Clinical trial NCT00047164: Monoclonal Antibody Therapy in Treating Patients With Lymphoma or Colon Cancer That Has Not Responded to Vaccine Therapy
Official title: A Pilot Study of Ipilimumab (MDX-CTLA4, MDX-010) in Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Lymphoma
Keywords: recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
contiguous stage II adult lymphoblastic lymphoma
noncontiguous stage II adult lymphoblastic lymphoma
recurrent adult lymphoblastic lymphoma
stage I adult lymphoblastic lymphoma
stage III adult lymphoblastic lymphoma
stage IV adult lymphoblastic lymphoma
noncontiguous stage II grade 3 follicular lymphoma
recurrent grade 3 follicular lymphoma
stage I grade 3 follicular lymphoma
stage III grade 3 follicular lymphoma
stage IV grade 3 follicular lymphoma
contiguous stage II grade 3 follicular lymphoma
contiguous stage II grade 2 follicular lymphoma
contiguous stage II grade 1 follicular lymphoma
contiguous stage II adult diffuse mixed cell lymphoma
noncontiguous stage II adult diffuse mixed cell lymphoma
recurrent adult diffuse mixed cell lymphoma
stage I adult diffuse mixed cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage IV adult diffuse mixed cell lymphoma
contiguous stage II adult diffuse large cell lymphoma
noncontiguous stage II adult diffuse large cell lymphoma
recurrent adult diffuse large cell lymphoma
stage I adult diffuse large cell lymphoma
stage III adult diffuse large cell lymphoma
stage IV adult diffuse large cell lymphoma
contiguous stage II adult immunoblastic large cell lymphoma
noncontiguous stage II adult immunoblastic large cell lymphoma
recurrent adult immunoblastic large cell lymphoma
stage I adult immunoblastic large cell lymphoma
stage III adult immunoblastic large cell lymphoma
stage IV adult immunoblastic large cell lymphoma
contiguous stage II adult Burkitt lymphoma
noncontiguous stage II adult Burkitt lymphoma
recurrent adult Burkitt lymphoma
stage I adult Burkitt lymphoma
stage III adult Burkitt lymphoma
stage IV adult Burkitt lymphoma
contiguous stage II mantle cell lymphoma
noncontiguous stage II mantle cell lymphoma
recurrent mantle cell lymphoma
stage I mantle cell lymphoma
stage III mantle cell lymphoma
stage IV mantle cell lymphoma
recurrent adult Hodgkin lymphoma
stage I adult Hodgkin lymphoma
stage II adult Hodgkin lymphoma
stage III adult Hodgkin lymphoma
stage IV adult Hodgkin lymphoma
recurrent adult diffuse small cleaved cell lymphoma
stage I adult diffuse small cleaved cell lymphoma
stage II adult diffuse small cleaved cell lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
contiguous stage II marginal zone lymphoma
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
noncontiguous stage II marginal zone lymphoma
recurrent marginal zone lymphoma
splenic marginal zone lymphoma
stage I marginal zone lymphoma
stage III marginal zone lymphoma
stage IV marginal zone lymphoma
contiguous stage II small lymphocytic lymphoma
noncontiguous stage II small lymphocytic lymphoma
recurrent small lymphocytic lymphoma
stage I small lymphocytic lymphoma
stage III small lymphocytic lymphoma
stage IV small lymphocytic lymphoma
recurrent adult T-cell leukemia/lymphoma
recurrent cutaneous T-cell non-Hodgkin lymphoma
stage I adult T-cell leukemia/lymphoma
stage I cutaneous T-cell non-Hodgkin lymphoma
stage II adult T-cell leukemia/lymphoma
stage II cutaneous T-cell non-Hodgkin lymphoma
stage III adult T-cell leukemia/lymphoma
stage III cutaneous T-cell non-Hodgkin lymphoma
stage IV adult T-cell leukemia/lymphoma
stage IV cutaneous T-cell non-Hodgkin lymphoma
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
Collaborators: name: National Cancer Institute (NCI)
First posted: 2003-01-27
Enrollment: 89
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: RATIONALE: Monoclonal antibodies such as anti-cytotoxic T-lymphocyte-associated antigen-4 can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells.

PURPOSE: This phase II trial is studying anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody to see how well it works in treating patients with lymphoma or colon cancer that has not responded to vaccine therapy.

Detailed description: OBJECTIVES:

Primary

* Determine the toxicity of anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody in patients with follicular or mantle cell lymphoma, colon cancer, or prostate cancer refractory to vaccine therapy. (part I) (prostate cancer and mantle cell lymphoma closed to accrual as of 3/10/2005; colon cancer closed to accrual as of 9/28/05)
* Determine the toxicity of this drug at escalating doses in patients with follicular lymphoma. (part II)
* Determine the toxicity of this drug at escalating doses in patients with non-Hodgkin's lymphoma or Hodgkin's lymphoma. (part III)

Secondary

* Determine the ability of this drug to increase tumor-specific T-cell responses in these patients.
* Determine the ability of this drug to produce clinical tumor response in these patients.
* Determine the effect of this drug on suppressor T-cell populations (CD4+ and CD25+ cells) in these patients.

OUTLINE: This is a pilot, partial dose-escalation study.

