Urinary Bladder Neoplasms
Conditions
Keywords
muscle-invasive, non-metastatic
Brief summary
This is a phase II trial to evaluate the tolerability, efficacy, and immune outcomes of AGEN1884 plus AGEN2034 concurrent with cisplatin and gemcitabine in the neoadjuvant treatment of muscle-invasive, non-metastatic bladder cancer prior to radical cystectomy.
Detailed description
We will begin with an initial safety run-in to establish the safety of the combination prior to expansion to the full planned phase II. The overall phase II will be an open-label, single arm study in two stages to evaluate the efficacy of the combination in pathologic downstaging of MIBC. Patients will receive four 21-day cycles of neoadjuvant therapy consisting of cisplatin and gemcitabine plus AGEN2034 in all 4 cycles and AGEN1884 in cycles 1 and 3. Patients will proceed to radical cystectomy within 10 weeks after the final dose of this therapy. The primary endpoint of pathologic tumor downstaging will be assessed at the time of cystectomy.
Interventions
Sponsors
The University of Texas Health Science Center at San Antonio
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a phase II trial to evaluate the tolerability, efficacy, and immune outcomes of AGEN1884 plus AGEN2034 concurrent with cisplatin and gemcitabine in the neoadjuvant treatment of muscle-invasive, non-metastatic bladder cancer prior to radical cystectomy. We will begin with an initial safety run-in to establish the safety of the combination prior to expansion to the full planned phase II. The overall phase II will be an open-label, single arm study in two stages to evaluate the efficacy of the combination in pathologic downstaging of MIBC.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of muscle-invasive, non-metastatic urothelial carcinoma of the bladder, cT2-4, N0-1, M0 2. Eligible to receive cisplatin-based chemotherapy, with eligibility defined as meeting all of the following criteria: 1. Eastern Cooperative Oncology Group performance status of ¬0-1 2. Creatinine clearance (CrCl) of \>50 mL/min, as measured by 24-hour urine collection or estimated by the CKD-EPI equation. Patients with CrCl between 50 - 60 mL/min are eligible for the study but will receive split dose cisplatin 3. Grade \< 2 hearing loss 4. Grade \< 2 peripheral neuropathy 5. New York Heart Association Class \< III heart failure 3. Eligible to receive gemcitabine as dosed here 4. Patients must have organ and marrow function meeting the criteria below: Absolute neutrophil count \> 2,000/mcL Hemoglobin \> 9.0 mg/mL Platelets \> 100,000/mcL Total bilirubin within normal limits or known to be elevated due to a benign conjugation defect such as Gilbert's syndrome, as evidenced by normal conjugated bilirubin level AST/ALT \< 3X institutional normal limits Creatinine clearance (CrCl) \> 50 mL/min/1.73m2, as measured with 24 hr urine collection or estimated by CKD-EPI, whichever is greater 5. Signed, written informed consents to allow transfer of tumor tissue and production of peptides and to receive experimental treatment and monitoring if agreeable, or monitoring without experimental treatment otherwise 6. Age ≥18 years 7. Available fresh tissue from surgical excision. If fresh tissue is not available, archival tissue may be used. 8. Female subjects of childbearing potential must have a negative serum pregnancy test at screening (within 72 hours of first dose of study medication). Non-childbearing potential (other than by medical reasons) is defined as 1 of the following: 1. ≥ 45 years of age and amenorrheic for \>1 year by self-report. 2. Amenorrheic for \>2 years without a hysterectomy and oophorectomy, and follicle-stimulating hormone value in the postmenopausal range upon pretrial (screening) evaluation. 3. Status post-hysterectomy, -oophorectomy, or -tubal ligation. If of childbearing potential, female subjects must be willing to use adequate birth control during the study, starting with the screening visit through 120 days after the last dose of study therapy. Male subjects with a female partner(s) of childbearing potential must agree to use a condom throughout the trial, starting with the screening visit through 120 days after the last dose of study therapy. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner. Note: Abstinence is acceptable for both female and male subjects if this is the subject's established and preferred contraception method.
