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Pembrolizumab and Ziv-aflibercept in Treating Patients With Advanced Solid Tumors

This study is currently recruiting participants.
Verified September 2017 by National Cancer Institute (NCI)
Sponsor:
ClinicalTrials.gov Identifier:
NCT02298959
First Posted: November 24, 2014
Last Update Posted: September 13, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
National Cancer Institute (NCI)
  Purpose
This phase I trial studies the side effects and best dose of ziv-aflibercept when given together with pembrolizumab in treating patients with solid tumors that have spread to other places in the body. Ziv-afibercept works by decreasing blood and nutrient supply to the tumor, which may result in shrinking the tumor. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells. Giving ziv-aflibercept together with pembrolizumab may be a better treatment for patients with advanced solid tumors.

Condition Intervention Phase
Adult Solid Neoplasm Metastatic Melanoma Metastatic Renal Cell Cancer Recurrent Colorectal Carcinoma Recurrent Melanoma Recurrent Ovarian Carcinoma Recurrent Renal Cell Carcinoma Stage IV Ovarian Cancer Stage IVA Colorectal Cancer AJCC v7 Stage IVB Colorectal Cancer AJCC v7 Other: Laboratory Biomarker Analysis Biological: Pembrolizumab Biological: Ziv-Aflibercept Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Trial of MK-3475 Plus Ziv-Aflibercept in Patients With Advanced Solid Tumors

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Recommended combination dose of ziv-aflibercept and pembrolizumab, assessed by dose-limiting toxicities [ Time Frame: 4 weeks ]
    Safety will be evaluated for all treated patients using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. All adverse events recorded during the trial will be summarized and presented by dose level. For patients enrolled in the dose expansion phase of the trial, adverse events summaries will also be summarized according to disease cohort. The proportion of patients with grade-3 or higher adverse events will be presented with 90% exact binomial confidence interval.


Secondary Outcome Measures:
  • Objective response rate (ORR) [ Time Frame: Between the date of first dose of trial therapy and the date of objectively documented disease progression or cessation of trial therapy, whichever occurs first, assessed up to 12 weeks ]
    The ORR will be the proportion of patients achieving complete or partial response as their best response to therapy. The analysis will be descriptive and will be used to assess for early indications of efficacy. Will be summarized by disease type and in the aggregate, if appropriate. ORR will be estimated and will be summarized with 90% confidence intervals estimated using exact binomial methods.

  • Overall survival [ Time Frame: Time from start of trial treatment to death from any cause, assessed up to 12 months ]
    The analysis will be descriptive and will be used to assess for early indications of efficacy. Will be summarized by disease type and in the aggregate, if appropriate. Will be summarized using the product-limit method of Kaplan-Meier; 90% confidence intervals will be based on log(-log[outcome]) methodology.

  • Progression-free survival [ Time Frame: Time from start of trial treatment until objective disease progression (per RECIST) or death, whichever occurs first, assessed up to 6 months ]
    The analysis will be descriptive and will be used to assess for early indications of efficacy. Will be summarized by disease type and in the aggregate, if appropriate. Will be summarized using the product-limit method of Kaplan-Meier; 90% confidence intervals will be based on log(-log[outcome]) methodology.

  • Time-to-progression [ Time Frame: Time interval between the dates of the start of trial treatment and first documentation of progressive disease, assessed up to 12 weeks ]
    The analysis will be descriptive and will be used to assess for early indications of efficacy. Will be summarized by disease type and in the aggregate, if appropriate. Will be summarized using the product-limit method of Kaplan-Meier; 90% confidence intervals will be based on log(-log[outcome]) methodology.


Other Outcome Measures:
  • Changes in antigen specific responses to known melanoma antigen epitopes (melanoma antigen recognized by T cells 1, NY-ESO-1) [ Time Frame: Baseline to up to 12 weeks ]
    Will be determined utilizing HLA-A20201 peptide system for antigen-presenting cells (including dendritic cell maturation and presentation) and targets.

  • Effects on tumor vasculature and vascular active molecules [ Time Frame: Up to 12 weeks ]
    Will investigate the effects on tumor vasculature and vascular active molecules as a function of treatment with the two-drug combination. Studies will include monitoring VEGF, basic fibroblast growth factor, and hepatocyte growth factor levels. Circulating endothelial cells and progenitors will be studied as a function of treatment.

