A Phase I Study of Ganetespib +/- Bortezomib in Patients With Relapsed and/or Refractory Multiple Myeloma

Inclusion Criteria:

- Males or females, age 18 years or older.

- Diagnosis of relapsed or refractory multiple myeloma (MM) and documentation of at
least 2 prior therapies which must have included bortezomib and an immunomodulatory
agent; there is no maximum number of prior regimens.

- Patients with measurable disease defined as at least one of the following:

1. Serum M-protein ≥ 0.5 g/dl (≥ 5 g/l)

2. Urine M-protein ≥ 200 mg/24 h

3. Serum free light-chain (FLC) assay: Involved FLC level ≥ 10 mg/dl (≥ 100 mg/l)
and an abnormal serum free light chain ratio (< 0.26 or > 1.65)

4. Measurable plasmacytoma (prior biopsy is acceptable, should be measured within
28 days of first study drug administration).

- Subject has an Eastern Cooperative Oncology Group (ECOG) ≤ 2 OR Karnofsky ≥ 60%
performance status.

- Females of childbearing potential*: Confirmation that the subject is not pregnant
must be established by a negative serum β-human chorionic gonadotropin (β-hCG)
pregnancy test result obtained during screening. Pregnancy testing is not required
for post-menopausal or surgically sterilized women. FCBP must also agree to ongoing
pregnancy testing. Men must agree to use a latex condom during sexual contact with a
FCBP even if they have had a successful vasectomy. *(FCBP - A female of childbearing
potential is a sexually mature woman who: 1) has not undergone a hysterectomy or
bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24
consecutive months).

- Ability to understand the purpose and risks of the study and provide signed and dated
informed consent and authorization to use protected health information (in accordance
with national and local subject privacy regulations).

- Voluntary written informed consent before performance of any study-related procedure
not part of routine medical care with the understanding that consent may be withdrawn
by the subject at any time without prejudice to future medical care.

- Inclusion clinical laboratories criteria

1. Absolute neutrophil count (ANC) ≥ 1,000 cells/dL (1.0 x 10⁹/L) (Growth factors
cannot be used within 7 days of first drug administration)

2. Platelet count ≥ 75 x 10⁹/L (platelet transfusions cannot be used within 4 days
of first drug administration)

3. Hemoglobin ≥ 8.0 g/dl

4. Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 1.5 x
upper limit of normal (ULN)

5. Serum creatinine ≤ 1.5 x ULN OR creatinine clearance ≥ 50 mL/min
(Cockcroft-Gault calculation)

6. Total bilirubin ≤ 1.5 x ULN

7. Serum calcium (corrected for serum albumin) or ionized calcium ≥ lower limit of
normal (LLN) (treatment of hypercalcemia is allowed and subject may enroll if
hypercalcemia returns to normal with standard treatment).

Exclusion Criteria:

- Patients who have received chemotherapy, immunomodulatory drugs (e.g., lenalidomide,
thalidomide or pomalidomide), immunotherapy, radiation therapy, or any
investigational drug(s) within 14 days before enrollment or who have not recovered
from the side effects of the therapy to at least grade 1. Localized radiation therapy
to a single site within 7 days is acceptable.

- Prior therapy with a heat shock protein 90 (HSP90) inhibitor.

- Daily requirement for corticosteroids (except for inhalational corticosteroids);
prednisone ≤ 10mg/day or equivalent is permitted for other medical conditions.

- Prior peripheral stem cell transplant within 12 weeks of the first dose of study
treatment.

- Use of venous access devices made of materials other than silicone for the infusion
of ganetespib. Patients with these devices are eligible as long as the device is not
used for the infusion.

- History of severe allergic or hypersensitivity reactions to excipients (e.g.,
Polyethylene glycol [PEG] 300 and Polysorbate 80).

- Baseline corrected QT interval (QTc) > 470 msec or previous history of QT
prolongation while taking other medications.

- Ventricular ejection fraction (Ef) ≤ 50 % at baseline.

- History of documented congestive heart failure (CHF), New York Heart Association
class II/III/IV, with a history of dyspnea, orthopnea or edema that requires current
treatment with angiotensin converting enzyme inhibitors, angiotensin II receptor
blockers, beta-blockers or diuretics. NOTE: Use of these medications for the
treatment of hypertension is allowed.

- High-risk uncontrolled arrhythmias (ventricular tachycardia, high-grade
atrioventricular [AV]-block, supra-ventricular arrhythmias which are not adequately
rate-controlled) that require current treatment with the following anti-arrythmic
drugs: flecainide, moricizine or propafenone.

- History of active current coronary artery disease or unstable angina.

- Peripheral neuropathy ≥ grade 2.

- Treatment with chronic immunosuppressants (e.g., cyclosporine following
transplantation).

- Uncontrolled intercurrent illness including, but not limited to, human
immunodeficiency virus (HIV)-positive subjects receiving combination antiretroviral
therapy, severe or systemic infection, or psychiatric illness/social situations that
would limit compliance with study requirements.

- Other medications, or severe acute/chronic medical or psychiatric condition, or
laboratory abnormality that may increase the risk associated with study participation
or study drug administration, or may interfere with the interpretation of study
results, and in the judgment of the investigator would make the subject inappropriate
for entry into this study.