Alemtuzumab and Clofarabine for Relapsed or Refractory Acute Lymphoblastic Leukemia

• ClinicalTrials.gov Identifier: NCT00983528
• Recruitment Status: Unknown
• First Posted: September 24, 2009
• Last Update Posted: May 4, 2011
• Sponsor: University of California, San Diego
• Collaborator: Genzyme, a Sanofi Company
• Information provided by: University of California, San Diego

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Acute Lymphoblastic Leukemia	Biological: Alemtuzumab; Drug: Clofarabine	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 28 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study of Alemtuzumab and Clofarabine for Relapsed or Refractory Acute Lymphoblastic Leukemia
• Study Start Date: September 2009
• Estimated Primary Completion Date: September 2011
• Estimated Study Completion Date: September 2011

Arms and Interventions

Intervention Details:

• Biological: Alemtuzumab
  3mg day 1,10mg day 2, 30mg day 3, 30mg day 5, 30mg day 8, then three times per calendar week thereafter for a total 12- 30mg doses
  Other Name: Campath
• Drug: Clofarabine

  Dose Escalation

  Cycle 1 (30 days or until alemtuzumab completed) Clofarabine 10,20,30 or 40 mg/m2 days 5-9

  Cycle 2 and subsequent cycles (administered no more frequently than every 28 days) 10,20,30 or 40 mg/m2 days 1-5

  Other Name: Clolar

Outcome Measures

Primary Outcome Measures :

1. To determine the maximum tolerated dose of clofarabine when administered in combination with alemtuzumab as measured by CTC version 3.0. (Phase 1) [ Time Frame: 2 years ]
2. To determine the complete response rate based on bone marrow morphologic assessment. (Phase 2) [ Time Frame: 2 years ]
3. To evaluate the safety and tolerability of clofarabine when administered in combination with alemtuzumab to patients with relapsed and refractory ALL as measured by CTC version 3.0 (Phase 2) [ Time Frame: 2 years ]

Secondary Outcome Measures :

1. Evaluate how many patients who are potential allogeneic stem cell transplant candidates receive stem cell transplant. [ Time Frame: 2 years ]
2. Determine progression-free survival and overall survival. [ Time Frame: 2 years ]

Eligibility Criteria

• Ages Eligible for Study: 16 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, California

Rebecca and John Moores UCSD Cancer Center

La Jolla, California, United States, 92093

UCSD Medical Center

San Diego, California, United States, 92103

Rady Children's Hospital

San Diego, California, United States, 92123

Sponsors and Collaborators

University of California, San Diego

Genzyme, a Sanofi Company

More Information

• Responsible Party: Danelle James, M.D., Rebecca and John Moores UCSD Cancer Center
• ClinicalTrials.gov Identifier: NCT00983528
• Other Study ID Numbers: 090331
• First Posted: September 24, 2009
• Last Update Posted: May 4, 2011
• Last Verified: May 2011

Keywords provided by University of California, San Diego:

cancer; lymphoblastic; leukemia

Additional relevant MeSH terms:

Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Alemtuzumab; Clofarabine; Antineoplastic Agents, Immunological; Antineoplastic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action