  • Humoral and cellular immune responses [ Time Frame: Up to 12 weeks ]
    Will be investigated by enzyme-linked immunosorbent assays, enzyme-linked immunospots, and cytotoxic T cell chromium release assays.

  • Phenotype changes in cell populations assessed by flow cytometry [ Time Frame: Baseline to up to 12 weeks ]
    Will be determined as a function of treatment. Subpopulations of peripheral blood mononuclear cells will be isolated, including but not limited to dendritic cells, T cells, and B cells. These include regulatory and effector immune panels, naïve and memory CD4, CD8 and natural killer lymphocyte populations.

  • Tie-2 expressing monocytes [ Time Frame: Up to 12 weeks ]
    Will be examined.


Estimated Enrollment: 36
Actual Study Start Date: March 13, 2015
Estimated Primary Completion Date: December 31, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (pembrolizumab and ziv-aflibercept)
Patients receive pembrolizumab IV over approximately 30 minutes and ziv-aflibercept IV over 1-2 hours on day 1. Courses repeat every 2 weeks for up to 2 years 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: Ziv-Aflibercept
Given IV
Other Names:
  • Aflibercept
  • AVE0005
  • Eylea
  • Vascular Endothelial Growth Factor Trap
  • VEGF Trap
  • VEGF Trap R1R2
  • VEGF-Trap
  • Zaltrap

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the safety, tolerability and recommended phase II dosing for the combination of ziv-aflibercept plus MK-3475 (pembrolizumab) in patients with unresectable stage III or stage IV melanoma, renal cell cancer, ovarian cancer, or colorectal cancer.

SECONDARY OBJECTIVES:

I. To obtain preliminary estimates of progression-free survival at 6 months. II. To obtain preliminary estimates of the rate of 1-year overall survival. III. To obtain preliminary estimates of the response rate. IV. To obtain preliminary estimates of time to progression. V. To perform a pilot assessment of positron emission tomography (PET) response versus Response Evaluation Criteria in Solid Tumors (RECIST) versus immune-related response criteria (irRC) criteria.

VI. To perform correlative sciences that provide information regarding the mechanisms of action for this combination treatment.

OUTLINE: This is a dose-escalation study of ziv-aflibercept.

Patients receive pembrolizumab intravenously (IV) over approximately 30 minutes and ziv-aflibercept IV over 1-2 hours on day 1. Courses repeat every 2 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for at least 12 weeks.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  • In dose escalation, patients must have histologically or cytologically confirmed metastatic disease from any solid tumor; in dose expansion, patients must have histologically or cytologically confirmed metastatic melanoma, renal cell carcinoma, ovarian cancer, or colorectal cancer
  • Renal cell patients must have had at least one prior vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI)
  • Ovarian cancer patients must be resistant to platinum therapy; therapy (i.e. within 6 months of last platinum therapy); patients who received greater than two prior platinum containing regimens will not be eligible
  • Patients with colorectal cancer should have failed at least one oxaliplatin-containing regimen
  • No more than two prior therapies for metastatic disease
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
  • Estimated life expectancy of greater than 6 months
  • Leukocytes >= 2,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Hemoglobin >= 9 g/dL OR >= 5.6 mmol/L
  • Serum total bilirubin =< 1.5 X upper limit of normal (ULN) or direct bilirubin =< ULN for patients with total bilirubin levels > 1.5 ULN
  • Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 2.5 × institutional ULN OR =< 5 X ULN for patients with liver metastases
  • Serum creatinine =< 1.5 X ULN or measured or calculated creatinine clearance (CrCl) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (glomerular filtration rate [GFR] can also be used in place of creatinine or CrCl); creatinine clearance should be calculated per institutional standard
  • International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy not requiring laboratory monitoring as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants; therapeutic Coumadin is not acceptable
  • 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
  • Urine protein-creatinine ratio (UPCR) =< 1 on spot urinalysis or protein =< 500 mg/24 hour urine
  • Archival tissue must be available or newly obtained core or excisional biopsy of a tumor lesion
  • 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; patients should continue contraceptive measures for 6 months from the last dose of all study medications
  • Female patients of childbearing potential should have a negative urine or serum pregnancy test within 24 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 and ziv-aflibercept administrations
  • Ability to understand and the willingness to sign a written informed consent document

