Four Drug Reinduction With Bortezomib for Relapsed or Refractory ALL or LL in Children and Young Adults

1.0 GOALS AND OBJECTIVES (SCIENTIFIC AIMS)

1.1 Primary Aims

1.1.1 To evaluate the feasibility and toxicity of using bortezomib in combination with the
ALL R3 re-induction regimen in pediatric patients with relapsed or refractory ALL or LL.

1.1.2 To determine the rate of complete response and negative minimal residual disease
status following bortezomib combined with R3 reinduction.

2.0 BACKGROUND

Despite the progress that has been made in the treatment of ALL in children, relapse of
disease remains a significant treatment problem. By itself, the number of patients with
relapsed ALL would be the 4th most common childhood malignancy and overall survival in these
patients is poor. Using conventional treatments, second remission rates after bone marrow
relapse in ALL are 81-93% and long-term event free survival (EFS) is only 27-50%. Initial
standard therapy for children following relapse includes a four drug reinduction strategy,
typically using prednisone, vincristine, PEG-asparaginase, and doxorubicin. For children
with first marrow relapse of ALL less than 36 months from diagnosis, this four drug
reinduction strategy results in a CR rate of 68%. However, 75% of patients in CR2 had
minimal residual disease (MRD) that was positive (>0.01%) at the end of reinduction. The
presence of MRD in relapsed ALL is strongly associated with worse long term outcomes. For
children with ALL that relapsed following a second (CR2) remission, outcomes are dismal with
5 year disease free survival of 15%.

In 2010, results were published of the ALL R3 trial from the Children's Cancer and Leukemia
Group in the United Kingdom and Ireland. This trial randomized children with first relapse
of ALL to receive a four drug reinduction using either mitoxantrone or idarubicin as the
anthracycline. The study was closed early due to a statistically significant improvement in
survival for children randomized to mitoxantrone. Children who received mitoxantrone had a 3
year disease free survival of 64.6% compared to 35.9% in the idarubicin group. Toxicities in
this study were not excessive, and children randomized to receive mitoxantrone had
significantly less toxicity than those in the idarubicin group. Based on the results of this
trial, the Children's Oncology Group (COG) has begun using this reinduction regimen as the
backbone for new clinical trials for children with relapsed ALL.

Despite the improvement in outcomes for the children with relapsed ALL treated with
mitoxantrone on the R3 study, there is still a need for continued efforts to improve
outcomes in patients with ALL and LL that experience a relapse. This is particularly true
for high risk groups such as those who have an early bone marrow relapse (<36 months from
diagnosis), second or greater relapse or relapsed LL where long term survival remains less
than 50% Bortezomib is a proteasome inhibitor that has demonstrated activity in a number of
cancer types including acute leukemias. Bortezomib acts by inhibiting the
ubiquitin-proteasome pathway resulting in the blockade of NF-κB activation and the
stabilization of multiple proapoptotic proteins including p53, p21, p27, and Bax.
Collectively, these effects induce apoptosis and enhance the cytotoxic effects of
chemotherapy. In the Pediatric Preclinical Testing Program (PPTP), bortezomib showed
activity against a number of ALL cell lines. As a single agent, bortezomib was effective at
inhibiting NF-κB but there was no clinical response in 9 heavily pretreated children with
ALL. Proteasome inhibition is able to induce apoptosis, and may be best utilized in
combination with other conventional chemotherapy drugs to help overcome resistance.
Preclinical evaluation of bortezomib with a number of drugs commonly used in pediatric ALL
therapy demonstrated synergy with dexamethasone and additive effects when given along with
vincristine, asparaginase, and doxorubicin.

In a phase 1 study of children with relapsed ALL of bortezomib combined with a four drug
reinduction using dexamethasone, vincristine, doxorubicin, PEG-asparaginase and intrathecal
therapy, bortezomib at a dose of 1.3 mg/m2 given on days 1, 4, 8 and 11 was well tolerated.
The phase 2 study of this regimen was able to produce a complete response or complete
response without platelet recovery in 73% of patients. These results are encouraging as
these were heavily pretreated patients treated with 2 or 3 previous regimens. Due to 3
deaths from infectious toxicities, the study was amended to require infectious prophylaxis
with vancomycin, levofloxacin, and voriconazole. No further deaths were seen in children
following this change. Other toxicities seen on this study include grade 3 peripheral
neuropathy in 2 patients.

This is a phase II study designed to investigate the combination of bortezomib with the
mitoxantrone reinduction regimen used in the ALL R3 trial. The study will enroll patients
with high risk ALL relapse including early bone marrow relapse and second or greater relapse
of any kind. Patients with relapsed LL will also be eligible. Bone marrow evaluation will be
performed after blood counts recover to assess the rate of CR (<5% bone marrow blasts) and
MRD status in children following this regimen. Further treatment with or without HSCT will
be at the discretion of the primary physician.

