Urothelial Carcinoma
Conditions
Brief summary
This is a phase II trial designed to estimate the activity of single agent tremelimumab in subjects with metastatic urothelial cancer with disease progression despite prior treatment with PD-1/PD-L1 blockade. The primary endpoint is objective response rate and the study will employ a Simon's 2-stage design.
Interventions
DRUGTremelimumab
Tremelimumab 750 mg IV on Day 1 of each 28 day cycle; up to 7 cycles. Subjects that complete all initial 7 cycles but later progress during follow up may receive an additional 7 cycles of tremelimumab providing they meet eligibility criteria.
Sponsors
AstraZeneca
Matthew Galsky
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Single group assignment
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. * ECOG Performance Status of 0 or 1 within 14 days prior to registration. * Histologically or cytologically documented urothelial cancer. Locally advanced (T4b, any N; or any T, N 2-3) or metastatic disease (M1, Stage IV) (also termed TCC or UCC of the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra). Subjects with mixed histologies are eligible provided that the predominant component is urothelial cancer. Locally advanced bladder cancer must be inoperable on the basis of involvement of pelvic sidewall or adjacent viscera (clinical Stage T4b) or bulky nodal metastasis (N2-N3). * Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (blocks preferred) or at least 15 unstained slides. If archival tissue is not available and the subject is undergoing a standard of care biopsy, tissue from the biopsy is required to be submitted for correlative analyses. Subjects without adequate baseline tumor tissue may be considered for enrollment on a case by case basis after discussion with the sponsor-investigator. * Measurable disease according to RECIST 1.1 within 28 days prior to registration. At least 1 lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have short axis ≥15 mm) with computed tomography (CT) (preferred) or magnetic resonance imaging (MRI) scans, preferably with IV contrast, and that is suitable for accurate repeated measurements as per RECIST 1.1 guidelines; lesions in a previously irradiated field can be used as a measurable disease provided that there has been demonstrated progression in the lesion. * A subject with prior brain metastasis may be considered if they have completed their treatment for brain metastasis at least 4 weeks prior to study registration, have been off of corticosteroids for ≥ 2 weeks, and are asymptomatic * Subjects must have progressed despite prior treatment with anti-PD-1/PD-L1 antibody therapy. In addition, subjects must meet the following criteria: * Subjects must not have progressed within 2 months of starting prior anti-PD-1/PD-L1 antibody therapy. * Subjects must have received at least 1 line of prior systemic therapy * Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy. * All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study with the exception of endocrine related AEs that are stable on replacement therapy (e.g., steroids, thyroid hormone) which may be considered eligible but must be discussed with the sponsor-investigator. * Must not have experienced a ≥ Grade 3 immune related AE or an immune related neurologic (neuro-muscular) or ocular AE of any grade while receiving prior immunotherapy. NOTE: Subjects with endocrine AE of ≤ Grade 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic. Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of \> 10 mg prednisone or equivalent per day. * Patients with Gr 3 AST/ALT elevation \< 8 fold that resolved with steroids without additional immunosuppression can be included (Patients who experienced Hy's law on PD-1/L1 therapy will be excluded) * Prior cancer treatment must be completed at least 28 days or 5 half-lives (whichever is shorter) prior to first dose of study drug. Subjects must have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to ≤ Grade 1 or baseline. * Demonstrate adequate organ function as defined in the table below. All screening labs to be obtained within 14 days prior to registration. * Absolute Neutrophil Count (ANC) ≥ 1500/mm3 * Hemoglobin (Hgb) ≥ 9 g/dL * Renal * Calculated creatinine clearance ≥ 30 cc/min OR * Creatinine ≤ 1.5 * Bilirubin ≤ 1.5 × upper limit of normal (ULN); This will not apply to * Aspartate aminotransferase (AST) ≤ 2.5 × ULN (≤ 5 x ULN for subjects with hepatic metastases * Alanine aminotransferase (ALT) ≤ 2.5 × ULN (≤ 5 x ULN for subjects with hepatic metastases * Evidence of postmenopausal status or negative urinary or serum pregnancy test for female premenopausal subjects. Women will be considered postmenopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: * Females of childbearing potential who are sexually active with a non-sterilized male partner must be willing to abstain from heterosexual activity or to use 1 highly of effective method of contraception from the time of informed consent until 90 days after the last dose of tremelimumab. Non-sterilized male partners of a female patient must use male condom plus spermicide throughout this period. See Table 2 for acceptable contraceptive methods. * Non-sterilized males who are sexually active with a female partner of childbearing potential must use a male condom plus spermicide from screening through 90 days after receipt of the final dose of tremelimumab. Female partners (of childbearing potential) of male subjects must also use a highly effective method of contraception throughout this period
Exclusion criteria
* Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study). * Known additional malignancy that is active and/or progressive requiring treatment. Patients with incidental histologic findings of prostate cancer (tumor/node/metastasis stage of T1a or T1b or prostate-specific antigen \<10) who have not received hormonal treatment may be included, pending a discussion with the sponsor-investigator * Treatment with any investigational drug within 28 days prior to registration. * Prior treatment with an anti-CTLA-4 antibody * Any unresolved toxicity National Cancer Institute (NCI) CTCAE Version 4.03 Grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and laboratory values defined in the inclusion criteria. * Subjects with Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after consultation with the Sponsor Investigator * Subjects with irreversible toxicity not reasonably expected to be exacerbated by treatment with tremelimumab (e.g., hearing loss) may be included after consultation with the sponsor-investigator * Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer related conditions (e.g., hormone replacement therapy) is acceptable. Note: Local treatment of isolated lesions, excluding target lesions, for palliative intent is acceptable (e.g., local