Clofarabine, Cytarabine and Mitoxantrone (CLAM) for Relapsed or Refractory AML

• ClinicalTrials.gov Identifier: NCT02686593
• Recruitment Status: Completed
• First Posted: February 19, 2016
• Last Update Posted: May 9, 2018
• Sponsor: The University of Hong Kong
• Information provided by (Responsible Party): The University of Hong Kong

Study Description

Brief Summary:

The study aims to evaluate the efficacy of the regimen CLAM in relapsed or refractory AML when used as first salvage for patients to relapse or fail after standard treatment with daunorubicin/cytarabine induction.

Condition or disease	Intervention/treatment	Phase
Acute Myeloid Leukemia	Drug: Clofarabine, AraC, mitoxantrone (CLAM)	Phase 2

Detailed Description:

Clofarabine, a second generation purine nucleoside analog, has been evaluated in several studies in relapsed AML.[1-3] Safety and dosages of clorafabine have already been determined in previous phase I/II studies. A demonstrable complete remission rate of up to 40% to 50% was shown in relapsed or refractory AML.[4-6] Since 2009, Clofarabine (40mg/m2/day for 5 days) in combination with high-dose cytarabine (2g/m2/day for 5 days) (CLARA) was adopted as the re-induction protocol for relapsed or refractory patients with AML at the Department of Medicine, Queen Mary Hospital. We have shown that this protocol is safe, tolerable and effective for relapsed AML. A recent updated analysis (Gill H et al., unpublished) showed a completed response rate of 50.8%. With the CLARA regimen, all patients (N=60) developed grade 3/4 neutropenia and thrombocytopenia. 8% developed grade 3/4 hepatotoxicity and 40% developed febrile neutropenia with clinical sepsis. There is increasing evidence to show that clofarabine is safe and efficacious when combined with the anthracyclines idarubicin or daunorubicin.7,8 In this prospective study, we combine clofarabine and cytarabine (Ara-C) with the topoisomerase II inhibitor mitoxantrone. In this protocol, the dosages of clofarabine and cytarabine will be reduced to 30mg/m2/day and 750mg/m2/day respectively, comparable to most clinical trials. In our previous publication of experience with the use of CLARA by Tse et al and Leung et al, clofarabine at 40mg/m2/day for 5 days was combined with high-dose cytarabine at 2g/m2/day.[5,6] The regimen was shown to be safe. The combination of clofarabine with anthracyclines has been evaluated. Mathiesen at al evaluated the CIA regimen comprising clofarabine at 20mg/m2/day from day 1 to day 5, idarubicin at 10mg/m2/day from day 1 to day 3 and cytarabine at 1g/m2/day from day 1 to day 5.[7] Abbie et al investigated the regimen comprising Clofarabine at 20mg/m2/day or 25mg/m2/day for 5 days in combination with mitoxantrone and etoposide.7 Based on the clinical trials and our extensive experience with the use of CLARA, the dosages of clofarabine in CLAM was determined. With the significant reduction in the dose of cytarabine to 750mg/m2/day for 5 days in CLAM, the dose of clofarabine was chosen at 30mg/m2/day for 5 days with the aim to maintain the efficacy seen with CLARA. The aim of this combination is to maintain or improve treatment efficacy seen with a lower treatment-related toxicity via dose reduction of clofarabine and cytarabine compared to CLARA. CLAM is expected to be safe and tolerable especially when used as first salvage in patient with a ECOG performance status of 0 or 1. The regimen CLAM has been approved by the institutional review board of Queen Mary Hospital/University of Hong Kong. In a pilot study, 4 patients used the regimen. 2 patients achieved a complete remission. Cardiotoxicity was not seen. Grade 3/4 hepatotoxicity was not seen. There were no treatment-related mortality observed. CLAM was shown to be safe and with manageable toxicity profile. In addition, less myeloid toxicity is expected during consolidation as patients who achieve a remission will have better marrow reserve when compared to those at relapse. Patients will have their cardiac, liver and renal function and performance status evaluated continuously and patients with cardiac dysfunction, significantly impaired renal or liver function and ECOG performance status of 2 or above will be excluded. Thus consolidation with the same dose as with induction is expected to be safe and tolerable.

The study aims to evaluate the efficacy of the regimen CLAM in relapsed or refractory AML when used as first salvage for patients to relapse or fail after standard treatment with daunorubicin/cytarabine induction. We aim to improve treatment efficacy at a more tolerable dose of clofarabine and cytarabine compared to CLARA.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 50 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Clofarabine, Cytarabine and Mitoxantrone (CLAM) for Relapsed or Refractory AML
• Actual Study Start Date: February 1, 2016
• Actual Primary Completion Date: March 31, 2018
• Actual Study Completion Date: May 1, 2018

Arms and Interventions

Arm	Intervention/treatment
Clofarabine, AraC, mitoxantrone (CLAM); This is the single arm with the intervention using Clofarabine, AraC, Mitoxantrone	Drug: Clofarabine, AraC, mitoxantrone (CLAM); The combination of clofarabine, cytarabine (Ara-C) and mitoxantrone will be used in patients with AML in first relapse or after failure of first salvage; Other Name: CLAM

Outcome Measures

Primary Outcome Measures :

1. Response rate [ Time Frame: Day 28 ]
   Remission status will be assessed on day 28 of treatment for the assessment of response rate using standard criteria

Secondary Outcome Measures :