Exclusion criteria
1. Subjects must not have previously received a checkpoint inhibitor ie, anti-PD-1, anti-PD L1, or anti CTLA-4 antibody. 2. Subjects must not have previously received anticancer medications or investigational drugs for the disease under study within the following windows: a. ≤ 28 days for prior monoclonal antibody used for anticancer therapy, with the exception of denosumab b. ≤ 7 days for immunosuppressive treatment for any reason, with the following exceptions: i. Physiologic steroid replacement for adrenal insufficiency (e.g., \<10 mg prednisone per day) is permitted. ii. Use of inhaled or topical corticosteroid for radiographic procedures is permitted. c. Systemic corticosteroids \< 7 days are not allowed except as defined above. d. ≤ 28 days before first dose of study drug for all other investigational study drugs or devices 3. Has persisting toxicity related to prior therapy of National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE) Grade \>1 severity. Note: Sensory neuropathy or alopecia of Grade ≤2 is acceptable. 4. Has known severe hypersensitivity reactions to fully human monoclonal antibodies (NCI-CTCAE Version 5.0 Grade ≥3), any history of anaphylaxis, or uncontrolled asthma. 5. Active or history of any autoimmune disease (subjects with diabetes type 1, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible). Patients with a history of inflammatory bowel disease (including Crohn's disease and ulcerative colitis) and autoimmune disorders such as rheumatoid arthritis, systemic progressive sclerosis \[scleroderma\], Systemic Lupus Erythematosus or autoimmune vasculitis \[e.g., Wegener's Granulomatosis\] are excluded from this study. 6. Any condition requiring systemic treatment with corticosteroids (\>10mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids and adrenal replacement steroids doses \>10mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. 7. Uncontrolled intercurrent illness, including but not limited to uncontrolled infection, interstitial lung disease or active, non-infectious pneumonitis, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or social situations that would limit compliance with study requirements in the opinion of the treating investigator or medical monitor. 8. History of intolerance or allergic reactions attributed to compounds of similar chemical or biologic composition to AGEN1884 or AGEN2034. 9. Women who are pregnant or breastfeeding. 10. Receipt of a live vaccine within 30 days prior to the first dose of study drug. 11. Inability to adhere to the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathologic Tumor Downstaging of >T2 to pT0 | Completion of four 21 day cycles (approximately 10 weeks) | pT0 or pCR (defined as no residual tumor in bladder and lymph nodes on resected specimen). Surgery should be performed within 6 weeks after completing up to 4 cycles (last dose) of neoadjuvant therapy, but can be done up to 10 weeks after treatment ends to be evaluable. Otherwise this patient must be replaced for response evaluation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival at 1 Year | 1 year | Number of subjects that survived to 1 year from study start without disease progression |
| Evaluation of Safety and Tolerability of AGEN1884 Plus AGEN2034 Plus Cisplatin and Gemcitabine | Baseline to 90 days | Evaluation of safety and tolerability of using Agen1884 plus AGEN2034 plus cisplating and gemcitabine chemotherapy in the neoadjuvant treatment of muscle-invasive bladder cancer prior to radial cystectomy. Number of adverse events assessed between 3-5 using the National Cancer Institution Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0) |
| Pathologic Downstaging to <T2 Rate | Baseline to Completion of four 21 day cycles (approximately 10 weeks) | Number of subjects who achieved downstaging of the tumor at completion of the possible 4 chemotherapy cycles. |
| Completion of Surgery | 90 days | Number of subjects that progressed from therapy to surgery |
Other
| Measure | Time frame | Description |
|---|---|---|
| Correlate Immune Outcomes | 2 years | To correlate clinical outcomes with immune and biologic endpoints and identify patient and tumor characteristics that can predict treatment responses |
Countries
United States
Participant flow
Recruitment details
The safety run-in phase will enroll initial subjects who will begin treatment with cisplatin and gemcitabine plus AGEN2034 and AGEN 19884. Dose limiting toxicities will be assessed before beginning Phase ll, Stage 1. Evaluation will occur after 2 cycles of therapy prior to administration of third and fourth cycle therapy and progression to planned surgery. If criteria are met to continue to Stage 2, additional subjects will be enrolled to reach the anticipated total of 36 subjects.
Participants by arm
| Arm | Count |
|---|---|
| Cisplatin, Gemcitabine Plus Human Monoclonal Antibodies Participants enrolled with muscle-invasive bladder cancer. | 4 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Safety Run in Phase | Progression of disease | 2 |
Baseline characteristics
| Characteristic | Cisplatin, Gemcitabine Plus Human Monoclonal Antibodies |
|---|---|
| Age, Continuous | 59.75 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 0 Participants |
| Race (NIH/OMB) White | 4 Participants |
| Region of Enrollment United States | 4 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 4 |
| other Total, other adverse events | 4 / 4 |
| serious Total, serious adverse events | 0 / 4 |
Outcome results
Primary
Pathologic Tumor Downstaging of >T2 to pT0
pT0 or pCR (defined as no residual tumor in bladder and lymph nodes on resected specimen). Surgery should be performed within 6 weeks after completing up to 4 cycles (last dose) of neoadjuvant therapy, but can be done up to 10 weeks after treatment ends to be evaluable. Otherwise this patient must be replaced for response evaluation.
Time frame: Completion of four 21 day cycles (approximately 10 weeks)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cisplatin, Gemcitabine Plus Human Monoclonal Antibodies | Pathologic Tumor Downstaging of >T2 to pT0 | 2 Participants |
Secondary
Completion of Surgery
Number of subjects that progressed from therapy to surgery
Time frame: 90 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cisplatin, Gemcitabine Plus Human Monoclonal Antibodies | Completion of Surgery | 4 Participants |
Secondary
Evaluation of Safety and Tolerability of AGEN1884 Plus AGEN2034 Plus Cisplatin and Gemcitabine
Evaluation of safety and tolerability of using Agen1884 plus AGEN2034 plus cisplating and gemcitabine chemotherapy in the neoadjuvant treatment of muscle-invasive bladder cancer prior to radial cystectomy. Number of adverse events assessed between 3-5 using the National Cancer Institution Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0)
Time frame: Baseline to 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cisplatin, Gemcitabine Plus Human Monoclonal Antibodies | Evaluation of Safety and Tolerability of AGEN1884 Plus AGEN2034 Plus Cisplatin and Gemcitabine | 5 adverse events |
Secondary
Pathologic Downstaging to <T2 Rate
Number of subjects who achieved downstaging of the tumor at completion of the possible 4 chemotherapy cycles.
Time frame: Baseline to Completion of four 21 day cycles (approximately 10 weeks)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cisplatin, Gemcitabine Plus Human Monoclonal Antibodies | Pathologic Downstaging to <T2 Rate | 3 Participants |
Secondary
Progression-free Survival at 1 Year
Number of subjects that survived to 1 year from study start without disease progression
Time frame: 1 year
Population: Due to early termination of the study, data were not collected for this outcome measure
Other Pre-specified
Correlate Immune Outcomes
To correlate clinical outcomes with immune and biologic endpoints and identify patient and tumor characteristics that can predict treatment responses
Time frame: 2 years
Population: Due to early termination, not data were collected for this outcome