Losartan + Sunitinib for Osteosarcoma

Recruiting at 3 trial locations

Overseen By Carrye Cost, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Colorado, Denver

Must not be taking: Corticosteroids, Investigational drugs, others

Disqualifiers: Pregnancy, Cardiac disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

41 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, Losartan and Sunitinib, to determine the safest dosage for people with osteosarcoma, a type of bone cancer that has returned or worsened after previous treatment. The first part of the trial increases drug doses to find the maximum amount patients can tolerate, followed by a second part that assesses the effectiveness of this dosage. Ideal candidates are individuals with recurring osteosarcoma who have tried other treatments without success and do not have ongoing brain metastases. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

Yes, you may need to stop taking certain medications. The trial does not allow participants to be on systemic corticosteroids, other anti-cancer agents, or medications that strongly affect certain liver enzymes (CYP3A4 or CYP2A9) or prolong QTc. You should discuss your current medications with the trial team to see if any need to be stopped.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research is testing the maximum dosage of Losartan and Sunitinib that people can take together without serious side effects. These studies remain in the early stages, so researchers are still learning about their combined safety in humans.

Losartan typically treats high blood pressure, while Sunitinib is approved for certain cancers. Their safety is known when used separately, but using them together is new. This trial aims to determine how well people can tolerate both drugs simultaneously.

Participants will start with low doses, gradually increasing them. This approach helps researchers identify the safest dose. Initial findings suggest that the combination is being monitored closely to ensure it is well-tolerated. However, since this is an early trial, researchers are still developing a complete safety profile. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Losartan and Sunitinib for osteosarcoma because these treatments bring a fresh approach to tackling the disease. Unlike current standard treatments like chemotherapy and surgery, Losartan is known for its ability to inhibit the angiotensin system, which may help reduce tumor blood supply. Sunitinib, on the other hand, is a targeted therapy that blocks specific proteins involved in cancer cell growth, making it a precise option against tumor development. Together, these drugs offer a dual mechanism that could potentially enhance effectiveness and reduce the reliance on more aggressive treatments.

What evidence suggests that this treatment might be an effective treatment for osteosarcoma?

This trial investigates the combination of losartan and sunitinib for treating osteosarcoma. Studies have shown that using these drugs together may help treat this type of bone cancer. Research with dogs that have this cancer showed that the treatment was safe and beneficial. Losartan blocks certain pathways that cancer cells use to grow, while sunitinib stops cancer cell growth. Ongoing trials, including this one, have shown positive results, suggesting this combination could be promising for osteosarcoma patients. Early findings are encouraging, but information specific to humans remains limited. ^{1 3 4 6 7}

Who Is on the Research Team?

Kelly E. Faulk

Principal Investigator

Children's Hospital Colorado

Are You a Good Fit for This Trial?

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.

Inclusion Criteria

My platelet count is above 75,000 and I haven't had a transfusion in the last week.

I have received previous treatments for my condition.

It's been over 14 days since my last long-acting growth factor dose or 7 days for a short-acting one.

Exclusion Criteria

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

Investigational Drugs: Patients currently receiving another investigational drug are not eligible.

Pregnancy

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Patients are accrued to the Dose Escalation phase using a 3+3 design to determine the Maximally Tolerated Dose of Losartan and Sunitinib.

6 weeks per cycle

Visits at the beginning and end of each cycle

Dose Expansion

Patients receive the pre-determined maximally tolerated dose to preliminarily assess efficacy.

6 weeks per cycle, up to 17 cycles

Visits at the beginning and end of each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Losartan
• Sunitinib

Trial Overview 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.

How Is the Trial Designed?

Group I: Dose Escalation and Expansion Experimental Treatment 2 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.

