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

Primary Purpose

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)

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
ipilimumab
therapeutic allogeneic lymphocytes
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Scripps Clinic - La Jolla
  • University of California San Diego
  • Blood and Marrow Transplant Group of Georgia
  • Northside Hospital
  • Dana-Farber Harvard Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (ipilmumab and donor lymphocyte infusion)

Arm Description

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.

Outcomes

Primary Outcome Measures

Incidence of grade 3 and 4 acute GVHD based on NCI CTC
Incidence of graft rejection following ipilimumab defined as the percentage of patients entered who demonstrate =< 10% donor T-cell chimerism
Autoimmune reaction defined as >= grade 3 dysfunction of a vital organ or the graft

Secondary Outcome Measures

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)
Incidence of extensive stage chronic GVHD
Disease response
Disease-free survival
Kaplan- Meier estimates of probability will be used.
Overall survival
Kaplan- Meier estimates of probability will be used.

Full Information

First Posted
May 6, 2003
Last Updated
March 26, 2013
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00060372
Brief Title
Ipilimumab After Allogeneic Stem Cell Transplant in Treating Patients With Persistent or Progressive Cancer
Official Title
CTLA-4 Blockade With MDX-010 to Induce Graft-Versus-Malignancy Effects Following Allogeneic Hematopoietic Stem Cell Transplantation
Study Type
Interventional

2. Study Status

Record Verification Date
March 2013
Overall Recruitment Status
Completed
Study Start Date
April 2003 (undefined)
Primary Completion Date
April 2008 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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, Ovarian Choriocarcinoma, Ovarian Embryonal Carcinoma, Ovarian Immature Teratoma, Ovarian Mature Teratoma, Ovarian Mixed Germ Cell Tumor, Ovarian Monodermal and Highly Specialized Teratoma, Ovarian Polyembryoma, Ovarian Yolk Sac Tumor, Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Diffuse Mixed Cell Lymphoma, Recurrent Adult Hodgkin Lymphoma, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Malignant Testicular Germ Cell Tumor, Recurrent Mantle Cell Lymphoma, Recurrent Neuroblastoma, Recurrent Ovarian Epithelial Cancer, Recurrent Ovarian Germ Cell Tumor, Refractory Chronic Lymphocytic Leukemia, Refractory Multiple Myeloma, Relapsing Chronic Myelogenous Leukemia, Stage I Multiple Myeloma, Stage II Multiple Myeloma, Stage II Ovarian Epithelial Cancer, Stage III Malignant Testicular Germ Cell Tumor, Stage III Multiple Myeloma, Stage III Ovarian Epithelial Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer, Stage IV Ovarian Epithelial Cancer, Testicular Choriocarcinoma, Testicular Choriocarcinoma and Embryonal Carcinoma, Testicular Choriocarcinoma and Seminoma, Testicular Choriocarcinoma and Teratoma, Testicular Choriocarcinoma and Yolk Sac Tumor, Testicular Embryonal Carcinoma, Testicular Embryonal Carcinoma and Seminoma, Testicular Embryonal Carcinoma and Teratoma, Testicular Embryonal Carcinoma and Teratoma With Seminoma, Testicular Embryonal Carcinoma and Yolk Sac Tumor, Testicular Embryonal Carcinoma and Yolk Sac Tumor With Seminoma, Testicular Teratoma, Testicular Yolk Sac Tumor, Testicular Yolk Sac Tumor and Teratoma, Testicular Yolk Sac Tumor and Teratoma With Seminoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
21 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (ipilmumab and donor lymphocyte infusion)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
ipilimumab
Other Intervention Name(s)
anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody, MDX-010, MDX-CTLA-4, monoclonal antibody CTLA-4
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
therapeutic allogeneic lymphocytes
Other Intervention Name(s)
ALLOLYMPH
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Incidence of grade 3 and 4 acute GVHD based on NCI CTC
Time Frame
60 days following administration of ipilimumab
Title
Incidence of graft rejection following ipilimumab defined as the percentage of patients entered who demonstrate =< 10% donor T-cell chimerism
Time Frame
Post-infusion day 60
Title
Autoimmune reaction defined as >= grade 3 dysfunction of a vital organ or the graft
Time Frame
Up to 5 years
Secondary Outcome Measure Information:
Title
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)
Time Frame
Up to 5 years
Title
Incidence of extensive stage chronic GVHD
Time Frame
Post-infusion day 360
Title
Disease response
Time Frame
Up to day 360 post ipilimumab infusion
Title
Disease-free survival
Description
Kaplan- Meier estimates of probability will be used.
Time Frame
Up to day 360 following antibody infusion
Title
Overall survival
Description
Kaplan- Meier estimates of probability will be used.
Time Frame
Up to 360 days post-infusion

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ewa Carrier
Organizational Affiliation
University of California, San Diego
Official's Role
Principal Investigator
Facility Information:
Facility Name
Scripps Clinic - La Jolla
City
La Jolla
State/Province
California
ZIP/Postal Code
92037
Country
United States
Facility Name
University of California San Diego
City
La Jolla
State/Province
California
ZIP/Postal Code
92093-0960
Country
United States
Facility Name
Blood and Marrow Transplant Group of Georgia
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30342
Country
United States
Facility Name
Northside Hospital
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30342
Country
United States
Facility Name
Dana-Farber Harvard Cancer Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
18974373
Citation
Bashey A, Medina B, Corringham S, Pasek M, Carrier E, Vrooman L, Lowy I, Solomon SR, Morris LE, Holland HK, Mason JR, Alyea EP, Soiffer RJ, Ball ED. CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood. 2009 Feb 12;113(7):1581-8. doi: 10.1182/blood-2008-07-168468. Epub 2008 Oct 30.
Results Reference
derived

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

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