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

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ClinicalTrials.gov Identifier: NCT03030378
Recruitment Status : Recruiting
First Posted : January 25, 2017
Last Update Posted : February 15, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Metastatic Malignant Solid Neoplasm Unresectable Solid Neoplasm Other: Laboratory Biomarker Analysis Biological: Pembrolizumab Biological: Recombinant Interleukin-12 Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study of MK-3475 (Pembrolizumab) in Combination With Recombinant Interleukin-12 in Patients With Solid Tumors
Actual Study Start Date : August 11, 2017
Estimated Primary Completion Date : August 31, 2020
Estimated Study Completion Date : August 31, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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 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.
Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Biological: Recombinant Interleukin-12
Given SC
Other Names:
  • Cytotoxic 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 24-7472




Primary Outcome Measures :
  1. Maximum tolerated dose [ Time Frame: Up to 3 years ]
  2. Recommended phase 2 dose [ Time Frame: Up to 3 years ]

Secondary Outcome Measures :
  1. Progression free survival [ Time Frame: At 6 months ]
    Will be evaluated in a descriptive manner and summarized by simple descriptive summary statistics.

  2. Number of confirmed clinical responses defined to be either complete or partial response [ Time Frame: Up to 3 years ]
    Will be evaluated in a descriptive manner and summarized by simple descriptive summary statistics.

  3. CD8+ T cell infiltration assessed by immunohistochemistry [ Time Frame: Up to 2 courses of treatment ]
    Will be compared to baseline biopsy specimens by the Wilcoxon signed-rank test.

  4. Serum cytokine levels [ Time Frame: Up to 3 years ]
    Descriptive as well as graphic statistics will be used to examine the biomarker level change after the treatment.

  5. PD-L1 and IDO expression [ Time Frame: Up to 3 years ]
    Descriptive as well as graphic statistics will be used to examine the biomarker level change after the treatment.

  6. Tumor infiltrating lymphocytes (CD3, CD4, CD8, FOXP3) evaluation [ Time Frame: Up to 3 years ]
    Descriptive as well as graphic statistics will be used to examine the biomarker level change after the treatment.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03030378


Locations
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United States, California
UC San Diego Moores Cancer Center Recruiting
La Jolla, California, United States, 92093
Contact: Site Public Contact    858-822-5354    cancercto@ucsd.edu   
Principal Investigator: Mina Nikanjam         
University of California Davis Comprehensive Cancer Center Recruiting
Sacramento, California, United States, 95817
Contact: Site Public Contact    916-734-3089      
Principal Investigator: Jonathan W. Riess         
UCSF Medical Center-Mount Zion Recruiting
San Francisco, California, United States, 94115
Contact: Site Public Contact    877-827-3222      
Principal Investigator: Pamela N. Munster         
United States, Colorado
University of Colorado Hospital Recruiting
Aurora, Colorado, United States, 80045
Contact: Site Public Contact    720-848-0650      
Principal Investigator: Bradley R. Corr         
United States, Connecticut
Smilow Cancer Center/Yale-New Haven Hospital Recruiting
New Haven, Connecticut, United States, 06510
Contact: Site Public Contact    203-785-5702    canceranswers@yale.edu   
Principal Investigator: Navid Hafez         
Yale University Recruiting
New Haven, Connecticut, United States, 06520
Contact: Site Public Contact    203-785-5702    canceranswers@yale.edu   
Principal Investigator: Navid Hafez         
United States, Florida
University of Florida Health Science Center - Gainesville Recruiting
Gainesville, Florida, United States, 32610
Contact: Site Public Contact    352-273-8010    cancer-center@ufl.edu   
Principal Investigator: Thomas J. George         
United States, Iowa
University of Iowa/Holden Comprehensive Cancer Center Recruiting
Iowa City, Iowa, United States, 52242
Contact: Site Public Contact    800-237-1225      
Principal Investigator: Mohammed M. Milhem         
United States, Maryland
Johns Hopkins University/Sidney Kimmel Cancer Center Recruiting
Baltimore, Maryland, United States, 21287
Contact: Site Public Contact    410-955-8804    jhcccro@jhmi.edu   
Principal Investigator: Nilofer S. Azad         
United States, Massachusetts
Massachusetts General Hospital Cancer Center Recruiting
Boston, Massachusetts, United States, 02114
Contact: Site Public Contact    877-726-5130      
Principal Investigator: Geoffrey I. Shapiro         
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Site Public Contact    888-823-5923    ctsucontact@westat.com   
Principal Investigator: Geoffrey I. Shapiro         
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Site Public Contact    617-667-9925      
Principal Investigator: Geoffrey I. Shapiro         
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Site Public Contact    877-442-3324      
Principal Investigator: Geoffrey I. Shapiro         
United States, Missouri
Siteman Cancer Center at West County Hospital Recruiting
Creve Coeur, Missouri, United States, 63141
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Andrea Wang-Gillam         
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Andrea Wang-Gillam         
Siteman Cancer Center-South County Recruiting
Saint Louis, Missouri, United States, 63129
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Andrea Wang-Gillam         
Siteman Cancer Center at Christian Hospital Recruiting
Saint Louis, Missouri, United States, 63136
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Andrea Wang-Gillam         
Siteman Cancer Center at Saint Peters Hospital Recruiting
Saint Peters, Missouri, United States, 63376
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Andrea Wang-Gillam         
United States, New Jersey
Rutgers Cancer Institute of New Jersey Recruiting
New Brunswick, New Jersey, United States, 08903
Contact: Site Public Contact    732-235-8675      
Principal Investigator: Roman Groisberg         
United States, North Carolina
UNC Lineberger Comprehensive Cancer Center Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Site Public Contact    877-668-0683    cancerclinicaltrials@med.unc.edu   
Principal Investigator: Carrie Lee         
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Site Public Contact    888-275-3853      
Principal Investigator: James L. Abbruzzese         
United States, Ohio
Cleveland Clinic Foundation Recruiting
Cleveland, Ohio, United States, 44195
Contact: Site Public Contact    866-223-8100    CancerAnswer@ccf.org   
Principal Investigator: Dale R. Shepard         
United States, Pennsylvania
University of Pittsburgh Cancer Institute (UPCI) Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Site Public Contact    412-647-8073      
Principal Investigator: James J. Lee         
United States, Virginia
Virginia Commonwealth University/Massey Cancer Center Recruiting
Richmond, Virginia, United States, 23298
Contact: Site Public Contact       mwellons@vcu.edu   
Principal Investigator: Sarah W. Gordon         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: James J Lee University of Pittsburgh Cancer Institute LAO

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03030378     History of Changes
Other Study ID Numbers: NCI-2017-00091
NCI-2017-00091 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
HCC 17-003
10061 ( Other Identifier: University of Pittsburgh Cancer Institute LAO )
10061 ( Other Identifier: CTEP )
UM1CA186690 ( U.S. NIH Grant/Contract )
First Posted: January 25, 2017    Key Record Dates
Last Update Posted: February 15, 2019
Last Verified: December 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Neoplasms
Pembrolizumab
Interleukin-12
Antineoplastic Agents, Immunological
Antineoplastic Agents
Adjuvants, Immunologic
Immunologic Factors
Physiological Effects of Drugs
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors