Losartan + Sunitinib for Osteosarcoma
Recruiting in Palo Alto (17 mi)
+3 other locations
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: University of Colorado, Denver
Must not be taking: Corticosteroids, Investigational drugs, others
Disqualifiers: Pregnancy, Cardiac disease, others
No Placebo Group
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.12345
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.12678
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.125910
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.
See 36 more
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.
See 13 more
Trial 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 (Angiotensin II Receptor Blocker)
- Sunitinib (Tyrosine Kinase Inhibitor)
Trial OverviewThe 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
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.
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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Colorado HospitalAurora, CO
Children's Hospital Los AngelesLos Angeles, CA
Children's Hospital ColoradoAurora, CO
Children's Hospital of AtlantaAtlanta, GA
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Who Is Running the Clinical Trial?
University of Colorado, DenverLead Sponsor
Cancer League of ColoradoCollaborator
Colorado State UniversityCollaborator
Swim Across AmericaCollaborator
References
Losartan Blocks Osteosarcoma-Elicited Monocyte Recruitment, and Combined With the Kinase Inhibitor Toceranib, Exerts Significant Clinical Benefit in Canine Metastatic Osteosarcoma. [2022]There is increasing recognition that progress in immuno-oncology could be accelerated by evaluating immune-based therapies in dogs with spontaneous cancers. Osteosarcoma (OS) is one tumor for which limited clinical benefit has been observed with the use of immune checkpoint inhibitors. We previously reported the angiotensin receptor blocker losartan suppressed metastasis in preclinical mouse models through blockade of CCL2-CCR2 monocyte recruitment. Here we leverage dogs with spontaneous OS to determine losartan's safety and pharmacokinetics associated with monocyte pharmacodynamic endpoints, and assess its antitumor activity, in combination with the kinase inhibitor toceranib.
The therapeutic potential of losartan in lung metastasis of colorectal cancer. [2020]Colorectal cancer (CRC) is a common cancer with a high incidence rate. Components of the renin-angiotensin system (RAS) have been reported to be dysregulated in several malignancies including CRC. Here, we have explored the potential anti-metastatic effects of a RAS inhibitor, losartan, in an experimental model of lung metastasis in CRC. A murine model of lung metastasis of CRC was used, which involved the intravenous injection of CT26 cells via a tail vein. Four experimental groups comprised: an untreated group; a group that received 5-FU which was administered intraperitoneally; a losartan group that received a combination group that received 5-FU plus losartan . We evaluated the anti-inflammatory effects of losartan by histopathological method, and the measurement of oxidative or antioxidant markers including malondialdehyde (MDA) and total-thiols (T-SH) tissue levels, superoxide-dismutase (SOD) and catalase activity. We found that losartan inhibited lung metastasis of CRC and there was a reduction of the IL-6 expression level in the tissue sample. It was also associated with reduced levels of the anti-angiogenic factor Vascular endothelial growth factor (VEGF). Furthermore, we found that losartan induced oxidative stress as assessed by an elevation of MDA level, reduction of T-SH, SOD and catalase activities in lung tissue. Our findings demonstrated that losartan ameliorates angiogenesis, inflammation and the induction of oxidative stress via Angiotensin II type I receptor (AT1R). This may shine some lights on targeting the RAS pathway as a potential therapeutic approach in the treatment of metastatic CRC patients.
Old antihypertensives as novel antineoplastics: angiotensin-I-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. [2019]Angiogenesis, cellular growth and invasion of a cancer cell are attractive targets for new treatment strategies of malignancies in recent years. The evidences are accumulating that ACE inhibitors and angiotensin II type 1 antagonists could be novel anti-angiogenic, anti-invasive, and even anti-growth agents against neoplastic tissues: The renin-angiotensin system promotes angiogenesis directly or indirectly and growth of neoplastic cell. Some tumors carry angiotensin II type 1 receptors. Angiotensin II antagonists and angiotensin-I-converting enzyme inhibitors have shown some anti-neoplastic actions. Angiotensin II receptor blocker losartan antagonises platelets, which are thought to modulate via vascular endothelial growth factor. They may even protect the patient from the major toxicity of chemotherapy and/or radiotherapy, myelotoxicity, enabling us to give higher doses and end up with higher success rate. We believe that these agents can be useful on clinical grounds and suggest their incorporation into clinical studies.
Angiotensin receptor blocker Losartan inhibits tumor growth of colorectal cancer. [2021]The renin-angiotensin system (RAS) is up-regulated in patients with colorectal cancer (CRC) and is reported to be associated with poor prognosis and chemo-resistance. Here we explored the therapeutic potential of targeting RAS in CRC using Losartan, an angiotensin receptor blocker. An integrative-systems biology approach was used to explore a proteome-level dataset of a gene signature that is modulated by Losartan. The anti-proliferative activity of Losartan was evaluated using 2- and 3-dimensional cell culture models. A xenograft model of colon cancer was used to investigate tumor growth with Losartan alone and in combination with 5-FU followed by histological staining (Hematoxylin & Eosin and Masson trichrome staining), biochemical analyses, gene expression analyses by RT-PCR, western blot/IHC, or MMP Gelatin Zymography studies. Effects on cell cycle and cell death were assessed by flow cytometry. Losartan inhibited cell growth and suppressed cell cycle progression, causing an increase in CRC cells in the G1 phase. Losartan significantly reduced tumor growth and enhanced tumor cell necrosis. An impact on the inflammatory response, including up-regulation of pro-inflammatory cytokines and chemokines in CRC cells are potential mechanisms that could partially explain Losartan's anti-proliferative effects. Moreover, metastasis and angiogenesis were reduced in Losartan-treated mice as observed by inhibited matrix metalloproteinase-2 and -9 activities and decreased tumor vasculature. These data demonstrate the therapeutic potential of combining chemotherapeutic regimens with Losartan to synergistically enhance its activity and target the renin-angiotensin system as a new approach in colorectal cancer treatment.
