a study on Sarcoma
This is the first study to evaluate the safety and clinical activity of the combination of oral pazopanib, intravenous or oral irinotecan, and oral temozolomide in pediatric and young adult patients with relapsed or refractory sarcomas. This study will use a 3 + 3 design for dose escalation (Part 1), followed by an expansion cohort (Part 2) at the recommended phase 2 dose level.
Phase 1 Study of Pazopanib in Combination With Irinotecan and Temozolomide (PAZIT) for Children and Young Adults With Relapsed or Refractory Sarcoma
The combination of irinotecan and temozolomide is well-tolerated and provides an active therapy option for heavily pre-treated patients with sarcoma. The toxicity profile and activity level suggest that this combination will provide a useful platform onto which novel compounds may be added. Pazopanib has been shown to demonstrate single-agent activity in sarcomas in the preclinical and clinical settings. Pazopanib has also been shown to have additive or synergistic effects in preclinical models of sarcomas when combined with cytotoxic chemotherapy. Pharmacokinetic studies of pazopanib and irinotecan as well as pharmacodynamic studies of pazopanib to assess anti-angiogenesis will be performed. Exploratory studies to assess non-invasive methods of monitoring tumor response (circulating tumor DNA and functional imaging by PET/MRI) will be performed.
Sarcoma Irinotecan Camptothecin Temozolomide Dacarbazine
Open to people ages 6–30
Diagnosis: Patients must have had histologic verification of one of the malignancies listed below at original diagnosis or at time of relapse.
Note: Patients with known involvement of the CNS by malignancy will be included if there is no evidence of active bleeding or intratumoral hemorrhage on radiographic imaging.
Performance Level: Karnofsky>/= 50% for patients> 16 years of age and Lansky>/=50% for patients = 16 years of age.
Note: Neurologic deficits in patients with metastatic CNS tumors must have been relatively stable for a minimum of 1 week prior to study enrollment. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
Myelosuppressive chemotherapy: Patients must not have received myelosuppressive therapy within 2 weeks of enrollment onto this study (6 weeks if prior nitrosourea).
Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.
Biologic (anti-neoplastic agent): At least 7 days must have passed after the last treatment with a biologic agent. For agents that have known adverse events occurring beyond 7 days from administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.
Immunotherapy: At least 4 weeks since the completion of any type of immunotherapy,e.g. tumor vaccines.
Monoclonal antibodies: At least 7 days or 3 half-lives, whichever is longer, must have elapsed since prior treatment with a monoclonal antibody.
XRT: ≥ 2 weeks must have elapsed for local palliative XRT (small port) and enrollment on study. At least 24 weeks must have elapsed since prior Total Body Irradiation(TBI), radiation to ≥50% of pelvis, or craniospinal radiation;>/= 6 weeks must have elapsed if the patient has received other substantial bone marrow radiation.
Stem Cell Transplant (SCT): No evidence of active GVHD and>/= 2 months must have elapsed since transplant or rescue.
Prior treatment with pazopanib, irinotecan, temozolomide: Patients may have received other VEGF blocking tyrosine kinase inhibitors, provided that they did not progress while receiving one of these agents. Patients may not have previously received pazopanib. Patients must have recovered from any VEGF blocking drug-related toxicity(e.g., proteinuria).
Patients previously treated with irinotecan and/or temozolomide will be eligible for this study provided they did not progress while receiving one of these agents.
Adequate Bone Marrow Function defined as:
Adequate Renal and Metabolic Function defined as:
A serum creatinine based on age/gender per protocol.
The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the CDC.
Adequate Liver Function defined as:
Total bilirubin = 1.5 x upper limit of normal (ULN) for age
SGPT (ALT) = 3.0 x ULN (for the purpose of this study, the ULN for SGPT is 45 U/L)
Adequate Cardiac Function defined as:
Adequate Blood Pressure Control defined as: A blood pressure (BP) = 95% percentile for age, height, and gender. Patients on stable doses of no more than one anti-hypertensive medication, with a baseline BP = 95% percentile for age, height, and gender will be eligible.
Central Nervous System Function defined as:
CNS toxicity = Grade 2.
Adequate pulmonary function defined as:
Adequate Coagulation defined as: PT and PTT = 1.5 x ULN and an INR = 1.2.
Corticosteroids: Patients requiring corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the 7 days prior to enrollment are not eligible.
Investigational Drugs: patients who are currently receiving another investigational drug are not eligible.
Anti-cancer Agents or Radiation Therapy: Patients who are currently receiving other anti-cancer agents or radiation therapy are not eligible.
Anti-hypertensive Medications: Patients who are currently receiving more than one anti-hypertensive medication or whose blood pressure is not controlled as defined by protocol are not eligible for study enrollment.
Anti-coagulation: Patients must not be on therapeutic anti-coagulation. Prophylactic anti-coagulation (i.e., intraluminal heparin) of venous or arterial access devices is allowed.
Anti-inflammatory and Anti-platelet Agents: Patients currently receiving aspirin,and/or ibuprofen, or other NSAIDs are not eligible.
Enzyme-inducing Anti-convulsants: Patients who are currently receiving enzyme-inducing anti-convulsants are not eligible.
CYP3A4 Substrates and Drugs Causing QTc Prolongation: Patients receiving drugs with a known risk of torsades de pointes are not eligible. A list of enzyme inducing, enzyme inhibiting, and other prohibited drugs is provided by the protocol.
Note: This list includes the prohibition of grapefruit for 14 days prior to enrollment.
Thyroid Replacement Therapy: Patients who require thyroid replacement therapy are not eligible if they have not been receiving a stable replacement dose for at least 4 weeks prior to study enrollment.
Bleeding and Thrombosis: Patients will be excluded if any of the following are present:
Surgery: Patients who have had or are planning to have the following invasive procedures will be excluded:
Note: Routine bone marrow aspirate and biopsy for the purposes of disease staging are not part of these exclusion guidelines.
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