This study is designed to evaluate response and survival of treatment with the combination of pembrolizumab and ramucirumab in patients with progressive metastatic TCC after immune checkpoint inhibitor treatment.
This is a phase II, non-randomized single center study designed to evaluate response and
survival of treatment with the combination of pembrolizumab and ramucirumab in patients with
progressive metastatic TCC after immune checkpoint inhibitor treatment.
The primary and secondary objectives are as follows:
- Objective: To evaluate overall response rate (ORR) in patients treated with
pembrolizumab and ramucirumab
- Hypothesis: The ORR will be ≥15% greater than the historical rate in published
literature of patients treated with pembrolizumab alone
- Objective: To evaluate progression free survival (PFS) in patients treated with
pembrolizumab and ramucirumab
- Hypothesis: The PFS will be ≥15% greater than the historical rate in published
literature of patients treated with pembrolizumab alone
- Objective: To evaluate overall survival (OS) in patients treated with pembrolizumab and
- Hypothesis: The OS will be ≥15% greater than the historical rate in published literature
of patients treated with pembrolizumab alone
- Objective: To evaluate differences in ORR, PFS and OS in patients treated with
pembrolizumab and ramucirumab stratified by Bellmunt criteria.
- Hypothesis: Patients with high Bellmunt criteria scores will have lower rates of ORR,
PFS and OS.
|Overal Status||Start Date||Phase||Study Type|
|Recruiting||September 18, 2020||Phase 2||Interventional|
Primary Outcome 1 - Measure: Overall response rate (ORR)
Primary Outcome 1 - Time Frame: Up to 24 months
1. Histologically confirmed transitional cell carcinoma of the urothelium (bladder,
urethra, or renal pelvis). Patients with mixed pathology are eligible only if they
have predominantly transitional cell tumor based on local pathology review.
2. Unresectable, locally advanced or metastatic disease.
3. Documented disease progression by RECIST 1.1 criteria to at least one prior line of
systemic therapy and no more than three. Prior therapy for advanced disease must
include an immune checkpoint inhibitor. Prior therapy in an adjuvant or neoadjuvant
setting is not considered as a prior line of systemic chemotherapy, unless patient has
rapidly progressed as defined by ≤ 6 months of last dose in this setting. If it is ≤ 6
months, it will be regarded as a prior line of treatment. Prior treatment with
intravesicular chemotherapy, bacillus Calmette -Guérin (BCG), or platinum given as a
radiation-sensitizing agent will not be considered as a systemic line of treatment.
4. A brain scan via CT with contrast or MRI is to be performed to confirm absence of
5. The presence of measurable disease based on the Response Evaluation Criteria In Solid
Tumors Version 1.1 (RECIST 1.1) as determined by the site study team. Tumor lesions
situated in a previously irradiated area are considered measurable if progression has
been demonstrated in such lesions.
a. Measurable disease must still be present after pretreatment core-needle or
6. Provided signed informed consent and are amenable to compliance with protocol
schedules and testing.
7. Provided tissue for biomarker analysis from a newly obtained core or excisional biopsy
of a tumor lesion using a non-significant risk procedure prior to enrollment. Repeat
samples may be required if adequate tissue is not provided.
8. ECOG Performance Status of 0 or 1.
9. Age: 18 years of age or older on day of signing consent.
10. Ability to understand and the willingness to sign a written informed consent. A signed
informed consent must be obtained prior to any study specific procedures.
11. The patient's urinary protein is ≤1+ on dipstick or routine urinalysis (UA; if urine
dipstick or routine analysis is ≥2+, a 24-hour urine collection for protein must
demonstrate <1000 mg of protein in 24 hours to allow participation in this protocol)
12. Adequate organ function, as defined in the table below, with all screening labs
performed within 14 days of treatment initiation:
13. Patients on full-dose anticoagulation must be on a stable dose (minimum duration 14
days) of oral anticoagulant or low molecular weight heparin. If receiving warfarin,
the patient must have an INR ≤ 3.0 and no active bleeding (i.e., no bleeding within 14
days prior to first dose of study treatment) or pathological condition present that
carries a high risk of bleeding (e.g., tumor involving major vessels or known
varices). Patients on anticoagulation therapy with unresected primary tumors or local
tumor recurrence following resection are not eligible.
