Neoplasms

Blood and Lymph Conditions

All Conditions

Immune System Diseases

Rare Diseases

Leukemia

Leukemia, T-Cell

Leukemia-Lymphoma, Adult T-Cell

Lymphoma

Neoplasms by Histologic Type

Hematologic Diseases

Leukemia, Lymphoid

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Adult T-cell Leukemia/lymphoma

Leukemia, T-cell, Chronic

Lymphosarcoma

All Drugs and Chemicals

Antineoplastic Agents

Antirheumatic Agents

Antibodies

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Immunoglobulins

Antibodies, Blocking

Immunotoxins

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Administer cycle 1 with Fludarabine and Cyclophosphamide (FC) alone. Two weeks after starting cycle 1, begin up to 6 cycles of FC plus LMB-2 at minimum 20-day intervals.

Begin with 30 mcg/Kg intravenous (IV) on days 3, 5 and 7. Escalate to 40 mcg/Kg if dose limiting toxicity (DLT) in 0/3 or 1/6 at 30 mcg/Kg. Continue at 40 mcg/Kg if 0-1 of 6 have DLT at 40 mcg/Kg.

LMB-2

Days 1-3:

Patients 1-7, 10-14, and \>18:25mg/m\^2/day Patients 8 - 9:30 mg/m\^2/day Patients 15- 17:20 mg/m\^2/day

Days 1-3:

Patients 1-7, 10 -14, and \>18:250 mg/m\^2/day Patients 8 - 9:300 mg/m\^2/day Patients 15-17:200 mg/m\^2/day

Robert J Kreitman, M.D.

BACKGROUND:

* Cluster of differentiation 25 (CD25) (p55, Tac or interleukin 2 receptor (IL2R) alpha) is strongly expressed in virtually 100% of patients with adult T-cell leukemia/lymphoma (ATL), a highly aggressive human T-lymphotropic virus type 1 (HTLV-1) related malignancy responding poorly to chemotherapy.
* In ATL, the humanized anti-CD25 monoclonal antibody (Mab) daclizumab produced 13-14% responses, and the anti-CD52 Mab Alemtuzumab (Campath-1H) produced response lasting greater than 2 months in 30% of 23 patients.
* LMB-2 is an anti-CD25 recombinant immunotoxin containing variable domains of murine MAb anti-Tac and truncated Pseudomonas exotoxin.
* In a phase I trial at National Cancer Institute (NCI), the maximum tolerated dose (MTD) of LMB-2 was 40 microg/Kg intravenous (IV) given every other day for 3 doses (every other day (QOD) times 3). LMB-2 induced greater than 90% tumor reduction rapidly in all 3 ATL patients on protocol, but achieved only 1 partial response due to rapid tumor progression and/or immunogenicity.
* In preclinical models, response from recombinant immunotoxins is limited by high concentrations of soluble receptor in the blood and especially in the interstitial space of the tumor. Synergism was observed with chemotherapy and immunotoxins, possibly due to reduction of soluble receptor in tumor interstitium.

OBJECTIVES:

-To determine, in nonrandomized fashion, if after verifying its safety, fludarabine and cyclophosphamide (FC) prior to LMB2 for ATL can result in low immunogenicity and a rate of major response lasting greater than 2 months, which may be an improvement over that demonstrated previously from Alemtuzumab (CAMPATH).

Secondary objectives:

* To determine the effect of 1 cycle of FC alone in ATL.
* To examine progression-free and overall survival in ATL after FC/LMB-2.
* Evaluate pharmacokinetics, toxicity, and monitor soluble CD25 and other tumor marker levels in the serum.
* To study the effects of LMB-2 plus FC on normal B- and T-cell subsets by fluorescence-activated cell sorting (FACS).

ELIGIBILITY:

* CD25 plus ATL, untreated or with prior therapy
* Eastern Cooperative Oncology Group (ECOG) 0-2, absolute neutrophil count (ANC), platelets and albumin at least 1000, 75,000, and 3.0.

DESIGN:

* Fludarabine 25 mg/m(2) IV days 1-3
* Cyclophosphamide 250 mg/m(2) IV days 1-3
* LMB-2 30-40 micro g/Kg IV days 3, 5 and 7.
* LMB-2 dose: Begin with 30 microg/Kg times 3. Escalate to 40 microg/Kg if dose limiting toxicity (DLT) in 0/3 or 1/6 at 30 microg/Kg. Continue at 40 microg/Kg if 0-1 of 6 have DLT at 40 microg/Kg.
* Administer cycle 1 with FC alone. Two weeks after starting cycle 1, begin up to 6 cycles of FC plus LMB-2 at minimum 20-day intervals.
* Accrual goals: 29-37 patients, which includes 4 replacements....

BACKGROUND:

* Cluster of differentiation 25 (CD25) (p55, Tac or interleukin receptor 2 (IL2Ra) is strongly expressed in virtually 100 % of patients with adult T-cell leukemia/lymphoma (ATL), a highly aggressive human T-lymphotropic virus type 1 (HTLV-1) related malignancy responding poorly to chemotherapy.
* In adult T-cell leukemia (ATL), the humanized anti-CD25 monoclonal antibody (Mab) daclizumab produced 13-14 % responses, and the anti-CD52 Mab Alemtuzumab (Campath- 1H) produced response lasting \> 8 weeks in of 30 % of 23 patients.
* LMB-2 is an anti-CD25 recombinant immunotoxin containing variable domains of murine MAb anti-Tac and truncated Pseudomonas exotoxin.
* In a phase I trial at National Cancer Institute (NCI), the maximum tolerated dose (MTD) of LMB-2 was 40 mcg/Kg dose intravenous (IV) given every other day for 3 doses (every other day (QOD) x3). LMB-2 induced \> 90 % tumor reduction rapidly in all 3 ATL patients on protocol, but achieved only 1 partial response due to rapid tumor progression and/or immunogenicity.
* In preclinical models, response from recombinant immunotoxins is limited by high concentrations of soluble receptor in the blood and especially in the interstitial space of the tumor. Synergism was observed with chemotherapy and immunotoxins, possibly due reduction of soluble receptor in tumor interstitium.

OBJECTIVES:

* To determine, in nonrandomized fashion, if after verifying its safety, fludarabine and cyclophosphamide (FC) prior to LMB2 for ATL can result in low immunogenicity and a rate of major response lasting \> 8 weeks which may be an improvement over that demonstrated previously from Alemtuzumab (CAMPATH).
* Secondary objectives

  * To determine the effect of 1 cycle of FC alone in ATL.
  * To examine progression-free and overall survival in ATL after FC/LMB-2.
  * Evaluate pharmacokinetics, toxicity, and monitor soluble CD25 and other tumor marker levels in the serum.
  * To study the effects of LMB-2 +FC on normal B- and T-cell subsets by FACS.

ELIGIBILITY:

* CD25+ ATL, untreated or with prior therapy, leukemic type without malignant masses \> 4 cm.
* Eastern Cooperative Oncology Group (ECOG) 0-2, absolute neutrophil count (ANC), platelets and albumin at least 1000, 75,000, and 3.0 respectively.

DESIGN:

* IV fludarabine and cyclophosphamide (FC) days 1-3 (doses listed respectively)
* Patients 1-7 and 10-14, and \>18: 25 and 250 mg/m\^2/day
* Patients 8-9: 30 and 300 mg/m\^2/day
* Patients 15-17: 20 and 200 mg/m\^2/day
* LMB-2 dose: Begin with 30 mcg/Kg IV on days 3,5 and 7. Escalate to 40 mcg/Kg if dose limiting toxicity (DLT) in 0/3 or 1/6 at 30 mcg/Kg. Continue at 40 mcg/Kg if 0-1 of 6 have DLT at 40 mcg/Kg.
* Administer cycle 1 with FC alone. Two weeks after starting cycle 1, begin up to 6 cycles of FC plus LMB-2 at minimum 20 day intervals.
* Accrual goals: 29-37 patients, which includes 4 replacements.

Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia

All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.

Response is based on the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma and must last \>8 weeks to meet the primary endpoint of the study. Complete remission (CR) is complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease related symptoms if present before therapy and normalization of those biochemical abnormalities definitely assignable to the lymphoma. Partial response is reduction by ≥50% of leukemia cell count or ≥50% reduction in the size of all measurable lesions, and no increase in size of any measurable or evaluable lesion or appearance of new lesion. Stable disease is neither a response nor progressive disease. Progressive disease is appearance of new lesions, or an increase of 50% or greater in the sum of the product of the perpendicular diameters of the measurable lesions or persistent (at least two determinations) doubling of the peripheral blood leukemic cell count.

The maximum analyte concentration in serum was reported using a cytotoxicity assay measuring the level of LMB-2 in the plasma and using purified LMB-2 as a standard curve.

PFS was determined by the Kaplan Meier method beginning at the on study date and continuing until progression or last follow-up without progression. Progressive disease is assessed by the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma, and is the appearance of new lesions, or an increase of 50% or greater in the sum of the product of the perpendicular diameters of the measurable lesions or persistent (at least two determinations) doubling of the peripheral blood leukemic cell count.

OS is the time between the first day of treatment to the day of disease progression. Progressive disease is assessed by the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma, and is the appearance of new lesions, or an increase of 50% or greater in the sum of the product of the perpendicular diameters of the measurable lesions or persistent (at least two determinations) doubling of the peripheral blood leukemic cell count.

Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

DLT is a grade II-IV LMB-2 or fludarabine and cyclophosphamide (FC)-related toxicity, except vascular leak syndrome, alopecia, grade II-III allergic reaction with asymptomatic bronchospasm or urticarial is considered DLT. Grade III aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, and fever are not considered DLT. Grade IV creatine phosphokinase associated with any other DLT or not resolving to \<grade II within 2 weeks is considered DLT. Hematologic toxicity is not considered DLT unless it fails to resolve to \<grade 2 or baseline by day 18 after cycle 1 or after day 25 after cycles 2-7. DLT from hepatotoxicity, creatine phosphokinase, and vascular leak syndrome is assumed from LMB-2, and hematologic toxicity from fludarabine and cyclophosphamide. Grade III proteinuria lasting \<2 weeks after the last dose of LMB-2 is not considered DLT, and needs to resolve to grade 0-2 prior to retreatment.

Tumor tissue, including lymph node or skin biopsies was examined and analysis performed by flow cytometry to determine the amount of cancer cells in the body by measuring proteins which fall off cancer cells and go into the blood.

AUC is a measure of the plasma concentration of drug over time. It is used to characterize drug absorption. Plasma levels were analyzed by cytotoxicity assay.

Peripheral blood was obtained and analyzed by flow cytometry.

Blood was drawn prior to each cycle of LMB-2 to determine if the level, \>75% neutralization of 1000ng/ml of LMB-2 of neutralizing antibodies is too high to give additional LMB-2. Analysis was performed by cytotoxicity assay.

Duration of response is defined as a response lasting for at least 4 weeks but \>8 weeks and is assessed by the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma. Complete remission (CR) is complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease related symptoms if present before therapy and normalization of those biochemical abnormalities definitely assignable to the lymphoma. Partial response is reduction by ≥50% of leukemia cell count or ≥50% reduction in the size of all measurable lesions, and no increase in size of any measurable or evaluable lesion or appearance of new lesion.

Dilutions of patient plasma was tested by cytotoxicity assays to determine plasma clearance of LMB-2.The CL is a quantitative measure of the rate at which a drug substance is removed from the body.

Dilutions of patient plasma were tested by cytotoxicity assays to determine volume of distribution of LMB-2. Volume distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. This was measured during the first 24 hours after administration of the dose on cycle 2 day 1.

Dilutions of patient plasma was tested by cytotoxicity assays to determine half life. Plasma decay half-life is the time measured for the plasma concentration of the drug to decrease by one half.

Adverse events is assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 3 (mild), Grade 4 (life threatening) and Grade 5 (death).

Adverse events is assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

National Cancer Institute (NCI)

Principal Investigator

Leukemic patients receiving LMB-2 and at least 25+250 mg/m\^2 fludarabine and cyclophosphamide; CF03-CF05, CF07-CF10, and CF12-CF14.

Leukemic Patients Receiving LMB-2 & At Least 25+250 mg/m^2 FC

Patients CF01-CF02, CF06, CF11, and CF15-CF18. This is a mixture of patients who did not receive LMB-2, who had lymphoma-type adult T-cell leukemia, and who received 20+250 mg/m\^2 of fludarabine cyclophosphamide (FC).

All Other Patients

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

African American

Tabago, Black

Peruvian, Hispanic

American from Jamaica, Black

Jamaican, Black

Ethiopian, Black

Jamaican

Barbados, Black

American, from Ghana, Black

Race/Ethnicity, Customized

United States

Region of Enrollment

CHOP

EPOCH-C

C, ESHAP, PTX, Gem

Medi507, Ontak, HAT

CHOP, C

EPOCH-RS

None

Hydroxyurea

CHOP, Hydroxyurea

LSG-15, radiation

Prior treatments included cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP), these 4 agents with etoposide (EPOCH) and campath (C or alemtuzumab, together EPOCH-C), etoposide, methylprednisolone, cytarabine, and cisplatin (ESHAP), pralatrexate (PTX), gemcitabine (Gem), siplizumab (Medi507), denileukin diftitox (Ontak), daclizumab or humanized anti-Tac (HAT) and EPOCH with rituximab and siplizumab (EPOCH-RS). The LSG-15 regimen includes prednisone, adriamycin, carmustine, etoposide, carboplatin, and vinorelbine.

One participant was not evaluable. Participant withdrew due to inability to receive second cycle, which was the first cycle containing LMB-2.

Prior Treatment

Acute

Type of Leukemia

Bone, lung, skin

Thigh (skin)

Pelvis

Muscle

Skin

Lymph node (LN)

Spleen, LN

Subcutaneous

Bone, subcutaneous

Spleen

Extravascular sites

Participants with High Lactate Hydrogenase (LDH)

High Calcium++ is a corrected calcium \> 2.74

Participants with High Calcium++

0 cells

1 cell

80 cells

206 cells

246 cells

408 cells

450 cells

687 cells

5,604 cells

7,737 cells

8,216 cells

13,153 cells

24,112 cells

210,000 cells

213,000 cells

Adult T-cell Leukemia (ATL) cells/mm^3 in the Peripheral Blood

<1 cm tumor

1.9 cm tumor

2 cm tumor

2.2 cm tumor

5.6 cm tumor

5.8 cm tumor

6 cm tumor

9 cm tumor

15, 2.5 cm tumor

17 cm tumor

17.5 cm tumor

18.5, 1.7 cm tumor

20, 1.8 cm tumor

Maximum tumor size is listed, respectively, with the maximum spleen diameter.

Maximum tumor size

Dr. Robert Kreitman

Overall Response

Complete Response

Partial Response

Stable Disease

Progressive Disease

Not Evaluable

All 10 patients receiving LMB-2 and at least 25+250 mg/m\^2 Fludarabine/Cyclophosphamide (FC) were evaluable for response.

Of the 8 other patients, only 5 received LMB-2 and were therefore evaluable for response.

Percentage of Participants With a Minimally Durable Clinical Response Rate

Peak Level of LMB-2 in Adult T-Cell Lymphoma

Published response duration of 15 patients with leukemic adult T cell leukemia treated with Alemtuzumab.

Progression Free Survival (PFS)

One participant withdrew due to inability to receive second cycle, which was the first cycle containing LMB-2.

Overall Survival (OS)

Number of Participants With Serious and Non-serious Adverse Events

Number of Participants With Dose Limiting Toxicity (DLT)

Soluble CD25, lowest post-treatment (nadir) value

Median sCD25 Nadir for responders

Median sCD25 Nadir for non-responders

Median sCD25 PRE-treatment for responders

Median sCD25 PRE-treatment for non-responders

The number 8 represents the number of responders in the Arm/Group and the number 2 represents the number of non-responders in the Arm/Group.

Soluble Cluster of Differentiation 25 (sCD25) Between Responders and Nonresponders

Three participants were non-evaluable. One participant withdrew due to inability to receive second cycle, which was the first cycle containing LMB-2. One participant had progressive disease before first cycle of LMB2, and one participant had progressive disease after first cycle of LMB2

Area Under the Plasma Concentration (AUC) - LMB2

Normal T-cells

Normal CD4+ cells

Normal CD8+ cells

Normal B-cells

One patient did not have flow cytometry measuring it.

Post Treatment Effects of LMB-2 + Fludarabine and Cyclophosphamide (FC) on Normal B and T Cell Subsets by Flow Cytometry

Percentage of Patients Who Developed Neutralizing Antibodies After One or More Cycles of LMB-2

Duration of Response (Complete Response + Partial Response)

Plasma Clearance (CL) of LMB-2

Volume of Distribution of LMB-2

Half Life (t1/2) of LMB-2

Neutropenia

Nausea/vomiting/anorexia

Fever/chills

Leukopenia/lymphopenia

Transaminases

Hypotension/tachycardia

Thrombocytopenia

Anemia

Myalgia/headache

Hypoalbuminemia

Hematuria

Proteinuria

Fatigue/dizziness

Edema

Abdominal pain

Diarrhea

Creatine phosphokinase (CPK)

Mucositis

Hypomagnesemia

Bilirubin

Alkaline phosphatase/gamma-glutamyl transferase

Pneumonitis

Low cluster of differentiation 4 (CD4) count

Lipase

Data for this outcome measure is reported as in the publication noted in the References module.

Count of Participants With Grades 3-5 Adverse Events of > 1 Adult T-Cell Leukemia (ATL) Patients Treated With 20+200, 25+250, and 30+300 mg/m^2 LMB-2/Fludarabine and Cyclophosphamide

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia	NCT00924170	Adult T-Cell Le...	LMB-2 Fludarabine Cyclophosphamid...	18 Years - 100 Years	National Institutes of Health Clinical Center (CC)
Study Evaluating SARS-CoV-2 (COVID-19) Humoral Response After BNT162b2 Vaccine in Immunocompromised Adults Compared to Healthy Adults	NCT04952766	Kidney Transpla... Myeloma Cancer Hematologic Mal... Multiple Sclero... Hypergammaglobu... Malignant Tumor Hiv Diabetes Type 2	Biological samp...	18 Years -	Centre Hospitalier Régional d'Orléans

Spots Global Cancer Trial Database for neutralization