A Study of ALT-801 in Patients With Bacillus Calmette-Guerin (BCG) Failure Non-Muscle Invasive Bladder Cancer

Study Overview
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Brief Summary
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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
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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. NMIBC tumors are usually treated by surgical resection and intravesical chemotherapy and immunotherapy. Immunotherapy usually consists of intravesical administration of Bacillus Calmette-Guerin (BCG). Recent studies suggest that BCG is superior in terms of efficacy and decreasing disease recurrence compared to other therapies. Although the mechanism of action for BCG therapy leading to clinical efficacy is unclear, macrophages, T lymphocytes and natural killer (NK) cells are implicated as the critical mediators of the anti-tumor immune response. Consequently, BCG is associated with significant toxicity, and approximately 20% of patients fail to complete the course of therapy. In addition, as many as 30% of patients either fail to respond to therapy or suffer disease recurrence within 5 years. Of these, 30% will eventually die of bladder cancer and 50% will undergo radical cystectomy. Thus, a novel therapy, either as first-line or salvage therapy, is desperately needed for NMIBC to prevent disease progression and allow for bladder preservation to preserve quality of life of patients. Alternatively, a novel therapy that moderates the significant and often treatment-limiting side effects of BCG immunotherapy is also warranted. Additionally, immunotherapy is a well-established approach for treating other cancer types. One strategy that has received attention is treatment with cytokines such as IL-2 to enhance anti-tumor immunity. IL-2 has been implicated as playing a pivotal role in the efficacy of BCG treatment of patients with NMIBC. Studies have demonstrated that a direct IL-2 intervention could be of benefit to patients who are refractory or resistant to BCG treatment. Unfortunately, the considerable toxicity associated with this treatment makes it difficult to achieve an effective dose at the site of the tumor and limits the population that can be treated. Thus, there is a critical need for innovative strategies that enhance the effects of IL-2, to reduce its toxicity without compromising clinical benefit, and to treat other diagnoses including NMIBC. Recombinant human IL-2 (rhIL-2; Proleukin®) is an approved agent for the treatment of adults with metastatic melanoma and renal cell carcinoma (RCC). In particular, high dose intravenous IL-2 treatment has demonstrated durable objective response rate in these indications. However, the major toxicities associated with this regimen have precluded its widespread application. 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. Animal studies have indicated that ALT-801 could be useful in a therapeutic approach for activating immune effector cells, bringing together effector cells and tumor cells and stimulating immune cell-mediated activity. In addition, pre-clinical studies of ALT-801 in an NMIBC tumor model indicate that ALT-801 monotherapy may provide clinical benefit to patients with NMIBC. Various mouse xenograft models also demonstrate that ALT-801 increases the efficacy but lessens the side effects of high-dose rhIL-2. Moreover, the results of a concluded phase I clinical study of a monotherapy with ALT-801 in patients with metastatic malignancies indicate that ALT-801 given daily for two 4-day cycles at a dose level of 0.04 mg/kg is well tolerated, exhibits a favorable PK drug profile and immunological potency, and provides clinical benefit in cancer patients. Also, a higher dosing level (0.08 mg/kg) of ALT-801 was associated with better clinical benefit. Based on these findings, 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.

Official Title
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A Phase Ib/II Study of ALT-801 in Patients With Bacillus Calmette-Guerin (BCG) Failure Non-muscle Invasive Bladder Cancer

Conditions
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Non-muscle Invasive Bladder Cancer

Intervention / Treatment
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* Biological: ALT-801
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gemcitabine in combination with ALT-801<br> | Biological: ALT-801<br>* Intravenous infusion: 2 treatment courses and 1 maintenance course; on Day 3, 5, 8 and 15 of each course.<br>* Other names: c264scTCR-IL2;Drug: Gemcitabine<br>* Intravenous infusion: 2 treatment courses and 1 maintenance course; on Day 1 and 8 of each course.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Profile | For Phase Ib & II Number and severity of treatment related AEs that occur or worsen after the first dose of study treatment | 12 weeks | 
| Tolerability of ALT-801 combined with gemcitabine and designation of the Recommended Dose level (RD) | For phase Ib only Tolerability of a well-tolerated dose level of ALT-801 combined with gemcitabine and designation of the recommended dose level (RD) | 12 weeks | 
| Clinical Benefit | For Phase Ib & II Number of participants with a complete response | up to 13 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response | For Phase Ib & II All responding patients will be followed every 3 months during years 1 and 2 and every 6 month during year 3 to determine their duration of response | up to 3 years | 
| Progression-free survival | For Phase Ib & II All patients receiving one complete dose of ALT-801 will be followed every 3 months during years 1 and 2 and every 6 month during year 3 to determine their progression-free survival | up to 3 years | 
| Event free survival | For Phase Ib & II All patients receiving one complete dose of ALT-801 will be followed every 3 months during years 1 and 2 and every 6 month during year 3 to determine their event-free survival | up to 3 years | 
| Overall survival | For Phase Ib & II All patients receiving one complete dose of ALT-801 will be followed every 3 months during years 1 and 2 and every 6 month during year 3 to determine their overall survival | up to 3 years | 
| Immunogenicity of ALT-801 | For Phase Ib & II Measures the anti-ALT-801 and IL-2 neutralizing effects | 8 weeks | 
| Tumor Typing | For Phase Ib & II Assess the relationship between the tumor presentation of HLA-A*0201/p53 aa 264-272 complexes and the safety, immune response and clinical benefit of study treatment | 1 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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