Sunitinib. [2019]Sunitinib is a small-molecule inhibitor of several receptor tyrosine kinases relevant to tumor angiogenesis, including the vascular endothelial growth factor (VEGF) receptor. Potent inhibition of this related family of receptors and consequent antiangiogenic effects have been demonstrated in vitro and in murine models. Human studies have established 50 mg daily dosing given on an intermittent schedule as a tolerable dose. Significant antitumor effects have been observed, most notably in advanced renal cell carcinoma (RCC) and imatinib refractory/intolerant gastrointestinal stromal tumor (GIST). Sunitinib has received regulatory approval in these two indications, and is at present being investigated across a broad array of solid tumors. Despite these initial results, several questions remain to optimize the utility of this agent.
Nonclinical safety evaluation of sunitinib: a potent inhibitor of VEGF, PDGF, KIT, FLT3, and RET receptors. [2019]Sunitinib malate (SUTENT) is a multitargeted receptor tyrosine kinase (RTK) inhibitor that is approved multinationally for the treatment of imatinib-resistant/-intolerant gastrointestinal stromal tumor and advanced renal cell carcinoma. This paper characterizes the organ toxicity of sunitinib in Sprague-Dawley rats and cynomolgus monkeys, and the reversibility of any treatment-induced effects. Rats and monkeys received sunitinib (0-15 and 0-20 mg/kg/day, respectively) orally on a consecutive daily dosing schedule for thirteen weeks or on an intermittent daily dosing schedule for up to nine months. Clinical observations and laboratory parameters were recorded. Necropsy was conducted following treatment/recovery periods, and histologic examinations were performed. In rats, sunitinib was generally tolerated at 0.3 and 1.5 mg/kg/day, and findings were reversible. In monkeys, the level at which there were no observed adverse effects was 1.5 mg/kg/day, and findings were similarly reversible (except for uterine/ovarian weight changes and skin pallor). Data suggest that inhibition of multiple RTK pathways may induce pharmacologic effects on organ systems in nonclinical species. Key pharmacologic effects of sunitinib included reversible inhibition of neovascularization into the epiphyseal growth plate, and impaired corpora lutea formation and uterine development during estrus. Similar observations have been noted with this class of RTK signaling inhibitors and are consistent with pharmacologic perturbations of physiologic/angiogenic processes associated with the intended molecular targets.
Angiotensin receptor signaling and prostate tumor growth in mice. [2020]The renin-angiotensin system, through its type 1 and type 2 angiotensin receptors (AT1R and AT2R, respectively) may have a role in prostate cancer. The objective of this pilot study was to explore that potential role by determining whether the AT1R blocker, losartan, would reduce the growth of LAPC-4 prostate cancer xenografts in nude mice. We also evaluated the tumor growth effects of using angiotensin II to activate both AT1R and AT2R simultaneously. Our data showed that losartan decreased tumor volumes by 56% versus control. This decrease reached statistical significance at day 54 (p = 0.0014). By day 54, Ki67 was also reduced in the losartan group, though not significantly so (p = 0.077). Losartan had no significant effect on AT1R or AT2R expression. Despite significant increases in both AT1R and AT2R at day 29 (p = 0.043 and 0.038, respectively), the administration of angiotensin II did not result in any significant differences in tumor volumes or ki67 at any time point. These data suggest that selective activation and induction of AT2R coupled with blockade of AT1R may slow prostate cancer growth. Future larger studies are needed to confirm these results.
Combining losartan with radiotherapy increases tumor control and inhibits lung metastases from a HER2/neu-positive orthotopic breast cancer model. [2021]Patients with metastatic HER2/neu-positive (HER2/neu +) breast cancer (BC) often experience treatment resistance, disease recurrences and metastases. Thus, new approaches for improving the treatment of HER2/neu + BC to prevent metastatic dissemination are urgently needed. Our previous studies have shown that losartan, an angiotensin receptor blocker, increases tumor perfusion and decreases hypoxia in a number of tumor models. Hypoxia reduces the efficacy of radiation and increases metastases. We therefore hypothesized that by modifying tumor stroma and increasing oxygenation, losartan will improve the outcome of radiotherapy and inhibit disease progression in a highly metastatic HER2/neu + murine BC model.
[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]Twenty four hour blood pressure (BP) monitoring was carried out and structural state of left ventricular myocardium assessed in 20 patients with mild and moderate hypertension before and after 24 weeks of therapy with Hyzaar - fixed dose combination of losartan (50 mg) and hydrochlorothiazide (12.5 mg). According to data of 24-hour BP monitoring the use of Hyzaar was associated with lowering of diurnal (by 26.9/17.2+/-3/2 mm Hg, p
Losartan for the treatment of hypertension and left ventricular hypertrophy: the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. [2019]Losartan is an orally active, selective, nonpeptide, angiotensin-II Type I-receptor antagonist, and was the first drug marketed in this class. It has been approved for the treatment of hypertension, and may be used alone or in combination with other antihypertensive agents. Based on the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, losartan has been approved for the reduction of cardiovascular events in patients with hypertension and left ventricular hypertrophy, but there is evidence that this benefit does not apply to black patients. Based on the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study, losartan is also indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria, in patients with Type 2 diabetes. The focus of this review is the LIFE study.