A Study of ALT-801 in Combination With Cisplatin and Gemcitabine in Muscle Invasive or Metastatic Urothelial Cancer

Sponsor
Altor BioScience (Industry)
Overall Status
Unknown status
CT.gov ID
NCT01326871
Collaborator
National Cancer Institute (NCI) (NIH)
90
16
2
76
5.6
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Study Details

Study Description

Brief Summary

This is a Phase Ib/II, open-label, multi-center, competitive enrollment and dose-escalation study of ALT-801 in a biochemotherapy regimen either containing cisplatin and gemcitabine or containing gemcitabine alone in patients who have muscle invasive or metastatic urothelial cancer of bladder, renal pelvis, ureters and urethra. The purpose of this study is to evaluate the safety, determine the maximum tolerated dose (MTD) and the recommended dose (RD), and assess the anti-tumor response of ALT-801 in combination with cisplatin and gemcitabine or ALT-801 in combination with gemcitabine alone. The pharmacokinetic profile of ALT-801 in combination with cisplatin and gemcitabine will also be assessed. The study includes a dose escalation phase (Phase Ib) and a dose expansion phase (Phase II). Phase II has two treatment groups, Expansion Group 1 and Expansion Group 2. Expansion Group 2 is for platinum-refractory patients, consisting of two treatment arms based on the patient's renal function. Patients will enroll to Expansion Group 2 after stage 1 of the Group 1 expansion is complete.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

Bladder cancer is the fourth most common malignancy in men and the ninth most common in women in the US, with an estimated 68,810 new cases and 14,070 deaths for the year 2008. Approximately 90% to 95% of newly diagnosed patients are with transitional cell carcinomas (TCC). Approximately 20% to 25% contain advanced (muscle invasive or metastatic) disease. Muscle invasive bladder cancer is life threatening. Clinical trials have demonstrated that TCC is a chemotherapy-sensitive malignancy. Most current cancer treatment strategies involve the use of chemotherapeutic or biological drugs that have a low therapeutic ratio. The limitations are a consequence of effects of the therapeutic drug on normal tissues. One approach to control systemic exposure effects is to target the drug itself into the site of the tumor. For example, antibodies have been developed for use as tumor targeting agents and have had success in the clinic. However, despite the promise of antibody-based immunotherapy, there are limitations with these class of reagents. Even so, immunotherapy remains a promising approach to treat cancer.

One strategy that has received attention is treatment with cytokines such as IL-2 to enhance anti-tumor immunity. IL-2 has stimulatory effects on a number of immune cell types including T and B cells, monocytes, macrophages, lymphokine-activated killer cells (LAK) and natural killer (NK) cells. Based on the ability of IL-2 to provide durable curative anti-tumor responses, systemic administration of IL-2 has been approved to treat patients with metastatic melanoma or renal carcinoma. 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 critical need for innovative strategies that enhance the effects of IL-2, to reduce its toxicity without compromising the clinical benefit, and to treat other diagnoses.

The study drug, ALT-801, is a biologic compound of interleukin-2 (IL-2) genetically fused to a humanized soluble T-cell receptor directed against the p53-derived peptides expressed on tumor cells. The p53 protein is one of the most important factors that protects from developing cancer and is also one of the most frequently mutated genes in many cancers, which include muscle-invasive bladder cancer. For any given cancer type, p53 dysfunction generally correlates with poor prognosis versus other the same site-of-origin. In some tumors, p53 mutation and over-expression also is associated with resistance to chemotherapy. This study is to further evaluate whether directing IL-2 activity using ALT-801 to the patient's tumor sites that over-express p53 results in clinical benefits

Study Design

Study Type:
Interventional
Anticipated Enrollment :
90 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase Ib/II Trial of ALT-801 in Combination With Cisplatin and Gemcitabine in Muscle Invasive or Metastatic Urothelial Cancer
Study Start Date :
Jun 1, 2011
Anticipated Primary Completion Date :
Jul 1, 2017
Anticipated Study Completion Date :
Oct 1, 2017

Arms and Interventions

Arm Intervention/Treatment
Experimental: ALT-801 with Cisplatin and Gemcitabine (Phase Ib and Phase II)

Drug: Cisplatin
Intravenous infusion; 3 initial treatment courses and an additional 3 maintenance courses for responders (maintenance revised for Phase II): on day 1 of each course (if given)

Drug: Gemcitabine
Intravenous infusion; 3 initial treatment courses and an additional 3 maintenance courses for responders (maintenance revised for Phase II); on day 1 and 8 of each course

Biological: ALT-801
Intravenous infusion; 3 initial treatment courses and an additional 3 maintenance courses for responders (maintenance revised for Phase II): on day 3, 5, 8, and 12 of each course
Other Names:
  • c264scTCR-IL2
  • Experimental: ALT-801 and Gemcitabine (Phase II only)

    Drug: Gemcitabine
    Intravenous infusion; 3 initial treatment courses and an additional 3 maintenance courses for responders (maintenance revised for Phase II); on day 1 and 8 of each course

    Biological: ALT-801
    Intravenous infusion; 3 initial treatment courses and an additional 3 maintenance courses for responders (maintenance revised for Phase II): on day 3, 5, 8, and 12 of each course
    Other Names:
  • c264scTCR-IL2
  • Outcome Measures

    Primary Outcome Measures

    1. Maximum Tolerated Dose (MTD) and/or the recommended dose (RD) for dose expansion of ALT-801 in combination with cisplatin and gemcitabine or ALT-801 in combination with gemcitabine alone [8 weeks]

    2. Safety Profile [8 weeks]

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

    3. Clinical Benefit [12 weeks]

      Number of participants with an objective response, which includes, a complete response,a partial response or a stable disease

    Secondary Outcome Measures

    1. Progression Free Survival [36 months]

      Number of participants with, 6-month, 9-month, 12-month, 18-month, 24-month, 30-month, or 36-month progression-free survival.

