Phase 2
N=18
Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia
Adult T-Cell Leukemia (ATL)
Bottom Line
View on ClinicalTrials.gov: NCT00924170 ↗Enrolled (actual)
18
Serious AEs
72.2%
Results posted
Sep 2017
Primary outcome: Primary: Percentage of Participants With a Minimally Durable Clinical Response Rate — 80; 0; 60; 0 percentage of participants
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- LMB-2 (Drug); Fludarabine (Drug); Cyclophosphamide (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- National Cancer Institute (NCI)
- Primary completion
- Jan 2016
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Percentage of Participants With a Minimally Durable Clinical Response Rate |
80; 0; 60; 0; 20; 0 | — |
| SECONDARY Peak Level of LMB-2 in Adult T-Cell Lymphoma |
602; 484 | — |
| SECONDARY Progression Free Survival (PFS) |
11.6; 1.05 | <0.0001 sig |
| SECONDARY Overall Survival (OS) |
18.6; 3.75 | — |
| SECONDARY Number of Participants With Serious and Non-serious Adverse Events |
10; 8 | — |
| SECONDARY Number of Participants With Dose Limiting Toxicity (DLT) |
0; 0 | — |
| SECONDARY Soluble Cluster of Differentiation 25 (sCD25) Between Responders and Nonresponders |
1094; 34591; 1082; 70713; 34591; 31893 | — |
| SECONDARY Area Under the Plasma Concentration (AUC) - LMB2 |
161; 144 | — |
| SECONDARY Post Treatment Effects of LMB-2 + Fludarabine and Cyclophosphamide (FC) on Normal B and T Cell Subsets by Flow Cytometry |
28; 23.5; 99.5; 186; 28; 23.5 | — |
| SECONDARY Percentage of Patients Who Developed Neutralizing Antibodies After One or More Cycles of LMB-2 |
40; 0 | — |
| SECONDARY Duration of Response (Complete Response + Partial Response) |
69.6; 0 | — |
| SECONDARY Plasma Clearance (CL) of LMB-2 |
109; 101 | — |
| SECONDARY Volume of Distribution of LMB-2 |
49.6; 26.6 | — |
| SECONDARY Half Life (t1/2) of LMB-2 |
360; 251 | — |
| SECONDARY 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 |
2; 10; 2; 2; 10; 2 | — |
| SECONDARY Count of Participants With Adverse Events Attributed At Least Possibly to Patients Treated With Fludarabine and Cyclophosphamide Dose Levels 20+200, 25+250, and 30+300 mg/m^2 |
1; 9; 2; 1; 9; 2 | — |
Summary
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....
Eligibility Criteria
- INCLUSION CRITERIA:
- Diagnosis of acute or lymphomatous adult T-cell leukemia (ATL) by flow cytometry of blood or immunohistochemistry of biopsy tissue, confirmed by National Cancer Institute (NCI) Laboratory of Pathology, and previously treated unless the patient is ineligible for or refuses other protocols or treatments for ATL.
- Neutralizing antibodies less than or equal to 75% neutralization of 200 ng/ml of LMB-2.
- At least 18 years old.
- Eastern Cooperative Oncology Group (ECOG) 0-2.
- Able to understand and give informed consent.
- Negative pregnancy test for females of childbearing potential.
- The transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must each be less than or equal to 3-times the upper limits of normal (UNL) or less than or equal to 10-times normal if due to ATL. Albumin must be greater than or equal to 3.0 gm/dL. Total bilirubin must be less than or equal to 1.5 mg/dL except in patients with Gilberts syndrome (as defined by greater than 80 percent unconjugated bilirubin) it must be less than 5mg/dl.
- Creatinine less than 2.0 mg/dL.
- Absolute neutrophil count (ANC) greater than or equal to 1000/uL and platelets greater than or equal to 50,000/uL.
- Current or prior features of acute ( corrected calcium (Ca)++ > 2.73 or lactate dehydrogenase (LDH) 2- fold above ULN) or chronic (LDH 1.5-2-fold above ULN or absolute lymphocyte count >4 x10^9/L with T-cells >3.5 x10^9/L) ATL. Patients with smoldering ATL (no acute or chronic features) and symptomatic ATL skin lesions are also eligible.
EXCLUSION CRITERIA
- Prior therapy with LMB-2.
- Central nervous system disease as evidenced by clinical symptomatology.
- Cytotoxic chemotherapy, steroids or monoclonal antibody (Mab) within 3 weeks of enrollment, except anti Tac Mab (i.e. daclizumab), which cannot be used within 12 weeks of enrollment. Hydroxyurea is considered different from cytotoxic chemotherapy and may be used up to the day before enrollment providing it is not increased during the week prior to enrollment and that patients disease burden is not decreasing during that time.
- Uncontrolled infection.
- Untreated or uncontrolled 2nd malignancy.
- Patients who are pregnant or breast-feeding.
- Patients who have human immunodeficiency virus (HIV) or hepatitis C, since in these patients reductions in normal T- or B-cells would increase the risk of exacerbation of their underlying disease. Patients would not be excluded for hepatitis B surface antigen positivity if on Lamivudine or Entecavir.
- Patients receiving warfarin (Coumadin [R])
- Patients with a left ventricular ejection fraction of less than 45%.
- Patients with a diffusing capacity of the lungs for carbon monoxide (DLCO) less than 50% of normal or an forced expiratory volume 1 (FEV1) less than 50% of normal.
- No concomitant use of alternative complimentary therapies or over the counter (OTC) agents allowed without prior approval of the principal investigator (PI).
- Tumor or lymph node masses > 4 cm.
Data sourced from ClinicalTrials.gov (NCT00924170). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.