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

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the drug Losartan + Sunitinib for treating osteosarcoma?

Research shows that Losartan, a drug that blocks certain receptors, can reduce tumor growth and spread in cancers like colorectal cancer by affecting blood vessel formation and inflammation. Sunitinib, another drug, has shown effectiveness in treating certain cancers by blocking signals that help tumors grow. These findings suggest potential benefits when these drugs are combined for osteosarcoma treatment. ^{1 2 3 4 5}

Is the combination of Losartan and Sunitinib safe for humans?

Losartan has been studied in various cancer models and is generally considered safe, though it may cause oxidative stress (an imbalance between free radicals and antioxidants in the body). Sunitinib has been tested in animals and is generally tolerated at certain doses, with some reversible side effects, but it can affect organ systems due to its action on multiple pathways. ^{1 2 6 7 8}

What makes the drug combination of Losartan and Sunitinib unique for treating osteosarcoma?

The combination of Losartan and Sunitinib is unique for treating osteosarcoma because Losartan, typically used for high blood pressure, may help block cancer spread by affecting immune cell recruitment, while Sunitinib targets blood vessel growth in tumors. This dual approach could offer a novel way to tackle osteosarcoma, especially since standard treatments have limited effectiveness. ^{1 2 5 9 10}

Research Team

Kelly E. Faulk

Principal Investigator

Children's Hospital Colorado

Eligibility Criteria

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.

My heart condition does not severely limit my daily activities.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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, 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]

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]

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]

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]

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]

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]

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]

References

1. United States 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. [2022]

2. Germany pubmed.ncbi.nlm.nih.gov

The therapeutic potential of losartan in lung metastasis of colorectal cancer. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Old antihypertensives as novel antineoplastics: angiotensin-I-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. [2019]

4. Germany pubmed.ncbi.nlm.nih.gov

Angiotensin receptor blocker Losartan inhibits tumor growth of colorectal cancer. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Sunitinib. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Nonclinical safety evaluation of sunitinib: a potent inhibitor of VEGF, PDGF, KIT, FLT3, and RET receptors. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Angiotensin receptor signaling and prostate tumor growth in mice. [2020]

8. England 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. [2021]

9. Russia (Federation) 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]. [2017]

10. England 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. [2019]