primary objectives:* Part 1 (dose escalation): To determine therecommended Phase 2 dose(s) (RP2D[s]) forTAR-210* Part 2 (dose expansion): To determine thesafety of TAR-210 administered at theRP2D(s)for up to 12 monthsSecondary objectives (Parts 1…
ID
Source
Brief title
Condition
- Renal and urinary tract neoplasms benign
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Endpoints:
*Incidence and severity of AEs, including dose-limiting toxicity (DLT)
Secondary outcome
Endpoints: *Plasma and urine concentration-time profiles and PK parameters for
erdafitinib Cohorts 1 and 2: * Recurrence-free survival (RFS) Cohort 3: *
Complete response (CR) rate * Duration of CR Cohort 4: * Pathological complete
response (pCR) rate * pT0 rate * Rate of downstaging to
Background summary
TAR-210 is a drug delivery system that delivers a drug called erdafitinib
directly into the bladder. It is also sometimes referred to as the erdafitinib
intravesical delivery system. TAR 210 is a pretzel-shaped tube. It is placed in
the bladder with a urinary placement catheter. TAR-210 is designed to release a
controlled amount of erdafitinib (an anti-cancer drug). Erdafitinib is an
anticancer medication approved by the U.S. Food and Drug Administration, or
"FDA," for the treatment of patients with more advanced and metastatic types of
bladder cancer with an FGFR gene alteration. Erdafitinib is an FGFR inhibitor,
which means it blocks the activity of a protein called fibroblast growth factor
receptor (FGFR). Erdafitinib is currently used as an oral medication (pill
taken by mouth). Erdafitinib has demonstrated efficacy in participants with
locally advanced or metastatic urothelial carcinoma. Oral erdafitinib is not
approved to treat NMIBC or MIBC.
Study objective
primary objectives:
* Part 1 (dose escalation): To determine the
recommended Phase 2 dose(s) (RP2D[s]) for
TAR-210
* Part 2 (dose expansion): To determine the
safety of TAR-210 administered at the
RP2D(s)for up to 12 months
Secondary objectives (Parts 1 and 2) :
* To assess the PK
* To assess preliminary clinical activity
Study design
This is an open-label, multicenter, Phase 1 study of the safety, PK, and
preliminary efficacy of
TAR-210 in adult participants with either NMIBC or MIBC. All participants will
be screened for
eligible FGFR mutations or fusions.
The study will enroll 4 cohorts of participants.
* Cohort 1: Recurrent, BCG-experienced high-risk papillary NMIBC (high-grade
Ta/T1),
refusing or ineligible for RC.
* Cohort 2: Recurrent, BCG-experienced high-risk papillary NMIBC (high-grade
Ta/T1),
scheduled for RC.
* Cohort 3: Recurrent, intermediate-risk NMIBC (Ta and T1) with previous
history of only
low-grade disease.
* Cohort 4: MIBC scheduled for RC who have refused or are ineligible for
cisplatin-based
neoadjuvant chemotherapy
The study will comprise 2 parts: Part 1 (dose escalation) and Part 2 (dose
expansion). The study
will initially enroll participants in Cohorts 1 and 3 in Part 1, dose
escalation. Participants in each
of the 4 cohorts may be enrolled in Part 2, dose expansion, at a given dose
level after that dose
level has been determined to be safe in Part 1.
An eligible FGFR alteration must be identified prior to start of study
treatment.
The study comprises molecular eligibility, screening, treatment, and follow-up
phases
Intervention
TAR-210 Drug-device combination product Intravesical system.
Study burden and risks
Potential Discomforts, Side Effects, and Risks Associated with TAR-210
Side effects are unwanted symptoms caused by a drug. All drugs can cause side
effects. Most side effects will go away after the patient stops treatment, but
some may be long lasting. Even if previous studies have shown that the study
treatment is normally well tolerated, the patient may still experience side
effects.
