Alemtuzumab and Clofarabine for Relapsed or Refractory Acute Lymphoblastic Leukemia

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Brief Title

Alemtuzumab and Clofarabine for Relapsed or Refractory Acute Lymphoblastic Leukemia

Official Title

A Phase I/II Study of Alemtuzumab and Clofarabine for Relapsed or Refractory Acute Lymphoblastic Leukemia

Brief Summary

      Clofarabine is approved by the FDA for the treatment of pediatric patients (1 to 21 years of
      age) with relapsed or refractory ALL. Alemtuzumab is approved by the FDA for treatment of
      B-cell chronic lymphocytic leukemia (B-CLL) in patients over the age of 18. These drugs have
      been used to treat patients with leukemia in other research studies like this one. Both drugs
      have individually been administered to adult patients with ALL with acceptable toxicity
      profiles. This study will evaluate the combination of clofarabine and alemtuzumab when
      administered to adult patients with relapsed or refractory ALL. Primary objectives of the
      study is to determine the maximum tolerated dose of clofarabine when administered with
      alemtuzumab, evaluate the safety of the combination, and assess for activity of the
      combination by evaluating response rate, effect on ALL progenitor cell population, and
      patients who are able to bridge to transplant.
    

Detailed Description

      The strategy for treating relapsed and refractory adult ALL patients is through reinduction
      chemotherapy followed by allogeneic stem cell transplantation, provided that the toxicity of
      the salvage regimen is acceptable. However, this leukemia is characterized as being highly
      refractory to standard chemotherapy and therefore novel therapeutic approaches are
      desperately needed. Clofarabine is a second generation nucleoside analog FDA approved for the
      treatment of relapsed and refractory pediatric ALL. Clofarabine has been administered to
      adult patients with hematologic malignancies with an acceptable toxicity profile with 8% of
      relapsed ALL patients attaining a complete response (CR). The maximum tolerated dose (MTD) of
      clofarabine IV in adult patients has been determined to be 40 mg/m2/day for 5 consecutive
      days, which is lower than the tolerable daily dose for pediatric patients, 52 mg/m2/day. More
      recently, Karp and colleagues reported their experience with clofarabine in combination with
      cyclophosphamide in 18 patients with refractory acute leukemias. Encouraging responses were
      seen in the refractory ALL patients with 67% (4/6) patients experiencing a CR. Toxicity did
      not allow dose escalation of clofarabine and the MTD was defined as 10 mg/m2 administered
      over 6 non-consecutive days when combined with cyclophosphamide 200-400mg/m2 over a total of
      7 days per cycle. As such, we are conservatively evaluating a clofarabine dose of 20mg/m2 for
      five days with a dose de-escalation step if there is dose limiting toxicity.

      The addition of monoclonal antibody therapy is an attractive approach in the treatment of
      relapsed and refractory ALL since it targets both B and T progenitor ALL subtypes and has
      different mechanisms of action and side effects than chemotherapy. Alemtuzumab is a humanized
      monoclonal antibody to CD52 which is expressed on the majority of neoplastic lymphocytes,
      including 70% of ALL and 100% of Philadelphia positive ALL. The CALGB evaluated alemtuzumab
      as consolidation in front-line therapy for patients with ALL and demonstrated feasibility and
      found alemtuzumab administration at 30mg subcutaneously administered for 12 doses to be safe
      and well tolerated in a frontline consolidation setting in ALL. In the present protocol
      targeting refractory and relapsed ALL patients, the maximal alemtuzumab dose will be 30 mg as
      in Stock's study, but will be administered intravenously in order to improve the induction
      chemotherapy pharmacokinetics. Premedication with dexamethasone, benadryl, and acetaminophen
      will be given to all patients prior to alemtuzumab infusion to prevent infusional reactions
      associated with intravenous dosing.

      The combination of purine analogs and alemtuzumab have been administered simultaneously
      safely with promising additive activity in other relapsed and refractory lymphocytic
      leukemias. A recent case series reported patients with relapsed and/or refractory ALL who
      failed several induction chemotherapies to achieve complete responses to fludarabine and
      alemtuzumab combination regimens. All patients were able to proceed to allogeneic SCT with
      refractory ALL patient relapsing at 8 months while relapsed patients remain in remission at 6
      and 24 months.

