To demonstrate the benefit of maintenance treatment with avelumab plus BSC vs. BSC alone in prolonging overall survival (OS) in patients with unresectable locally advanced or metastatic UC whose disease did not progress on or following completion of…
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Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Overall Survival (OS).
Secondary outcome
* Progression free survival (PFS) based on Blinded Independent Central Review
(BICR) assessment per RECIST v1.1.
* Investigator assessed Progression-Free Survival (PFS). Objective Response
(OR), Time to Tumor Response (TTR), Duration of Response (DR), and Disease
Control (DC), as assessed per RECIST v1.1 by BICR and investigator.
* Safety: Adverse events (AEs) and laboratory abnormalities as graded by
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events
(CTCAE) v.4.03; vital signs (blood pressure, pulse rate).
* Pharmacokinetics (PK): maximum concentrations (Cmax) and trough
concentrations (Ctrough) for avelumab.
* Immunogenicity: Anti-drug antibodies (ADA; neutralizing antibody [Nab])
against avelumab.
* Biomarkers: Tumor tissue biomarkers including, but not limited to, PD-L1
expression and tumor-infiltrating CD8+ T lymphocytes.
* Patient-Reported Outcomes: patient-reported bladder cancer symptom,
functioning, global quality of life (QOL), and Time to Deterioration (TTD)
using the NCCN-FACT FBlSI-18; and health status using the EQ-5D.
Background summary
Urothelial cancer (UC) includes tumors originating from the urothelial cells
lining the bladder, renal pelvis, ureter, and urethra. Bladder cancer alone
accounts for 90% of UC, and is the ninth most prevalent cancer worldwide, with
approximately 400,000 new cases diagnosed and 150,000 deaths attributed to this
disease each year. UC occurs more frequently in developed countries; in Europe
it is the eighth most common cause of mortality due to cancer, and in the
United States, it also occurs at a very high annual incidence rate (20.5 per
100,000 persons).The incidence and mortality of bladder cancer have remained
unchanged over the last 25 years.
Combination chemotherapy with platinum-based regimens is the standard of care
for locally advanced or metastatic bladder cancer. Despite the favorable
response and survival rates associated with the combination of methotrexate,
vinblastine, doxorubicin, and cisplatin (MVAC) toxicities associated with this
regimen can be significant and lead to death in 3-4% of patients.Subsequently,
the combinations of gemcitabine + cisplatin and gemcitabine + carboplatin were
shown to have comparable efficacy and an improved safety compared to MVAC, with
the latter combination used in the 30 50% of patients ineligible for cisplatin
based chemotherapy due to renal impairment. As such, these two regimens are now
the preferred regimens for the initial treatment of patients with locally
advanced or metastatic UC.
Durable and complete responses following first-line chemotherapy in patients
with advanced UC are uncommon. Complicated treatment regimens and severe side
effects limit long-term use of these agents and most patients will ultimately
experience disease progression within 9 months after initial response. Optimal
treatment in the second-line treatment setting still needs to be determined.20
In the United States, no second-line therapies have been approved. Single and
combination agents evaluated in this treatment setting have been associated
with low median progression-free survival (PFS, 1.5-3.0 months) and overall
survival (OS, 4.6. 6.9 months), and are also associated with significant
toxicities.
In 2009, vinflunine was approved in Europe for the second-line treatment of UC
after failure of first-line platinum-based therapy.
The current *watch-and-wait* approach for the management of metastatic UC
following response to first line chemotherapy prior to initiation of
second-line treatment has not proven to be effective because almost all
patients eventually relapse. A multicenter Phase 2 study of sunitinib as
maintenance therapy in patients with advanced UC was recently reported.25
Although the study terminated prematurely due to low patient recruitment, it
provided a different perspective on the treatment of this disease (ie,
maintenance therapy following response to first-line chemotherapy in an attempt
to improve the durability of the initial response). Recently, Powles et al
reported the results of a Phase 2/3 study of lapatinib as maintenance treatment
after first-line chemotherapy in patients with HER1/HER2 positive UC.26 The
median PFS, median OS, and objective response rate (ORR) for patients receiving
lapatinib (n = 116) vs. placebo (n = 116) were 4.6 months (95% confidence
interval [CI]: 2.8 * 5.4) vs. 5.3 months (95% CI: 3.0 * 5.9) (hazard ratio [HR]
1.04 [95% CI: 0.79 * 1.39] p = 0.77), and 12.6 months (95% CI: 9.5 * 16.2) vs.