* Part I (patients with prostate or colon cancer or follicular or mantle cell lymphomas) (prostate cancer and mantle cell lymphoma closed to accrual as of 3/10/2005; colon cancer closed to accrual as of 9/28/05): Patients receive anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-CTLA4) IV over 90 minutes on day 1. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.
* Part II (dose-escalation) (patients with follicular lymphomas only): Patients receive MDX-CTLA4 as in part I. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of MDX-CTLA4 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

* Part III (dose-escalation\*) (patients with non-Hodgkin's or Hodgkin's lymphoma): Patients receive MDX-CTLA4 as in part II.

NOTE: No dose-escalation for lymphoma patients who have previously been treated with an allogeneic stem cell transplantation.

Patients are followed every other month.

PROJECTED ACCRUAL: A total of 89 patients will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed prostate cancer (closed to accrual as of 3/9/2005)

  * Prior therapy on protocol NCI-00-C-0137 or NCI-00-C-0154
  * Progressive disease (2 consecutively rising PSA levels, new bone scan lesion, or progression of soft tissue)
  * PSA at least 5 ng/mL
  * Progressive androgen-independent disease

    * Disease progression at least 4 weeks after flutamide withdrawal OR
    * Disease progression at least 6 weeks after bicalutamide or nilutamide withdrawal OR
* Histologically confirmed follicular or mantle cell non-Hodgkin's lymphoma (mantle cell lymphoma closed to accrual as of 3/9/2005)

  * Prior therapy on protocol NCI-00-C-0133, NCI-01-C-0169, or NCI-00-C-0050
  * Progressive disease after standard treatment
  * Relapsed disease OR
* Histologically confirmed colon cancer (colon cancer closed to accrual as of 9/28/05)

  * Prior therapy on protocol NCI-99-C-0023
  * Progressive disease OR
* Histologically confirmed non-Hodgkin's lymphoma or Hodgkin's lymphoma

  * Progressive disease after standard treatment
  * No curative therapy exists
  * Prior allogeneic stem cell transplantation from a matched sibling or matched unrelated donor for an aggressive lymphoma allowed

    * Last infusion of allogeneic cells (either hematopoietic stem cells or donor lymphocytes) must have occurred \> 90 days prior to study enrollment
* No other standard therapy available or refused such therapy
* No symptomatic or rapidly progressive malignancy requiring therapy
* No symptomatic CNS metastases

PATIENT CHARACTERISTICS:

Age

* 18 and over

Performance status

* Karnofsky 80-100%

Life expectancy

* More than 2 months

Hematopoietic

* WBC at least 2,500/mm\^3
* Granulocyte count at least 1,500/mm\^3
* Platelet count at least 50,000/mm\^3
* Hemoglobin at least 10 g/dL
* Hematocrit at least 30%

Hepatic

* Bilirubin no greater than 3.0 mg/dL (unless due to Gilbert's disease)
* SGOT and SGPT no greater than 3 times upper limit of normal
* Hepatitis B surface antigen negative
* Hepatitis C antibody negative

Renal

* Creatinine no greater than 2.0 mg/dL

Immunologic

* HIV negative
* Rheumatoid factor negative if history or evidence of arthritis
* Anti-nuclear antibody (ANA) titer no greater than 1:80 if history or clinical signs or symptoms of connective tissue disease
* No prior or active autoimmune disease (e.g., uveitis, rheumatoid arthritis, lupus erythematosus, autoimmune hemolytic anemia, ulcerative and hemorrhagic colitis, endocrine disorders \[e.g., thyroiditis, hyperthyroidism, hypothyroidism, autoimmune hypophysitis/hypopituitarism, or adrenal insufficiency\], sarcoid granuloma, myasthenia gravis, polymyositis,or Guillain-Barre syndrome)
* No positive antibody titers to autoimmune diseases

  * Rheumatoid factor positive allowed unless ANA titer is greater than 1:80 and there is a history of or clinical signs or symptoms of connective tissue disease
* No active infection

Other

* No other active malignancy within the past 5 years except adequately treated squamous cell or basal cell skin cancer, carcinoma in situ of the cervix, or superficial bladder cancer
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception during and for 4 months after study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

* See Disease Characteristics
* Recovered from prior vaccine therapy
* No prior anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-CTLA4) for patients in part I of study

  * Patients in part II of study may have had up to 4 prior treatments with MDX-CTLA4
* No concurrent vaccine therapy
* No concurrent infliximab

Chemotherapy

* At least 4 weeks since prior cytotoxic chemotherapy
* No concurrent mercaptopurine, methotrexate, or cyclophosphamide

Endocrine therapy

* See Disease Characteristics
* At least 4 weeks since prior steroids
* No concurrent systemic, inhaled, or topical steroids

Radiotherapy

* At least 4 weeks since prior radiotherapy

Surgery

* At least 4 weeks since prior major surgery

Other

* Prior intervening therapy for prostate cancer, non-Hodgkin's lymphoma or colon cancer allowed
* No other concurrent investigational therapy
* No other concurrent immunosuppressants (e.g., cyclosporine or its analog)

Primary outcomes:
measure: Toxicity after every 3 courses of treatment and every month for up to a year after completion of study treatment
Secondary outcomes:
measure: T-cell response after every 3 courses of treatment and every month for up to a year after completion of study treatment
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
state: Maryland
Study officials:
affiliation: NCI - Metabolism Branch;MET
name: John E. Janik, MD
role: STUDY_CHAIR
References: