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BRIEF TITLE: Tazemetostat and MK-3475 (Pembrolizumab) in Advanced Urothelial Carcinoma

A Pilot Study of Tazemetostat and MK-3475 (Pembrolizumab) in Advanced Urothelial Carcinoma


  • Org Study ID: NCI-2019-01035
  • Secondary ID: NCI-2019-01035,ETCTN 10183,10183,10183,P30CA060553
  • NCT ID: NCT03854474
  • NCT Alias:
  • Sponsor: National Cancer Institute (NCI) - NIH
  • Source: National Cancer Institute (NCI)

Brief Summary

This phase I/II trial studies the side effects and best dose of tazemetostat and how well it works when given together with pembrolizumab in treating patients with urothelial carcinoma that has spread to nearby tissue or lymph nodes or other places in the body (locally advanced/metastatic). Tazemetostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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 tazemetostat and pembrolizumab may work better in treating patients with urothelial carcinoma compared to pembrolizumab without tazemetostat.

Detailed Description


PRIMARY OBJECTIVE:

I. To conduct a safety lead-in phase that identifies the safe recommended phase II dose for
combination tazemetostat and MK-3475 (pembrolizumab).

SECONDARY OBJECTIVES:

I. To assess the safety and tolerability of MK-3475 (pembrolizumab) in combination with
tazemetostat.

II. To evaluate the objective disease response rate of combination tazemetostat and MK-3475
(pembrolizumab) in patients with advanced urothelial carcinoma that is cisplatin resistant
(Arm A) or cisplatin ineligible (Arm B).

III. To evaluate the progression free survival to combination tazemetostat and MK-3475
(pembrolizumab) inhibitor in patients with advanced urothelial carcinoma that is cisplatin
resistant (Arm A) or cisplatin ineligible (Arm B).

IV. To evaluate immune-related response using tumor response by immune-related Response
Evaluation Criteria In Solid Tumors (irRECIST) in combination tazemetostat and MK-3475
(pembrolizumab) inhibitor in patients with advanced urothelial carcinoma that is cisplatin
resistant (Arm A) or cisplatin ineligible (Arm B) based on irRECIST criteria.

CORRELATIVE OBJECTIVES:

I. To determine if EZH2 and H3K27me3 chromatin methylation determines disease response to
EZH2 and PD1 inhibition in metastatic urothelial carcinoma by analyzing baseline tissue
samples.

II. To determine if mutations in genes associated with histone methylation determine disease
response to EZH2 and PD1 inhibition in metastatic urothelial carcinoma by analyzing baseline
tissue samples.

III. To identify the immune response (T cell phenotypes), T-cell clonality with comparison to
T-cell infiltrating lymphocytes and neoantigen profile of responsive and resistant urothelial
carcinoma treated with combination anti-PD1 and EZH2i by analyzing blood and tissue samples
throughout the study.

OUTLINE:

Patients receive tazemetostat orally (PO) twice daily (BID) on days 1-21 and pembrolizumab
intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in
the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year.

Overal Status Start Date Phase Study Type
Recruiting May 17, 2019 Phase 1/Phase 2 Interventional

Primary Outcomes:

Primary Outcome 1 - Measure: Objective response rate (ORR)

Primary Outcome 1 - Time Frame: Up to 1 year

Condition:

  • Advanced Urothelial Carcinoma
  • Locally Advanced Urothelial Carcinoma
  • Metastatic Bladder Urothelial Carcinoma
  • Metastatic Urothelial Carcinoma
  • Stage III Bladder Cancer AJCC v8
  • Stage IIIA Bladder Cancer AJCC v8
  • Stage IIIB Bladder Cancer AJCC v8
  • Stage IV Bladder Cancer AJCC v8
  • Stage IVA Bladder Cancer AJCC v8
  • Stage IVB Bladder Cancer AJCC v8

Eligibility

Criteria:
Inclusion Criteria:

- Patients in Arm A may begin treatment after this registration

- Patients in Arm B will be required to undergo a second registration by meeting PD-L1
eligibility criteria. A tissue sample must be submitted for central analysis of PD-L1
after eligibility are confirmed

- Patients must have pathologically confirmed urothelial carcinoma

- Note: patients with mixed histology (with predominant urothelial carcinoma) are
eligible