11.9 months (95% CI: 10.6 * 15.8) (HR 0.98 [95% CI: 0.71 * 1.35] p = 0.89); and
13.8% vs. 7.8%, respectively (p = 0.14). In addition, a study evaluating
vinflunine27,28 as a maintenance UC treatment is currently ongoing.
Study objective
To demonstrate the benefit of maintenance treatment with avelumab plus BSC vs.
BSC alone in prolonging overall survival (OS) in patients with unresectable
locally advanced or metastatic UC whose disease did not progress on or
following completion of first line platinum containing chemotherapy in each co
primary UC patient population: 1) patients determined to have PD L1 positive
tumors (including infiltrating immune cells) by a verified GMP PD L1 IHC test,
and 2) all randomized patients.
Secondary Objectives
* To compare the PFS of avelumab plus BSC vs. BSC alone in patients determined
to have PD L1 positive tumors (including infiltrating immune cells) by a
verified GMP PD L1 IHC test, and in all randomized patients.
* To evaluate the anti-tumor activity of avelumab plus BSC and BSC alone
according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in
patients determined to have PD L1 positive tumors (including infiltrating
immune cells) by a verified GMP PD L1 IHC test, and in all randomized patients.
* To evaluate the overall safety profile of avelumab plus BSC and BSC alone.
* To evaluate the pharmacokinetics (PK) of avelumab in each of the co-primary
populations treated with avelumab.
* To assess the immunogenicity of avelumab in each of the co-primary
populations treated with avelumab.
* To evaluate candidate predictive biomarkers of sensitivity or resistance to
avelumab in pre-treatment tumor tissue in each of the co-primary populations
treated with avelumab.
* To evaluate the effect of avelumab plus BSC and BSC alone on patient-reported
outcomes (PROs) in each of the co-primary populations.
Exploratory Objectives
* To explore the predictive and/or pharmacodynamic (PD) characteristics of
peripheral blood and additional tumor tissue biomarkers relevant to the
mechanism of action of or resistance to avelumab.
* To explore the anti-tumor activity of avelumab plus BSC and BSC alone in each
of the co primary UC patient populations according to immune-related RECIST
(irRECIST).50
Study design
Patients randomized to avelumab plus BSC (Arm A) will be administered avelumab
as a 1-hour intravenous (IV) infusion at a dose of 10 mg/kg once every 2 weeks
(Q2W) together with BSC (see below).
To mitigate potential infusion-related reactions, patients in Arm A will be
premedicated prior to avelumab administration as described in . If an infusion
related reaction is observed, the infusion rate should be decreased to a
maximum infusion time of 120 minutes
* Arm B: Best Supportive Care Alone
Patients randomized to BSC alone (Arm B) will be cared for as deemed
appropriate by the treating physician. This could include treatment with
antibiotics, nutritional support, correction of metabolic disorders, optimal
symptom control and pain management (including palliative radiotherapy), etc.
BSC does not include any active anti-tumor therapy, however local radiotherapy
of isolated lesions with palliative intent is acceptable.
All patients will be followed for survival until death, end of the study, or
patient withdrawal of consent, whichever comes first, regardless of initiation
of new anti cancer therapy(ies). Long term follow up survival assessments
(every 3 months) may be completed at the investigative site or by telephone
contact.
Intervention
Avelumab will be given as an intravenous infusion, over 1 hour, every 2
weeks.The infusion will occur during clinic visits under close supervision of
yhe study doctor and their staff. About 30-60 minutes before each dose of
Avelumab, patients will also receive either by mouth or intravenously an
anti-histamine (H1 blocker) and acetaminophen (also called paracetamol). This
is to help reduce the risk of an allergic reaction to Avelumab.
