Losartan + Sunitinib in Treatment of Osteosarcoma

NCT03900793 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 18-2740.ccNCI-2019-06119
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 4

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.

Conditions

Osteosarcoma

Keywords

Pediatrics; Adults; Phase 1; Losartan; Sunitinib; Maximum Tolerated Dose; Recommended Phase 2 Dose

Outcome Measures

Primary Outcomes (3)

• Assessment of Dose-Limiting Toxicities of Losartan and Sunitinib Combination

  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

  Beginning of study to end of study, up to 4 years

• Maximally Tolerated Dose of Losartan and Sunitinib

  The MTD will be defined as the dose level below that at which 1/3 or 2/6 patients experience DLTs.

  Beginning of study to end of study, up to 4 years

• Recommended Phase 2 Dose of Losartan and Sunitinib

  The dose than less that 33% of patients experience DLTs.

  Beginning of study to end of study, up to 4 years

Secondary Outcomes (9)

• 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)

• 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)

• 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)

• 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)

• 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)

Study Arms (1)

Dose Escalation and Expansion

EXPERIMENTAL

Part 1: This is a study escalating doses (Dose level 1-3) of losartan on a continuous daily dosing schedule and sunitinib (escalating on dose level 4) on a daily dosing with 4 weeks on, 2 weeks off. A cycle of therapy is 6 weeks (42 days).Dosing will be performed based on body surface area (BSA). This portion of the study uses a 3+3 design (i.e. cohort sizes of 3 patients for the first and second cohort at each dose level). Part 2: Once the Maximally Tolerated Dose (MTD) has been determined, 12 patients will enroll to the expansion cohort. These patients will receive the MTD as long as less then 33% of patients experience dose-limiting toxicities.

Drug: Losartan; Drug: Sunitinib

Interventions

Losartan DRUG

Losartan will be administered orally daily on days 1-42 (6 weeks) with dose level assignments. Dosing will be performed based on weight in kilograms and rounded to the nearest 12.5 mg (half of 25 mg tablet). Dose level 1 dosing will not exceed 50 mg daily, dose level 2 dosing will not exceed 100 mg daily, and dose level 3 dosing will not exceed 150 mg total daily (75 mg twice daily). Doses should be taken at approximately the same time daily and patients should fast for at least 4 hours prior to dosing

Dose Escalation and Expansion

Sunitinib DRUG

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.

Also known as: Sunitinib Malate

Dose Escalation and Expansion

Eligibility Criteria

• Age: 10 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• \. 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).
• \. Stated willingness to comply with all study procedures and be available for the duration of the study.
• \. 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.
• \. 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.
• \. Performance status:
• ECOG performance status (≥18 years old) ≤ 2 or Karnofsky performance score (\<18 years old)≥ 50.
• \. 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.
• 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).
• 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.

You may not qualify if:

• \. 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.
• \. 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.
• \. 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.
• \. Ability to take and retain oral medications. NOTE: Medication can be administered via nasogastric or gastrostomy tube.
• Patients who underwent major surgery within 14 days prior to start of treatment are not eligible.
• NOTE: Core biopsy or central line placement are considered minor and are allowed within any time limitations.

Sponsors & Collaborators

• University of Colorado, Denver: lead
• Cancer League of Colorado: collaborator
• Colorado State University: collaborator
• Swim Across America: collaborator

Study Sites (4)

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

RECRUITING

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

RECRUITING

University of Colorado Hospital

Aurora, Colorado, 80045, United States

RECRUITING

Children's Hospital of Atlanta

Atlanta, Georgia, 30322, United States

RECRUITING

MeSH Terms

Conditions

Osteosarcoma

Interventions

Losartan; Sunitinib

Condition Hierarchy (Ancestors)

Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma

Intervention Hierarchy (Ancestors)

Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Tetrazoles; Pyrroles; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Kelly Faulk, MD

  Children's Hospital Colorado

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kelly Faulk, MD, MSCS

CONTACT

720-777-6503; kelly.faulk@childrenscolorado.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Dose escalation for Phase 1 with dose levels described in Arms and interventions.

Study Record Dates

• First Submitted: March 12, 2019
• First Posted: April 3, 2019
• Study Start: August 26, 2019
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): February 1, 2027
• Last Updated: February 3, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)