Papaverine + SBRT for Non-Small Cell Lung Cancer

Overseen By Miranda Bean

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Ohio State University Comprehensive Cancer Center

Must not be taking: Cytotoxic chemotherapy, Immunotherapy

Disqualifiers: Pregnancy, Pneumonectomy, Hepatic insufficiency, others

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

Compensation: Varies

Number of Visits: 8

Duration: 2 weeks

24 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and how well papaverine hydrochloride and stereotactic radiation therapy body (SBRT) work in treating patients with non-small cell lung cancer. Papaverine hydrochloride may help radiation therapy work better by making tumor cells more sensitive to the radiation therapy. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Giving papaverine hydrochloride with SBRT may work in treating patients with non-small cell lung cancer.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you must wait at least 2 weeks after your last dose of any prior chemotherapy, targeted therapy, or immunotherapy before starting the trial.

What data supports the effectiveness of the drug Papaverine Hydrochloride in combination with radiation therapy for treating non-small cell lung cancer?

Research shows that Papaverine can make tumors more sensitive to radiation by improving oxygen levels in the tumor, which can enhance the effectiveness of radiation therapy. This approach has been shown to increase the radiation response in solid tumors, suggesting potential benefits for lung cancer treatment. ^{1 2 3 4 5}

Is the combination of Papaverine and CyberKnife SABR safe for treating non-small cell lung cancer?

CyberKnife SABR has been shown to be safe for treating various cancers, including lung cancer, with acceptable levels of side effects. However, specific safety data for the combination of Papaverine and CyberKnife SABR is not available in the provided research. ^{6 7 8 9 10}

How is the treatment Papaverine + SBRT for non-small cell lung cancer different from other treatments?

This treatment combines Papaverine, a drug that may enhance blood flow, with Stereotactic Body Radiation Therapy (SBRT), which precisely targets tumors with high doses of radiation in fewer sessions. The use of Papaverine with SBRT is unique as it may improve the effectiveness of radiation by increasing oxygen delivery to the tumor, potentially leading to better outcomes compared to SBRT alone. ^{7 11 12 13 14}

Research Team

Jeremy Brownstein, MD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Eligibility Criteria

This trial is for adults with non-small cell lung cancer or lung metastases from solid tumors, who have not had prior radiation in the same area. They must be physically stable (ECOG 0-2), have a tumor <=5 cm that can be treated with SBRT, and expect to live at least 12 weeks. Participants need proper liver and kidney function, no severe connective tissue disease or pulmonary fibrosis, and agree to use contraception if applicable.

Inclusion Criteria

Histologically or cytologically proven NSCLC for whom SBRT to a single lesion has been chosen as the primary treatment modality (planned dose 50 Gy in 4-5 daily fractions). Patients with lung metastases from solid tumors are eligible.

No prior radiation resulting in overlapping fields

Eastern Cooperative Oncology Group (ECOG) performance status 0-2

Exclusion Criteria

You have had a surgery called pneumonectomy in the past.

You have a history of certain diseases like scleroderma, idiopathic pulmonary fibrosis, or pneumonitis.

Hepatic insufficiency resulting in jaundice and/or coagulation defects, or not meeting laboratory values (albumin, total bilirubin, AST/ALT)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive papaverine hydrochloride IV and undergo SBRT for up to 4-5 sessions over 2 weeks

2 weeks

4-5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 12 months

Visits at 4-6 weeks, 3 and 6 months, 1 and 2 years, then every 3 months for 2 years, and every 6 months for 3 years

Treatment Details

Interventions

• Papaverine Hydrochloride
• Stereotactic Body Radiation Therapy

Trial Overview The trial is testing whether combining papaverine hydrochloride with stereotactic body radiation therapy (SBRT) improves treatment outcomes for non-small cell lung cancer. Papaverine may make cancer cells more sensitive to radiation, while SBRT targets tumors precisely to minimize damage to healthy tissue.

Participant Groups

Group I: Treatment (BOLD fMRI, papaverine hydrochloride, SBRT) Experimental Treatment 3 Interventions

Patients undergo BOLD fMRI and receive papaverine hydrochloride IV on day 1. Within 30-90 minutes, patients undergo a second BOLD fMRI. Patients then receive papaverine hydrochloride IV and within 30-90 minutes after dose undergo SBRT for a up to 4-5 sessions over 2 weeks.

Who Is Running the Clinical Trial?

Ohio State University Comprehensive Cancer Center

Lead Sponsor

Trials

350

Recruited

295,000+

Findings from Research

A review of clinical trials from 1970 to 1998 found that most chemical agents used alongside irradiation for cervical cancer did not improve outcomes compared to radiation alone.

