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

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

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.

Study Overview

• Status: Unknown
• Conditions: Non-muscle Invasive Bladder Cancer
• Intervention / Treatment: Biological: ALT-801; Drug: Gemcitabine

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.

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.

• Study Type: Interventional
• Enrollment (Anticipated): 52
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama Comprehensive Cancer Center
  • California
    • Sacramento, California, United States, 95817
      • University of California Davis
  • Florida
    • Orlando, Florida, United States, 32806
      • UF Health Center at Orlando Health
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Science Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Altor BioScience
• Collaborators: James and Esther King Biomedical Research Program
• Investigators: Study Chair: Hing C Wong, PhD, Altor BioScience

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): April 1, 2015
• Study Completion (Anticipated): March 1, 2018

Study Registration Dates

• First Submitted: June 19, 2012
• First Submitted That Met QC Criteria: June 19, 2012
• First Posted (Estimate): June 21, 2012

Study Record Updates

• Last Update Posted (Estimate): January 24, 2017
• Last Update Submitted That Met QC Criteria: January 23, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: immunotherapy; cancer; bladder cancer; urothelial cancer; targeted; interleukin-2; gemcitabine; antitumor; TCR; T-cell receptor; p53; p53 gene; p53 tumor supressor protein; HLA-A2 positive; HLA-A*0201/p53 aa264-272; HLA complex; relapsed; refractory; BCG; carcinoma in situ; transitional cell carcinoma; non-muscle invasive; multi-focal
• Additional Relevant MeSH Terms: Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Urinary Bladder Diseases; Urinary Bladder Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gemcitabine
• Other Study ID Numbers: CA-ALT-801-01-12

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO