Ipilimumab After Allogeneic Stem Cell Transplant in Treating Patients With Persistent or Progressive Cancer

Phase 1

Completed

• Conditions: Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Childhood Myelodysplastic Syndromes; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Disseminated Neuroblastoma; Malignant Neoplasm
• Interventions: Drug: ipilimumab; Drug: therapeutic allogeneic lymphocytes

• Registration Number: NCT00060372
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Study Start: 2003-04
• Study First Submitted: 2003-05-06
• Study First Submitted QC: 2003-05-06
• Study First Posted: 2003-05-07
• Primary Completion: 2008-04
• Status Verified: 2013-03
• Last Update Submitted: 2013-03-26
• Last Update Posted: 2013-03-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 21

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

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (ipilmumab and donor lymphocyte infusion)	ipilimumab	Patients receive ipilimumab IV over 90 minutes. Cohorts of 3-6 patients receive escalating doses of ipilimumab until the 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.
Treatment (ipilmumab and donor lymphocyte infusion)	therapeutic allogeneic lymphocytes	Patients receive ipilimumab IV over 90 minutes. Cohorts of 3-6 patients receive escalating doses of ipilimumab until the 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.

Primary Outcome Measures

Name	Time	Method
Incidence of grade 3 and 4 acute GVHD based on NCI CTC	60 days following administration of ipilimumab
Incidence of graft rejection following ipilimumab defined as the percentage of patients entered who demonstrate =< 10% donor T-cell chimerism	Post-infusion day 60
Autoimmune reaction defined as >= grade 3 dysfunction of a vital organ or the graft	Up to 5 years

Secondary Outcome Measures

Name	Time	Method
Polyclonal T-cell activation monitored by clinical assessment and laboratory evidence (anti CD3, CD4, CD8) and markers of activation (anti CD69, CD25, CD44 and MHC class II)	Up to 5 years
Incidence of extensive stage chronic GVHD	Post-infusion day 360
Disease response	Up to day 360 post ipilimumab infusion
Disease-free survival	Up to day 360 following antibody infusion	Kaplan- Meier estimates of probability will be used.
Overall survival	Up to 360 days post-infusion	Kaplan- Meier estimates of probability will be used.

Trial Locations

Locations (5)

Scripps Clinic - La Jolla; 🇺🇸 La Jolla, California, United States

University of California San Diego; 🇺🇸 La Jolla, California, United States

Blood and Marrow Transplant Group of Georgia; 🇺🇸 Atlanta, Georgia, United States

Dana-Farber Harvard Cancer Center; 🇺🇸 Boston, Massachusetts, United States

Northside Hospital; 🇺🇸 Atlanta, Georgia, United States