Denileukine Diftitox for Relapsed ALCL

A Phase II Pilot Multicenter Study of Denileukin Diftitox Alone and in Combination With ICE (ICED) Chemotherapy in Children, Adolescents and Young Adults (CAYA) With Relapsed or Refractory Anaplastic Large Cell Lymphoma

The purpose of this study is to determine is Denileukin diftitox will be safe, well tolerated and induce a significant overall response alone and in combination with chemotherapy: ifosfamide, carboplatin and etoposide (ICE) and will be safe and well tolerated in a population of children, adolescents and young adults with relapsed or refractory anaplastic large cell lymphoma (ALCL).

Study Overview

• Status: Withdrawn
• Conditions: Anaplastic Large-Cell Lymphoma
• Intervention / Treatment: Drug: Denileukin Diftitox; Drug: Denileukin diftitox, ifosfamide, cyclophosphamide, etoposide

Detailed Description

Despite significant progress in the treatment and outcome for childhood ALCL, the prognosis for children who develop progressive or recurrent disease is poor with < 30% DFS. Novel therapies are urgently needed for these subgroups of patients. One potential approach is the investigation of a new class of receptor targeted cytotoxic fusion proteins (denileukin diftitox{DD}). We have previously demonstrated that > 85% of children with ALCL express CD25. The human IL-2 receptor exists in three forms, low (CD25), intermediate (CD122/CD132) and high (CD25/CD122/CD132) affinity. DD is a recombinant DNA-derived cytotoxic fusion protein composed of the amino acid sequences for diphtheria toxin fragments followed by the binding sequences for the interleukin-2 receptor. Malignant cells expressing one or more of the subunits of the IL-2 receptor are found in certain leukemias and lymphomas including cutaneous T-cell lymphoma (CTCL). Clinical studies have shown therapeutic efficacy of DD alone and in combination with CHOP chemotherapy in CD25 expressing malignancies such as CTCL, CLL and lymphoma. We hypothesize that DD will be safe and efficacious in children with relapsed ALCL.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 months to 22 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age: Patients must be ≥ 2.00 year and ≤ 24.99 years of age at the time of study entry.
• Diagnosis:

Patients must have previous histologic verification of anaplastic large cell lymphoma (ALCL). Patients must be in first, second or third relapse or initial induction failure.

- Disease Status: Patients must have measurable radiographic disease.

- Performance Level: Karnofsky > 60% for patients > 16 years of age and Lansky > 60 for patients <16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

- Prior Therapy

Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. Patients who are post-allogeneic transplant should be off immunosuppressive agents prior to starting therapy. Steroid doses should also be stable or decreasing for at least 1 week prior to starting therapy.

Myelosuppressive chemotherapy: Must not have received within 2 weeks of entry onto this study (6 weeks if prior nitrosourea).

Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. These patients must be discussed with the Study Chair on a case-by-case basis.

XRT: > 2 wks for local palliative XRT (small port); > 2 months must have elapsed if prior TBI, craniospinal XRT or if > 50% radiation of pelvis; > 6 wks must have elapsed if other substantial BM radiation.

Stem Cell Transplant or Rescue: No evidence of active graft vs. host disease and > 2 months must have elapsed since SCT.

Patients may not have received prior therapy with Denileukin Diftitox

- Organ Function Requirements

Adequate Bone Marrow Function Defined As:

1. For patients without bone marrow involvement:

   • Peripheral absolute neutrophil count (ANC) > 1,000
   • Platelet count > 100,000 (transfusion independent)
   • Hemoglobin > 8.0 gm (RBC transfusion independent)

2. For patients with bone marrow involvement:

   • Peripheral absolute neutrophil count (ANC) > 1,0
   • Platelet count > 20,000 (may receive platelet transfusions)
   • Hemoglobin > 8.0 (may receive RBC transfusions)

Adequate Renal Function Defined As:

Creatinine clearance or radioisotope GFR 70mL/min/1.73m2

OR

A serum/plasma creatinine GFR calculation using the Schwartz formula (Schwartz et al. J. Peds, 106:522, 1985)

Estimated Creatinine Clearance (in mL/min/1.73 m2) = (k)(L)/Pcr

Where L = child's length in cm Pcr = plasma (or serum) creatinine (in mg/dL)

k Values = 0.33 low birth weight infant 0.45 term infant 0.55 child 0.55 adolescent female 0.70 adolescent male

Adequate Liver Function Defined As:

• Bilirubin (sum of conjugated + unconjugated) < 1.5 x upper limit of normal (ULN) for age, and
• SGPT (ALT) < 3 x upper limit of normal (ULN) for age
• Serum albumin > 2 g/dL.

Exclusion Criteria:

• Patients must not be currently receiving another investigational drug.
• Patients must not be currently receiving other anti-cancer agents.
• Patients must have a negative pregnancy test and Nursing mothers must agree not to breast-feed.
• Patients who have a documented uncontrolled infection requiring IV antibiotics
• Patients with CNS disease are not eligible.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: DD Alone; Patients will get Denileukin Diftitox for 5 days every 3 weeks for a total of 4 cycles.	Drug: Denileukin Diftitox; Denileukin Diftitox: 18 mcg/kg/day: days 1-5 in cycles 1,2,3,4; Other Names: Ontak
Experimental: DD with ICE Chemotherapy; For patients who show a response to DD alone after 4 cycles or for patients who show progressive disease after 2 cycles, DD will be given with ICE chemotherapy for 2 cycles.	Drug: Denileukin diftitox, ifosfamide, cyclophosphamide, etoposide; Denileukin Diftitox: 18 mcg/kg/day days 1-2 in cycles 5 and 6 Ifosfamide: 3000mg/m²/IV/d X 3 days + Mesna 3000 mg/m2/d X 3 days Carboplatin: 635mg/m2/d X 1 day Etoposide: 100mg/m2/d X 3 days; Other Names: Ontak

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Toxicity	5 months
Determine response rate	6 months
Evaluate safety of combination of Denileukin Diftitox and ICE chemotherapy	6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Biology Studies of ALCL	6 months

Collaborators and Investigators

• Sponsor: Columbia University
• Investigators: Principal Investigator: Mitchell S Cairo, MD, Columbia University

Study record dates

Study Major Dates

• Study Start: December 1, 2008
• Primary Completion (Anticipated): December 1, 2011
• Study Completion (Anticipated): June 1, 2012

Study Registration Dates

• First Submitted: December 3, 2008
• First Submitted That Met QC Criteria: December 3, 2008
• First Posted (Estimate): December 4, 2008

Study Record Updates

• Last Update Posted (Estimate): May 15, 2013
• Last Update Submitted That Met QC Criteria: May 14, 2013
• Last Verified: October 1, 2009

More Information

Terms related to this study

• Keywords: lymphoma; pediatric; adolescent; relapsed; refractory; denileukin diftitox; Ontak
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma, T-Cell; Lymphoma; Lymphoma, Large-Cell, Anaplastic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Cyclophosphamide; Etoposide; Ifosfamide; Interleukin-2; Denileukin diftitox
• Other Study ID Numbers: AAAC8963