Anti-Osteoclast Therapy as Neoadjuvant in Treatment of Chondrosarcoma - Phase 1b Trial

This is a single arm open label phase 1b clinical trial assessing the safety and efficacy of
neoadjuvant zoledronic acid in patients with resectable any grade chondrosarcoma as measured
by pathological characteristics and recurrence free survival. Prior to surgery, subjects will
receive 1 standard dose of IV zoledronic acid given over 15 minutes. Surgery will be
performed 21-31 days after the dose as per standard of care. The second standard dose of
zoledronic acid will be given 3 weeks after surgery.

Phase 1b:

The Phase 1b portion of this study is to ensure the safety and tolerability of standard dose
of zoledronic acid intravenously as assessed by incidence of dose limiting toxicities (DLT).
Although the safety of use of this drug has been established in patients with bone metastases
from solid tumors (breast, prostate) and in patients with hypercalcemia of malignancy and
multiple myeloma, it has not been tested in patients with chondrosarcoma. Surgery will be
performed between day 21 to 31 from the dose of zoledronic acid to allow its effect on the
tumor and resolution of toxicities. A total of 6 patients will be enrolled in this run-in
phase 1b. Patients will be followed post operatively as per NCCN guidelines with local and
systemic imaging.

Expansion Cohort:

The phase 1b expansion cohort of the study will provide an estimate of the relative treatment
effect of zoledronic acid on any grade chondrosarcoma specimens. Subjects will receive a
total of 2 doses of zoledronic acid, one dose prior to surgery and the second dose 21 days
after surgery. Patients will undergo standard of care surgery 21-31 days from the first dose
of zoledronic acid. 9 subjects will be enrolled in this cohort for a total of 15 planned
subject enrollment over 3 years. Patients will be followed post operatively for recurrence
with imaging and survival and as per NCCN guidelines.

Inclusion Criteria:

1. Male or female patients aged ≥ 18 years old

2. ECOG Performance Status of ≤ 2

3. Ability to provide written informed consent obtained prior to participation in the
study and any related procedures being performed

4. Patients must meet the following laboratory criteria:

1. Hematology: Neutrophil count of >1500/mm3; Platelet count of > 100,000/mm3;
Hemoglobin ≥ 9 g/dL

2. Biochemistry: AST/SGOT and ALT/SGPT ≤ 2.5 x upper limit of normal (ULN) or ≤ 5.0
x ULN if the transaminase elevation is due to disease involvement; Serum
bilirubin ≤ 1.5 x ULN; Serum creatinine ≤ 1.5 x ULN or estimated creatinine
clearance ≥ 50 ml/min by Cockcroft-Gault equation: GFR=(140-age)*(wt in kg)*(0.85
if female)/(72xCr); Total serum calcium (corrected for serum albumin) ≥ 8.5 mg/dL
or ionized calcium ≥ 3.8 mg/dL; Serum potassium ≥ LLN; Serum sodium ≥ LLN; Serum
albumin ≥ 3g/dl

5. Any patient with a biopsy proven diagnosis of chondrosarcoma that is grade I, II or
III or

6. Patients with biopsy proven dedifferentiated chondrosarcoma that chose not to pursue
neoadjuvant chemotherapy.

7. Patients must not have received zoledronic acid (ZA) for any reason prior to the
study.

8. Patients with metastatic disease are allowed, if indication to remove primary tumor.

Exclusion Criteria:

1. Prior use of Osteoclast inhibitors for osteoporosis will not be allowed.

2. Impaired cardiac function

3. Uncontrolled hypertension

4. Creatinine >1.5 or history of renal disease preventing use of ZA.

5. Other concurrent severe and/or uncontrolled medical conditions including need for
urgent dentoalveolar surgery as indicated by preventative dental exam

6. Concomitant use of any anti-cancer therapy or radiation therapy

7. Women who are pregnant or breast feeding or WOCBP not willing to use a double barrier
method of contraception during the study and 3 months after the end of treatment. One
of these methods of contraception must be a barrier method. WOCBP are defined as
sexually mature women who have not undergone a hysterectomy or who have not been
naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses
any time in the preceding 12 consecutive months).