2.1 Bortezomib for Injection 2.1.1 Scientific Background Bortezomib for Injection is a
small-molecule proteasome inhibitor developed by Millennium Pharmaceuticals, Inc.,
(Millennium) as a novel agent to treat human malignancies. Bortezomib is currently approved
by the United States Food and Drug Administration (US FDA) for the treatment of patients
with multiple myeloma (MM). It is also indicated for the treatment of patients with mantle
cell lymphoma (MCL) who have received at least 1 prior therapy. In the European Union (EU),
bortezomib in combination with melphalan and prednisone is indicated for the treatment of
patients with previously untreated MM who are not eligible for high-dose chemotherapy with
bone marrow transplant. Bortezomib is indicated as monotherapy for the treatment of
progressive MM in patients who have received at least 1 prior therapy and who have already
undergone or are unsuitable for bone marrow transplantation.

By inhibiting a single molecular target, the proteasome, bortezomib affects multiple
signaling pathways. The antineoplastic effect of bortezomib likely involves several distinct
mechanisms, including inhibition of cell growth and survival pathways, induction of
apoptosis, and inhibition of expression of genes that control cellular adhesion, migration,
and angiogenesis. Thus, the mechanisms by which bortezomib elicits its antitumor activity
may vary among tumor types, and the extent to which each affected pathway is critical to the
inhibition of tumor growth could also differ. Bortezomib has a novel pattern of cytotoxicity
in National Cancer Institute (NCI) in vitro and in vivo assays.(19) In addition, bortezomib
has cytotoxic activity in a variety of xenograft tumor models, both as a single agent and in
combination with chemotherapy and radiation. Notably, bortezomib induces apoptosis in cells
that over express bcl-2, a genetic trait that confers unregulated growth and resistance to
conventional chemotherapeutics.

The mechanisms of action leading up to apoptosis have been more clearly defined and include
initiation of the unfolded protein response and direct/indirect effects on various molecular
targets including cell cycle control proteins p27 and p21, cyclins, signal transduction
molecules, transcription factors c-jun and HIF1-, tumor suppressor protein p53, angiogenesis
factors, and many others. Bortezomib is thought to be efficacious in multiple myeloma via
its inhibition of nuclear factor B (NF-B) activation, its attenuation of interleukin-6
(IL-6)-mediated cell growth, a direct apoptotic effect, and possibly anti-angiogenic and
other effects.

Inclusion Eligibility Criteria

- Age: > 1 and < 40 years of age at the time of enrollment

- Diagnosis: Precursor B-cell ALL with bone marrow (BM) or combined BM/extramedullary
relapse; T-cell ALL with relapsed disease; LL with relapsed disease, or ALL(T or
pre-B) with primary refractory disease after at least two regimens

- Performance Score: 50% for patients

- Prior Therapy Patients who relapse while receiving standard ALL maintenance
chemotherapy will not be required to have a waiting period before entry onto this
study.

Patients who relapse on therapy other than standard ALL maintenance therapy must have
fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or
radiotherapy prior to entering this study. In addition, the following requirements must be
met:

Cytotoxic therapy: At least 14 days since the completion of cytotoxic therapy with the
exception of hydroxyurea, which is permitted up to 24 hours prior to the start of protocol
therapy.

Biologic (anti-neoplastic) agent: At least 7 days since the completion of therapy with a
biologic agent or donor lymphocyte infusions (DLI).

Stem cell transplant or rescue: No evidence of active graft-vs-host disease (GVHD) and ≥ 4
months must have elapsed from time of transplant. Must not be receiving GVHD prophylaxis.

- Adequate Organ Function Requirements

- Reproductive Function: Female patients of childbearing potential must have a negative
pregnancy test confirmed within 2 weeks prior to enrollment, must agree not to
breastfeed their infants while on this study.Male and female patients of
child-bearing potential must agree to use 2 effective methods of contraception
approved by the investigator, at the same time, from the time of signing the informed
consent form and for a minimum of 6 months after study treatment, or agree to
completely abstain from heterosexual intercourse.

- Signed written informed consent. Assent from children will be obtained per
institutional guidance.

Exclusion Eligibility Criteria

- known allergy to any of the drugs on the study with the exception of PEG-asparaginase

- Isolated CNS or isolated testicular disease

- Systemic fungal, bacterial, viral or other infection that is exhibiting ongoing
signs/symptoms related to the infection without improvement despite appropriate
antibiotics or other treatment. The patient needs to be off pressors and have
negative blood cultures for 48 hours.

- Known optic nerve and/or retinal involvement

- Patients with concomitant genetic syndrome

- Cumulative prior anthracycline exposure must not exceed 400 mg/m2

- Patients who have previously received bortezomib or other proteasome inhibitors

- Patients taking anticonvulsants known to activate the cytochrome p450 system

- Patients who cannot receive any asparaginase products

- Patients who are pregnant or breast-feeding

- Patients with planned non-protocol chemotherapy, radiation therapy, or immunotherapy
during the study period.

- Significant concurrent disease, illness, psychiatric disorder or social issue that
would compromise patient safety or compliance with the protocol treatment or
procedures, interfere with consent, study participation, follow up, or interpretation
of study results.

- Patients with myocardial infarction within 6 months prior to enrollment or has New
York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina,
severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of
acute ischemia or active conduction system abnormalities.

- Diagnosed or treated for another malignancy within 2 years of enrollment

- Participation in clinical trials with other investigational agents not included in
this trial, within 14 days of the start of this trial and throughout the duration of
this trial.Radiation therapy within 3 weeks before randomization.