Clinical Trials /

Pembrolizumab and Recombinant Interleukin-12 in Treating Patients With Solid Tumors

NCT03030378

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab and Recombinant Interleukin-12 in Treating Patients With Solid Tumors
  • Official Title: A Phase 1 Study of MK-3475 (Pembrolizumab) in Combination With Recombinant Interleukin-12 in Patients With Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-00091
  • SECONDARY ID: NCI-2017-00091
  • SECONDARY ID: HCC 17-003
  • SECONDARY ID: 10061
  • SECONDARY ID: 10061
  • SECONDARY ID: UM1CA186690
  • NCT ID: NCT03030378

Conditions

  • Metastatic Malignant Solid Neoplasm
  • Unresectable Solid Neoplasm

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (recombinant interleukin-12, pembrolizumab)
Recombinant Interleukin-12Cytotoxic Lymphocyte Maturation Factor, IL-12, Interleukin 12, Interleukin-12, Natural Killer Cell Stimulatory Factor, NM-IL-12, Recombinant human interleukin-12 (IL-12) cytokine, Ro 24-7472Treatment (recombinant interleukin-12, pembrolizumab)

Purpose

This phase I trial studies the side effects and best dose of pembrolizumab and recombinant interleukin-12 in treating patients with solid tumors. Monoclonal antibodies, such as pembrolizumab, 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 in treating patients with solid tumors.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of
      recombinant human interleukin (rhIL)-12 in combination with MK-3475 (pembrolizumab).

      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.

      II. Measure CD8+ T cell infiltration by immunohistochemistry in tumor biopsies obtained at
      baseline, after one week of rhIL-12 and after 2 cycles of MK-3475 (pembrolizumab) in
      combination with rhIL-12.

      IV. Conduct exploratory translational laboratory correlative studies utilizing banked
      biospecimens (tumor and blood) obtained at baseline 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 course 1 and day 1 of subsequent
      courses. Treatment continues for 28 days for course 1 and repeats every 21 days for
      subsequent courses for up to 8 courses in the absence of disease progression or unacceptable
      toxicity. Patients then receive recombinant interleukin-12 SC on days 2, 5, 9, and 12.
      Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up for 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (recombinant interleukin-12, pembrolizumab)ExperimentalPatients receive recombinant interleukin-12 SC on days 2, 5, 9, and 12 and pembrolizumab IV over 30 minutes on day 8 of course 1 and day 1 of subsequent courses. Treatment continues for 28 days for course 1 and repeats every 21 days for subsequent courses for up to 8 courses in the absence of disease progression or unacceptable toxicity. Patients then receive recombinant interleukin-12 SC on days 2, 5, 9, and 12. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.
  • Pembrolizumab
  • Recombinant Interleukin-12

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed malignancy that is metastatic or
             unresectable and for which standard Food and Drug Administration (FDA)-approved
             systemic curative or palliative antitumor therapies do not exist or are no longer
             effective or for which MK-3475 (pembrolizumab) is FDA-approved as standard of care
             therapy

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

          -  Life expectancy of greater than 12 weeks

          -  Within 14 days of treatment initiation: Leukocytes >= 2,000/mcL

          -  Within 14 days of treatment initiation: Absolute neutrophil count >= 1,500/mcL

          -  Within 14 days of treatment initiation: Platelets >= 100,000/mcL

          -  Within 14 days of treatment initiation: Hemoglobin >= 9 g/dL OR >= 5.6 mmol/L

          -  Within 14 days of treatment initiation: Serum total bilirubin =< upper limit of normal
             (ULN) OR direct bilirubin =< ULN for patients with total bilirubin levels > ULN;
             (except patients with Gilbert's syndrome, who must have a total bilirubin less than
             3.0 mg/dL)

          -  Within 14 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 14 days of treatment initiation: Serum creatinine =< 1.5 x ULN OR measured or
             calculated creatinine clearance (CrCl) (glomerular filtration rate [GFR] can also be
             used in place of creatinine or CrCl) >= 60 mL/min for subject with creatinine levels >
             1.5 X institutional ULN

          -  Within 14 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 14 days of treatment initiation: Activated partial thromboplastin time (aPTT)
             =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as prothrombin
             time (PT) or partial thromboplastin time (PTT) is within therapeutic range of intended
             use of anticoagulants