      Other approaches utilizing combination chemotherapy have failed to demonstrate consistent
      activity that would qualify them as standard of care. Therefore the standard of care for
      patients with relapsed and refractory ALL is enrollment into clinical trials.

      All patients will receive alemtuzumab in a dose escalation fashion (3, 10, 30mg). Successive
      escalating doses will be administered if the previous dose is tolerated. Previously, Stock et
      al established the safety of 12 doses of 30mg of alemtuzumab in ALL. The treatment regimen is
      designed to have alemtuzumab administered prior to administration of clofarabine to allow
      dose escalation of the monoclonal antibody and decrease confounding acute toxicities such as
      infusion reactions and cytokine release. Clofarabine dose is modeled after previous trials in
      adult and pediatric ALL. The starting dose of clofarabine is lower than standard phase II
      doses for adult hematologic malignancy to conservatively evaluate tolerability and toxicity
      of clofarabine in combination with alemtuzumab. Alemtuzumab dosing will be limited to a total
      of 12. However, patients can continue with additional cycles of clofarabine if they do not
      show progressive disease or have unacceptable toxicity.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

To determine the maximum tolerated dose of clofarabine when administered in combination with alemtuzumab as measured by CTC version 3.0. (Phase 1)

Secondary Outcome

 Evaluate how many patients who are potential allogeneic stem cell transplant candidates receive stem cell transplant.

Condition

Acute Lymphoblastic Leukemia

Intervention

Alemtuzumab


Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

28

Start Date

September 2009

Completion Date

September 2011

Primary Completion Date

September 2011

Eligibility Criteria

        Inclusion Criteria:

          1. Provide signed written informed consent. If a patient is under the 18 years of age the
             parent or the guardian will also need to provide written informed consent.

          2. Diagnosis of ALL (B or T lineage) who have received therapy with at least 1 but not
             more than 3 prior different induction regimens and have been deemed to have relapse or
             refractory disease. The phase II component of the study enrollment will be limited to
             2 different prior induction regimens if patients are older than 30 years.

          3. ALL lymphoblasts with CD52 expression on at least 10% on lymphoblasts.

          4. Age >= 16 years of age.

          5. ECOG PS 0-2.

          6. Have adequate renal and hepatic functions.

          7. Subject or their patient or guardian is capable of understanding the investigational
             nature, potential risks and benefits of the study, and able to provide valid informed
             consent.

          8. Female patients of childbearing potential must have a negative serum pregnancy test
             within 2 weeks prior to enrollment.

          9. Male and female patients must use an effective contraceptive method during the study
             and for a minimum of 6 months after study treatment. Subjects 16 and 17 years old must
             also adhere to effective contraception methods or abstinence during the study and for
             a minimum of 6 months after study and the nature of contraception or abstinence must
             be documented.

         10. CMV PCR negative prior to enrollment

        Exclusion Criteria:

          1. Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as
             specified in the protocol.

          2. Use of investigational agents within 30 days or any anticancer therapy within 2 weeks
             before study entry with the exception of hydroxyurea, CNS treatment or prophylaxis, or
             tyrosine kinase inhibitors for individuals with Philadelphia chromosome positive ALL.
             The patient must have recovered from all acute toxicities from any previous therapy.

          3. Lack of bone marrow or blood involvement by leukemia such as a documented CNS or
             testicular only relapse.

          4. Have any other severe concurrent disease, or have a history of serious organ
             dysfunction or disease involving the heart, kidney, liver, or other organ system that
             may place the patient at undue risk to undergo treatment.

          5. Patients with any known or suspected Hepatitis B, C and HIV infections.

          6. Patients with a systemic fungal, bacterial, viral, or other infection not controlled
             (defined as exhibiting ongoing signs/symptoms related to the infection and without
             improvement, despite appropriate antibiotics or other treatment).

          7. Pregnant or lactating patients.

          8. Any significant concurrent disease, illness, or psychiatric disorder that would
             compromise patient safety or compliance, interfere with consent, study participation,
             follow up, or interpretation of study results.
      

Gender

All

Ages

16 Years - N/A

Accepts Healthy Volunteers

No

Contacts

, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00983528

Organization ID

090331



Study Sponsor

University of California, San Diego

Collaborators

 Genzyme, a Sanofi Company

Study Sponsor

, , 


Verification Date

May 2011