LCI-GU-URO-CRI-001: Crizotinib in Patients With c-MET or RON-Positive Metastatic Urothelial Cancer

Phase 2

Terminated

Conditions: Urethral Neoplasms
Ureteral Neoplasms
Urinary Bladder Neoplasms

Interventions: Drug: Crizotinib

Registration Number: NCT02612194

Lead Sponsor: Wake Forest University Health Sciences

Brief Summary: This is a single arm two-stage phase II study with crizotinib (Xalkori®) in the treatment of subjects with metastatic urothelial cancer of the bladder, upper (ureter or renal pelvis) or lower (urethra) urinary tracts. The purpose of this study is to see if this experimental drug has a potential benefit in subjects with stage 4 urothelial cancer.

This study tests crizotinib used alone in subjects with urothelial cancer, previously treated with chemotherapy, and whose tumors have certain proteins. Proteins are complex natural substances essential to the structure and function of all living cells. These proteins, c-MET or RON, may trigger molecular pathways that are involved in the growth and spread of bladder or upper urinary tract cancer. Crizotinib is a drug taken by mouth that blocks these pathways. Early laboratory research suggests that crizotinib may benefit patients with urothelial and other cancers with these molecular pathways.

Detailed Description: This is a single arm two-stage phase II study designed to evaluate the objective response rate in subjects with metastatic urothelial cancer demonstrating c-MET or RON overexpression who have received prior therapy with a cisplatin or carboplatin containing regimen.

Subjects will be recruited at Levine Cancer Institute (LCI) and other participating sites.

Immunohistochemistry will be utilized to define tumor sample c-MET and RON protein expression patterns for assignment into molecular cohorts as described in section 12.1.

In the first stage of this study, subjects will be enrolled in parallel to three molecularly defined cohorts as follows:

1. c-MET high (\>50%), RON null (0-9%) (n = 14 subjects)

2. c-MET-positive (10-100%), RON-positive (10-100%) (n = 7 subjects)

3. c-MET null (0-9%), RON-positive (10-100%) (n = 7 subjects)

All enrolled subjects will continue with study treatment until criteria for treatment discontinuation has been met.

If Stage 1 response criteria are met in a cohort, the cohort may be considered for expansion, and additional subjects (16 in Cohort 1 or 25 in Cohorts 2 or 3) may then be enrolled into that cohort in Stage 2. An expansion cohort will be defined by the Sponsor- Investigator following review of all available trial data which will be conducted after the first Stage 1 cohort has completed accrual and at least every six months thereafter until all Stage 1 cohorts have completed accrual.

If more than one cohort meets Stage 1 response criteria (2 responses out of 14 subjects for Cohort 1 or 1 response out of 7 subjects for each of Cohorts 2 and 3), then the cohort showing the highest response rate will be given highest consideration for expansion.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 8

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Cohort 2	Crizotinib	c-MET + (10-100%), RON + (10-100%)
Cohort 3	Crizotinib	c-MET null (0-9%), RON + (10-100%)
Cohort 1	Crizotinib	c-MET high (\> 50%), RON null (0-9%)

Primary Outcome Measures

Name	Time	Method
Overall Response	From enrollment to best response while on crizotinib; Subjects remained on treatment until disease progression or death or unacceptable toxicity (subjects were on treatment for an average of 6 weeks)	Overall response will be determined as the best treatment response for each patient as a binary variable indicating whether or not the patient achieved a Complete Response (CR) or Partial Response (PR) as determined by RECIST v1.1 criteria. Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1):Complete Response (CR) is the disappearance of all lesions (target and non target); Partial Response (PR) is at least 30% decrease in the sum of the diameters of target lesions from baseline and no new lesions or unequivocal progression in non target lesions from baseline; Stable Disease (SD) is neither sufficient shrinkage in target lesions to qualify for PR (less than 30% decrease) nor sufficient increase in target lesions (versus smallest sum of diameters) to qualify for PD (less than 20% increase), with no new lesions or unequivocal progression in non target lesions from baseline. For the purposes of response determination, confirmatory scan for CR and PR is required.

Secondary Outcome Measures

Name	Time	Method
Overall Survival	From date of treatment start to date of death, or censored as described above; assessed for approximately 2 years.	Overall survival was defined as the duration from enrollment date to the date of death from any cause. Subjects who were alive or lost to follow-up at the time of the analysis were censored at the last known date they were alive.
Progression Free Survival	From date of treatment start to date of progression or death, or censored as described above; assessed for approximately 2 years.	PFS was defined as duration of time from enrollment to the study to time of progression or death. Disease progression (PD) can be objectively determined as per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors, where PD is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in non-target lesion, or the appearance of new lesions) or progression can be subjective as determined by the investigator. Evidence for subjective progressions must be documented in medical records. For surviving subjects who do not have documented PD, PFS will be censored at last radiologic assessment. For subjects who receive subsequent anti-cancer therapy prior to documented PD, PFS will be censored at last radiologic assessment prior to commencement of subsequent therapy. Subjects who experience a PFS event following an interval equal to two or more scheduled assessments will be censored at date of last assessment prior to first missed assessment.