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
  • 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
  • Lesions suspected to be at higher-risk for bleeding such as bowel involvement with tumor that invades into the bowel wall or involves the intraluminal component of bowel by imaging or direct visualization or central pulmonary lesions
  • Ulcerated skin lesions
  • Full anti-coagulant therapy Coumadin; patients may be receiving therapeutic Lovenox, Fragmin, or other heparin product that does not require laboratory monitoring
  • Poorly-controlled hypertension as defined blood pressure (BP) > 150/100 mmHg, or systolic (S) BP > 180 mmHg when diastolic (D) BP < 90 mmHg, on at least 2 repeated determinations on separate days within 3 months prior to study enrollment
  • Pregnant or nursing women
  • Patients with known brain 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 3 months 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 trial treatment
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-3475 and ziv-aflibercept
  • 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-programmed cell death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti-programmed cell death 1 ligand 2 (PD-L2), anti-cluster of differentiation 137 (CD137), ziv-aflibercept or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)(prior treatment with bevacizumab is not an exclusion criteria)
  • 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
  • If 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 from this study; breastfeeding should be discontinued if the mother is treated with 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); patients should continue contraceptive measures for 6 months from the last dose of all study medications
  • 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 a cluster of differentiation (CD)4 count of greater than 250 cells/mcL
    • They must not be receiving prophylactic therapy for an opportunistic infection
  • 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
  • History within 6 months prior to treatment of myocardial infarction, severe/unstable angina pectoris, coronary artery bypass graft (CABG), New York Heart Association (NYHA) class III or IV congestive heart failure (CHF), stroke or transient ischemic attack (TIA)
  • History within 3 months prior to treatment of grade 3-4 gastrointestinal (GI) bleeding/hemorrhage, treatment resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolus, or other uncontrolled thromboembolic event
  • Patients who are less than 4 weeks post-operative (op) after major surgery
  Contacts and Locations
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): NCT02298959


Locations
United States, Florida
Moffitt Cancer Center Recruiting
Tampa, Florida, United States, 33612
Contact: Mayer N. Fishman    800-456-7121    canceranswers@moffitt.org   
Principal Investigator: Mayer N. Fishman         
United States, Massachusetts
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Frank S. Hodi    877-442-3324      
Principal Investigator: Frank S. Hodi         
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Frank S. Hodi    877-442-3324      
Principal Investigator: Frank S. Hodi         
Canada, British Columbia
BCCA-Vancouver Cancer Centre Recruiting
Vancouver, British Columbia, Canada, V5Z 4E6
Contact: Daniel J. Renouf    888-939-3333      
Principal Investigator: Daniel J. Renouf         
Canada, Ontario
University Health Network-Princess Margaret Hospital Recruiting
Toronto, Ontario, Canada, M5G 2M9
Contact: Philippe L. Bedard    416-946-4501    clinical.trials@uhn.on.ca   
Principal Investigator: Philippe L. Bedard         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Frank Hodi Dana-Farber - Harvard Cancer Center LAO
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02298959     History of Changes
Other Study ID Numbers: NCI-2014-01984
NCI-2014-01984 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
15-703
15-703 ( Other Identifier: Dana-Farber - Harvard Cancer Center LAO )
9676 ( Other Identifier: CTEP )
P30CA006516 ( U.S. NIH Grant/Contract )
U01CA062490 ( U.S. NIH Grant/Contract )
UM1CA186644 ( U.S. NIH Grant/Contract )
UM1CA186709 ( U.S. NIH Grant/Contract )
First Submitted: November 21, 2014
First Posted: November 24, 2014
Last Update Posted: September 13, 2017
Last Verified: September 2017

Additional relevant MeSH terms:
Carcinoma
Melanoma
Colorectal Neoplasms
Carcinoma, Renal Cell
Ovarian Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Nevi and Melanomas
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Kidney Diseases
Urologic Diseases
Endocrine Gland Neoplasms
Ovarian Diseases


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