However, cisplatin-based therapy combined with concurrent irradiation showed a survival advantage, highlighting its potential effectiveness in treating cervical cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modification of the Radiation Response of Patients With Carcinoma of the Uterine Cervix. Grigsby, PW.[2019]

Targeting mitochondrial respiration with the FDA-approved drug papaverine can significantly reduce tumor cells' oxygen demand, leading to improved oxygenation and enhanced effectiveness of radiation therapy.

Papaverine's ability to inhibit mitochondrial complex I is directly linked to increased tumor oxygenation and radiation response, and its derivatives may serve as radiosensitizers with fewer side effects, specifically sparing well-oxygenated normal tissues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism. Benej, M., Hong, X., Vibhute, S., et al.[2020]

In a pilot study of 24 patients with locally advanced cervical cancer, the combination of Carboplatin or Nedaplatin with conventional radiotherapy resulted in a high response rate, with 9 out of 13 evaluable patients achieving complete responses.

The treatment was found to be safe and well-tolerated, with no significant renal damage or severe hematological toxicity, suggesting that these platinum-based drugs could effectively enhance the efficacy of radiation therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Concurrent chemoradiotherapy for advanced cervical cancer--a pilot study]. Kodama, J., Hashimoto, I., Seki, N., et al.[2013]

Cisplatin is the primary systemic anti-cancer agent used in conjunction with radiation for locally advanced cervical cancer, but its overall effectiveness is limited.

Recent phase 3 trials show that adding bevacizumab to chemotherapy regimens (cisplatin/paclitaxel or paclitaxel/topotecan) significantly improves overall survival for patients with metastatic or recurrent cervical cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in cervical cancer pharmacotherapies. Markman, M.[2015]

In a study involving 220 patients with small cell lung cancer (SCLC) who had a response to initial chemotherapy, the PARP inhibitor olaparib did not significantly improve progression-free survival (PFS) compared to placebo, with median PFS of 3.7 months for olaparib versus 2.5 months for placebo.

Common side effects of olaparib included fatigue, nausea, and anemia, and the rate of treatment discontinuation due to toxicity was similar to that seen in other studies, indicating that while olaparib is generally well-tolerated, it does not provide a clear benefit in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib as maintenance treatment in patients with chemosensitive small cell lung cancer (STOMP): A randomised, double-blind, placebo-controlled phase II trial. Woll, P., Gaunt, P., Danson, S., et al.[2022]

Stereotactic ablative radiotherapy (SABR) using Cyberknife demonstrated high effectiveness in treating stage I non-small-cell lung cancer, with 2-year local control, progression-free, and overall survival rates of 91.9%, 61.7%, and 84.8%, respectively, based on a study of 153 patients.

The treatment was generally safe, with only 8.1% of patients experiencing severe toxicities, including one case of grade 5 radiation pneumonitis, indicating that while SABR is effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic Ablative Radiotherapy Using CyberKnife for Stage I Non-small-cell Lung Cancer: A Retrospective Analysis. Hayashi, K., Suzuki, O., Shiomi, H., et al.[2022]

Stereotactic ablative radiotherapy (SABR) is an effective treatment for early-stage non-small cell lung cancer, especially for patients who cannot undergo surgery, showing high local tumor control rates with manageable side effects.

The CyberKnife system is particularly advantageous for SABR in lung tumors due to its ability to accurately target moving tumors during breathing, enhancing treatment precision.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CyberKnife stereotactic ablative radiotherapy for lung tumors. Gibbs, IC., Loo, BW.[2022]

In a study of 20 patients with recurrent or metastatic gynecological cancers, CyberKnife stereotactic ablative radiotherapy (SABR) achieved local tumor control in 82% of cases, indicating its efficacy as a treatment option.

The treatment was well-tolerated, with no recorded instances of severe toxicity (grade ≥ 3), suggesting a favorable safety profile for patients undergoing this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CyberKnife Stereotactic Ablative Radiotherapy for Recurrent or Oligometastatic Gynecological Cancers. Kataria, T., Naga, P., Banerjee, S., et al.[2021]

Cyberknife stereotactic ablative radiotherapy (SABR) demonstrated a 71.6% objective response rate in 53 patients with unresectable hepatocellular carcinoma (HCC), indicating its efficacy as a salvage treatment when other therapies failed.

The median survival time for patients treated with SABR was 20 months, with 1- and 2-year overall survival rates of 70.1% and 45.4%, respectively, suggesting that while SABR is effective, there is a need to address issues like out-field recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic ablative radiotherapy for unresectable hepatocellular carcinoma patients who failed or were unsuitable for transarterial chemoembolization. Lo, CH., Huang, WY., Lee, MS., et al.[2022]

CyberKnife stereotactic ablative radiotherapy (SABR) for treating intermediate- to very-high-risk prostate cancer showed a high 3-year biochemical relapse-free survival rate of 90.2%, indicating its efficacy in managing this condition.

