Iscador® P (Mistletoe) Immunotherapy for Recurrent Resectable Osteogenic Sarcoma

This will be a phase II, single arm study of osteosarcoma patients with fully resected pulmonary metastases. The MTD corresponds to the dosage recommendations of the manufacturer of Iscador® P which is licensed in Sweden, New Zealand, South Korea, Germany and Switzerland for the treatment of solid tumors and precancerous lesions.

Iscador® P is to be injected subcutaneously (abdominal) 3 times/week. All patients will start with Series 0 (0.01mg, 0.01mg, 0.1mg, 0.1mg, 1mg, 1mg, 1mg). If tolerated, they will receive this series for 2 consecutive boxes (2 x 7 vials per box). This will then be followed by Series 1 (0.1mg, 0.1mg, 1mg, 1mg, 10mg, 10mg, 10mg), which will be administered for the following 2 consecutive boxes (2 x 7 vials per box). If tolerated, patients will proceed to Series 2 (1mg, 1mg, 10mg, 10mg, 20mg, 20mg 20mg), which will be continued through week 52 (13 cycles).

The study population includes patients with relapse of osteosarcoma in the lung following surgical resection of all gross disease (2nd or greater CR). Following completion of final thoracotomy, they will be treated with Iscador® P at concentrations up to the MTD with surveillance imaging via CT scan to monitor for relapsed disease.

Inclusion criteria

• Histologic diagnosis of osteosarcoma.
• Patients with at least one episode of relapse in the lung (without limitation of number of episodes), following surgical resection of all gross metastatic disease.
• Surgical resection of all possible sites of suspected pulmonary metastases in order to achieve a complete remission within 8 weeks prior to study enrollment. Note: If surgery related changes such as atelectasis are seen on the post-operative CT scan, patients will remain eligible to enroll as long as the operating surgeon believes that all sites of metastases were resected. Patients with positive microscopic margins will be eligible to enroll.
• Pathological confirmation of metastases from at least one of the resected sites.
• Age ≥ 8 years of age and <30 years of age.
• Patients must be able to receive subcutaneous injections.
• Performance level as measured by Karnofsky ≥60% for patients > 16 years of age or Lansky ≥ 60% for patients ≤ 16 years of age.
• Female patients of childbearing potential must have a negative serum blood pregnancy test during screening and a negative urine pregnancy test within 3 days prior to receiving the first dose of study drug. If the screening serum test is done within 3 days prior to receiving the first dose of study drug, a urine test is not required. If a patient is of childbearing potential the patient must agree to use effective contraception during the study and for 120 days after the last dose of study drug.
• If male, agrees to use an adequate method of contraception starting with the first dose of study drug through 120 days after the last dose of study drug
• Life expectancy of > two months
• Experienced resolution of toxic effect(s) of the most recent prior anti-cancer therapy to Grade <1 (except alopecia, cytopenia, or neuropathy). If a patient underwent major surgery or radiation therapy of >30 Gy, they must have recovered from the toxicity and/or complications from the intervention.
• Patients must meet the following laboratory criteria

• Adequate hepatic function with serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 times the upper limit of normal (ULN) and total serum bilirubin < 2.5 times the ULN or Direct bilirubin ≤ ULN for patients with total bilirubin levels > 2.5 X ULN
• Absolute neutrophil count ≥ 500/dL
• Platelet count ≥ 20,000/L
• Creatinine ≤ 1.5 X the ULN or measurement of calculated creatinine clearance (CrCl) ≥ 60 ml/minute

Exclusion criteria

• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator, including, but not limited to:

• Another known malignancy other than osteosarcoma that is progressing or requires active treatment.
• Any prior history of other cancer within the prior 5 years with the exception of adequately treated basal cell carcinoma or cervical intraepithelial neoplasia [CIN]/cervical carcinoma in situ or melanoma in situ).
• Active infection requiring systemic therapy.
• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
• New recurrence of osteosarcoma metastasis in any location other than lung
• Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
• Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study drug.
• Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
• Known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C (e.g., hepatitis C virus ribonucleic acid [qualitative]). Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBc Ab] and absence of HBsAg) are eligible. HBV DNA test must be performed in these patients prior to study treatment. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• Known history of chronic granulomatous diseases, florid autoimmune diseases, diseases treated with immunosuppressive drugs, hyperthyroidism with tachycardia, tuberculosis, parasitosis or Crohn's disease.
• If female, is pregnant or breastfeeding.
• Patients must have had no systemic chemotherapy or immunotherapy in the three weeks prior to enrollment and must have fully recovered from side effects of prior treatment at enrollment.
• Patients may not receive any additional chemotherapeutic agent (either conventional or experimental) while on study.
• Patients must not have received radiation therapy for up to two weeks prior to enrollment.
• Patients must have no known prior allergy to Iscador® P or any other Viscum album products.
• Patients must not receive concomitant treatment with immunostimulant or immunosuppressive drugs.