Pazopanib Hydrochloride, Irinotecan, and Temozolomide in Treating Children and Young Adults with Relapsed or Refractory Sarcoma
This phase I clinical trial studies the side effects and best dose of pazopanib hydrochloride when given together with irinotecan and temozolomide in treating children and young adults with sarcoma that has come back or does not respond to treatment. Pazopanib hydrochloride, irinotecan, and temozolomide may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
- Eligible patients have a body surface area >= 0.7 m^2 AND be able to swallow whole tablets at the time of study enrollment
- Patients must have had histologic verification of one of the malignancies listed below at original diagnosis or at time of relapse * Ewing sarcoma/peripheral primitive neuroectodermal tumor (PNET) * Osteosarcoma * Rhabdomyosarcoma * Non-rhabdomyosarcoma soft tissue sarcoma * Desmoplastic small round cell tumor Note: Patients with known involvement of the central nervous system (CNS) by malignancy will be included if there is no evidence of active bleeding or intratumoral hemorrhage on radiographic imaging
- Patients must have either measurable or evaluable disease
- Patient’s current disease state must be one for which there is not known curative therapy or therapy proven to prolong survival with an acceptable quality of life
- 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
- Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy
- Patients must not have received myelosuppressive therapy within 2 weeks of enrollment onto this study (6 weeks if prior nitrosourea)
- 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
- 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
- At least 4 weeks since the completion of any type of immunotherapy, e.g. tumor vaccines
- >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
- >= 2 weeks must have elapsed for local palliative radiation therapy (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
- No evidence of active graft versus host disease (GVHD) and >= 2 months must have elapsed since transplant or rescue
- Patients may have received other vascular endothelial growth factor (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
- Peripheral absolute neutrophil count (ANC) >= 750/uL
- Platelet count >= 75,000/ul (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment)
- Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions)
- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or
- A serum creatinine based on age/gender as follows: * Age: 1 to < 2 years; maximum serum creatinine (mg/dl): 0.6 * Age: 2 to < 6 years; maximum serum creatinine (mg/dl): 0.8 * Age: 6 to < 10 years; maximum serum creatinine (mg/dl): 1.0 * Age: 10 to < 13 years; maximum serum creatinine (mg/dl): 1.2 * Age: 13 to < 16 years; maximum serum creatinine (mg/dl): 1.5 (male) 1.4 (female) * Age: >= 16 years; maximum serum creatinine (mg/dl): 1.7 (male) 1.4 (female)
- Urine protein to creatinine ratio of < 1, a urinalysis that is negative for protein, or a 24-hour urine protein level < 1000 mg/dL
- No more than grade 1 abnormalities of potassium, calcium (confirmed by ionized calcium), magnesium, and phosphorus (supplementation allowed)
- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
- Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3.0 x ULN (for the purpose of this study, the ULN for SGPT is 45 U/L)
- Serum albumin >= 2 g/dL
- Must not have active liver or biliary disease (with the exception of Gilbert’s syndrome or asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease per investigator assessment); * Note: Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis
- No known positivity of hepatitis B surface antigen (HBsAg), or of positive hepatitis C antibody
- Shortening fraction of >= 27% by echocardiogram (while not receiving medications for cardiac function), or
- Ejection fraction of >= 50% by gated radionuclide study (while not receiving medications for cardiac function)
- Corrected QT interval (QTc) < 480 msec
- Must not have a history of myocardial infarction, severe or unstable angina, peripheral vascular disease or familial QT prolongation
- 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
- Patients with a known history of seizures must have well-controlled seizures and may not be receiving enzyme-inducing anti-convulsants
- CNS toxicity =< grade 2
- No evidence of dyspnea at rest
- No exercise intolerance
- Prothrombin time (PT) and partial thromboplastin time (PTT) =< 1.5 x ULN
- International normalized ratio (INR) =< 1.2
- Pregnant or breastfeeding women will not be entered on this study; negative pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method; the definition of adequate contraception will be based on the judgment of the principal investigator or designated associate; breastfeeding women are excluded