14. An anticipated life expectancy of ≥3 months.
15. Resolution, except where otherwise stated in the inclusion criteria, of all clinically
significant toxic effects of prior systemic cancer therapy, surgery, or radiotherapy
to Grade ≤1 by National Cancer Institute (NCI) Common Terminology Criteria for Adverse
Events (CTCAE), Version 5.0 (v 5.0)
16. For male patients, are sterile (including vasectomy confirmed by post-vasectomy semen
analysis) or agree to use a reliable method of birth control and to not donate sperm
during the study and for at least 120 days following the last dose of study treatment.
Note: Abstinence is acceptable if this is the established and preferred contraception
for the patient.
17. For female patients, are surgically sterile, are postmenopausal, or agree to use a
highly effective method of birth control (2 methods preferred) during the study and
for 120 days following the last dose of study treatment.
18. If female and of childbearing potential, must have a negative serum or urine pregnancy
test within 7 days prior to enrollment.
Note: Non-childbearing potential (by other than medical reasons). Note: Abstinence is
acceptable if this is the established and preferred contraception for the patient.
1. Have non-measurable disease
2. Have known brain metastases, uncontrolled spinal cord compression, or leptomeningeal
3. Have received ≥3 lines of prior systemic anticancer therapy for advanced disease in
urothelial cancer patients
4. Have a serious illness or medical condition(s) including, but not limited to, the
1. Diagnosis of immunodeficiency or are receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of
trial treatment. The use of physiologic doses of corticosteroids may be approved
after evaluation by the Sponsor-Investigator.
2. Active autoimmune disease that has required systemic treatment in past 2 years
(that is, with use of disease-modifying agents, corticosteroids or
immunosuppressive drugs). Replacement therapy (for example, thyroxine, insulin,
or physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment.
3. Received a prior autologous or allogeneic organ or tissue transplantation
4. Has a history of (non-infectious) pneumonitis that required steroids or current
5. History of interstitial lung disease
6. Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency
syndrome (AIDS)-related illness
7. Known active Hepatitis B or Hepatitis C infection
8. Liver cirrhosis at a level of Child-Pugh B (or worse)
9. Liver cirrhosis (any degree) and a history of hepatic encephalopathy or
clinically meaningful ascites resulting from cirrhosis. Clinically meaningful
ascites is defined as ascites resulting from cirrhosis and requiring ongoing
treatment with diuretics and/or paracentesis.
10. Have a serious cardiac condition, such as congestive heart failure; unstable
angina pectoris; myocardial infarction within the last 6 months; valvulopathy
that is severe, moderate, or deemed clinically significant; or arrhythmias that
are symptomatic or require treatment (not including patients with rate-controlled
11. Active or uncontrolled clinically serious infection
5. The patient is pregnant or breast-feeding.
6. The patient has radiologically documented evidence of major blood vessel invasion or
encasement by cancer.
7. Known psychiatric or substance abuse disorders
8. Known allergy or hypersensitivity reaction to any of the treatment components
9. History of hematologic malignancy, malignant primary brain tumor, malignant sarcoma,
or other malignant priory solid tumor not under study, except:
1. no evidence of that disease for 5 years
2. adequately treated non-melanoma skin cancer
3. curatively treated cervical carcinoma in situ or other noninvasive carcinoma or
in situ neoplasm
10. Have received any previous systemic therapy (including investigational agents)
targeting VEGF/VEGF receptor. Prior therapy with anti-CD137 or anti-CTLA-4 antibody is
11. Have received a live vaccine within 30 days prior to enrollment 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.
