Clinical Stage IV Cutaneous Melanoma AJCC v8, Metastatic Colorectal Carcinoma, Metastatic Malignant Solid Neoplasm, Metastatic Melanoma, Metastatic Ovarian Carcinoma, Metastatic Renal Cell Carcinoma, Platinum-Resistant Ovarian Carcinoma, Recurrent Melanoma, Recurrent Renal Cell Carcinoma, Refractory Melanoma, Refractory Renal Cell Carcinoma, Sarcoma, Stage IV Colorectal Cancer AJCC v8, Stage IV Ovarian Cancer AJCC v8, Stage IV Renal Cell Cancer AJCC v8
Conditions
Brief summary
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 that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of 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.
Detailed description
PRIMARY OBJECTIVE: 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. Cycles repeat every 2 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan, magnetic resonance imaging (MRI), blood sample collection and tumor biopsy throughout the study. After completion of study treatment, patients are followed up for at least 12 weeks.
Interventions
PROCEDUREBiopsy Procedure
Undergo tumor biopsy
PROCEDUREBiospecimen Collection
Undergo blood sample collection
PROCEDUREComputed Tomography
Undergo CT scan
PROCEDUREMagnetic Resonance Elastography
Undergo MRI
BIOLOGICALPembrolizumab
Given IV
BIOLOGICALZiv-Aflibercept
Given IV
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* In dose escalation, patients must have histologically or cytologically confirmed metastatic disease from any solid tumor (NOS 10029000). In dose expansion part 1, patients must have histologically or cytologically confirmed metastatic melanoma (10053571), renal cell carcinoma (NOS 10038485), ovarian cancer (NOS 10033272), or colorectal cancer (10009951,10038045). In dose expansion part 2, patients must have PD-1 resistant melanoma (10053571), PD-1 resistant renal cancer (NOS 10038485), or sarcoma (10061271) * 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 * Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of MK-3475 in combination with ziv-aflibercept 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 =\< 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 X 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 not requiring laboratory monitoring 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 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 * The effects of MK-3475 and ziv-aflibercept on the developing human fetus are unknown; for this reason, 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 PD-1/PD-L1 resistant or refractory 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 sarcoma only: subjects must have received standard of care treatment
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 because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events * 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-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or ziv-aflibercept (prior treatment with bevacizumab is not an
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended combination dose of ziv-aflibercept and pembrolizumab | 4 weeks | Will be assessed by dose-limiting toxicities. 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
| Measure | Time frame | Description |
|---|---|---|
| Objective response rate (ORR) | 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. |
| Progression-free survival | 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. |
| Overall survival | 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. |
| Time-to-progression | 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. |
Countries
Canada, United States
Contacts
PRINCIPAL_INVESTIGATORFrank S Hodi
Dana-Farber - Harvard Cancer Center LAO
Outcome results
None listed