The treatment was well-tolerated, with no patients experiencing severe toxicity (≥ grade 3), and only mild genitourinary and gastrointestinal side effects were reported, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic ablative radiotherapy with CyberKnife in the treatment of locally advanced prostate cancer: preliminary results. Fan, CY., Chao, HL., Huang, WY., et al.[2017]

Stereotactic ablative radiation therapy (SABR) was found to be effective for treating pulmonary metastases, with a median follow-up of 23 months showing improved overall survival (OS) for patients with 3 or fewer metastases compared to those with more (74.2% vs. 59.3% at 24 months).

Patients with less responsive primary tumors (like adrenal or pancreatic cancers) had higher local failure rates, suggesting that higher doses of SABR or surgical options may be necessary for these cases to improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic ablative radiation therapy for pulmonary metastases: Improving overall survival and identifying subgroups at high risk of local failure. Pasalic, D., Lu, Y., Betancourt-Cuellar, SL., et al.[2021]

Stereotactic ablative radiotherapy (SABR) is an effective treatment for early-stage non-small cell lung cancers (NSCLCs) that are medically inoperable, providing local control and toxicity levels comparable to surgical resection.

SABR is gaining interest as a noninvasive treatment option for patients with borderline resectable lung cancers, although further randomized studies are needed to evaluate its survival benefits in operable patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic ablative radiotherapy (SABR) for non-small cell lung cancer. Iyengar, P., Westover, K., Timmerman, RD.[2013]

Stereotactic ablative radiotherapy (SABR) demonstrated excellent 5-year overall survival (OS) rates of 56.5% and effective local control for patients with isolated recurrent non-small cell lung cancer (NSCLC) after previous treatment, based on a study of 59 patients with a median follow-up of 58.3 months.

The treatment showed minimal toxicity, with only 5% of patients experiencing grade 3 adverse events, indicating that SABR is a safe and effective salvage option for this patient population, comparable to outcomes seen in early-stage NSCLC treated with definitive SABR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Outcomes of Salvage Stereotactic Ablative Radiotherapy for Isolated Lung Recurrence of Non-Small Cell Lung Cancer: A Phase II Clinical Trial. Sun, B., Brooks, ED., Komaki, R., et al.[2022]

Stereotactic body radiotherapy (SBRT) is effective for treating early-stage non-small cell lung cancer (NSCLC) in patients who cannot undergo surgery, showing good outcomes and low toxicity for tumors located in the periphery.

However, the risk of severe toxicity increases for tumors near critical structures like the bronchial tree or mediastinum, highlighting the importance of careful dose-fractionation planning in these cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An optimal dose-fractionation for stereotactic body radiotherapy in peripherally, centrally and ultracentrally located early-stage non-small lung cancer. Zarębska, I., Harat, M.[2023]

References

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

Modification of the Radiation Response of Patients With Carcinoma of the Uterine Cervix. [2019]

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

Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism. [2020]

3. Japan pubmed.ncbi.nlm.nih.gov

[Concurrent chemoradiotherapy for advanced cervical cancer--a pilot study]. [2013]

4. England pubmed.ncbi.nlm.nih.gov

Advances in cervical cancer pharmacotherapies. [2015]

5. Ireland pubmed.ncbi.nlm.nih.gov

Olaparib as maintenance treatment in patients with chemosensitive small cell lung cancer (STOMP): A randomised, double-blind, placebo-controlled phase II trial. [2022]

6. Greece pubmed.ncbi.nlm.nih.gov

Stereotactic Ablative Radiotherapy Using CyberKnife for Stage I Non-small-cell Lung Cancer: A Retrospective Analysis. [2022]

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

CyberKnife stereotactic ablative radiotherapy for lung tumors. [2022]

8. India pubmed.ncbi.nlm.nih.gov

CyberKnife Stereotactic Ablative Radiotherapy for Recurrent or Oligometastatic Gynecological Cancers. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Stereotactic ablative radiotherapy for unresectable hepatocellular carcinoma patients who failed or were unsuitable for transarterial chemoembolization. [2022]

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

Stereotactic ablative radiotherapy with CyberKnife in the treatment of locally advanced prostate cancer: preliminary results. [2017]

11. Ireland pubmed.ncbi.nlm.nih.gov

Stereotactic ablative radiation therapy for pulmonary metastases: Improving overall survival and identifying subgroups at high risk of local failure. [2021]

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

Stereotactic ablative radiotherapy (SABR) for non-small cell lung cancer. [2013]

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

Long-Term Outcomes of Salvage Stereotactic Ablative Radiotherapy for Isolated Lung Recurrence of Non-Small Cell Lung Cancer: A Phase II Clinical Trial. [2022]

14. Singapore pubmed.ncbi.nlm.nih.gov

An optimal dose-fractionation for stereotactic body radiotherapy in peripherally, centrally and ultracentrally located early-stage non-small lung cancer. [2023]