          -  Optional tumor biopsies: Patients will be asked permission (consent) to provide tissue
             from a recent (within 6 weeks of study entry) archival tissue sample or newly obtained
             core or excisional biopsy of a tumor lesion; in addition, for on-study biopsies (after
             one week and after 7 weeks of initiating study therapy) and for baseline tumor biopsy
             if an archival tissue sample is not available: willingness to undergo biopsies will be
             asked; patients who consent to provide tumor biopsies for research should have tumors
             deemed relatively safely accessible for biopsies with low likelihood of complication

          -  Patients must have measurable disease based on RECIST 1.1

          -  Women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry and for
             the duration of study participation

               -  Female patients of childbearing potential should have a negative urine or serum
                  pregnancy test 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 patients of childbearing potential should be willing to use 2 methods of
                  birth control or be surgically sterile, or abstain from heterosexual activity for
                  the course of the study through 120 days after the last dose of study medication;
                  patients of childbearing potential are those who have not been surgically
                  sterilized or have not been free from menses for > 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 MK-3475 (pembrolizumab) 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 who have had chemotherapy, targeted small molecule therapy, or radiotherapy
             within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
             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 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., =< grade 1 or at baseline) from adverse events (AEs) due to agents
             administered more than 4 weeks earlier; non-clinically significant adverse events may
             be considered as an exception after discussion with and approval by the principal
             investigator

          -  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

          -  Patients with known brain active and untreated metastases should be excluded from this
             clinical trial

          -  Patients with carcinomatous meningitis should also be excluded

          -  Patients with previously treated brain metastases may participate provided they are
             stable (without evidence of progression by imaging for at least 4 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 requiring steroids
             for at least 7 days prior to trial treatment

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to MK-3475 (pembrolizumab) and/or rhIL-12 or other agents used in study

          -  Has an active autoimmune disease requiring systemic treatment within the past 3 months
             or a documented history of clinically severe autoimmune disease, or a syndrome that
             requires systemic steroids or immunosuppressive agents; patients with vitiligo or
             resolved childhood asthma/atopy would be an exception to this rule; patients that
             require intermittent use of bronchodilators or local steroid injections would not be
             excluded from the study; patients with hypothyroidism stable on hormone replacement or
             Sjogren's syndrome will not be excluded from the study

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the patient's
             participation for the full duration of the trial, or is not in the best interest of
             the patient 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

          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
             anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically
             targeting T-cell co-stimulation or checkpoint pathways)

          -  Patients on any systemic corticosteroid therapy within one week before the planned
             date for first dose on study would not be eligible; exception: patients on physiologic
             replacement doses of corticosteroids are permitted

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, interstitial lung disease or active, non-infectious pneumonitis,
             symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or
             psychiatric illness/social situations that would limit compliance with study
             requirements

          -  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; pregnant women are excluded;
             breastfeeding should be discontinued if the mother is treated MK-3475

          -  Men and non-pregnant, non-breast-feeding women may be enrolled if they are willing to
             use 2 methods of birth control or are considered highly unlikely to conceive; highly
             unlikely to conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a
             woman who is >= 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)

          -  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

          -  Patient would not be eligible if he/she has known psychiatric or substance abuse
             disorders that would interfere with cooperation with the requirements of the trial
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose
Time Frame:Up to 3 years
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Progression free survival
Time Frame:At 6 months
Safety Issue:
Description:Will be evaluated in a descriptive manner and summarized by simple descriptive summary statistics.
Measure:Number of confirmed clinical responses defined to be either complete or partial response
Time Frame:Up to 3 years
Safety Issue:
Description:Will be evaluated in a descriptive manner and summarized by simple descriptive summary statistics.
Measure:CD8+ T cell infiltration assessed by immunohistochemistry
Time Frame:Up to 2 courses of treatment
Safety Issue:
Description:Will be compared to baseline biopsy specimens by the Wilcoxon signed-rank test.
Measure:Serum cytokine levels
Time Frame:Up to 3 years
Safety Issue:
Description:Descriptive as well as graphic statistics will be used to examine the biomarker level change after the treatment.
Measure:PD-L1 and IDO expression
Time Frame:Up to 3 years
Safety Issue:
Description:Descriptive as well as graphic statistics will be used to examine the biomarker level change after the treatment.
Measure:Tumor infiltrating lymphocytes (CD3, CD4, CD8, FOXP3) evaluation
Time Frame:Up to 3 years
Safety Issue:
Description:Descriptive as well as graphic statistics will be used to examine the biomarker level change after the treatment.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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