12. Have received transfusion of blood products (including platelets or red blood cells)
or administration of colony-stimulating factors (including granulocyte
colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor
[GM-CSF], or recombinant erythropoietin) within 4 weeks prior to Cycle 1 Day 1
13. Have a significant bleeding disorder or vasculitis or had a Grade ≥3 bleeding episode
within 12 weeks prior to enrollment
14. Have experienced any arterial thrombotic event, including myocardial infarction,
unstable angina, cerebrovascular accident, or transient ischemic attack, within 6
months prior to enrollment
15. Have experienced any Grade 3 or 4 venous thromboembolic event (VTE) that is considered
by the investigator to be life threatening or that is symptomatic and not adequately
treated by anticoagulation therapy, within 6 months prior to enrollment
16. Have a history of gastrointestinal perforation and/or fistula within 6 months prior to
enrollment or risk factors for perforation.
17. Have a bowel obstruction, history or presence of inflammatory enteropathy or extensive
intestinal resection (hemicolectomy or extensive small intestine resection, either
condition with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic
18. Have uncontrolled hypertension, as defined as Grade >2 CTCAE Version 5.0 (clinically,
the patient continues to experience elevated blood pressure [systolic >160 mmHg and/or
diastolic >100 mmHg] despite medications)
19. Are receiving chronic therapy with any of the following within 7 days prior to
enrollment (note: aspirin use at doses up to 325 mg/day is permitted):
1. nonsteroidal anti-inflammatory agents (NSAIDs; such as indomethacin, ibuprofen,
naproxen, or similar agents)
2. other anti-platelet agents (such as clopidogrel, ticlopidine, dipyridamole, or
20. Have had a serious or non-healing wound, ulcer, or bone fracture within 28 days prior
21. Have an elective or a planned major surgery during the course of the trial or has
undergone major surgery within 28 days prior to enrollment, or central venous access
device placement within 7 days prior to enrollment. Note: If patient received major
surgery, the patient must have recovered adequately from the toxicity and/or
complications from the intervention prior to starting therapy.
22. Have had chemotherapy, targeted small molecule therapy, or radiation therapy within 2
weeks and/or monoclonal antibody treatment within 4 weeks prior to enrollment or not
recovered (that is, ≤ Grade 1 or at baseline) from previously administered agents.
Note: Neuropathy (≤ Grade 2) or nonserious and nonlife-threatening toxicities, such as
alopecia, altered taste, or nail changes, are an exception to this criterion. Note:
Palliative radiotherapy during the study, if clinically indicated, can be considered
after consultation with the medical monitor.
23. Are currently enrolled in a clinical trial involving an investigational product or
non-approved use of a drug, or concurrently enrolled in any other type of medical
research judged not to be scientifically or medically compatible with this study or
discontinued study drug within 28 days or 5 half-lives of the drug, whichever is
longer, prior to enrollment. Patients participating in surveys or observational
studies are eligible to participate in this study.
24. Are or have an immediate family member (for example, spouse, parent/legal guardian,
sibling, or child) who is investigational site or sponsor staff directly involved with
this trial, unless prospective institutional review board (IRB) approval (by chair or
designee) is given allowing exception to this criterion for a specific patient
25. Have radiographic evidence of intratumor cavitation
26. Have a history of gross hemoptysis (defined as bright red blood or ≥1/2 teaspoon)
within 2 months prior to enrollment
27. Have pleural effusion, pericardial fluid, or ascites requiring drainage every other
week or more frequently
28. Have superior vena cava syndrome
29. Have preexisting idiopathic pulmonary fibrosis as evidenced by CT scan/X-ray at
baseline; have or had any disease of acute lung injury, idiopathic pulmonary fibrosis,
or pneumoconiosis evident on an X-ray; have or had any disease of radiation pneumonia
or drug-induced pneumonia.
30. Has a known history of active TB (Bacillus Tuberculosis).
31. Unable to have a pretreatment core-needle or excisional biopsy.
Minimum Age: 18 Years
Maximum Age: N/A
Healthy Volunteers: No
Name: Michael Hurwitz, PhD, MD
Role: Principal Investigator
Affiliation: Assistant Professor of Medicine (Medical Oncology) Yale University
Name: Matthew Piscatelli, BS
Phone: (203) 785-6821
New Haven, Connecticut 06520