Protocol No.: OCR17388
Sponsor Protocol No.: 10061
Protocol Title.: Pembrolizumab and Recombinant Interleukin-12 in Treating Patients With Solid Tumors
Principal Investigator: George, Thomas
Objective: This phase I trial studies the side effects and best dose of pembrolizumab and recombinant interleukin-12 in treating patients with solid tumors. 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. Recombinant interleukin-12 may kill tumor cells by blocking blood flow to the tumor and by stimulating white blood cells to kill tumor cells. Giving pembrolizumab and recombinant interleukin-12 may work better than giving pembrolizumab alone in treating patients with solid tumors.
Description: PRIMARY OBJECTIVE: I. Establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of edodekin alfa (recombinant human interleukin [rhIL]-12) in combination with pembrolizumab (MK-3475). SECONDARY OBJECTIVES: I. Evaluate the safety of the regimen by continuously monitoring adverse events that will be documented utilizing Common Terminology Criteria for Adverse Events (CTCAE) version (v).5.0. II. Evaluate the overall response rate (Response Evaluation Criteria in Solid Tumors [RECIST] v.1.1) and the progression free survival of patients enrolled on the study. III. Measure CD8+ T cell infiltration by immunohistochemistry in tumor biopsies obtained pre-treatment, after one week of rhIL-12 and after 2 cycles of pembrolizumab (MK-3475) in combination with rhIL-12. EXPLORATORY OBJECTIVE: I. Conduct exploratory translational laboratory correlative studies utilizing banked biospecimens (tumor, blood, and stool) obtained pre-treatment and during therapy. OUTLINE: This is a dose-escalation study of recombinant interleukin-12. Patients receive recombinant interleukin-12 subcutaneously (SC) on days 2, 5, 9, and 12 and pembrolizumab intravenously (IV) over 30 minutes on day 8 of cycle 1 and day 1 of subsequent cycles. Treatment continues for 28 days for cycle 1 and repeats every 21 days for subsequent cycles for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patient then receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 8 additional cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 12 weeks for 2 year and then every 24 weeks for up to 5 years.
Phase: Phase I
Age Group: Adult
Age: 18 Years - N/A
Experimental: Treatment (recombinant interleukin-12, pembrolizumab)Patients receive recombinant interleukin-12 SC on days 2, 5, 9, and 12 and pembrolizumab IV over 30 minutes on day 8 of cycle 1 and day 1 of subsequent cycles. Treatment continues for 28 days for cycle 1 and repeats every 21 days for subsequent cycles for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patient then receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 8 additional cycles in the absence of disease progression or unacceptable toxicity.
Detailed Eligibility: Inclusion Criteria: - Patients must have histologically confirmed malignancy that is metastatic or unresectable - Eligibility is restricted to patients who have tumors for which anti-PD-(L)1 therapy is indicated; and must have progressed past anti-PD(L)1 singly or in combination. There is no restriction on the number of prior lines of therapy - Age >= 18 years - Because no dosing or adverse event data are currently available on the use of pembrolizumab (MK-3475) in combination with rhIL-12 in patients < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials - Eastern Cooperative Oncology Group (ECOG) performance status == 70%) - Life expectancy of greater than 12 weeks - Leukocytes >= 2,000/mcL (within 28 days of treatment initiation) - Absolute neutrophil count >= 1,500/mcL (within 28 days of treatment initiation) - Platelets >= 100,000/mcL (within 28 days of treatment initiation) - Hemoglobin >= 9 g/dL OR >= 5.6 mmol/L (within 28 days of treatment initiation) - Serum total bilirubin =< upper limit of normal (ULN) OR direct bilirubin = ULN; (except patients with Gilbert's syndrome, who must have a total bilirubin less than 3.0 mg/dL) (within 28 days of treatment initiation) - Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamate pyruvate transaminase (SGPT) =< 2.5 x institutional ULN (within 28 days of treatment initiation) - Serum creatinine == 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN (within 28 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 (within 28 days of treatment initiation) - Activated partial thromboplastin time (aPTT) = 1 year - Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately - Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of pembrolizumab (MK-3475) and/or rhIL-12 administration - Ability to understand and the willingness to sign a written informed consent document - Patients who are human immunodeficiency virus (HIV) positive may participate IF they meet the following eligibility requirements: - They must be stable on their anti-retroviral regimen, and they must be healthy from an HIV perspective - They must have an undetectable viral load - They must have a CD4 count of greater than 250 cells/mcL - They must not be receiving prophylactic therapy for an opportunistic infection Exclusion Criteria: - Patients with a secondary active hematological malignancy including but not limited to chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), Hodgkins lymphoma, non-Hodgkins lymphoma (NHL) - NOTE: Patients with a history of hematological malignancy that was previously treated and resolved may be enrolled if otherwise meeting I/E criteria - Patients with a prior history of autoimmune cytopenias of any etiology including hemolytic anemia, (AIHA), idiopathic thrombocytopenia purpura (ITP), and/or other cytopenia are excluded - NOTE: This exclusion is regardless of whether or not this cytopenia(s) required prior therapy - Patients who have had chemotherapy, targeted small molecule therapy, or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to first dose of trial treatment, or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier - Note: Patients with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study - Note: If patients received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy - Patients who are currently participating in or have participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of trial 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 - Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not recovered (i.e., == 45 years of age and has not had menses for greater than 2 years will be considered postmenopausal), or 3) not heterosexually active for the duration of the study; the two birth control methods can be barrier method or a barrier method plus a hormonal method to prevent pregnancy; patients should start using birth control from study visit 1 throughout the study period up to 120 days after the last dose of study therapy; the following are considered adequate barrier methods of contraception: diaphragm, condom (by the partner), copper intrauterine device, sponge, or spermicide; appropriate hormonal contraceptives will include any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents) - Patients should be informed that taking the study medication may involve unknown risks to the fetus (unborn baby) if pregnancy were to occur during the study; in order to participate in the study they must adhere to the contraception requirement (described above) for the duration of the study and during the follow-up period of pregnancy and lactation; if there is any question that a patient will not reliably comply with the requirements for contraception, that patient should not be entered into the study - Pregnancy: If a patient inadvertently becomes pregnant while on treatment with pembrolizumab (MK-3475), the patient will immediately be removed from the study; the site will contact the patient at least monthly and document the patient's status until the pregnancy has been completed or terminated; the outcome of the pregnancy will be reported without delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening complication to the mother or newborn); the study investigator will make every effort to obtain permission to follow the outcome of the pregnancy and report the condition of the fetus or newborn; if a male patient impregnates his female partner the study personnel at the site must be informed immediately and the pregnancy reported and followed - It is unknown whether pembrolizumab (MK-3475) is excreted in human milk; since many drugs are excreted in human milk, and because of the potential for serious adverse reactions in the nursing infant, patients who are breast-feeding are not eligible for enrollment - 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 prior to the first dose of trial treatment