Study burden and risks
Side effects observed in 10% or more of patients:
* General signs or symptoms: Tiredness; Nausea; Loose or watery stools
(diarrhea); Constipation; Reduced appetite; Decrease in weight; Vomiting; Low
number of red blood cells (anemia); Belly pain; Cough; Fever; Shortness of
breath; Swelling of feet and legs; Back pain; Joint pain.
* Reactions that occur during or following the infusion: may include chills or
shaking, fever, flushing, back pain, belly pain, shortness of breath or
wheezing, decrease in blood pressure, hives. These infusion reactions are
mostly mild or moderate and generally resolve with a slowdown or
discontinuation of the infusion and administration of medications such as
anti-allergic and pain-killer drugs. In some cases these reactions may be
severe or life-threatening (in less than 1% of patients) and can require
intensive medical care.
Immune side effects
Immune side effects observed in 5% to less than 10% of patients
* Abnormal function of the thyroid gland (could include low or high function or
inflammation of the thyroid gland): may include rapid heartbeat; increased
sweating; extreme tiredness; weight gain or weight loss; hair loss; changes in
mood or behavior such as irritability or forgetfulness; feeling cold;
constipation; voice gets deeper.
* Inflammation of the skin (rash): may include skin rash, itchy skin, skin
redness, skin blisters, or peeling.
Immune side effects observed in 1% to less than 5% of patients
* Inflammation of the large intestine (colitis): may include diarrhea (loose
stools) or more frequent bowel movements than usual; blood in stools or dark,
tarry, sticky stools; severe stomach area (abdomen) pain or tenderness.
* Inflammation of the lungs (pneumonitis): may include new or worsening cough,
shortness of breath, chest pain.
Immune side observed in less than 1% of patients:
* Inflammation of the liver (hepatitis): may include yellowing of skin or of
the whites of eyes; severe nausea or vomiting; pain on the right side of
stomach area (abdomen); drowsiness; dark urine (tea colored); bleeding or
bruising more easily than normal; feeling less hungry than usual.
* Inflammation of the kidneys (nephritis): may include urinating less than
usual; blood in urine; swelling in ankles; loss of appetite.
* Low function of the adrenal glands (glands on top of the kidneys), which may
be due to the reduced function of the pituitary gland (a gland in the head):
may include very low blood pressure; extreme tiredness.
* Increase in blood sugar (diabetes): may include urinating more often than
usual; feeling more hungry or thirsty than usual, nausea or vomiting, stomach
area (abdomen) pain.
* Inflammation of the eyes (uveitis): may include changes in eyesight.
* Inflammation of the muscles (myositis): may include severe or persistent
muscle or joint pain; severe muscle weakness.
* Inflammation of the heart (myocarditis): may include chest pain or tightness;
tiredness; changes in heartbeat, such as beating fast, or seeming to skip a
beat, or pounding sensation; swelling of feet and legs; trouble breathing.
* Inflammation of the nerves (Guillain-Barre syndrome): may include "pins and
needles" sensations in arms and legs; weakness in legs that spreads to the
upper body and may lead to temporary paralysis.
Risks from Study Procedures
* Blood samples: A blood draw may cause inflammation of the vein, pain,
bruising, discomfort redness, burning or bleeding at the site where the needle
is placed to draw the blood. You may feel dizzy or you may faint. There is a
slight chance of infection.
* Intravenous Catheter: The use of an intravenous catheter may cause pain,
bruising, clotting, bleeding, leakage of drug solution, and possibly infection
at the catheter site.
* ECG: The risks from an ECG can include skin irritation and a rash from the
gel that is used or from wearing or removing the patches.
* Questionnaires: A questionnaire may contain questions that are sensitive in
nature. You may refuse to answer any question that makes you feel
uncomfortable. If you have concerns after completing the questionnaire, you
should contact your study doctor.
* Bone Scan: A bone scan exposes you to a small dose of radiation. Although all
radiation you receive builds up over your lifetime, this amount of radiation
should not create a significant risk to your health.
