What side effects are associated with this type of intervention?

Common treatments for osteosarcoma, particularly those involving Angiotensin II Receptor Antagonists like Losartan and Tyrosine Kinase Inhibitors like Sunitinib, have distinct side effect profiles. Losartan can cause dizziness, hyperkalemia, and renal impairment. Sunitinib is associated with hypertension, fatigue, diarrhea, hand-foot syndrome, and nephrotoxicity. Combining these treatments may result in overlapping toxicities, requiring careful monitoring of renal function and blood pressure.

What prior FDA approvals exist?

There is limited specific information on FDA approvals for the combination of Angiotensin II Receptor Antagonists and Tyrosine Kinase Inhibitors in the treatment of Osteosarcoma. However, Tyrosine Kinase Inhibitors (TKIs) like Sunitinib have been studied in various cancers, including Osteosarcoma, for their potential to inhibit tumor growth and angiogenesis. The combination of Losartan (an Angiotensin II Receptor Antagonist) and Sunitinib is currently being investigated in clinical trials to determine its efficacy and safety in treating Osteosarcoma.

What other types of research exist?

Promising novel alternatives for osteosarcoma treatment in 2024 include: 1) Immune checkpoint inhibitors such as pembrolizumab, which have shown potential benefits in various sarcomas. 2) CDK4/6 inhibitors like palbociclib, ribociclib, and abemaciclib, which are being investigated for their efficacy in sarcomas. 3) mTOR inhibitors such as everolimus and temsirolimus, which have been used in specific sarcoma subtypes. 4) Combination therapies involving gemcitabine and docetaxel, which have been effective in soft tissue sarcomas and may be applicable to osteosarcoma.

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Angiotensin II Receptor Blocker

Losartan + Sunitinib for Osteosarcoma

Phase 1

Recruiting

Led By Carrye Cost, MD

Research Sponsored by University of Colorado, Denver

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Patients with surface or periosteal osteosarcoma are not eligible.

NOTE: Patients with history of cardiac irradiation with mean cardiac dose > 15 Gy are not eligible.

Must not have

Drug interactions: Patients who require treatment with medications that are strong inhibitors or inducers of CYP3A4 or inhibitors of CYP2A9 or have received these medications in the 7 days prior to enrollment, are not eligible. Patients who require treatment with enzyme inducing anticonvulsants are not eligible (see Appendix III).

Patients with symptomatic cardiac disease (i.e. New York Heart Association or Modified Ross Heart Failure Classification for Children > class 2) are not eligible.

Timeline

Screening 3 weeks

Treatment Varies

Follow Up beginning of study to end of study, up to 4 years

Awards & highlights

Summary

This trial is testing a combination of two drugs, Losartan and Sunitinib. It aims to find the highest dose that patients can handle without severe side effects. The study will first increase doses to find the limit, then test how well that dose works. Sunitinib has been studied extensively with other drugs for advanced solid tumors, showing varying degrees of success and side effects.

Who is the study for?

This trial is for individuals over 10 years old with osteosarcoma that has recurred or progressed after prior therapy. They must be able to take oral medication, have stable thyroid function on current meds, and not be pregnant or breastfeeding. Participants need normal organ function and can't have had major surgery within the last two weeks or a history of significant heart disease.

What is being tested?

The study tests the combination of Losartan and Sunitinib to find the highest dose patients can tolerate without severe side effects (Phase 1). After determining this dose, more patients will receive it to see how effective it is against osteosarcoma (Phase 1b), using a step-by-step approach where doses increase gradually.

What are the potential side effects?

Possible side effects include high blood pressure from Losartan and fatigue, diarrhea, skin problems, mouth sores, nausea, vomiting, high blood sugar levels from Sunitinib. There may also be risks due to lowered immune system function leading to increased infection risk.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My osteosarcoma is not just on the surface or outer layer of the bone.

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I have not received heart radiation exceeding 15 Gy.

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It's been over 21 days since my last antibody treatment and any side effects are mild.

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It has been more than 14 days since my last corticosteroid dose.

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My liver is working well.

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My kidney function is good based on tests.

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My bilirubin levels are within the normal range for my age.

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My heart pumps well, with an ejection fraction over 50%.

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I haven't taken any cancer drugs that lower blood counts in the last week.

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I had my own stem cell infusion more than 42 days ago.

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My disease can be measured or evaluated.

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I am mostly self-sufficient and can carry out daily activities.

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My osteosarcoma has returned or worsened after treatment and cannot be cured.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I am not taking, nor have I taken in the last week, any strong medication that affects enzyme activity.

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My heart condition does not severely limit my daily activities.

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I have no history of serious heart problems or strokes.

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I am not on medications that affect heart rhythm.

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I have not received heart radiation over 15 Gy.

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My blood pressure is controlled with one or no medication.

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I do not have any uncontrolled bleeding disorders or significant active bleeding.

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I am not currently taking any cancer treatment drugs.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ beginning of study to end of study, up to 4 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~beginning of study to end of study, up to 4 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and beginning of study to end of study, up to 4 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Assessment of Dose-Limiting Toxicities of Losartan and Sunitinib Combination

Maximally Tolerated Dose of Losartan and Sunitinib

Recommended Phase 2 Dose of Losartan and Sunitinib

Secondary study objectives

Pharmacodynamics of Losartan and Sunitinib in Pediatric and Adult Patients: CCL2-Mediated Chemotactic Index

Pharmacodynamics of Losartan and Sunitinib in Pediatric and Adult Patients: CCR2+ Monocyte Population

Pharmacodynamics of Losartan and Sunitinib in Pediatric and Adult Patients: Plasma CCL2 Levels

+4 more

Side effects data

From 2021 Phase 4 trial • 227 Patients • NCT02188121

43%

Laboratory values outside normal range

23%

Psychiatric Hospitalization

Medical Hospitalization

Elevated creatine kinase level

Muscle pain

Hypotension

Dehydration

Leukemia

Placed on Lithium while on Losartan

100%

80%

60%

40%

20%

Study treatment Arm

Statin and/or Angiotensin Receptor Blocker

Usual Treatment

Trial Design

1Treatment groups

Experimental Treatment

Group I: Dose Escalation and ExpansionExperimental Treatment2 Interventions

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.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Losartan

2003

Completed Phase 4

~3000

Sunitinib

2014

Completed Phase 3

~4380

0 / 21Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The combination therapy of Losartan and Sunitinib for Osteosarcoma involves two distinct mechanisms of action. Losartan, an angiotensin II receptor antagonist, reduces blood pressure and may alter the tumor microenvironment, making it less conducive to cancer growth. Sunitinib, a tyrosine kinase inhibitor, targets multiple receptor tyrosine kinases that are essential for tumor growth, angiogenesis, and metastasis. This dual approach is significant for Osteosarcoma patients as it offers a strategy to both directly inhibit tumor growth and modify the surrounding environment to enhance treatment efficacy.

Losartan Alleviates the Side Effects and Maintains the Anticancer Activity of Axitinib.Radiogenomics Monitoring in Breast Cancer Identifies Metabolism and Immune Checkpoints as Early Actionable Mechanisms of Resistance to Anti-angiogenic Treatment.Medical Management of Pancreatic Neuroendocrine Tumors: Current and Future Therapy.