1. Leukemia-free survival [ Time Frame: 2 years ]
   This is defined as time (in months) from remission after CLAM regimen to relapse (event), death (censor), HSCT (censor) or latest follow-up (censor).
2. Overall survival [ Time Frame: 5 years ]
   This is defined as the time (in months) from recruitment to death (event) or latest follow-up (censor).
3. Toxicity [ Time Frame: 1 year ]
   Toxicity will be defined using the NCI Common Terminology Criteria for Adverse Events (CTCAE). Data on all toxicities listed will be recorded.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Relapsed or refractory acute myeloid leukemia (AML) after one first-line chemotherapy regimen
2. Patients aged 18 - 65 inclusively
3. European Cooperative Oncology Group (ECOG) performance status of less than 2

Exclusion Criteria:

1. Patients aged less than 18 or above 65
2. ECOG performance status of 2 or more
3. Acute promyelocytic leukaemia
4. Uncontrolled active infection
5. Uncontrolled arrhythmia
6. Altered renal dysfunction with serum creatinine > 1.5 x ULN and/or creatinine clearance < 50 mL/min
7. Significant neurologic (grade > 2) or psychiatric disorder, dementia or seizures
8. Clinical symptoms suggesting active central nervous system leukemia
9. Severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock or disseminated intravascular coagulation
10. Patients with known HIV, Hepatitis B or C infection or history of cirrhosis
11. Patients Significant hepatic dysfunction: Direct bilirubin > 1.5 x upper limit of normal (ULN) for age; ALT or AST > 3 x upper limit of normal (ULN) for age; Lipase > 2.0 x upper limit of normal (ULN) for age
12. Females of childbearing potential must have a negative pregnancy test

Contacts and Locations

Locations

Hong Kong

The University of Hong Kong

Hong Kong, Hong Kong

Sponsors and Collaborators

The University of Hong Kong

Investigators

• Principal Investigator: Harinder Singh, Harry Gill, MD; The University of Hong Kong

More Information

Publications:

Faderl S, Gandhi V, Kantarjian HM. Potential role of novel nucleoside analogs in the treatment of acute myeloid leukemia. Curr Opin Hematol. 2008 Mar;15(2):101-7. doi: 10.1097/MOH.0b013e3282f46e94. Review.

Faderl S, Ferrajoli A, Wierda W, Huang X, Verstovsek S, Ravandi F, Estrov Z, Borthakur G, Kwari M, Kantarjian HM. Clofarabine combinations as acute myeloid leukemia salvage therapy. Cancer. 2008 Oct 15;113(8):2090-6. doi: 10.1002/cncr.23816.

Sampat K, Kantarjian H, Borthakur G. Clofarabine: emerging role in leukemias. Expert Opin Investig Drugs. 2009 Oct;18(10):1559-64. doi: 10.1517/13543780903173222.

Becker PS, Kantarjian HM, Appelbaum FR, Petersdorf SH, Storer B, Pierce S, Shan J, Hendrie PC, Pagel JM, Shustov AR, Stirewalt DL, Faderl S, Harrington E, Estey EH. Clofarabine with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapsed and refractory acute myeloid leukaemia. Br J Haematol. 2011 Oct;155(2):182-9. doi: 10.1111/j.1365-2141.2011.08831.x. Epub 2011 Aug 18.

Tse E, Leung AY, Sim J, Lee HK, Liu HS, Yip SF, Kwong YL. Clofarabine and high-dose cytosine arabinoside in the treatment of refractory or relapsed acute myeloid leukaemia. Ann Hematol. 2011 Nov;90(11):1277-81. doi: 10.1007/s00277-011-1223-2. Epub 2011 Apr 1.

Leung AY, Tse E, Hwang YY, Chan TS, Gill H, Chim CS, Lie AK, Kwong YL. Primary treatment of leukemia relapses after allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning second transplantation from the original donor. Am J Hematol. 2013 Jun;88(6):485-91. doi: 10.1002/ajh.23439. Epub 2013 May 2.

Nazha A, Kantarjian H, Ravandi F, Huang X, Choi S, Garcia-Manero G, Jabbour E, Borthakur G, Kadia T, Konopleva M, Cortes J, Ferrajoli A, Kornblau S, Daver N, Pemmaraju N, Andreeff M, Estrov Z, Du M, Brandt M, Faderl S. Clofarabine, idarubicin, and cytarabine (CIA) as frontline therapy for patients ≤60 years with newly diagnosed acute myeloid leukemia. Am J Hematol. 2013 Nov;88(11):961-6. doi: 10.1002/ajh.23544. Epub 2013 Sep 9.

Vigil CE, Tan W, Deeb G, Sait SN, Block AW, Starostik P, Griffiths EA, Thompson JE, Greene JD, Ford LA, Wang ES, Wetzler M. Phase II trial of clofarabine and daunorubicin as induction therapy for acute myeloid leukemia patients greater than or equal to 60 years of age. Leuk Res. 2013 Nov;37(11):1468-71. doi: 10.1016/j.leukres.2013.07.036. Epub 2013 Aug 15.

Abbi KK, Rybka W, Ehmann WC, Claxton DF. Phase I/II study of clofarabine, etoposide, and mitoxantrone in patients with refractory or relapsed acute leukemia. Clin Lymphoma Myeloma Leuk. 2015 Jan;15(1):41-6. doi: 10.1016/j.clml.2014.06.005. Epub 2014 Jun 11.

• Responsible Party: The University of Hong Kong
• ClinicalTrials.gov Identifier: NCT02686593 History of Changes
• Other Study ID Numbers: CLOFAL07200
• First Posted: February 19, 2016
• Last Update Posted: May 9, 2018
• Last Verified: May 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by The University of Hong Kong:

Clofarabine; Acute Myeloid Leukemia

Additional relevant MeSH terms:

Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia; Neoplasms by Histologic Type; Neoplasms; Cytarabine; Clofarabine; Mitoxantrone; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors