Osteosarcoma
Conditions
Keywords
Pediatrics, Adults, Phase 1, Losartan, Sunitinib, Maximum Tolerated Dose, Recommended Phase 2 Dose
Brief summary
This study is a Phase 1/1b clinical trial that aims to determine the Maximally Tolerated Dose of Losartan and Sunitinib Combination Therapy. Patients will first be accrued to the Dose Escalation phase of the study, using a 3+3 design. Medication dosages will increase until a maximally tolerated dose is found. Patients will then be accrued to the Dose Expansion phase of the trial, where efficacy of pre-determined dose will be preliminarily assessed.
Interventions
DRUGLosartan
Losartan will be administered orally daily on days 1-42 (6 weeks) of each 42-day cycle according to assigned dose level. Dosing will be performed based on weight in kilograms and rounded to the nearest 12.5 mg (half of 25 mg tablet). Dose Levels 1 and 2 are closed to enrollment. Dose level 1 does not exceed 50mg daily. Dose level 2 does not exceed 100mg daily. Dose levels 3 and 4 do not exceed 150mg total daily. Doses should be taken at approximately the same time daily and patients should fast for at least 4 hours prior to and 1 hour after the morning dose. No fasting is required for evening dose.
DRUGSunitinib
Sunitinib will be administered orally daily on days 1-28 (4 weeks), followed by 14-day rest period (2 weeks). Dosing will be performed based on body surface area (BSA) in mg/m2. Sunitinib is given as capsules or liquid formulation. Doses should be taken at approximately the same time daily.
Sponsors
University of Colorado, Denver
Cancer League of Colorado
Colorado State University
Swim Across America
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
During Part A, patients are enrolled using a standard 3+3 dose-escalation design across up to four dose levels. Losartan is initially escalated while sunitinib is administered at a fixed body-surface-area based dose. If tolerated, enrollment proceeds to a fourth dose level that includes escalation of sunitinib. Participants are monitored for dose-limiting toxicities during Cycle 1 to determine the maximally tolerated dose. Following determination of the MTD, Part B enrolls an expansion cohort of 12 additional participants treated at the MTD to further evaluate safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity.
Eligibility
Sex/Gender
ALL
Age
10 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 1\. Provision to sign and date the consent form (if individual is a minor, provision of a parent or legal guardian to sign and date the consent form and provision of individual to provide assent for study). 2\. Stated willingness to comply with all study procedures and be available for the duration of the study. 3\. Male or female aged ≥ 10 years old. 4. Histologically confirmed osteosarcoma (at either original diagnosis or relapse) that has either recurred or progressed after at least one prior systemic therapy and for which no curative therapy exists. * Patients with surface or periosteal osteosarcoma are not eligible. * Patients with active CNS metastasis are not eligible. Previously treated CNS metastases which occurred 3 months or more prior, without evidence of active recurrence, are acceptable. 5\. Disease status * Dose Escalation (Part A): Patients must have measurable or evaluable disease. * Cohort Expansion (Part B): Patients with measurable or evaluable disease and those with completely resected disease are eligible. 6\. Performance status: * Performance status ECOG performance status (\>18 years old) ≤ 2 or Karnofsky performance score (\<18 years old) \> 50 7. Prior Therapy: * Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. If after the required timeframe, the numerical eligibility criteria are met (e.g., blood count criteria) the patient is considered to have recovered adequately. 1. Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive. At least 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea). 2. Anti-cancer agents not known to be myelosuppressive (e.g., not associated with reduced platelet or ANC counts): ≥ 7 days after the last dose of agent. i. Antibodies: ≥ 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. ii. Corticosteroids: ≥ 14 days must have elapsed since last dose of corticosteroid. iii. Hematopoietic growth factors: ≥ 14 days after the last dose of a long- acting growth factor (e.g., pegfilgrastim) or 7 days for short-acting growth factor. iv. Interleukins, Interferons and Cytokines (other than hematopoietic growth factors): ≥ 21 days after the completion of interleukins, interferon or cytokines (other than Hematopoietic Growth Factors). v. Stem cell Infusions: Autologous stem cell infusion, including boost infusion: ≥ 42 days. vi. Cellular Therapy: ≥ 42 days after the completion of any type of cellular therapy (e.g., modified T cells, NK cells, dendritic cells, etc.) vii. XRT/External Beam Irradiation including protons: ≥ 14 days after local XRT; ≥ 150 days after TBI, craniospinal XRT or if radiation to ≥ 50% of the pelvis; ≥ 42 days if other substantial bone marrow radiation. * NOTE: Patients with history of cardiac irradiation with mean cardiac dose \> 15 Gy are not eligible (see
Exclusion criteria
). 8\. Adequate bone marrow function, defined as: * Peripheral absolute neutrophil count (ANC) ≥ 750/mm3 * Platelet count ≥ 75,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment). * Hemoglobin ≥ 8 g/dL (with or without transfusion) 9. Adequate renal function, defined as: * Creatinine clearance or radioisotope GFR \> 70 mL/min/1.73 m2 OR a serum creatinine based on age/gender. 10\. Adequate hepatic function, defined as: * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age * SGPT (ALT) ≤ 135 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L. * Serum albumin ≥ 2.8 g/dL 11. Patients with ≥ trace protein on urinalysis at screening will be allowed to enroll in the study at investigator discretion. A baseline urine protein creatinine ratio (UPC) should be obtained for patients with ≥ trace protein on urinalysis for consideration regarding Section 6.3.7 dose modification requirements. 12\. Adequate cardiac function, defined as: * Current cardiac ejection fraction \> 50% by biplane Simpson method on echocardiogram * QTc ≤ 480 ms 13. Patients with preexisting hyper- or hypothyroidism must be on a stable dose of medication. 14\. Ability to take and retain oral medications. NOTE: Medication can be administered via nasogastric or gastrostomy tube.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of Dose-Limiting Toxicities of Losartan and Sunitinib Combination | Beginning of study to end of study, up to 4 years | Assessment of Dose-Limiting Toxicities (DLTs) according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5 to assess the safety of the combination |
| Maximally Tolerated Dose of Losartan and Sunitinib | Beginning of study to end of study, up to 4 years | The MTD will be defined as the dose level below that at which 1/3 or 2/6 patients experience DLTs. |
| Recommended Phase 2 Dose of Losartan and Sunitinib | Beginning of study to end of study, up to 4 years | The dose than less that 33% of patients experience DLTs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics of Losartan and Sunitinib in Pediatric and Adult Patients: Maximum Peak Concentration | Days 1, 15, and 29 of Cycle 1 (Cycle length is 42 days) | Determined through blood samples |
| Pharmacokinetics of Losartan and Sunitinib in Pediatric and Adult Patients: Time to Peak Concentration | Days 1, 15, and 29 of Cycle 1 (Cycle length is 42 days) | Determined through blood samples |
| Pharmacodynamics of Losartan and Sunitinib in Pediatric and Adult Patients: CCL2-Mediated Chemotactic Index | Beginning of study to end of treatment, up to 2 years (up to 17 cycles and cycle length is 42 days) | Determined through a monocyte mitigation assay and reported as a change in chemotactic index from baseline |
| Pharmacodynamics of Losartan and Sunitinib in Pediatric and Adult Patients: Plasma CCL2 Levels | Beginning of study to end of treatment, up to 2 years (up to 17 cycles and cycle length is 42 days) | Assessed by Enzyme Linked Immunosorbent Assay (ELISA). |
| Pharmacodynamics of Losartan and Sunitinib in Pediatric and Adult Patients: CCR2+ Monocyte Population | Beginning of study to end of treatment, up to 2 years (up to 17 cycles and cycle length is 42 days) | Assessed by Flow Cytometry |
| Preliminary Antitumor Activity of Losartan and Sunitinib in Pediatric and Adult Patients: Disease Control Rate (DCR) | Beginning of study, end of cycle 1 (each cycle is 6 weeks), and at the end of odd cycles (up to 17 cycles) | Stable disease determined according to RECIST 1.1 criteria |
| Preliminary: Progression Free Survival (PFS) | Beginning of study, end of cycle 1 (each cycle is 6 weeks), and at the end of odd cycles (up to 17 cycles) | Determined according to irRECIST criteria. |
Countries
United States
Contacts
CONTACTKelly Faulk, MD, MSCS
PRINCIPAL_INVESTIGATORKelly Faulk, MD
Children's Hospital Colorado
Outcome results
None listed