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

Phase 1/Phase 2
16 Years
Open (Enrolling)
Acute Lymphoblastic Leukemia

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Trial Information

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

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.

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

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

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.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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

Outcome Time Frame:

2 years

Safety Issue:



United States: Food and Drug Administration

Study ID:




Start Date:

September 2009

Completion Date:

September 2011

Related Keywords:

  • Acute Lymphoblastic Leukemia
  • cancer
  • lymphoblastic
  • leukemia
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma



Rebecca and John Moores UCSD Cancer CenterLa Jolla, California  92093-0658
UCSD Medical CenterLa Jolla, California  92093
Rady Children's HospitalSan Diego, California  92123