* CT scans: You may experience fear of being in a narrow or enclosed space
while having a CT scan. You will be asked not to move during the test and to
relax and breathe normally. A CT scan exposes you to a small dose of
radiation. Although all radiation you receive builds up over your lifetime,
this amount of radiation should not create a significant risk to your health.
* MRI Scans: There are risks from an MRI if you are pregnant or have one of the
following: an artificial heart valve, pacemaker, metal plate, pin or other
metallic objects in your body (including gun shot or shrapnel). You may also
become anxious from lying in a tight space without moving. The MRI scan does
not cause any pain and does not expose you to x-ray radiation.
* Contrast Dye for CT & MRI Scans: Contrast dye is usually injected when you
get a scan. A contrast dye may cause pain or burning when it is injected, and
may worsen kidney function in people who already have kidney disease or who are
dehydrated (have not had enough liquids that day). The contrast dye may also
cause allergic reactions, which could be severe or life-threatening.
* Biopsy: The risks of a biopsy can include bleeding, pain and infection. To
reduce these risks, the site of the biopsy will be numbed and sterile
techniques will be used.
* Genetic Research Risks: The pharmacogenomics / biomarker research that may be
performed using your tissue and blood samples may involve genetic testing.
Although procedures have been put into place that are designed to make it very
difficult for the results from genetic research to be linked to you, there is a
remote possibility that information from your participation in this study could
adversely affect you or your family in some way if a genetic disorder were
discovered.
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Inclusion criteria
1. Histological diagnosis of confirmed, unresectable locally advanced or
metastatic transitional cell carcinoma of the urothelium. patients with
documented Stage IV disease (per American Joint Committee on
cancer/International Union for Cancer Control Tumor Node Metastasis (TNM)
system 7th edition) at the start of first-line chemotherapy and measurable
disease prior to the start of first-line chemotherapy by RECIST v1.1., 2. Prior
first-line chemotherapy must have consisted of at least 4 cycles and no more
than 6 cycles of gemcitabine + cisplatin and/or gemcitabine + carboplatin. No
other chemotherapy regimens are allowed in this study. The last dose of
first-line chemotherapy must have been recieved no less than 4 weeks, and no
more than 10 weeks, prior to randomization; , 3. Patients without progressive
disease as per RECIST v1.1 guidelines (ie, with an ongoing CR, PR, or SD)
following completion of 4 to 6 cycles of first-line chemotherapy. Eligibility
based on this criterion will be determined by investigator review of
pre-chemotherapy and post-chemotherapy radiological assessments (CT/MRI
scans);, 4. Provision of a recent formalin-fixed, paraffin-embedded (FFPE)
tumor tissue block (subsection thereof) from the most recent primary or
metastatic tumor biopsy or resection obtained prior to treatment with first
line chemotherapy but within 24 monthsof randomization, with no intervening
systemic anti-cancer therapy. If a FFPE tissue block cannot be provided 15
freshly cut unstained slides (10 minimum) will be acceptable. Tumor tissue from
cytologic sampling (eg, fine needle aspiration, including FFPE cell pellet
material) or bone metastases are not acceptable and should not be sumbitted;,
5. Evidence of a signed and dated informed consent document indicating that the
patient (or a legally acceptable representative, as allowed by local
guideline/practice) has been informed of all pertinent aspects of the study, ,
6. Patients who are willing and able to comply with scheduled visits, treatment
plans, laboratory tests, and other study procedures;, 7. Age above 18 years;,
8. Estimated life expectancy of at least 3 months; , 9. Eastern Cooperative
Oncology Group (ECOG) performance status (PS) 0 or 1; , 10. Adequate bone
marrow, renal and liver function; , 11. Negative serum pregnancy test at
screening (for females of childbearing potential); , 12. Female patients able
to have children must agree to use a highly effective method of contraception
throughout the study and for at least 30 days after the last dose of assigned
treatment.
