Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

Monoclonal Antibody and Sargramostim in Treating Patients With Metastatic Prostate Cancer

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Biomarker/Laboratory analysis, Treatment	Closed	18 and over	NCI	UCSF-02558 02558, NCI-6032, NCT00064129, 6032

Objectives

Primary

1. Determine the maximum tolerated dose of anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-010) administered with sargramostim (GM-CSF) in patients with metastatic androgen-independent prostate cancer. (Phase I)
2. Determine the safety of this regimen in these patients. (Phase I)
3. Evaluate the efficacy as measured by reduction in PSA associated with combining GM-CSF with CTLA-4 blockade with ipilimumab at a dosage of 3 mg/kg given monthly x 6 doses (d1 of courses 1-6). (Cohort Expansion)

Secondary

1. Determine the T-cell immunity and T-cell response in patients treated with this regimen. (Phase I)
2. Determine the pharmacokinetics of MDX-010 in these patients. (Phase I)
3. Determine the prostate-specific antigen and/or objective responses in patients treated with this regimen. (Phase I)
4. Determine the percentages of activated, naive, and memory T-cells. (Cohort Expansion)
5. Determine the measurement of T-cell response to describe epitopes from prostate antigens including PSA, PSMA, and PAP. (Cohort Expansion)
6. Quantitate T-cell response to antigens in patients with relevant HLA allele using HLA*0201 tetramers. (Cohort Expansion)
7. Evaluate the toxicity of this regimen in these patients. (Cohort Expansion)
8. Determine the initial efficacy as measured by reduction in PSA associated with combining GM-CSF with CTLA-4 blockade with ipilimumab at a dosage of 3 mg/kg given monthly x 6 doses (d1 of courses 1-6). (Cohort Expansion)
9. Determine objective response by post-therapy measurable disease changes using RECIST criteria. (Cohort Expansion)

Entry Criteria

Disease Characteristics:

• Histologically confirmed prostate cancer
  • Metastatic disease



• Progressive disease after prior androgen deprivation as defined by at least 1 of the following criteria:
  • Patients with measurable disease must have an increase of at least 20% in the sum of the longest diameter of target lesions OR the appearance of 1 or more new lesions
  • Patients with nonmeasurable disease must have a positive bone scan and a prostate-specific antigen (PSA) level of at least 5 ng/mL, which has risen on at least 2 successive occasions at least 2 weeks apart*
    • At least 1 PSA level must be obtained at least 4 weeks after flutamide (6 weeks after bicalutamide or nilutamide)

   [Note: *An additional PSA level is required if the confirmatory PSA is not greater than the screening PSA]




• Testosterone no greater than 50 ng/dL
  • Patients with no prior orchiectomy must continue luteinizing hormone-releasing hormone agonist therapy



• No history or radiologic evidence of CNS metastases

Prior/Concurrent Therapy:

Biologic therapy

• No prior immunotherapy (e.g., vaccines or investigational)
• No other concurrent colony-stimulating factors

Chemotherapy

• No prior chemotherapy
• No concurrent chemotherapy

Endocrine therapy

• See Disease Characteristics
• At least 4 weeks since prior systemic corticosteroids
• At least 4 weeks since other prior hormonal therapy, including megestrol and finasteride
• No concurrent systemic steroid therapy except inhaled or topical steroids
• No other concurrent hormonal therapy
  • Hormones administered for nondisease-related conditions (e.g., insulin for diabetes) allowed

Radiotherapy

• At least 4 weeks since prior radiotherapy and recovered
• More than 8 weeks since prior radiopharmaceuticals (e.g., strontium chloride Sr 89 and samarium Sm 153 lexidronam pentasodium)
• Prior irradiation of a symptomatic lesion or one that may produce disability (e.g., unstable femur) allowed
• No concurrent palliative radiotherapy

Surgery

• See Disease Characteristics

Other

• At least 4 weeks since prior herbal products known to decrease PSA levels (e.g., PC-SPES or saw palmetto)

Patient Characteristics:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• At least 12 weeks

Hematopoietic

• Absolute neutrophil count greater than 1,500/mm³
• Platelet count at least 100,000/mm³
• Hemoglobin at least 8 g/dL

Hepatic

• Bilirubin less than 1.5 times upper limit of normal (ULN)
• SGOT and SGPT no greater than 2.5 times ULN

Renal

• Creatinine no greater than 1.5 times ULN

Cardiovascular

• No significant cardiovascular disease
• No New York Heart Association class III or IV congestive heart failure
• No active angina pectoris
• No myocardial infarction within the past 6 months

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception prior to, during, and for 3 months after study participation
• No history of autoimmune disease including, but not limited to, any of the following:
  • Autoimmune hemolytic anemia
  • Ulcerative and hemorrhagic colitis
  • Endocrine disorders (e.g., thyroiditis, hyperthyroidism, hypothyroidism of immune etiology, autoimmune hypophysitis/hypopituitarism, or adrenal insufficiency)
  • Sarcoid granuloma
  • Myasthenia gravis
  • Polymyositis
  • Guillain-Barre syndrome
  • Systemic lupus erythematosis
  • Rheumatoid arthritis
  • Inflammatory bowel disease
• No other medical or psychiatric illness that would preclude study participation or giving informed consent
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or stage I or II cancer currently in complete remission

Expected Enrollment

A total of 18-36 patients will be accrued for this study within 6-7 months.

Outline

This is a multicenter, dose-escalation study of anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-010).

Patients receive MDX-010 IV over 90 minutes on day 1 and sargramostim (GM-CSF) subcutaneously on days 1-14. Treatment repeats every 28 days for 4-6 courses. GM-CSF continues beyond 4 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of MDX-010 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Some patients undergo blood sample collection periodically for laboratory and pharmacokinetic studies. Samples are analyzed for human anti-human antibodies, IgG antibodies to MDX-010 via semi-quantitative ELISA assay, and plasma concentrations of MDX-CTL4A via quantitative ELISA assay.

Patients are followed at 30 days.

Fong L, Kwek SS, O'Brien S, et al.: Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF. Cancer Res 69 (2): 609-15, 2009.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

UCSF Helen Diller Family Comprehensive Cancer Center

Eric Small, MD, Protocol chair		Ph: 415-353-7095; 800-888-8664

Registry Information
Official Title		A Phase I Study of Repetitive Dosing of Anti-CTLA-4 Antibody (MDX-010) in Combination with GM-CSF in Patients with Metastatic, Androgen-Independent Prostate Cancer
Trial Start Date		2003-05-13
Trial Completion Date		2003-11-29 (estimated)
Registered in ClinicalTrials.gov		NCT00064129
Date Submitted to PDQ		2003-05-22
Information Last Verified		2006-12-05
NCI Grant/Contract Number		CA82103

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