- Patients must have locally advanced or metastatic disease with either:

- Arm A: disease progression during or following (within 12 months) platinum-based
chemotherapy (cisplatin or carboplatin)

- Note: no minimum number of cycles on platinum-based chemotherapy are
required. Patients who have had multiple rounds of platinum-based
chemotherapy with events of intermittent progressive disease (PD) are
eligible as long as progression has been confirmed while on or within 12
months from platinum based therapy OR

- Arm B: cisplatin ineligible as defined by the following criteria:

- Impaired renal function with measured or calculated creatinine clearance
(CrCl) < 60 mL/min (calculated by Cockcroft-Gault method or measured by 24
hour urine collection)

- Eastern Cooperative Oncology Group (ECOG) performance status >= 2

- Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4 grade
>= 2 audiometric hearing loss (25 dB in two consecutive wave ranges)

- CTCAE v.4 grade >= 2 peripheral neuropathy

- New York Heart Association (NYHA) class III heart failure

- Patients must undergo central analysis of tissue for PD-L1 status

- Patients must be positive for PD-L1

- If archival tissue is unavailable or insufficient for PD-L1 central analysis, a
new biopsy must be performed

- All patients must have measurable disease in accordance with RECIST criteria v1.1

- Note: radiological evaluation should occur within 28 days prior to study
registration

- Patients must be naive to prior PD-L1 or EZH2 inhibitors

- Note: patients in Arm A should have received platinum-based chemotherapy only

- ECOG performance status =< 2

- Patients must have a blood smear or manual differential performed at screening showing
no significant morpholic abnormalities on complete blood count (CBC) testing

- Leukocytes >= 3000/mcL (within 10 days of treatment initiation)

- Absolute neutrophil count (ANC) >= 1500/mcL (within 10 days of treatment initiation)

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

- Hemoglobin >= 9 g/dL or >= 4.9 mmol/L (within 10 days of treatment initiation)

- Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine
clearance (CrCl) >= 30 mL/min for patient with creatinine levels > 1.5 x institutional
ULN (within 10 days of treatment initiation)

- Creatinine clearance (CrCl) should be calculated per institutional standard

- Glomerular filtration rate (GFR) can also be used in place of creatinine or CrCl

- Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for patients with total
bilirubin levels > 1.5 x ULN (within 10 days of 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 patients with liver metastases (within 10 days of treatment
initiation)

- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless
patient is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (PTT) is within therapeutic range of intended use of anticoagulants (within 10
days of treatment initiation)

- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless patient 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)

- The effects of MK-3475 and tazemetostat on the developing human fetus are unknown. For
this reason and because PD-1 inhibitors as well as EZH2 inhibitors are known to be
teratogenic, 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

- Female patients of childbearing potential must have a negative urine or serum
pregnancy test within 72 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 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. Note: abstinence is acceptable if this is the
usual lifestyle and preferred contraception for the patient

- Male patients of childbearing 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 patient

- Should a woman become pregnant or suspect she is pregnant while she or her
partner 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 or tazemetostat
administration

- Ability to understand and the willingness to sign an Institutional Review Board (IRB)
approved written informed consent document

- Participants with impaired decision-making capacity (IDMC) who have a legally
authorized representative (LAR) or caregiver are eligible

Exclusion Criteria:

- Patients with disease that is suitable for local therapy administered with curative
intent are not eligible

- Patients who have had chemotherapy, targeted small molecule therapy, or radiotherapy
within 4 weeks prior to entering the study are not eligible

- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1) are not eligible

- Note: patients with =< grade 2 neuropathy or =< grade 2 alopecia 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 are not eligible who are currently participating and receiving study therapy
or have 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

- Patients who 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 the first dose of
treatment are not eligible

- Patients with a 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 are not eligible

- Note: the use of physiologic doses of corticosteroids may be approved after
consultation with the study principal investigator (PI)

- Patients with thrombocytopenia, neutropenia, or anemia of grade 3 (per CTCAE 5.0
criteria) or any prior history of myeloid malignancies, including myelodysplastic
syndrome (MDS) are not eligible