Losartan is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Cozaar for:

• Hypertension
• Diabetic nephropathy
• Stroke prevention in hypertension and left ventricular hypertrophy

Approved in European Union as Cozaar for:

• Hypertension
• Diabetic nephropathy
• Heart failure

Approved in Canada as Cozaar for:

• Hypertension
• Diabetic nephropathy
• Heart failure

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

Cancer League of Colorado

Collaborator

Trials

13

Recruited

450+

Colorado State University

Collaborator

Trials

138

Recruited

38,200+

Swim Across America

Collaborator

Trials

11

Recruited

410+

Published Research Related to This Trial

Losartan, a renin-angiotensin system inhibitor, effectively reduced lung metastasis in colorectal cancer (CRC) in a murine model, showing potential as a therapeutic option for metastatic CRC.

The treatment with losartan was associated with decreased inflammation and angiogenesis, evidenced by lower IL-6 and VEGF levels, while also inducing oxidative stress, suggesting a complex mechanism of action through the Angiotensin II type I receptor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The therapeutic potential of losartan in lung metastasis of colorectal cancer. Hashemzehi, M., Naghibzadeh, N., Asgharzadeh, F., et al.[2020]

Sunitinib malate is generally well-tolerated in both Sprague-Dawley rats and cynomolgus monkeys at lower doses (0.3 mg/kg/day in rats and 1.5 mg/kg/day in monkeys), with most treatment-induced effects being reversible after cessation of treatment.

The study highlights that sunitinib's inhibition of multiple receptor tyrosine kinase pathways can lead to pharmacologic effects on organ systems, including reversible changes in neovascularization and reproductive organ development, which are consistent with the drug's mechanism of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonclinical safety evaluation of sunitinib: a potent inhibitor of VEGF, PDGF, KIT, FLT3, and RET receptors. Patyna, S., Arrigoni, C., Terron, A., et al.[2019]

In a pilot study involving nude mice with LAPC-4 prostate cancer, the AT1R blocker losartan significantly reduced tumor growth by 56% compared to control, indicating its potential efficacy in slowing prostate cancer progression.

The study suggests that selectively blocking AT1R while activating AT2R may be a promising strategy for prostate cancer treatment, although further research with larger sample sizes is necessary to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin receptor signaling and prostate tumor growth in mice. Scott-Emuakpor, J., Allot, E., Johnson, SA., et al.[2020]

ACE inhibitors and angiotensin II type 1 antagonists may serve as novel treatments for cancer by inhibiting angiogenesis, cellular growth, and invasion of cancer cells, as they target the renin-angiotensin system which promotes tumor growth.

The angiotensin II receptor blocker losartan has shown potential in reducing chemotherapy-related toxicity, allowing for higher doses and potentially improving treatment success rates, suggesting a need for further clinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Old antihypertensives as novel antineoplastics: angiotensin-I-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. Abali, H., Güllü, IH., Engin, H., et al.[2019]

Losartan, an angiotensin receptor blocker, shows promise in treating colorectal cancer (CRC) by inhibiting cell growth, reducing tumor size, and enhancing tumor cell necrosis in both cell culture and xenograft models.

The study suggests that Losartan's anti-proliferative effects may be linked to its impact on inflammatory responses and the reduction of metastasis and angiogenesis, indicating its potential as a complementary treatment alongside traditional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin receptor blocker Losartan inhibits tumor growth of colorectal cancer. Hashemzehi, M., Rahmani, F., Khoshakhlagh, M., et al.[2021]

In a study involving 28 dogs with lung metastatic osteosarcoma, the combination of losartan and toceranib was well-tolerated and resulted in a clinical benefit rate of 50%, indicating potential efficacy in treating this type of cancer.

Losartan effectively inhibited monocyte migration by blocking the CCL2-CCR2 axis, suggesting that this mechanism could be leveraged for further evaluation in pediatric osteosarcoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Losartan Blocks Osteosarcoma-Elicited Monocyte Recruitment, and Combined With the Kinase Inhibitor Toceranib, Exerts Significant Clinical Benefit in Canine Metastatic Osteosarcoma. Regan, DP., Chow, L., Das, S., et al.[2022]

Losartan is an effective treatment for hypertension and has been shown to reduce cardiovascular events in patients with hypertension and left ventricular hypertrophy, based on the LIFE study.

