Pembrolizumab and Trebananib in Treating Patients with Solid Tumors That Are Advanced, Metastatic, or Cannot Be Removed by Surgery
This phase Ib trial studies side effects and best dose of trebananib when given with pembrolizumab in treating patients with solid tumors that have spread to other places or cannot be removed by surgery. 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. Trebananib may kill tumor cells by blocking blood vessels that supply the tumor with nutrients and oxygen. Giving pembrolizumab and trebananib may work better in treating patients with solid tumors.
- Be willing and able to provide written informed consent for the trial
- Have measurable disease based on RECIST 1.1
- In dose escalation (Phase I), patients must have histologically or cytologically confirmed metastatic disease from any solid tumor that is incurable and fulfills one of the following criteria: * Has demonstrated progression of disease following at least one line of effective systemic therapy; prior treatment with anti-CTLA-4 antibody (including ipilimumab) is allowable OR * For which effective therapy does not exist
- In dose expansion (part 2), patients must have histologically or cytologically confirmed unresectable or metastatic melanoma, renal cell carcinoma, ovarian cancer, or colorectal cancer
- Renal cell patients must have had at least one prior VEGF tyrosine kinase inhibitor (TKI)
- Ovarian cancer patients must be resistant to platinum therapy (i.e. within 6 months of last platinum therapy)
- Patients with colorectal cancer should have progressed on at least one fluorouracil plus irinotecan or oxaliplatin containing regimen
- Patients with melanoma should have unresectable or metastatic disease; melanoma patients with BRAF V600E or V600K mutation-positive melanoma who have previously received a BRAF inhibitor with or without a MEK inhibitor) are eligible
- In the dose expansion cohort patients should be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion (pre-treatment) and an on-treatment biopsy; newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on day 1; patients for whom newly-obtained samples cannot be provided (e.g., inaccessible, subject safety concern, or unwilling to undergo biopsy) may submit an archived specimen only upon agreement from the sponsor; an on-treatment biopsy will be collected approximately halfway through the induction period, about 6 weeks from the start of study treatment (sometime between cycle 2 day 8 - cycle 3 day 1)
- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale up to 28 days before treatment initiation
- Absolute neutrophil count (ANC) >= 1,500/mcL (up to 28 days before treatment initiation)
- Platelets >= 100,000 / mcL (up to 28 days before treatment initiation)
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) (up to 28 days before treatment initiation)
- Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN (up to 28 days before treatment initiation)
- Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (up to 28 days before treatment initiation)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN OR =< 5 x ULN for subjects with liver metastases (up to 28 days before treatment initiation)
- Albumin >= 2.5 mg/dL (up to 28 days before 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 (up to 28 days before 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 (up to 28 days before treatment initiation)
- Negative protein on screening urinalysis
- Female subject of childbearing potential should have a negative serum pregnancy test performed during the screening period * Female subjects of childbearing potential must be willing to use an adequate method of contraception, for the course of the study through 120 days after the last dose of study medication; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately * Note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
- Male subjects of reproductive potential must agree to use an adequate method of contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy * Note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
- Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
- Has a diagnosis of immunodeficiency including subjects infected with human immunodeficiency virus (HIV)
- Is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
- Has a known history of active TB (Bacillus tuberculosis)
- Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent * Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study * Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
- Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
- 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
- Poorly-controlled hypertension as defined blood pressure (BP) > 150/100 mmHg, or systolic blood pressure (SBP) > 180 mmHg when diastolic blood pressure (DBP) < 90 mmHg, on at least 2 repeated determinations on separate days within 3 months prior to study enrollment
- History within 6 months prior to treatment of myocardial infarction, severe/unstable angina pectoris, coronary artery bypass grafting (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-op after major surgery
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to pembrolizumab and trebananib including history of allergic reactions to bacterially produced proteins
- Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four 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 using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
- Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
- Treatment within 30 days prior to enrollment/randomization with strong immune modulators including but not limited to systemic cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, methotrexate, azathioprine, rapamycin, thalidomide, and lenalidomide
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, interstitial lung disease or active, non-infectious pneumonitis, nephritis, pancreatitis, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
- Has an active infection requiring systemic therapy
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject 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
- 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
- Patient with ovarian cancer and colorectal cancer who have received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PDL2 antibody; melanoma and renal cell carcinoma patients who received prior anti-PD-1 or anti-PD-L1 or CTLA-4 antibodies are allowed to participate
- Has received trebananib or another angiopoietin-2 directed therapy (prior treatment with bevacizumab is not an exclusion criteria)
- Has 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 of planned start of study therapy; Note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
Locations & Contacts
Contact: James W. Mier
Contact: Osama E. Rahma
Contact: Osama E. Rahma
Trial Objectives and Outline
I. To determine the safety, tolerability, and recommended phase 2 dose (RP2D) for trebananib when given with pembrolizumab in patients with metastatic solid tumor. (Part 1)
II. To determine the safety and tolerability of the RP2D of trebananib, determined in Part 1, when given with pembrolizumab in patients with unresectable stage III or stage IV melanoma, metastatic renal cell, ovarian, or colorectal cancer. (Part 2 [expansion cohort])
I. To obtain preliminary estimates of progression free survival (PFS) at 6 months.
II. To obtain preliminary estimates of the rate of 1-year overall (OS).
III. To obtain preliminary estimates of the response rate (RR).
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.
I. To determine the effect of the combination on vasculopathy, immune infiltration, and tumor necrosis by staining pathologic specimens for VEGF/VEGFR expression, phosphoTie-2 and other targets.
II. To investigate immune responses in the periphery to VEGFR, Tie-2, and other angiogenic molecules and tumor-specific antigens as a function of treatment.
OUTLINE: This is a dose escalation study of trebananib.
Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1, and trebananib IV over 30-60 minutes on days 1, 8, and 15. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then continue pembrolizumab alone for up to 2 years.
After completion of study treatment, patients are followed up at 30 days, then every 12 weeks for up to 1 year.
Trial Phase & Type
Dana-Farber Harvard Cancer Center
Osama E. Rahma
Secondary IDs NCI-2017-01707
Clinicaltrials.gov ID NCT03239145