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CTLA-4 Blockade With MDX-010 to Induce Graft-Versus-Malignancy Effects Following Allogeneic Hematopoietic Stem Cell Transplantation


Phase 1
18 Years
N/A
Not Enrolling
Both
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

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Trial Information

CTLA-4 Blockade With MDX-010 to Induce Graft-Versus-Malignancy Effects Following Allogeneic Hematopoietic Stem Cell Transplantation


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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Incidence of grade 3 and 4 acute GVHD based on NCI CTC

Outcome Time Frame:

60 days following administration of ipilimumab

Safety Issue:

Yes

Principal Investigator

Ewa Carrier

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of California, San Diego

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00042

NCT ID:

NCT00060372

Start Date:

April 2003

Completion Date:

Related Keywords:

  • 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
  • Congenital Abnormalities
  • Breast Neoplasms
  • Burkitt Lymphoma
  • Neoplasms
  • Carcinoma
  • Choriocarcinoma
  • Dermoid Cyst
  • Teratoma
  • Endodermal Sinus Tumor
  • Hodgkin Disease
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Myelodysplastic Syndromes
  • Preleukemia
  • Neuroblastoma
  • Seminoma
  • Testicular Neoplasms
  • Lymphoma, Large-Cell, Immunoblastic
  • Neoplasms, Germ Cell and Embryonal
  • Carcinoma, Embryonal
  • Germinoma
  • Ovarian Neoplasms
  • Lymphoma, Mantle-Cell
  • Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
  • Neoplasms, Glandular and Epithelial

Name

Location

University of California San DiegoLa Jolla, California  92093
Blood and Marrow Transplant Group of GeorgiaAtlanta, Georgia  30342-1601
Northside HospitalAtlanta, Georgia  30342
Dana-Farber Harvard Cancer CenterBoston, Massachusetts  02115
Scripps Clinic - La JollaLa Jolla, California  92037