Brief Title
Study of Tipifarnib in Patients With Previously-Treated, Advanced, HRAS Mutant Urothelial Carcinoma
Official Title
An Open Label Phase II Study of Tipifarnib in Patients With Previously-Treated, Advanced, HRAS Mutant Urothelial Carcinoma
Brief Summary
Platinum-based chemotherapy is now regarded a standard first-line treatment for patients with
advanced urothelial carcinoma (UC). However, patients who failed to response or experienced
progression after platinum-based chemotherapy have a grim prognosis and a standard salvage
treatment is not available.
UC is known to harbor multiple mutations. In the investigators' own high-throughput molecular
profiling study, the most commonly observed mutations included TP53, FGFR3(fibroblast growth
factor receptor 3 ) and HRAS. Since RAS signaling can be attenuated using selective farnesyl
transferase (FTase) inhibitors, tipifarnib, a highly potent and selective inhibitor of FTase,
was proposed to be an effective therapeutic approach in the treatment of UC.
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
6-month progression-free survival
Secondary Outcome
Duration of response
Condition
Urothelial Carcinoma
Intervention
tipifarnib
Study Arms / Comparison Groups
tipifarnib
Description: Tipifarnib will be administered at a starting dose of 900 mg, po, bid on days 1-7 and 15-21 of 28-day treatment cycles.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
18
Start Date
November 12, 2015
Completion Date
March 2020
Primary Completion Date
December 2019
Eligibility Criteria
Inclusion Criteria:
1. Subject is at least 20 years of age.
2. Subject has a histologically or cytologically confirmed diagnosis of urothelial
carcinoma arising from urinary bladder or upper urinary tract.
3. Subject has been treated with platinum-based chemotherapy for advanced disease. They
must have refractory or progressive disease for which there is no further curative
therapy available.
4. Subject has been treated with platinum-based chemotherapy for advanced disease. They
must have refractory or progressive disease for which there is no further curative
therapy available.
Subject has a tumor that carries a missense HRAS mutation according to a standard
methodology using Illumina HiSeqTM. (missence non-synonymous HRAS mutation and/or
STK11: rs2075606 (T>C))HRAS status may have been assessed either in primary tumor
tissue, recurrent or metastatic disease.
5. Subject has consented to provide at least 10 unstained tumor slides for retrospective
testing of HRAS gene tumor status.
6. Must have a life expectancy of 3 months or more
7. Subject has measurable disease according to RECIST(Response Evaluation Criteria in
Solid Tumors ) v1.1 and has relapsed (progressive disease) or is refractory to prior
therapy.
8. At least 2 weeks since the last systemic therapy regimen prior to enrolment. Subjects
must have recovered to NCI CTCAE v. 4.03 < Grade 2 from all acute toxicities
(excluding Grade 2 toxicities that are not considered a safety risk by the Sponsor and
Investigator) or toxicity must be deemed irreversible by the Investigator.
9. At least 2 weeks since last radiotherapy if radiation was localized to the only site
of measurable disease, unless there is documentation of disease progression of the
irradiated site. Patients must have recovered from all acute toxicities from
radiotherapy.
10. ECOG(Eastern Cooperative Oncology Group ) performance status of 0 or 1.
11. Acceptable liver function:
1. Bilirubin ≤ 1.5 times upper limit of normal (x ULN); does not apply to subjects
with Gilbert's syndrome diagnosed as per institutional guidelines.
2. AST (SGOT,aspartate aminotransferase ) and ALT (SGPT,Alanine aminotransferase) ≤
3 x ULN; if liver metastases are present, then ≤ 5 x ULN is allowed.
12. Acceptable renal function with serum creatinine ≤ 1.5 x ULN or a calculated creatinine
clearance ≥ 60 mL/min using the Cockcroft-Gault or MDRD(Modification of Diet in Renal
Disease ) formulas. Serum potassium with normal or ≤ CTCAE Grade 1 with or without
supplementation.
13. Acceptable hematologic status (without growth factor support or transfusion
dependency):
1. ANC(absolute neutrophil count )>1500 cells/μL.
2. Platelet count >100,000/μL.
3. Hemoglobin >9.0 g/dL.
14. Female subjects must be either:
1. Of non-child-bearing potential (surgically sterilized or at least 2 years
post-menopausal); or
2. If of child-bearing potential, subject must use an adequate method of
contraception consisting of two-barrier method or one barrier method with a
spermicide or intrauterine device. Both females and male subjects with female
partners of child-bearing potential must agree to use an adequate method of
contraception for 2 weeks prior to screening, during, and at least 4 weeks after
last dose of trial medication. Female subjects must have a negative serum or
urine pregnancy test within 72 hours prior to start of trial medication.
3. Not breast feeding at any time during the study.
15. Written and voluntary informed consent understood, signed and dated.
Exclusion Criteria:
1. Ongoing treatment with an anticancer agent not contemplated in this protocol.
2. Prior treatment (at least 1 full treatment cycle) with an FTase inhibitor.
3. Any history of clinically relevant coronary artery disease or myocardial infarction
within the last 3 years, New York Heart Association (NYHA) grade III or greater
congestive heart failure, cerebrovascular attack within the prior year, or current
serious cardiac arrhythmia requiring medication except atrial fibrillation.
4. Known uncontrolled brain, leptomeningeal or epidural metastases (unless treated and
well controlled for at least 4 weeks prior to Cycle 1 Day 1). Subjects that develop
brain metastasis during the study may have their treatment interrupted to receive a
course of cranial radiation and restart trial medication after a recovery period of at
least 1 week. High dose corticosteroids may be employed for the management of cranial
radiation but must be tapered off before resuming treatment.
5. Non-tolerable > Grade 2 neuropathy or evidence of unstable neurological symptoms
within 4 weeks of Cycle 1 Day 1.
6. Major surgery, other than diagnostic surgery, within 4 weeks prior to Cycle 1 Day 1,
without complete recovery.
7. Double primary cancer of other site(s), except for cured ones at the discretion of
investigator
8. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic
therapy. Known infection with HIV, or an active infection with hepatitis B or
hepatitis C.
9. Subjects who have exhibited allergic reactions to tipifarnib, structural compounds
similar to tipifarnib or to its excipients.
10. Concomitant disease or condition that could interfere with the conduct of the study,
or that would, in the opinion of the Investigator, pose an unacceptable risk to the
subject in this study.
11. The subject has legal incapacity or limited legal capacity.
12. Dementia or significantly altered mental status that would limit the understanding or
rendering of informed consent and compliance with the requirements of this protocol.
Unwillingness or inability to comply with the study protocol for any reason.
13. QTcF interval ≥ 470 msecs
Gender
All
Ages
20 Years - N/A
Accepts Healthy Volunteers
No
Contacts
, 2-3410-3459, [email protected]
Location Countries
Korea, Republic of
Location Countries
Korea, Republic of
Administrative Informations
NCT ID
NCT02535650
Organization ID
2015-05-039
Responsible Party
Principal Investigator
Study Sponsor
Samsung Medical Center
Study Sponsor
, ,
Verification Date
September 2019