The possible discomforts, side effects, and risks related to TAR-210 treatment
are not known. Possible risks are based on testing of TAR-210 in animals and
the risks associated with oral erdafitinib and intravesical delivery systems
similar to TAR-210 are described below.
Erdafitinib Risks
So far, erdafitinib intravesical delivery system (TAR-210) has not been studied
in people, however erdafitinib taken orally has been investigated in several
clinical studies and has been approved for treatment of advanced urothelial
cancer. As of 11 April 2021, 933 participants have been treated with oral
erdafitinib in 18 clinical studies. Safety data from 7 global studies, which
enrolled 737 participants with cancer, mostly urothelial cancer, who were
treated with erdafitinib, are summarized below. Animals treated with TAR-210
had very low levels of erdafitinib outside of the bladder and did not show any
of the side effects described below for oral erdafitinib.
Risks and side effects that could be related to oral erdafitinib include:
Very Common (affects more than 1 out of 10 users))
• Higher than normal levels of phosphate in the blood
• Dryness of the mouth
• Ulcers, blisters or pain in the mouth including cheeks, tongue, or lips
• Diarrhea
• Nail changes and disorders, including nails separating from the nail bed,
nail pain, nail bleeding, breaking of the nails, color or texture changes in
the nails
• Skin problems including dryness and cracking
• Skin reactions with peeling, redness, swelling tingling or pain in palms of
the hands and soles of the feet, called hand-foot syndrome
• Dryness of eyes
• Redness and irritation of the eye, maybe associated with increased tearing of
the eyes, itchy eyes, inflamed eyes
• Loss of hair
• Decreased appetite
Common (affects 1-10 out of 100 users)
• Eye disorders pertaining to fluid build-up under the retina (the
light-sensitive layer at the back of the eye) that may or may not be associated
with visual symptoms such as blurred or diminished vision or loss of vision
• Infected skin around the nail
• Itching
• Dryness of nose
Most side effects experienced by participants were mild to moderate in
severity, and most of the side effects were reversible when oral erdafitinib
was stopped. In rare cases, some subjects experienced serious side effects.
Because TAR-210 is not expected to deliver as much erdafitinib to the rest of
the body as taking erdafitinib by mouth, these side effects may not be seen at
all and are less likely to be severe if they do occur.
Turnhoutseweg 30
Beerse 2340
BE
Turnhoutseweg 30
Beerse 2340
BE
Listed location countries
Age
Inclusion criteria
Age 1. >=18 years (or the legal age of consent in the jurisdiction in which the
study is taking place) at the time of informed consent. Type of Participant and
Disease Characteristics 2. Recurrent, non-muscle-invasive or muscle-invasive
urothelial carcinoma of the bladder. a) Mixed histology tumors are allowed if
urothelial differentiation is predominant (ie, <20% variant histology).
However, the presence of micropapillary, signet ring cell, plasmacytoid,
neuroendocrine, or sarcomatoid features are exclusionary. b)High-risk papillary
disease (Cohorts 1 [Parts 1 and 2] and 2 [Part 2 only]), defined as
histologically confirmed high-grade Ta/T1 lesion. Concurrent CIS is not
allowed. All visible tumor must be completely resected prior to the start of
study treatment and documented on screening cystoscopy c) Intermediate-risk
papillary disease (Cohort 3, Parts 1 and 2) defined as all previous tumors
being low grade, Ta or T1, and no previous CIS. Cystoscopic documentation of
recurrence is sufficient. Negative urine cytology for high grade urothelial
carcinoma is required. Visible disease must be present at the time of first
TAR-210 insertion. d) Muscle-invasive disease (Cohort 4, Part 2 only) cT2-T3a,
N0. Participants must have a total tumor size <=3 cm after TURBT at cystoscopic
assessment within 8 weeks prior to the start of study treatment or must have a
second debulking TURBT to reduce the tumor(s) to <=3 cm in order to be eligible.