However, the cardiovascular benefits of losartan do not extend to black patients, highlighting the need for tailored treatment approaches in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Losartan for the treatment of hypertension and left ventricular hypertrophy: the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Devereux, RB., Lyle, PA.[2019]

Sunitinib is an effective small-molecule inhibitor that targets receptor tyrosine kinases involved in tumor blood vessel formation, particularly the VEGF receptor, showing significant antiangiogenic effects in laboratory and animal studies.

In human trials, a daily dose of 50 mg has been found to be tolerable and effective, especially for advanced renal cell carcinoma and gastrointestinal stromal tumors that are resistant to imatinib, leading to its regulatory approval for these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sunitinib. Rini, BI.[2019]

In a study of 20 patients with mild to moderate hypertension, 24 weeks of treatment with Hyzaar (losartan and hydrochlorothiazide) significantly lowered both daytime and nighttime blood pressure, achieving target levels in 70% of patients.

The treatment also led to a significant reduction in left ventricular myocardial mass, indicating cardioprotective effects that were independent of the blood pressure-lowering effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Therapy of patients with arterial hypertension with fixed dose combination of losartan and hydrochlorothiazide. Effect on 24 hour blood pressure and left-ventricular hypertrophy]. Chazova, IE., Ratova, LG., Dmitriev, VV., et al.[2017]

In a study using a murine model of metastatic HER2/neu-positive breast cancer, combining losartan with radiation therapy significantly increased tumor growth delay by an additional 5 to 8 days compared to radiation alone, indicating enhanced treatment efficacy.

Losartan treatment also reduced lung metastasis and improved animal survival, likely by increasing tumor vascularity and decreasing hypoxia, suggesting it could be a promising strategy for improving outcomes in HER2-positive breast cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combining losartan with radiotherapy increases tumor control and inhibits lung metastases from a HER2/neu-positive orthotopic breast cancer model. Li, W., Li, S., Chen, IX., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03900793

Losartan + Sunitinib in Treatment of Osteosarcoma This study is a Phase 1/1b clinical trial that aims to determine the Maximally Tolerated Dose of Losartan and Sunitinib Combination Therapy.

2. georgiacancerinfo.org georgiacancerinfo.org/clinical-trials/detail/5063

Losartan and Sunitinib for the Treatment of Relapsed or ... This phase I/Ib trial studies the side effects, best dose, and anti-tumor activity of losartan and sunitinib in treating patients with osteosarcoma that has ...

3. withpower.com withpower.com/trial/phase-1-osteosarcoma-7-2019-3137a

Losartan + Sunitinib for Osteosarcoma In a study involving 28 dogs with lung metastatic osteosarcoma, the combination of losartan and toceranib was well-tolerated and resulted in a clinical benefit ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8000603/

Pathogenesis and Current Treatment of Osteosarcoma Losartan + sunitinib in treatment of osteosarcoma, Recruiting. NCT03932071 ... osteosarcoma in multiple ongoing trials with positive results [95]. A ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8866227/

Losartan Blocks Osteosarcoma-Elicited Monocyte ... Conclusions: Losartan inhibits the CCL2–CCR2 axis, and in combination with toceranib, exerts significant biological activity in dogs with metastatic ...

6. cancer.gov cancer.gov/clinicaltrials/NCI-2019-06119

Losartan and Sunitinib for the Treatment of Relapsed or ... This phase I/Ib trial studies the side effects, best dose, and anti-tumor activity of losartan and sunitinib in treating patients with osteosarcoma that has ...

7. news.cuanschutz.edu news.cuanschutz.edu/cancer-center/v-foundation-pediatric-osteosarcoma-that-spreads-to-the-lungs

V Foundation Funds CU Cancer Center Research on ... In his initial trial of the losartan-sunitinib combination in dogs, Regan saw 50% of patients achieve longer-term disease stabilization and ...