A Study of ALT-801 in Patients With Relapsed or Refractory Multiple Myeloma

Multiple Myeloma (MM) is a plasma cell malignancy that makes up 1% of all cancers and 10% of
hematologic neoplasma, and is the second most commonly diagnosed hematologic malignancy.
There are an estimated 20,520 new cases of MM and 10,610 deaths due to MM in the United
States. Historically, standard first-line therapy for MM consisted of combination therapy
with an alkylating agent, such as melphalan and prednisone. Response rates with such
combination therapy are approximately 50%, but five-year survival rates remain low at 33%.
For younger patients, debulking chemotherapy followed by autologous stem cell transplant
(ASCT) with melphalan is the treatment of choice to increase the potential for a sustained
durable remission. However, a large percentage of patients diagnosed with MM are not
suitable candidates for ASCT because of age or comorbidities. The approach to MM treatment
has undergone a radical transformation over the past decade with the introduction of the
proteasome inhibitor, bortezomib, and immunomodulatory drugs (ImiDs), thalidomide or
lenalidomide. Despite some advances in the treatment of MM, the disease remains incurable
due to the persistence of minimal residual disease. Thus, novel modalities complementing or
improving current treatment options are needed.

There is ample evidence that immunomodulatory drugs are effective against myeloma.
Lenalidomide and thalidomide have been shown to stimulate T cells in the presence of antigen
presenting cells via costimulatory pathway. Also, modulation of NK cell function has been
associated with anti-tumor activity observed in MM patients treated with lenalidomide. It
has been demonstrated that NK cells exhibit potent anti-MM activity following IL-2
administration, and ex vivo IL-2-activated and intravenously administered NK cells prolong
survival in MM-bearing mice. Thus further demonstrating the role and importance of NK cells
in the treatment of MM. Taken together, these data suggest that the use of a potent
immunotherapeutic is an attractive approach to provide durable immune responses to or even
potentially curing patients with MM.

Additionally, immunotherapy is a well-established approach for treating other cancer types.
One strategy that has received attention is treatment with cytokines such as IL-2 to enhance
anti-tumor immunity. Unfortunately, the considerable toxicity associated with this treatment
makes it difficult to achieve an effective dose at the site of the tumor and limits the
population that can be treated. Thus, there is a critical need for innovative strategies
that enhance the effects of IL-2, reduce its toxicity without compromising clinical benefit,
provide a more convenient dosing regimen, and treat other diagnoses including MM.

Altor Bioscience Corp. has developed a tumor-targeted IL-2 fusion protein, ALT-801,
comprising human recombinant IL-2 genetically linked to a TCR domain capable of binding a
tumor associated human p53 peptide presented in the context of HLA-A2. Animal studies have
indicated that ALT-801 could be useful in a therapeutic approach for activating immune
effector cells, bringing together effector cells and tumor cells and stimulating immune
cell-mediated activity. In addition, in various mouse xenograft models, this molecule
increases the efficacy but lessens the side effects of high-dose rhIL-2.

Moreover, human studies indicate ALT-801 given daily for two 4-day cycles at the MTD (i.e.
0.04 mg/kg) is well tolerated, exhibits a favorable PK drug profile, exhibits immunological
potency in humans, provides evidence of clinical benefit in cancer patients and a higher
dosing level (0.08 mg/kg) of ALT-801 in a monotherapy treatment was associated with better
clinical benefit in patients with metastatic cancer.

Also, the results of pre-clinical studies in various tumors with diverse origins and
relevant MM models indicates ALT-801 is a potent immunostimulatory molecule capable
increasing NK cell and CD8+ T cell numbers and percentages in myeloma tumor-bearing mice,
ALT-801 in single or multidose treatment regimens exhibits potent anti-tumor activity and
induced long-lasting immunologic memory against well-established myeloma cells in the
immunocompetent mouse model, suggesting the potential of curative treatment for patients
with MM.

Based on these findings, ALT-801 as a single-agent therapeutic may provide durable clinical
benefit to patients with relapsed or relapsed and refractory MM. In this study, we will
establish the tolerable dose level of ALT-801 in MM patients, and estimate the anti-tumor
activity and characterize the pharmacokinetic and immunogenicity profile of ALT-801 in such
patients.

ENTRY CRITERIA:

DISEASE CHARATERISTICS:

- Confirmed diagnosis of relapsed/refractory multiple myeloma after treatment with at
least two different previous regimens.

- Refractory disease is defined as progressive disease while on therapy or
progression within 60 days of therapy.

- Progressive disease is defined by a 25% increase from the lowest response value
in specified tests.

- Measurable disease as defined by at least one of the following:

- Serum M-protein ≥ 1g/dL (for IgG, IgM) or 0.5 g/dL (for IgA)

- Urine M-protein ≥ 200mg/24hours

- Serum free light chains ≥ 10 mg/dL and abnormal kappa/lambda ratio

PRIOR/CONCURRENT THERAPY:

- No anti-myeloma treatments within 28 days before the start of study treatment.

- Must have recovered from side effects of prior treatments.

PATIENT CHARACTERISTICS:

Age

• ≥ 18 years

Performance Status

• ECOG 0, 1, or 2

Bone Marrow Reserve

- Absolute neutrophil count (AGC/ANC) ≥ 1,000/uL

- Platelets ≥ 30,000/uL

- Hemoglobin ≥ 8g/dL

Renal Function

• Glomerular Filtration Rate (GFR) > 45mL/min/1.73m^2

Hepatic Function

- Total bilirubin ≤ 2.0 X ULN

- AST, ALT, ALP ≤ 3.0 X ULN, or ≤ 5.0 X ULN (if liver metastases exist)

Cardiovascular

- No congestive heart failure < 6 months

- No unstable angina pectoris < 6 months

- No myocardial infarction < 6 months

- No history of ventricular arrhythmias

- No history of supraventricular arrhythmias

- No NYHA Class > II CHF

- Normal Transthoracic Echocardiogram (TTE) is required for patients with history of
EKG abnormalities, CHF, coronary artery disease or other cardiac disease, or with a
history of having received adriamycin or doxorubicin

- Patients with a left ventricular ejection fraction (LVEF) of less than 50% will be
excluded from study entry

Pulmonary

• Normal clinical assessment of pulmonary function

Other

- Negative serum pregnancy test if female and of childbearing potential

- Women who are not pregnant or nursing

- Subjects, both females and males, with reproductive potential must agree to use
effective contraceptive measures for the duration of the study

- No known autoimmune disease other than corrected hypothyroidism

- No known prior organ allograft or allogeneic transplantation

- Not HIV positive

- No history or evidence of uncontrollable CNS disease

- No psychiatric illness/social situation

- No other illness that in the opinion of the investigator would exclude the subject
from participating in the study

- Must provide informed consent and HIPPA authorization and agree to comply with all
protocol-specified procedures and follow-up evaluations

- Active systemic infection requiring parenteral antibiotic therapy.

- No ongoing chronic systemic steroid therapy required.