Clinical Trials /

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

NCT02298959

Description:

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 (advanced). Ziv-afibercept works by decreasing blood and nutrient supply to the tumor, which may result in shrinking the tumor. 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. Giving ziv-aflibercept together with pembrolizumab may be a better treatment for patients with advanced solid tumors.

Related Conditions:
  • Colorectal Carcinoma
  • Malignant Solid Tumor
  • Melanoma
  • Ovarian Carcinoma
  • Renal Cell Carcinoma
  • Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab and Ziv-aflibercept in Treating Patients With Advanced Solid Tumors
  • Official Title: A Phase 1 Trial of MK-3475 Plus Ziv-Aflibercept in Patients With Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: NCI-2014-01984
  • SECONDARY ID: NCI-2014-01984
  • SECONDARY ID: 15-703
  • SECONDARY ID: 9676
  • SECONDARY ID: 9676
  • SECONDARY ID: P30CA006516
  • SECONDARY ID: U01CA062490
  • SECONDARY ID: UM1CA186644
  • SECONDARY ID: UM1CA186709
  • NCT ID: NCT02298959

Conditions

  • Malignant Solid Neoplasm
  • Metastatic Melanoma
  • Metastatic Renal Cell Cancer
  • Microsatellite Stable
  • Recurrent Colorectal Carcinoma
  • Recurrent Melanoma
  • Recurrent Ovarian Carcinoma
  • Recurrent Renal Cell Carcinoma
  • Refractory Melanoma
  • Sarcoma
  • Stage IV Ovarian Cancer AJCC v6 and v7
  • Stage IVA Colorectal Cancer AJCC v7
  • Stage IVB Colorectal Cancer AJCC v7

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pembrolizumab and ziv-aflibercept)
Ziv-AfliberceptAFLIBERCEPT, AVE0005, Eylea, vascular endothelial growth factor trap, VEGF Trap, VEGF Trap R1R2, VEGF-Trap, ZaltrapTreatment (pembrolizumab and ziv-aflibercept)

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. 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. Giving ziv-aflibercept together with pembrolizumab may be a better treatment for patients with advanced solid tumors.

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, colorectal cancer, or sarcoma.

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

      OUTLINE: This is a dose-escalation and dose expansion 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pembrolizumab and ziv-aflibercept)ExperimentalPatients 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.
  • Pembrolizumab
  • Ziv-Aflibercept

Eligibility Criteria

        Inclusion Criteria:

          -  In dose escalation, patients must have histologically or cytologically confirmed
             metastatic disease from any solid tumor; in dose expansion part 1, patients must have
             histologically or cytologically confirmed metastatic melanoma, renal cell carcinoma,
             ovarian cancer, or colorectal cancer. In dose expansion part 2, patients must have
             PD-1 resistant melanoma, PD-1 resistant renal cancer, sarcoma, or microsatellite
             stable (MSS) 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 (within 10 days of treatment initiation)

          -  Absolute neutrophil count >= 1,500/mcL (within 10 days of treatment initiation)

          -  Platelets >= 100,000/mcL (within 10 days of treatment initiation)

          -  Hemoglobin >= 9 g/dL OR >= 5.6 mmol/L (within 10 days of treatment initiation)

          -  Serum total bilirubin =< 1.5 X upper limit of normal (ULN) or direct bilirubin =< ULN
             for patients with total bilirubin levels > 1.5 ULN (within 10 days of treatment
             initiation)

          -  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 (within 10
             days of treatment initiation)

          -  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 (within 10 days of treatment
             initiation)

          -  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 (within 10 days of treatment
             initiation)

          -  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 (within 10 days of treatment initiation)

          -  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

          -  Dose expansion part 2 melanoma and renal cell cancer only: Subjects must have received
             prior immunotherapy with an anti-PD-1 or anti-PD-L1 containing regimen and must have
             progressive or recurrent disease after prior PD-1/PD-L1 directed therapy. Primary
             resistance is determined at the time of initial restaging from initiation of
             treatment, as evidenced by progression by RECIST 1.1. Acquired resistance would be a
             subject who had a best overall RECIST response of stable disease, partial response, or
             complete response confirmed radiographically by a second scan who subsequently
             developed progressive disease by RECIST 1.1 at any time thereafter

          -  Dose expansion part 2 colorectal cancer only: Subjects must have microsatellite
             stability (MSS) expression detected by an accredited laboratory per local process.

        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

          -  Dose escalation and dose expansion part 1 only: 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 (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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended combination dose of ziv-aflibercept and pembrolizumab, assessed by dose-limiting toxicities
Time Frame:4 weeks
Safety Issue:
Description: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

Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure:Overall survival
Time Frame:Time from start of trial treatment to death from any cause, assessed up to 12 months
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.

Details

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

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