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

Study Overview
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Brief Summary
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The purpose of this single arm open label phase 1b clinical study is to see what effect zoledronic acid has on tumors in patients with resectable any grade chondrosarcoma prior to surgery.

Detailed Description
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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.

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

Conditions
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Chondrosarcoma

Intervention / Treatment
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* Drug: Zoledronic Acid


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Male or female patients aged >/= 18 years old ECOG Performance Status of </= 2 Written informed consent from subject or the subject's legally authorized representative, obtained prior to participation in the study and any related procedures being performed Patients must meet the following laboratory criteria: Hematology: Neutrophil count of >1500/mm Platelet count of > 100,000/mm3 Hemoglobin &#8805; 9 g/dL 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; for subjects with Gilbert's syndrome, direct bilirubin </=1.5×ULN and indirect bilirubin </=3×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 Any patient with a biopsy proven diagnosis of chondrosarcoma that is grade I, II or III or in cases where histological and radiological correlation suggests low grade chondrosarcoma as per multidisciplinary discussion. Patients with biopsy proven dedifferentiated chondrosarcoma that chose not to pursue neoadjuvant chemotherapy are allowed. Patients must not have received zoledronic acid (ZA) for any reason prior to the study. Patients with metastatic disease are allowed, if indication to remove primary tumor. Exclusion criteria Prior use of Osteoclast inhibitors for osteoporosis within 6 months from screening will not be allowed. Impaired cardiac function Uncontrolled hypertension Creatinine >1.5 or history of Renal disease preventing use of ZA. Other concurrent severe and/or uncontrolled medical conditions including need for urgent dentoalveolar surgery as indicated by preventative dental exam Concomitant use of any anti-cancer therapy or radiation therapy 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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zoledronic Acid<br>1 cycle of Zoledronic Acid (ZA) at 4mg IVP prior to surgery and a second cycle of ZA at 4 mg IVP 3 weeks after surgery | Drug: Zoledronic Acid<br>* Zoledronic acid, a member of bisphosphonate class, inhibits bone resorption.<br>* Other names: Zometa®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b cohort: Dose Limiting Toxicity - to examine the toxicity related to the therapy by measuring the number of treatment related adverse events in patients | Toxicity will be assessed using the NIH-NCI Common Terminology Criteria for Adverse Events, version 4.0 (CTCAEv4.) | All eligible patients that have initiated treatment will be considered evaluable for assessing adverse event rate(s) up to 4 weeks post Cycle 2 | 
| Expansion cohort: Response Rate - Change at evaluations | Response and progression will be assessed by tumor viability, osteoclast activity, and bone destruction compared to the initial biopsy in subjects with localized any grade chondrosarcoma. | Changes on 2 consecutive evaluations at screening phase (days 1-14); Cycle 2 at 3 weeks post operatively; EOT visit at 4 weeks post Cycle 2; and then at follow up visits every 6 months for up to 5 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence (local or metastatic) free survival | Recurrence-free survival will be estimated using the Kaplan-Meier method. | All eligible patients that have initiated treatment will be considered evaluable for assessing recurrence free survival for up to 2 years. | 
| Overall survival | Overall survival will be estimated using the Kaplan-Meier method. | All eligible patients that have initiated treatment will be considered evaluable for assessing overall survival up to 5 years. |