Non-muscle Invasive Bladder Cancer
Conditions
Keywords
cancer, immunotherapy, targeted, non-muscle invasive, interleukin-2, antitumor, TCR, T-cell receptor, p53, p53 gene, p53 tumor supressor protein, urothelial cancer, bladder cancer, HLA-A2 positive, HLA-A*0201/p53 aa264-272, HLA complex, refractory, relapsed, BCG, multi-focal, carcinoma in situ, transitional cell carcinoma, gemcitabine
Brief summary
This is a Phase Ib/II, open-label, multi-center and competitive enrollment study of ALT-801 combined with gemcitabine for patients who have BCG failure (defined as refractory, relapsing or intolerant), non-muscle invasive bladder cancer and refuse or are not medically fit to undergo a radical cystectomy recommended by the participating urologist as the standard next therapy per urologic guidelines. The purpose of this study is to confirm the safety and tolerability of a well-tolerated dose level of ALT-801, to determine the Recommended Dose level (RD) and characterize the immunogenicity of ALT-801 combined with gemcitabine in treated patients. The anti-tumor responses will also be assessed.
Detailed description
Bladder cancer is the fifth most common cancer in the United States with an estimated 71,000 new cases and approximately 14,000 deaths in 2009. Bladder cancer is also the costliest to treat per patient of all cancers, with annual direct medical expenditures in excess of $3.7 billion in the United States. This is largely because approximately 70% of all new cases of bladder cancer present as non-muscle invasive bladder cancer (NMIBC), which tends to recur, requiring repeated interventions and long-term follow-up. Altor Bioscience Corp. has developed a tumor-targeted IL-2 fusion protein, ALT-801, comprising human recombinant IL-2 genetically linked to a TCR domain capable of binding a tumor associated human p53 peptide presented in the context of HLA-A2. ALT-801 will be evaluated as to whether it can prevent disease progression and allow for bladder preservation to maintain the quality of life for patients with BCG failure, defined as refractory, relapsing or intolerant, non-muscle invasive bladder cancer who refuse or are not medically fit to undergo a radical cystectomy recommended by the participating urologist as the standard next therapy per urologic guidelines.
Interventions
BIOLOGICALALT-801
Intravenous infusion: 2 treatment courses and 1 maintenance course; on Day 3, 5, 8 and 15 of each course.
DRUGGemcitabine
Intravenous infusion: 2 treatment courses and 1 maintenance course; on Day 1 and 8 of each course.
Sponsors
James and Esther King Biomedical Research Program
Altor BioScience
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
ENTRY CRITERIA: DISEASE CHARATERISTICS: * Histologically confirmed high-risk (high grade Ta, T1 or carcinoma in situ, tumor \>4 cm or multi-focal) transitional cell carcinoma s/p TURBT with no remaining resectable disease within 4 weeks of study entry * Intolerant of treatment with BCG or failure (refractory or relapsing) of at least one prior treatment with BCG * Refuse or intolerant of a radical cystectomy * No Evidence of regional and/or distant metastasis PRIOR/CONCURRENT THERAPY: * No concurrent radiotherapy, other chemotherapy, or other immunotherapy * No scheduled radiotherapy, chemotherapy, other immunotherapy, or surgery before the scheduled response evaluation * Must have recovered from side effects of prior treatments * No concurrent use of other investigational agents PATIENT CHARACTERISTICS: Age • ≥ 18 years Performance Status • ECOG 0, 1, or 2 Bone Marrow Reserve * Absolute neutrophil count (AGC/ANC) ≥ 1,000/uL * Platelets ≥ 100,000/uL * Hemoglobin ≥ 8 g/dL Renal Function • Glomerular Filtration Rate (GFR) ≥ 50mL/min Hepatic Function * Total bilirubin ≤ 2.0 X ULN * AST, ALT, ALP ≤ 3.0 X ULN Cardiovascular * No congestive heart failure \< 6 months * No severe/unstable angina pectoris \< 6 months * No myocardial infarction \< 6 months * No history of ventricular arrhythmias * No NYHA Class \> II CHF * No uncontrollable supraventricular arrhythmias * No history of a ventricular arrhythmia * No other clinical signs of severe cardiac dysfunction * Normal Transthoracic Echocardiogram (TTE) is required for patients who have history of EKG abnormalities, CHF, coronary artery disease or other cardiac disease, or have history of having received adriamycin or doxorubicin * No patients with a left ventricular ejection fraction (LVEF) of less than 50% Pulmonary • Normal clinical assessment of pulmonary function Other * Negative serum pregnancy test if female and of childbearing potential * Women who are not pregnant or nursing * Subjects, both females and males, with reproductive potential must agree to use effective contraceptive measures for the duration of the study * No known autoimmune disease other than corrected hypothyroidism * No known prior organ allograft or allogeneic transplantation * Not HIV positive * No active systemic infection requiring parenteral antibiotic therapy * No ongoing systemic steroid therapy required * No history or evidence of uncontrollable CNS disease * No psychiatric illness/social situation * No other illness that in the opinion of the investigator would exclude the subject from participating in the study * Must provide informed consent and HIPAA authorization and agree to comply with all protocol-specified procedures and follow-up evaluations