3. Activating tumor FGFR mutation or fusion, as determined by local* or central
testing, approved by the sponsor prior to the start of study treatment: * Local
tissue-based results (if already existing) from next-generation sequencing
(NGS) or polymerase chain reaction (PCR) tests performed in CLIA-certified or
equivalent laboratories, or results from commercially available PCR or NGS
tests. 4. Cohorts 1 and 2: BCG experienced, or participants with no BCG
experience because BCG was not available as a treatment option in the
participant*s location within the previous 2 years and is currently
unavailable. Participants who received an abbreviated course of BCG due to
toxicity are still eligible. BCG experienced is defined as: - Recurrent
high-grade Ta/T1 disease within 18 months of completion of prior BCG therapy -
Prior BCG (minimumtreatment requirements ): At least 5 of 6 full doses of an
initial induction course. Full dose BCG defined as 1 full vial containing a
minimum of 1 X 108 colony forming units. Note: Cohort 3 has no predefined prior
BCG or intravesical chemotherapy requirement. 5. Cohort 1 only: Refuses or is
not eligible for radical cystectomy 6. Cohorts 2 and 4 : willing and eligible
for radical cystectomy 7. Cohort 4: Refuses (and understands the risks and
benefits of doing so) cisplatin-based combination chemotherapy or is deemed
ineligible for cisplatin-based chemotherapy by meeting at least one of the
following criteria: - Creatinine clearance (CrCl)<60 mL/min - NCI-CTCAE v.5.0
Grade >=2 audiometric hearing loss - NCI-CTCAE v.5.0 Grade >=2 peripheral
neuropathy 8. Eastern Cooperative Oncology Group (ECOG) performance status
score of <=2 (Cohorts 1 and 3)or <=1 (Cohorts 2 and 4)(see Section 10.9 for ECOG
scoring) 9. Adequate bone marrow, liver, and renal function: a. Bone marrow
function (without the support of growth factors or transfusions in preceding 2
weeks): - Absolute neutrophil count (ANC) >=1,000/mm3 - Platelet count >=75,000/
mm3 - Hemoglobin >=8.0 g/dL b. Liver function: - Total bilirubin <=1.5 x the
upper limit of normal (ULN) OR direct bilirubin <=1.5 x ULN for participants
with Gilbert*s syndrome who have total bilirubin levels >1.5 x ULN - Alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) <=2.5 x ULN c. Renal
function: - Estimated glomerular filtration rate >30 mL/min calculated using
the Modified Diet in Renal Disease (MDRD)formula (see Appendix 11) 10. A female
participant of childbearing potential must have a negative serum test at
screening and a negative urine test (or serum test if required by local
regulations) within 72 hours of the first dose (ie, first insertion)of study
treatment, and must agree to further serum or urine pregnancy tests during the
study. 11. A female participant must be following contraceptive and barrier
(see protocol for elaboration) 12. A male participant must wear a condom(see
protocol for elaboration) 13. Must sign an informed consent form
(ICF)indicating that the participant understands the purpose of, and procedures
required for, the study and is willing to participate in the study 14. Willing
and able to adhere to the lifestyle restrictions specified in this protocol.
Exclusion criteria
Medical Conditions 1. Concurrent extra-vesical (ie, urethra, ureter, renal
pelvis) transitional cell carcinoma of the urothelium. 2. Prior treatment with
an FGFR inhibitor. 3. Known hypersensitivity to any study component including:
- Erdafitinib (or other drug excipients) or chemically related drugs, - TAR-210
device constituent materials, - UPC materials. Refer to the TAR-210 IB for
complete information on excipients, device constituent materials, and UPC
materials 4. Received pelvic radiotherapy <=6 months prior to the planned start
of study treatment. If received pelvic radiotherapy >6 months prior to the
start of study treatment, there must be no cystoscopic evidence of radiation
cystitis. 5. Presence of any bladder or urethral anatomic feature that in the
opinion of the investigator may prevent the safe placement, indwelling use, or
removal of TAR-210. 6. Indwelling urinary catheter. Intermittent
catheterization is acceptable. 7. Cystoscopic evidence of bladder perforation
unless such perforation has resolved prior to dosing. 8. Bladder post-void
residual volume (PVR) >350 mL after second voided urine. 9. History of
clinically significant polyuria with recorded 24-hour urine volumes >4,000 mL.