- Patients with abnormalities known to be associated with MDS (e.g. del 5q, chr 7 abn)
and myeloproliferative neoplasms (MPN, e.g. JAK2 V617F) observed in cytogenetic
testing and deoxyribonucleic acid (DNA) sequencing are not eligible

- Patients with a prior history of T-cell lymphoblastic lymphoma (T-LBL) or T-cell acute
lymphoblastic leukemia (T-ALL) are not eligible

- Patients who have received prior PD-L1/PD-1/PD-L2 or EZH2 inhibitor therapy are not
eligible

- Patients who have 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 are not eligible

- Patients with a known additional malignancy that is progressing or requires active
treatment are not eligible. Exceptions include basal cell carcinoma of the skin,
squamous cell carcinoma of the skin that has undergone potentially curative therapy,
or in situ cervical cancer

- Patients with known brain metastases or carcinomatous meningitis are 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

- Note: patients with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging using the identical
imaging modality for each assessment, either magnetic resonance imaging [MRI] or
computed tomography [CT] scan, for at least 4 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

- Patients with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to MK-3475 or tazemetostat are not eligible

- Patients with an 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) are not eligible

- Note: 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

- Patients with a history of (non-infectious) pneumonitis that required steroids or
current pneumonitis are not eligible

- Patients with a prolongation of corrected QT interval (Fridericia's correction formula
[QTcF]) of > 450 msec are not eligible

- Patients with major surgery within 3 weeks before the first dose of study drugs

- Note: minor surgery (e.g. minor biopsy of an extracranial site, central venous
catheter placement, shunt revision) has no restriction

- Patients must not have 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

- Patients receiving any medications or substances that are strong inhibitors or
inducers of CYP3A =< 14 days prior to study treatment are not eligible

- Note: The study team should check a frequently-updated medical reference for a
list of drugs to avoid or minimize use of. As part of the enrollment/informed
consent procedures, the patient will be counseled on the risk of interactions
with other agents, and what to do if new medications need to be prescribed or if
the patient is considering a new over-the-counter medicine or herbal product

- Patients who are unable to take oral medication OR have malabsorption syndrome or any
other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea, vomiting) that
might impair the bioavailability of tazemetostat are not eligible

- Patients with 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,
uncontrolled arterial hypertension, stroke within 6 months prior to starting study
treatment, or psychiatric illness/social situations that would limit compliance with
study requirements are not eligible

- Pregnant women are excluded from this study because MK-3475 and tazemetostat are
agents with the potential for teratogenic or abortifacient effects. Because there is
an unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with MK-3475 and tazemetostat, breastfeeding should be
discontinued if the mother is treated with MK-3475 or tazemetostat

- MK-3475 may have adverse effects on a fetus in utero. Furthermore, it is not
known if MK-3475 has transient adverse effects on the composition of sperm.
Patients are excluded from this study if pregnant or breastfeeding, or expecting
to conceive or father children within the projected duration of the trial,
starting with the screening visit through 120 days after the last dose of trial
treatment

- 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 CD4 count of greater than 250 cells/mcL

- They must not be receiving prophylactic therapy for an opportunistic infection

- Patients with a known history of hepatitis B (defined as hepatitis B surface antigen
[HBsAg] reactive) or known hepatitis C virus (defined as HCV ribonucleic acid [RNA]
[qualitative] is detected) infection are not eligible

- Note: no testing for hepatitis B and hepatitis C is required unless mandated by
local health authority

- Patients who have received a live vaccine within 30 days of planned treatment start
are not eligible

- Note: seasonal flu vaccines that do not contain live virus are permitted

- PD-L1 ELIGIBILITY (ARM B ONLY):

- Patients in Arm B must have positive PD-L1 status as confirmed by central analysis
prior to second step registration and treatment initiation

- NOTE: positive PD-L1 expression is defined as a combined positive score (CPS) >=
10 and will be confirmed in a report from HistoGeneX
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Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Official Information

Name: Maha H Hussain

Role: Principal Investigator

Affiliation: Northwestern University EDDOP

Locations

Facility Status Contact
Northwestern University
Chicago, Illinois 60611
United States
Recruiting Site Public Contact
312-695-1301
cancer@northwestern.edu
University of Kentucky/Markey Cancer Center
Lexington, Kentucky 40536
United States
Recruiting Site Public Contact
859-257-3379