Trivalent Ganglioside Vaccine With Immunological Adjuvant or Immunological Adjuvant Alone in Metastatic Sarcoma Patients Who Are Rendered Disease Free

A Randomized, Multicenter, Double-Blind, Phase II Trial of a KLH Conjugated Trivalent Ganglioside Vaccine Containing GM2, GD2 Lactone, and GD3 Lactone With the Immunological Adjuvant OPT-821 Versus OPT-821 Alone in Metastatic Sarcoma Patients Who Are Rendered Disease Free

Sarcoma patients are at high risk for their cancer to recur even when the sarcoma has been removed surgically or treated with radiation or chemotherapy. The patients in the study will be randomized (like flipping a coin) to receive either a vaccine that is combined with an immune system stimulant or the immune system stimulant alone. The immune system stimulant is called OPT-821 and is an immunological booster. The trivalent vaccine is being developed to teach the patient's immune system to recognize 3 types of sugars called GM2, GD2 and GD3 that are found primarily on the surface of sarcoma cells. If the trivalent vaccine can stimulate the patient's immune system to develop antibodies which recognize and target the GM2, GD2 and GM3 sugars, then the patient's antibodies could attack and kill any remaining sarcoma cells potentially preventing the recurrence of sarcoma.

This study is a Phase II randomized, double-blind, multi-center study of a trivalent ganglioside vaccine plus the immunological adjuvant OPT-821 (Arm A) versus OPT-821 alone (Arm B) for patients with metastatic sarcoma at initial presentation or with relapsed disease who have been rendered disease-free following either surgical resection or multi-modality therapy. The primary aim of this study is to demonstrate the efficacy of vaccine therapy over non-specific immune therapy. Another aim of this study is to obtain sufficient data to further the development of this specific vaccine therapy as well as guide future study designs for therapeutic cancer vaccines in general.

To be eligible, patients must have histologically confirmed sarcoma, must be clinically free of disease after surgery or multimodality therapy, and must be within 8 weeks of completion of such therapy. Given the limited data regarding ganglioside expression in Ewing sarcoma, rhabdomyosarcoma, and gastrointestinal stromal tumors, patients with these sarcoma subtypes with the exception of pleomorphic/anaplastic rhabdomyosarcoma will be excluded. Patients must have a history of distant metastatic disease; patients with locally recurrent disease only will not be eligible, as these patients demonstrate a different natural history from those with metastatic disease.

All treatment will be performed in the outpatient setting. Patients will be randomized in a 1:1 ratio to receive a total of 10 treatments of either the vaccine plus OPT-821 (Arm A) or OPT-821 alone (Arm B). Treatment will be administered on Visit Weeks 1, 2, 3, 8, 16, 28, 40, 52, 68, and 84. All patients will receive 150 mcg of OPT-821.

Inclusion Criteria:

1. Male or female, 16 years or older.

2. American Joint Committee on Cancer (AJCC) Stage IV sarcoma with no current radiological evidence of residual disease following either surgery alone or multi-modality therapy for treatment of metastatic or relapsed disease. Patients must have presented with either newly diagnosed metastatic sarcoma or distant relapsed disease. Patients who present with more than one site of metastases are eligible as long as at least one new site is distant from the original site and the surgical resection(s) results in clear margins as assessed by the site pathologist. Non-surgical local ablative therapies such as SRS or cryotherapy cannot replace surgical resection of disease for the purpose of eligibility.

3. Histological confirmation of sarcoma, as performed by a pathologist at one of the participating study sites, prior to entry on study.

4. Patients must have undergone surgical metastectomy within 8 weeks prior to initiation of treatment on this study.

5. Patients previously treated with neoadjuvant chemotherapy and/or radiotherapy as part of a multi-modality treatment for metastatic disease must have recovered from all adverse effects of treatment and have returned to baseline status.

6. Imaging study performed within 4 weeks prior to administration of first vaccination documenting that patient has no evidence of disease. Study must include CT scan of chest, abdomen, and pelvis.

7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1.

8. Weight ≥ 40 kg.

9. Have organ and marrow function as defined below:

   WBC ≥ 3.0 cells/mm3 Platelets ≥ 100,000/mm3 Total bilirubin ≤ 2.0 mg/dL AST (SGOT)/ALT (SGPT) ≤ 1.5 x ULN

10. Current use of an acceptable form of birth control.

11. Ability to understand English and to provide written informed consent and authorization for protected health information disclosure whether by self or by legally authorized representative.

Exclusion Criteria:

1. Patients with evidence of local or metastatic disease or who are not disease free at the time of the first vaccination.
2. Patients who develop locally recurrent disease only with no evidence of concurrent or previous distant metastatic disease. Patients with a primary retroperitoneal and/or uterine sarcoma that present with recurrence within the retroperitoneum or pelvis only are not eligible. Patients must have evidence of hematogenously disseminated distant disease.
3. Patients with brain or bone metastasis even if they are able to undergo complete surgical resection.
4. Patients with Ewing sarcoma, rhabdomyosarcoma (except for pleomorphic/anaplastic rhabdomyosarcoma), or gastrointestinal stromal tumors. Patients with pleomorphic/anaplastic rhabdomyosarcoma are eligible.
5. Patients previously treated with KLH or ganglioside containing vaccines or monoclonal antibodies (mAbs) against gangliosides.
6. Females of childbearing potential that are pregnant or intend to become pregnant or who are breastfeeding. Females must have negative βHCG test within two weeks of first vaccination.
7. Current active malignancy or history of malignancy, other than sarcoma, within the past two years, except for cervical carcinoma in situ or superficial skin cancer that has been surgically removed.
8. Any medical condition that may limit the ability of the patient to complete the full course of treatment or to respond immunologically to vaccination, (including autoimmune or neurodegenerative disorders such as multiple sclerosis and amyotrophic lateral sclerosis).
9. Patients requiring continuous doses of anti-inflammatory medications (steroids including inhaled steroids, non-steroidal anti-inflammatory drugs, or full dose aspirin). Episodic use of steroids or non-steroidal anti-inflammatory drugs permitted as long as they are not given within one week prior to or following vaccine administration. Continuous dosing of low-dose aspirin (≤ 81 mg/day) is acceptable.
10. Use of or treatment with a drug that has not received regulatory approval or participation in a drug or device study during the 28 days preceding the first vaccination.
11. Known history of HIV-positivity OR serologic evidence of HIV at screening or any immunodeficiency disorders or illnesses. Serologic positivity for the Hepatitis B Virus (HBV) or the Hepatitis C Virus (HCV), unless explained by a documented vaccination.
12. Inability or unwillingness to meet the attendance requirements of the study.
13. Any clinically significant abnormal finding at Screening (as determined by the principal investigator, in consultation with the Medical Monitor and the Sponsor), that would interfere with study participation, that would interfere with the evaluation or quality of the data, or that would put the patient at increased risk of illness or injury.