10 Subjects with active bladder stones or history of bladder stones <6 months
prior to the start of study treatment. 11. Active malignancies (ie, progressing
or requiring treatment change in the last 24 months) other than the disease
being treated under study. Potential allowed exceptions include the following
(others maybe allowed with sponsor approval) a. skin cancer (non-melanoma or
melanoma)that is considered completely cured. b. non-invasive cervical cancer
that is considered completely cured. c. adequately treated lobular carcino main
situ(LCIS)and ductal CIS d. history of localized breastcancer and receiving
antihormonal agents e. history of localized prostate cancer (N0M0) and
receiving androgen deprivation therapy f. Localized prostate cancer (N0M0) -
with a Gleason score of 6, treated within the last 24 months or untreated and
under surveillance, - with a Gleason score of3+4 that has been treated more
than 6 months prior to full study Screening and considered to have a very low
risk of recurrence, - or history of localized prostate cancer and receiving
androgen deprivation therapy and considered to have a very low risk of
recurrence. 12. Current central serous retinopathy or retinal pigment
epithelial detachment of any grade. 13. History of uncontrolled cardiovascular
disease including: - Any of the following within 3 months prior to the start of
study treatment: unstable angina, myocardial infarction, ventricular
arrhythmias or clinically significant atrial arrythmias (eg, atrial
fibrillation with uncontrolled rate), cardiac arrest, or known congestive New
York Heart Association Class III-IV heart failure (Appendix 10),
cerebrovascular accident, or transient ischemic attack. - Pulmonary embolism or
other venous thromboembolism within 1 month prior to the planned start of study
treatment. 14. Active or chronic hepatitis B or C infection according to the
following criteria: - Seropositive for hepatitis B: defined by a positive test
for hepatitis B surface antigen [HBsAg]. Participants with resolved infection
(ie, participants who are HbsAg negative with antibodies to total hepatitis B
core antigen [anti-HBc] with or without the presence of hepatitis B surface
antibody [anti-HBs]) must be screened using real-time polymerase chain reaction
(RT-PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are
RT-PCR positive will be excluded. Participants with anti-HBs positivity as the
only serologic marker AND a known history of prior HBV vaccination do not need
to be tested for HBV DNA by RT-PCR. - Hepatitis C infection defined by a
positive hepatitis C antibody (anti-HCV) test. Participants who test positive
for anti-HCV are eligible if RNA viral load is undetectable (spontaneous
recovery or after completing treatment for hepatitis C virus infection). 15.
Major surgery within 4 weeks before Day 1 (TURBT is not considered major
surgery) 16. Active bacterial, viral, fungal infection, including urinary tract
infection*, requiring oral or systemic therapy within 7 days prior to Day 1.
*Urinary tract infection is defined as a symptomatic infection with a positive
urine culture with a bacterial count of >=10e5 colony forming units (CFU)/mL in
urine voided from women, or >10e4 CFU/mL in urine voided from men, or in
straight-catheter urine from women. Symptoms may include dysuria, urgency,
frequency, and/or systemic symptoms such as fever, chills, elevated white blood
cell, and/or abdominal/flank pain. Participants free from symptoms for 7 days
with no culture evidence of >10e5 CFUs may be eligible. (See protocol for the
remaining exclusion criteria 17, 18, 19, 20, and 21)
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 | EUCTR2021-004144-22-NL |
| CCMO | NL80199.091.22 |