surgery or radiotherapy) * Radiation therapy within 14 days of first dose of study drug * Major surgical procedure within 28 days prior to first dose of study treatment * History of allogeneic organ transplantation that requires use of immunosuppressive agents * Active or prior documented autoimmune of inflammatory disorders (including but not limited to inflammatory bowel disease \[eg, colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome \[granulomatosis with polyangiitis\], Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc). The following are exceptions to this criterion: * Subjects with vitiligo * Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement * Any chronic skin condition that does not require systemic therapy * Subjects without active disease in the last5 years may be considered for enrollment after discussion with the sponsor-investigator * Subjects with celiac disease controlled by diet alone may be considered for enrollment after discussion with the sponsor-investigator * QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated. Any clinically significant abnormalities detected require triplicate ECG results and a mean QTcF \<470 ms calculated from 3 ECGs obtained over a brief period (eg, 30 minutes) * Past medical history of Interstitial Lung Disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease. * History of active primary immunodeficiency
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | Up to a maximum of 12 months | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. ORR is defined as the proportion of all subjects with confirmed PR or CR according to RECIST 1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events | AE had been recorded from time of consent until 30 days after discontinuation of study drug or until a new anti-cancer treatment starts, whichever occurs first; up to a maximum of 13 months | Number of participants with adverse events are reported according to the National Cancer Institute's Common Terminology Criteria for Adverse Events(CTCAE) version 4. |
| Disease Control Rate | Up to a maximum of 12 months | The disease control rate is defined as the percentage of patients who have achieved complete response, partial response and stable disease by RECIST 1.1 |
| Duration of Response | Up to a maximum of 24 months | Duration of response (DoR) is defined as the time from randomization to disease progression or death in patients who achieve complete or partial response. |
| Progression Free Survival (PFS) | Time of treatment start until the criteria for disease progression or death. Up to a maximum of 24 months. | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. PFS is defined as time from registration until disease progression met by RECIST 1.1 or death from any cause. |
| Overall Survival | Time of treatment start until death or date of last contact, up to a maximum of 42 months. | Overall survival is defined as the time from treatment start until death or date of last contact. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tremelimumab Tremelimumab 750 mg IV Day 1 of each 28 day cycle. Up to 7 cycles.
Tremelimumab: Tremelimumab 750 mg IV on Day 1 of each 28 day cycle; up to 7 cycles.
Subjects that complete all initial 7 cycles but later progress during follow up may receive an additional 7 cycles of tremelimumab providing they meet eligibility criteria. | 26 |
| Total | 26 |
Baseline characteristics
| Characteristic | Tremelimumab |
|---|---|
| Age, Continuous | 71 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Primary Tumor Site Renal Pelvis | 6 Participants |
| Primary Tumor Site Ureter | 2 Participants |
| Primary Tumor Site Urinary Bladder | 18 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 19 Participants |
| Region of Enrollment United States | 26 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 19 / 26 |
| other Total, other adverse events | 22 / 26 |
| serious Total, serious adverse events | 14 / 26 |
Outcome results
Primary
Objective Response Rate
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. ORR is defined as the proportion of all subjects with confirmed PR or CR according to RECIST 1.1.
Time frame: Up to a maximum of 12 months
Population: Out of 26, two patients were not evaluable for response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tremelimumab | Objective Response Rate | 8.3 Percentage of participants |
Secondary
Adverse Events
Number of participants with adverse events are reported according to the National Cancer Institute's Common Terminology Criteria for Adverse Events(CTCAE) version 4.
Time frame: AE had been recorded from time of consent until 30 days after discontinuation of study drug or until a new anti-cancer treatment starts, whichever occurs first; up to a maximum of 13 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tremelimumab | Adverse Events | Number of patients had at least one grade 3 or greater adverse event | 19 Participants |
| Tremelimumab | Adverse Events | Number of patients had at least one grade 3 or greater treatment related adverse event | 11 Participants |
| Tremelimumab | Adverse Events | Number of patients having serious adverse event | 14 Participants |
Secondary
Disease Control Rate
The disease control rate is defined as the percentage of patients who have achieved complete response, partial response and stable disease by RECIST 1.1
Time frame: Up to a maximum of 12 months
Population: Out of 26, two patients were not evaluable for response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tremelimumab | Disease Control Rate | 29.17 Percentage of participants |
Secondary
Duration of Response
Duration of response (DoR) is defined as the time from randomization to disease progression or death in patients who achieve complete or partial response.
Time frame: Up to a maximum of 24 months
Population: Out of 26, two patients were not evaluable for response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tremelimumab | Duration of Response | 17.45 Months |
Secondary
Overall Survival
Overall survival is defined as the time from treatment start until death or date of last contact.
Time frame: Time of treatment start until death or date of last contact, up to a maximum of 42 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tremelimumab | Overall Survival | 7.75 Months |
Secondary
Progression Free Survival (PFS)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. PFS is defined as time from registration until disease progression met by RECIST 1.1 or death from any cause.
Time frame: Time of treatment start until the criteria for disease progression or death. Up to a maximum of 24 months.
Population: Out of 26 patients, only 24 patients were evaluable for PFS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tremelimumab | Progression Free Survival (PFS) | 1.83 Months |