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety Profile | 12 weeks | Confirmation of the safety and tolerability (dose limiting toxicity count) of ALT-801 combined with gemcitabine. |
| Disease Response Rate | From start of study treatment to up to 13 weeks | The response rate was calculated as the ratio of the number of patients who demonstrated a complete response (by RECIST v1.1) divided by the number of patients evaluable for response. A complete response was defined as having negative bladder biopsy results. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | From confirmed complete response to up to 3 years | Duration of response was defined as the time from the date of first complete response (by RECIST v1.1) to the date of disease progression (by RECIST v1.1) or death (from any cause), whichever occured first. A complete response was defined as having negative bladder biopsy results. Disease progression by RECIST v1.1 is defined as at least a 20% increase in the sum of diameters of target lesions in reference to the smallest sum on study and an absolute increase of at least 5 mm; the appearance of any new lesions is also considered progression. |
| Progression-free Survival | From start of study treatment to up to 3 years | The progression-free survival was defined as the time from the start of study treatment to first documentation of objective tumor progression or disease recurrence (by RECIST v1.1). Disease progression by RECIST v1.1 is defined as at least a 20% increase in the sum of diameters of target lesions in reference to the smallest sum on study and an absolute increase of at least 5 mm; the appearance of any new lesions is also considered progression. |
| Event-free Survival | From start of study treatment to up to 3 years | The event-free survival was defined as the time from the start of study treatment to first documentation of objective tumor progression (by RECIST v1.1), disease recurrence, bladder resection or irradiation, other anti-bladder cancer therapy, or to death due to any cause, which ever came first. Disease progression by RECIST v1.1 is defined as at least a 20% increase in the sum of diameters of target lesions in reference to the smallest sum on study and an absolute increase of at least 5 mm; the appearance of any new lesions is also considered progression. |
| Overall Survival | From start of study treatment to up to 3 years | OS was defined as the time from start of study treatment to death resulting from any cause. |
Countries
United States
Participant flow
Pre-assignment details
Only Phase 1B was enrolled, no subjects were enrolled in Phase 2.
Participants by arm
| Arm | Count |
|---|---|
| 0.06 mg/kg ALT-801 With 1000 mg/m^2 Gemcitabine ALT-801 at 0.06 mg/kg with Gemcitabine at 1000 mg/m\^2
ALT-801: Intravenous infusion: 2 treatment courses and 1 maintenance course; on Day 3, 5, 8 and 15 of each course.
Gemcitabine: Intravenous infusion: 2 treatment courses and 1 maintenance course; on Day 1 and 8 of each course. | 9 |
| 0.08 mg/kg ALT-801 With 1000 mg/m^2 Gemcitabine ALT-801 at 0.08 mg/kg with Gemcitabine at 1000 mg/m\^2
ALT-801: Intravenous infusion: 2 treatment courses and 1 maintenance course; on Day 3, 5, 8 and 15 of each course.
Gemcitabine: Intravenous infusion: 2 treatment courses and 1 maintenance course; on Day 1 and 8 of each course. | 3 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 0 |
| Overall Study | Disease Progression | 2 | 0 |
| Overall Study | PI and subject decided to terminate treatment | 0 | 1 |
| Overall Study | Study Terminated by Investigator | 2 | 0 |
Baseline characteristics
| Characteristic | 0.06 mg/kg ALT-801 With 1000 mg/m^2 Gemcitabine | 0.08 mg/kg ALT-801 With 1000 mg/m^2 Gemcitabine | Total |
|---|---|---|---|
| Age, Continuous | 63.1 years STANDARD_DEVIATION 11.36 | 71.0 years STANDARD_DEVIATION 4.36 | 65.1 years STANDARD_DEVIATION 10.49 |
| Patients with Bacillus Calmette-Guerin (BCG) Failure Non-Muscle Invasive Bladder Cancer | 9 Participants | 3 Participants | 12 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 3 Participants | 11 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 7 Participants | 2 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 9 | 1 / 3 |
| other Total, other adverse events | 9 / 9 | 3 / 3 |
| serious Total, serious adverse events | 3 / 9 | 1 / 3 |
Outcome results
Primary
Disease Response Rate
The response rate was calculated as the ratio of the number of patients who demonstrated a complete response (by RECIST v1.1) divided by the number of patients evaluable for response. A complete response was defined as having negative bladder biopsy results.