- 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
- Patients who are currently receiving another investigational drug are not eligible
- Patients who are currently receiving other anti-cancer agents or radiation therapy are not eligible
- Patients who are currently receiving more than one anti-hypertensive medication (grade 3) or whose blood pressure is not controlled are not eligible for study enrollment
- Patients must not be on therapeutic anti-coagulation; prophylactic anti-coagulation (i.e., intraluminal heparin) of venous or arterial access devices is allowed
- Patients currently receiving aspirin, and/or ibuprofen, or other non-steroidal anti-inflammatory drugs (NSAIDs) are not eligible
- Patients who are currently receiving enzyme-inducing anti-convulsants are not eligible
- Patients receiving drugs with a known risk of torsades de pointes are not eligible; Note: This list includes the prohibition of grapefruit for 14 days prior to enrollment
- 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
- Patients who are unable to swallow whole tablets are not eligible
- Patients who have an active or uncontrolled infection are not eligible
- Patients will be excluded if any of the following are present: * Evidence of active bleeding, intratumoral hemorrhage, or bleeding diathesis * History (within 6 months prior to study enrollment) of pulmonary embolism, deep vein thrombosis (DVT), or other venous thromboembolic event * History of hemoptysis within 6 weeks prior to study enrollment
- 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
- Patients who have had or are planning to have the following invasive procedures will be excluded: * Major surgical procedures, laparoscopic procedure, open biopsy, or significant traumatic injury within 28 days prior to day 1 therapy; subcutaneous port placement or central line placement is not considered major surgery, but must be placed greater than 48 hours from planned day 1 of therapy * Core biopsy within 7 days prior to day 1 therapy * Fine needle aspirate or central line placement within 48 hours prior to day 1 therapy Note: Routine bone marrow aspirate and biopsy for the purposes of disease staging are not part of these exclusion guidelines
- Patients with serious or non-healing wound, ulcer, or bone fracture
- History of abdominal fistula, gastrointestinal perforation, pneumothorax, or intra-abdominal abscess within 28 days of study enrollment
- Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
- Patients with history of allergic reactions attributed to compounds of similar composition to pazopanib, irinotecan, or temozolomide are not eligible
Locations & Contacts
Contact: Jennifer Gibney Michlitsch
Phone: 510-428-3372 Email: firstname.lastname@example.org
Contact: Kieuhoa Tran Vo
Phone: 415-476-3831 Email: email@example.com
Contact: Steven G. DuBois
Phone: 617-632-5640 Email: firstname.lastname@example.org
Trial Objectives and Outline
I. To estimate the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of pazopanib hydrochloride (pazopanib) administered in combination with fixed doses of irinotecan and temozolomide (PAZIT) every 3 weeks to children and young adults with relapsed or refractory sarcoma.
II. To determine the dose-limiting toxicity (DLT) and describe the toxicities of the combination of PAZIT when administered on this schedule.
I. To preliminarily define the anti-tumor activity of PAZIT within the confines of a phase 1 study.
I. To describe the pharmacokinetics of pazopanib and irinotecan in patients receiving PAZIT.
II. To describe changes in plasma angiogenic factors in patients receiving PAZIT.
III. To collect preliminary data regarding the quantification of cell free deoxyribonucleic acid (DNA) and/or specific somatic mutations in circulating tumor DNA as markers of clinical response in patients receiving PAZIT.
IV. To describe the sensitivity and specificity of somatic mutation detection in circulating tumor (ct)DNA in plasma as compared with paired archival tumor tissue, if available.
V. To explore the utility of multiparametric functional imaging with positron emission tomography (PET)/magnetic resonance imaging (MRI) in patients receiving PAZIT.
OUTLINE: This is a dose-escalation study of pazopanib hydrochloride.
Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on days 1-21. Patients also receive temozolomide PO QD on days 1-5 and irinotecan intravenously (IV) over 1 hour on days 1-5 of course 1 and IV or PO QD on days 1-5 of subsequent courses. Courses repeat every 21 days for 12 months in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up periodically.
Trial Phase & Type
UCSF Medical Center-Mount Zion
Kieuhoa Tran Vo
Secondary IDs NCI-2017-01929, 16-21064
Clinicaltrials.gov ID NCT03139331