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

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by Altor Bioscience Corporation
Sponsor:
Collaborator:
Florida Department of Health James and Esther King Biomedical Research
Information provided by (Responsible Party):
Altor Bioscience Corporation
ClinicalTrials.gov Identifier:
NCT01625260
First received: June 19, 2012
Last updated: January 27, 2014
Last verified: January 2014
  Purpose

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.


Condition Intervention Phase
Non-muscle Invasive Bladder Cancer
Biological: ALT-801
Drug: Gemcitabine
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase Ib/II Study of ALT-801 in Patients With Bacillus Calmette-Guerin (BCG) Failure Non-muscle Invasive Bladder Cancer

Resource links provided by NLM:


Further study details as provided by Altor Bioscience Corporation:

Primary Outcome Measures:
  • Safety Profile [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]

    For Phase Ib & II

    Number and severity of treatment related AEs that occur or worsen after the first dose of study treatment


  • Tolerability of ALT-801 combined with gemcitabine and designation of the Recommended Dose level (RD) [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]

    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)


  • Clinical Benefit [ Time Frame: up to 13 weeks ] [ Designated as safety issue: No ]

    For Phase Ib & II

    Number of participants with a complete response



Secondary Outcome Measures:
  • Duration of response [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]

    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


  • Progression-free survival [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]

    For Phase Ib & II

    All enrolled patients will be followed every 3 months during years 1 and 2 and every 6 month during year 3 to determine their progression-free survival


  • Event free survival [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]

    For Phase Ib & II

    All enrolled patients will be followed every 3 months during years 1 and 2 and every 6 month during year 3 to determine their event-free survival


  • Overall survival [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]

    For Phase Ib & II

    All enrolled patients will be followed every 3 months during years 1 and 2 and every 6 month during year 3 to determine their overall survival


  • Immunogenicity of ALT-801 [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]

    For Phase Ib & II

    Measures the anti-ALT-801 and IL-2 neutralizing effects


  • Tumor Typing [ Time Frame: 1 month ] [ Designated as safety issue: No ]

    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



Estimated Enrollment: 52
Study Start Date: April 2012
Estimated Study Completion Date: July 2014
Estimated Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
Intervention Details:
    Biological: ALT-801
    Intravenous infusion: 2 treatment courses and 1 maintenance course; on Day 3, 5, 8 and 15 of each course.
    Other Name: c264scTCR-IL2
    Drug: Gemcitabine
    Intravenous infusion: 2 treatment courses and 1 maintenance course; on Day 1 and 8 of each course.
  Hide Detailed Description

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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/1.73m^2

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01625260

Locations
United States, Alabama
University of Alabama Comprehensive Cancer Center Recruiting
Birmingham, Alabama, United States, 35294
Contact: Dayle Craig    205-975-8080    dc0350@uab.edu   
Principal Investigator: Guru P Sonpavde, MD         
United States, California
University of California Davis Recruiting
Sacramento, California, United States, 95817
Contact: Frances Lara    916-734-8134    francis.lara@ucdmc.ucdavis.edu   
Principal Investigator: Chong-xian Pan, MD         
United States, Florida
MD Anderson Cancer Center Orlando Active, not recruiting
Orlando, Florida, United States, 32806
Martin Health System Recruiting
Stuart, Florida, United States, 34994
Contact: Lucinda Fasig, RN    772-223-5945 ext 3776    lucinda.fasig@martinhealth.org   
Principal Investigator: Guillermo Abesada-Terk, Jr., M.D.         
United States, North Carolina
Carolinas Medical Center Recruiting
Charlotte, North Carolina, United States, 28203
Contact: Tesa Adams, RN, CCRP    704-446-5145    Tesa.Adams@carolinashealthcare.org   
Principal Investigator: John Mahoney, M.D.         
United States, Oklahoma
University of Oklahoma Health Science Center Recruiting
Oklahoma City, Oklahoma, United States, 73104
Contact: Allison McClure, RN    405-271-8001 ext 48442    allison-mcclure@ouhsc.edu   
Principal Investigator: Puneet Sindhwani, MD         
United States, Pennsylvania
UPMC Cancer Center Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Diana Long, RN    412-647-8258    longdl@upmc.edu   
Principal Investigator: Rahul Parikh, MD         
Sponsors and Collaborators
Altor Bioscience Corporation
Florida Department of Health James and Esther King Biomedical Research
Investigators
Principal Investigator: Charles J Rosser, M.D. MD Anderson Cancer Center Orlando
  More Information

No publications provided

Responsible Party: Altor Bioscience Corporation
ClinicalTrials.gov Identifier: NCT01625260     History of Changes
Other Study ID Numbers: CA-ALT-801-01-12
Study First Received: June 19, 2012
Last Updated: January 27, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Altor Bioscience Corporation:
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

Additional relevant MeSH terms:
Urinary Bladder Neoplasms
Neoplasms
Neoplasms by Site
Urinary Bladder Diseases
Urogenital Neoplasms
Urologic Diseases
Urologic Neoplasms
BCG Vaccine
Gemcitabine
Adjuvants, Immunologic
Anti-Infective Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antiviral Agents
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Radiation-Sensitizing Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014