    2. Overall survival [36 months]

      Number of participants with 6-month, 9-month, 12-month, 18-month, 24-month, 30-month or 36-month overall survival

    3. Pharmacokinetics and immunogenicity [9 weeks]

      Area under the plasma concentration-time curve from time zero to infinity (AUC) and the half-life of ALT-801 for patients enrolled up to the stage 1 expansion. Measures of anti-ALT-801 and IL-2 neutralizing antibodies

    4. Tumor Typing [1 month]

      Assess the relationship between the tumor presentation of HLA-A*0201/p53 aa 264-272 complexes and the safety and clinical benefits of study treatment

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    ENTRY CRITERIA:
    DISEASE CHARATERISTICS:
    • Muscle invasive or metastatic urothelial cancer of bladder, ureters, renal pelvis, and urethra

    • Histologically or cytologically confirmed with a clinical plan that would potentially include cisplatin* plus gemcitabine systemic therapy or with disease refractory to a first-line platinum-based therapy (as defined in the protocol).

    • Does not apply to patients screened for Phase II expansion
    • Surgically incurable
    PRIOR/CONCURRENT THERAPY:
    • No concurrent radiotherapy, other chemotherapy, or other immunotherapy

    • Must have recovered from side effects of prior treatments

    • If prior Proleukin® treatment, must have had a clinical benefit

    • No use of other investigational agents within 30 days of start or concurrently

    PATIENT CHARACTERISTICS:

    Age

    • ≥ 18 years

    Performance Status

    • ECOG 0 or 1

    Bone Marrow Reserve

    • Absolute neutrophil count (AGC/ANC) ≥ 1,500/uL

    • Platelets ≥ 100,000/uL

    • Hemoglobin ≥ 10g/dL

    Renal Function

    • Glomerular Filtration Rate (GFR):

    • ≥ 50mL/min/1.73m^2 for cisplatin-containing regimen

    • ≥ 40mL/min/1.73m^2 for non-cisplatin-containing regimen

    Hepatic Function

    • Total bilirubin ≤ 1.5 X ULN

    • AST, ALT, ALP ≤ 2.5 X ULN, or ≤ 5.0 X ULN (if liver metastases exists)

    • PT INR ≤ 1.5 X ULN

    Cardiovascular

    • No congestive heart failure < 6 months

    • No unstable angina pectoris < 6 months

    • No myocardial infarction < 6 months

    • No history of ventricular arrhythmias

    • No NYHA Class > II CHF

    • Normal cardiac stress test required for subjects who are ≥ 50 years old, or have a history of EKG abnormalities, or have symptoms of cardiac ischemia or arrhythmia

    • No uncontrolled hypertension

    Pulmonary

    • Not receiving chronic medication for asthma

    • Normal clinical assessment of pulmonary function

    Hematologic

    • No evidence of bleeding diathesis or coagulopathy

    Other

    • Negative serum pregnancy test if female and of childbearing potential

    • No women who are 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 CNS disease (Controlled brain metastases treated with radiation therapy or surgery where the disease has been clinically stable for a period of a least 3 months before screening is allowed)

    • 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

    Locations

    Site City State Country Postal Code
    1 The University of Arizona Cancer Center Tucson Arizona United States 85724
    2 UF Health Center at Orlando Health Orlando Florida United States 32806
    3 Martin Health System Stuart Florida United States 34994
    4 H. Lee Moffitt Cancer Center and Research Institute Tampa Florida United States 33612
    5 Emory University Atlanta Georgia United States 30322
    6 Robert Lurie Comprehensive Cancer Center of Northwestern University Chicago Illinois United States 60611
    7 University of Iowa Hospitals and Clinics Iowa City Iowa United States 52242
    8 University of Kansas Cancer Center Fairway Kansas United States 66205
    9 Karmanos Cancer Center Detroit Michigan United States 48201
    10 University of Minnesota Minneapolis Minnesota United States 55455
    11 Washington University St. Louis Missouri United States 63110
    12 Levine Cancer Institute Charlotte North Carolina United States 28203
    13 University of Oklahoma Health Science Center Oklahoma City Oklahoma United States 73104
    14 St. Luke's Hospital and Health Network Easton Pennsylvania United States 18045
    15 Thomas Jefferson University Hospital Philadelphia Pennsylvania United States 19107
    16 UPMC Cancer Center Pittsburgh Pennsylvania United States 15232

    Sponsors and Collaborators

    • Altor BioScience
    • National Cancer Institute (NCI)

    Investigators

    • Study Chair: Hing C Wong, PhD, Altor BioScience

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Altor BioScience
    ClinicalTrials.gov Identifier:
    NCT01326871
    Other Study ID Numbers:
    • CA-ALT-801-01-10
    First Posted:
    Mar 31, 2011
    Last Update Posted:
    Apr 13, 2016
    Last Verified:
    Apr 1, 2016

    Study Results

    No Results Posted as of Apr 13, 2016