Time frame: From start of study treatment to up to 13 weeks
Population: The population only included patients evaluable for response. 2 participants had no disease response information provided.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 0.06 mg/kg ALT-801 With 1000 mg/m^2 Gemcitabine | Disease Response Rate | 43 percentage of participants |
| 0.08 mg/kg ALT-801 With 1000 mg/m^2 Gemcitabine | Disease Response Rate | 67 percentage of participants |
Primary
Safety Profile
Confirmation of the safety and tolerability (dose limiting toxicity count) of ALT-801 combined with gemcitabine.
Time frame: 12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 0.06 mg/kg ALT-801 With 1000 mg/m^2 Gemcitabine | Safety Profile | 2 Number of DLTs |
| 0.08 mg/kg ALT-801 With 1000 mg/m^2 Gemcitabine | Safety Profile | 1 Number of DLTs |
Secondary
Duration of Response
Duration of response was defined as the time from the date of first complete response (by RECIST v1.1) to the date of disease progression (by RECIST v1.1) or death (from any cause), whichever occured first. A complete response was defined as having negative bladder biopsy results. Disease progression by RECIST v1.1 is defined as at least a 20% increase in the sum of diameters of target lesions in reference to the smallest sum on study and an absolute increase of at least 5 mm; the appearance of any new lesions is also considered progression.
Time frame: From confirmed complete response to up to 3 years
Population: Subjects with complete response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 0.06 mg/kg ALT-801 With 1000 mg/m^2 Gemcitabine | Duration of Response | NA Months |
| 0.08 mg/kg ALT-801 With 1000 mg/m^2 Gemcitabine | Duration of Response | 2.1 Months |
Secondary
Event-free Survival
The event-free survival was defined as the time from the start of study treatment to first documentation of objective tumor progression (by RECIST v1.1), disease recurrence, bladder resection or irradiation, other anti-bladder cancer therapy, or to death due to any cause, which ever came first. Disease progression by RECIST v1.1 is defined as at least a 20% increase in the sum of diameters of target lesions in reference to the smallest sum on study and an absolute increase of at least 5 mm; the appearance of any new lesions is also considered progression.
Time frame: From start of study treatment to up to 3 years
Population: The population only included patients evaluable for response. 2 participants had no disease response information provided.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 0.06 mg/kg ALT-801 With 1000 mg/m^2 Gemcitabine | Event-free Survival | 3.4 Months |
| 0.08 mg/kg ALT-801 With 1000 mg/m^2 Gemcitabine | Event-free Survival | 2.9 Months |
Secondary
Overall Survival
OS was defined as the time from start of study treatment to death resulting from any cause.
Time frame: From start of study treatment to up to 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 0.06 mg/kg ALT-801 With 1000 mg/m^2 Gemcitabine | Overall Survival | NA Months |
| 0.08 mg/kg ALT-801 With 1000 mg/m^2 Gemcitabine | Overall Survival | NA Months |
Secondary
Progression-free Survival
The progression-free survival was defined as the time from the start of study treatment to first documentation of objective tumor progression or disease recurrence (by RECIST v1.1). Disease progression by RECIST v1.1 is defined as at least a 20% increase in the sum of diameters of target lesions in reference to the smallest sum on study and an absolute increase of at least 5 mm; the appearance of any new lesions is also considered progression.
Time frame: From start of study treatment to up to 3 years
Population: The population only included patients evaluable for response. 2 participants had no disease response information provided.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 0.06 mg/kg ALT-801 With 1000 mg/m^2 Gemcitabine | Progression-free Survival | 3.4 Months |
| 0.08 mg/kg ALT-801 With 1000 mg/m^2 Gemcitabine | Progression-free Survival | 2.9 Months |