIMARY OBJECTIVES:
I. To characterize the safety and tolerability of combining nivolumab with ipilimumab followed by isolated limb infusion (ILI) with melphalan.
SECONDARY OBJECTIVES:
I. To determine the safety and tolerability of the combination of nivolumab 3 mg/kg plus ipilimumab 1mg/kg every (q)3 weeks for 2 doses.
II. To determine pathologic response from biopsies after completion of systemic therapy before ILI (week 12) AND determine pathologic response at week 24 (12 weeks after ILI).
III. To determine the complete response rate (CR) of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg q3 weeks for 2 doses followed by ILI with melphalan.
IV. To determine the progression free survival both locoregionally and systemically in patients who receive the treatment regimen.
TERTIARY OBJECTIVES:
I. Define how melphalan, drug pharmacokinetics (PK) contributes to limb toxicity and tumor response in patients receiving therapy.
II. Determine if PD-L1 expression via immunohistochemistry (IHC) on pretreatment tissue correlates with response. (Including potential markers of T cell exhaustion such as PD-1+ CTLA4+ CD8+ T cells).
III. Describe how immune cell populations change after treatment with systemic nivolumab and ipilimumab plus melphalan via ILI + and determine if these changes are associated with of clinical response.
IV. Describe the makeup in the colon microbiome prior to and during treatment with nivolumab and ipilimumab and whether this predicts the development of colitis or impacts treatment responses.
OUTLINE:
Patients receive nivolumab intravenously (IV) over 60 minutes and ipilimumab IV over 90 minutes on weeks 1 and 4 for 2 doses. At 12 weeks, patients with stable disease, responding disease, or disease that is only progressing in the extremity, who have recovered from toxicities associated with systemic therapy will undergo ILI with melphalan intra-arterially (IA) over 30 minutes. Patients with complete response to nivolumab and ipilimumab or patients who received ILI after nivolumab and ipilimumab, continue to receive nivolumab every 2 weeks until week 36 in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 2, 6, 12, and 24 weeks and then every 3 months for 2 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationDuke University Medical Center
Principal InvestigatorApril Kelly Scott Salama
- Primary IDPro00046479
- Secondary IDsNCI-2014-01416
- ClinicalTrials.gov IDNCT02115243