Ipilimumab After Allogeneic Stem Cell Transplant in Treating Patients With Persistent or Progressive Cancer
Ipilimumab After Allogeneic Stem Cell Transplant in Treating Patients With Persistent or Progressive Cancer
This phase I trial is studying how well ipilimumab works after allogeneic stem cell
 transplant in treating patients with persistent or progressive cancer. Monoclonal antibodies
 can locate cancer cells and either kill them or deliver cancer-killing substances to them
 without harming normal cells.
PRIMARY OBJECTIVES:

 I. To determine the dose of MDX-010 (ipilimumab) that can safely be administered to patients
 with persistent or progressive malignancy following allo-HCT.

 II. To determine the pharmacokinetics of different doses of MDX-010 administered as a single
 dose to patients with persistent or progressive malignancy following allo-HCT.

 III. By assessment of aims 1 and 2, to determine the best dosing regimen for further study of
 CTLA-4 blockade in conjunction with escalating dose donor-leukocyte infusions (DLI) in
 patients with evidence of residual or progressive malignancy following allo-HCT.

 IV. To assess if there is preliminary evidence of efficacy following the administration of
 MDX-010 in this population.

 OUTLINE:

 Patients receive ipilimumab intravenously (IV) over 90 minutes.

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

 Patients with persistent or progressive disease at 60 days after ipilimumab administration
 and no evidence of graft-versus-host disease receive donor lymphocyte infusions every 60 days
 for a total of 3 infusions.

 Patients are followed at 4, 5, 6, 9, and 12 months and then annually thereafter.
Inclusion Criteria:

 -  Diagnosis of persistent or progressive hematologic malignancy or solid tumor after
 allogeneic hematopoietic stem cell transplantation (AHSCT)

 -  Patients are eligible for study entry at any time between post-transplantation day 90
 and 3 years after withdrawal of immunosuppressive therapy

 -  Acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) that meets any of
 the following criteria: hematologic relapse by standard criteria, hematologic
 persistence evidenced by bone marrow blasts > 10% after day 30 post-AHSCT

 -  Cytogenetic progression as evidenced by an increase in the percentage of Philadelphia
 chromosome (Ph)1-positive metaphases (or Ph1-positive cells by fluorescent in situ
 hybridization) from complete cytogenetic response (0% Ph1-positive cells) to partial
 response (1-34% Ph1-positive cells); PR to minor response (35-94% Ph1-positive cells);
 or MR to no response (95-100% Ph1-positive cells)

 -  Resistance to imatinib mesylate, defined as disease progression (hematologic,
 cytogenetic, or molecular) during OR failure to respond to (i.e., lack of complete
 hematologic response after 3 months, lack of partial cytogenetic response after 6
 months, or lack of complete cytogenetic response after 12 months) prior imatinib
 mesylate therapy

 -  Myelodysplastic syndromes that meet any of the following criteria:

 Hematologic relapse by standard criteria, cytogenetic relapse evidenced by recurrence of
 clonal abnormality in patients who achieved CCR after AHSCT, hematologic persistence
 evidenced by cytopenias not attributable to other post-transplant causes accompanied by
 characteristic morphological changes more than 90 days after AHSCT

 -  OR; Hematologic persistence evidenced by cytopenias not attributable to other
 post-transplant causes accompanied by characteristic morphological changes more than
 90 days after AHSCT, or cytogenetic persistence evidenced by persistence of clonal
 abnormality more than 90 days after AHSCT

 -  Chronic lymphocytic leukemia that meets any of the following criteria:

 greater than 25% increase in absolute lymphocytosis of > 5,000/mm3, greater than 25%
 increase in measurable lymphadenopathy, persistence of absolute lymphocytosis of >
 5,000/mm3 at day 90 or later after AHSCT, persistence of lymphadenopathy of ≥ 3 cm in
 diameter at day 90 or later after AHSCT

 -  Aggressive non-Hodgkin's lymphoma (e.g., diffuse large cell lymphoma, lymphoblastic
 lymphoma, mantle cell lymphoma, or peripheral T cell lymphoma), Hodgkin's lymphoma, OR
 solid tumor that meets any of the following criteria: greater than 50% increase in
 measurable or evaluable disease, persistence of measurable lesions > 3.0 cm in
 diameter at day 90 or later after AHSCT OR;

 -  Persistence of malignancy by biopsy or positron emission tomography scan unless there
 is clear evidence of progression

 -  Multiple myeloma with demonstrated resistance to or intolerance of prior thalidomide
 and bortezomib unless these agents are contraindicated (e.g., due to peripheral
 neuropathy) and meeting any of the following criteria: greater than 25% increase in
 paraprotein band, abnormal quantitative immunoglobulin level, or urine protein
 excretion OR

 -  Greater than 25% increase in percent of plasma cells in the bone marrow (if > 15%),
 presence of new lytic bone lesions, new extramedullary lesions OR ≥ 25% enlargement of
 existing extramedullary lesions, persistence of paraprotein band, abnormally elevated
 quantitative immunoglobulin level, or bone marrow plasmacytosis > 15% for a period of
 at least 90 days after AHSCT

 -  At least 1 bidimensionally measurable lesion ≥ 1.5 cm in diameter

 -  Evaluable disease is defined as disease that is assessable for response (e.g., pleural
 effusion, elevated serum tumor)

 -  Bone metastases that can be assessed by CT scan or MRI considered evaluable

 -  Leukemia is considered evaluable disease

 -  Patients who met criteria for persistence or progression with AML, ALL, CML, or
 aggressive NHL AND are currently in complete remission after reinduction therapy do
 not require measurable or evaluable disease to be eligible

 -  At least 50% donor chimerism in the T-cell lineage OR full (≥ 90%) donor chimerism in
 unseparated blood on last assessment within 3 months before study entry

 -  No evidence on consecutive testing of > 10% decline in T-cell chimerism beyond the
 error of the test

 -  ECOG 0-2

 -  Life expectancy: More than 3 months

 -  No prior grade 3 or 4 acute graft-vs-host disease

 -  No concurrent autoimmune diseases requiring the chronic use of immunosuppressive
 medications, active connective tissue disease, CNS disease including multiple
 sclerosis or demyelinating disease, inflammatory bowel disease, autoimmune hepatitis

 -  No ongoing serious infection

 -  Negative pregnancy test

 -  Fertile patients must use effective contraception during and for at least 4 months
 after study therapy

 -  No other serious ongoing medical condition that would preclude study participation

 -  No other malignancy within the past 5 years

 -  No psychological or psychiatric condition that would preclude study participation

 -  No prior anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody
 (MDX-010)

 -  At least 6 weeks since prior immunosuppressive agents

 -  At least 2 weeks since prior imatinib mesylate

 -  No concurrent imatinib mesylate

 -  At least 6 weeks since prior and no concurrent immunosuppressive agents for clinically
 active graft-versus-host disease (GVHD) prophylaxis or treatment

 -  No other concurrent investigational agents

 -  OR Cytogenetic persistence evidenced by any Ph1-positive metaphases in bone marrow
 after day 90 post-AHSCT