Exclusion criteria
1. Patients whose disease progressed by RECIST v1.1 on or after first-line
chemotherapy for urothelial cancer; , 2. Prior adjuvant or neoadjuvant
(systemic) therapy within 12 months of randomization; , 3. Prior immunotherapy
with IL-2, IFN-*, or an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
CTLA-4 antibody (including ipilimumab), or any other antibody or drug
specifically targeting T-cell co-stimulation or immune checkpoint pathways;, 4.
Major surgery within 4 weeks or major radiation therapy within 2 weeks prior to
randomization. Prior palliative radiotherapy (<= 10 fractions) to metastatic
lesion(s) is permitted, provided it has been completed at least 48 hours prior
to patient randomization;, 5. Patients with known symptomatic central nervous
system (CNS) metastases requiring steroids. Patients with previously diagnosed
CNS metastases are eligible if they have completed their treatment and have
recovered from the acute effects of radiation therapy or surgery prior to
randomization, have discontinued corticosteroid treatment for these metastases
for at least 4 weeks, and are neurologically stable;, 6. Persisting toxicity
related to prior therapy NCI CTCAE v4.0 Grade >1; however, alopecia, sensory
neuropathy Grade <= 2 is acceptable, or other grade <= adverse events not
constituting a sefetey risk based on the investigator's judgement are
acceptable;, 7. Diagnosis of any other malignancy within 5 years prior to
randomization, except for adequately treated basal cell or squamous cell skin
cancer, or carcinoma in situ of the breast or of the cervix, or low-grade
(Gleason 6 or below) prostate cancer on surveillance without any plans for
treatment intervention (eg, surgery, radiation, or castration), or prostate
cancer that had been adequatley treated with prostatectomy or radiotherapy and
currentley with no evidence of disease or symptoms;, 8. Participation in other
studies involving investigational drug(s) within 4 weeks prior to
randomization. Observational studies are permitted;, 9. Active autoimmune
disease that might deteriorate when receiving an, immunostimulatory agent.
Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid
disease not requiring immunosuppressive treatment are eligible;, 10.
Clinically significant (ie, active) cardiovascular disease; cerebral vascular
accident/stroke (<6 months prior to enrolment), myocardial infarction (<6months
prior to enrolment), unstable angina, congestive heart failure, or serious
cardiac arrhythmia requiring medication;
11. Active infection requiring systemic therapy;, 12. Known severe
hypersensitivity reactions to monoclonal antibodies (Grade >= 3), any
history of anaphylaxis, or uncontrolled asthma;, 13. Known prior or suspected
hypersensitivity to study drugs or any component in their formulations;, 14.
Current or prior use of immunosuppressive medication within 7 days prior to
randomization;, 15. Diagnosis of prior immunodeficiency or organ transplant
requiring immunosuppressive therapy. 16. Positive test for human
immunodeficiency virus (HIV) infection or know acquired immunodeficiency
syndrome (AIDS)
17. Hepatitis B virus (HBV) or hepatitis C virus (HCV) at screening;, 18.
Vaccination within 4 weeks of the first dose of study treatment and while on
trial is prohibited except for administration of inactivate vaccines (for
example, inactivated influenza vaccines); , 19. Patients who are
investigational site staff members directly involved in the conduct of the
study and their family members, site staff members otherwise supervised by the
investigator, or patients who are Pfizer employees directly involved in the
conduct of the study;
20. Pregnant female patients; breastfeeding female patients and female patients
of childbearing potential who are unwilling or unable to use a highly effective
method of contraception as outlined in the protocol for the duration of the
study and for at least 30 days after the last dose of investigational product;
21. Other severe acute or chronic medical conditions including colitis,
inflammatory bowel disease, and pneumonitis and pulmonary fybrosis; psychiatric
condition including recent (within the past year) or active suicidal ideation
or behavior; or laboratory abnormality that may increase the risk associated
with study participation or study treatment administration or may interfere
with the interpretation of study results and, in the judgment of the
investigator, would make the patient inappropriate for entry into this study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-003262-86-NL |
| ClinicalTrials.gov | NCT02603432 |
| CCMO | NL56203.056.16 |