Continuous Infusion Chemotherapy (CI-CLAM) for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Other High-Grade Myeloid Neoplasms

Dose-Finding (Phase 1) Study of Continuous Infusion Cladribine, Cytarabine and Mitoxantrone (CI-CLAM) for Adults With Relapsed/Refractory Acute Myeloid Leukemia or Other High-Grade Myeloid Neoplasms Treated at UW/SCCA

This phase I trial studies the side effects and best dose of a chemotherapy regimen given by continuous intravenous infusion (CI-CLAM), and to see how well it works in treating patients with acute myeloid leukemia that has come back (relapsed) or does not respond to treatment (refractory) or other high-grade myeloid neoplasms. Drugs used in CI-CLAM include cladribine, cytarabine and mitoxantrone, and work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Continuous intravenous infusion involves giving drugs over a time duration of equal to or more than 24 hours. Giving CLAM via continuous infusion may result in fewer side effects and have similar effectiveness when compared to giving CLAM over the shorter standard amount of time.

Study Overview

• Status: Terminated
• Conditions: Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; Myeloid Neoplasm
• Intervention / Treatment: Drug: Cytarabine; Drug: Mitoxantrone; Drug: Cladribine; Biological: Recombinant Granulocyte Colony-Stimulating Factor

Detailed Description

OUTLINE: This is a dose-escalation study.

Patients receive CI-CLAM consisting of cladribine and cytarabine via continuous intravenous infusion (CIV) on days 1-2, 1-3, 1-4, 1-5, or 1-6 depending on dose level assignment, and mitoxantrone via CIV on days 1-2 or 1-3 depending on dose level assignment. G-CSF may be added at the discretion of the treating physician, as per standard of care. Patients that do not achieve a response of minimal residual disease (MRD)-negative complete remission (CR) after the first cycle are eligible to receive a second cycle of CI-CLAM. Treatment continues for 2 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for up to 5 years.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Initial presentation with > 10% myeloid blasts in peripheral blood or marrow and, after at least one course of induction treatment, now with > 5% blasts in peripheral blood or marrow, as assessed by morphology or multiparameter flow cytometry (MFC). Outside diagnostic material is acceptable if reviewed here. Patients may never have achieved an initial complete remission (< 5% blasts in marrow, absolute neutrophil count > 1,000 per microliter, platelet count > 100,000 per microliter) or may have relapsed from such a remission. Note that although "AML" is formally denoted by > 20% blasts and other high-grade myeloid neoplasm by 10-20% blasts, these two entities often have similar prognoses and respond similarly to therapy, with trials at University of Washington (UW)/Seattle Cancer Care Alliance (SCCA) as well as MD Anderson and various European cooperative groups not distinguishing between AML and other high grade myeloid neoplasms
• Treatment related mortality (TRM) score < 13.1
• Bilirubin < 2.0 mg/dl unless abnormalities thought due to organ infiltration by AML as suggested for example by white blood cell (WBC) > 25,000 and rising rapidly
• Creatinine < 2.0 mg/dl unless abnormalities thought due to organ infiltration by AML as suggested for example by WBC > 25,000 and rising rapidly
• Left ventricular ejection fraction > 45% by multigated acquisition scan (MUGA) scan or echocardiography, performed within 6 months prior to consent
• Off any active therapy for AML other than hydroxyurea for at least 1 week prior to study registration unless patient has rapidly progressive disease with resolution of all grade 2-4 non-hematologic toxicities. Patients with symptoms/signs of hyperleukocytosis or WBC > 100,000 and in whom there is a delay in scheduling a MUGA scan or other logistical delays can receive two doses of cytarabine (500 mg/m^2 each, but dosing is ultimately based on physician discretion)
• Men and women of childbearing potential must agree to use adequate contraception
• Not pregnant or lactating
• Not receiving other investigational agents
• Provision of informed written consent on study-specific consent form

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (CI-CLAM, G-CSF); Patients receive CI-CLAM consisting of cladribine and cytarabine via CIV on days 1-2, 1-3, 1-4, 1-5, or 1-6 depending on dose level assignment, and mitoxantrone via CIV on days 1-2 or 1-3 depending on dose level assignment. G-CSF may be added at the discretion of the treating physician, as per standard of care. Patients that do not achieve a response of MRD-negative CR after the first cycle are eligible to receive a second cycle of CI-CLAM. Treatment continues for 2 cycles in the absence of disease progression or unacceptable toxicity.

Drug: Cytarabine; Given IV; Other Names: .beta.-Cytosine arabinoside; 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-.beta.-D-Arabinofuranosylcytosine; 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-Beta-D-arabinofuranosylcytosine; 1.beta.-D-Arabinofuranosylcytosine; 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-; 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-; Alexan; Ara-C; ARA-cell; Arabine; Arabinofuranosylcytosine; Arabinosylcytosine; Aracytidine; Aracytin; Aracytine; Beta-Cytosine Arabinoside; CHX-3311; Cytarabinum; Cytarbel; Cytosar; Cytosine Arabinoside; Cytosine-.beta.-arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Udicil; WR-28453; Drug: Mitoxantrone; Given IV; Other Names: Dihydroxyanthracenedione; Mitozantrone; Drug: Cladribine; Given IV; Other Names: 2-CdA; CdA; 2CDA; Cladribina; Leustat; Leustatin; Leustatine; RWJ-26251; Biological: Recombinant Granulocyte Colony-Stimulating Factor; Given subcutaneously; Other Names: rhG-CSF; Recombinant Colony-Stimulating Factor 3; 143011-72-7

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose (MTD)	Will use the Bayesian Optimal Interval ("BOIN") design to select the MTDs for continuous infusion G-CSF, cladribine, cytarabine and mitoxantrone (CI GCLAM).	Up to 35 days from start of treatment (or 28 days only if a patient presents with an absolute blast count (white blood count x percent blasts) > 50,000 or one that is doubling every 3 days and is > 25,000)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment responses	Will assess treatment responses (e.g. complete response [CR] +/- minimal residual disease [MRD] , incomplete CR, morphologic leukemia free state, partial response, resistant disease).	Up to 5 years post treatment
Incidence of adverse events	Will use the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 for toxicity and adverse event reporting.	Up to 5 years post treatment

Collaborators and Investigators

• Sponsor: University of Washington
• Investigators: Principal Investigator: Mary-Beth Percival, MD, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): May 8, 2020
• Primary Completion (Actual): October 13, 2021
• Study Completion (Actual): October 13, 2021

Study Registration Dates

• First Submitted: December 10, 2019
• First Submitted That Met QC Criteria: December 10, 2019
• First Posted (Actual): December 12, 2019

Study Record Updates

• Last Update Posted (Actual): December 28, 2023
• Last Update Submitted That Met QC Criteria: December 19, 2023
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: Myeloid and Monocytic Leukemia; Other Hematopoietic
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Adjuvants, Immunologic; Lenograstim; Cytarabine; Mitoxantrone; Cladribine; 2-chloro-3'-deoxyadenosine
• Other Study ID Numbers: RG1005551 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium); 10310 (Fred Hutch/University of Washington Cancer Consortium); NCI-2019-07696 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No