RP-3500 + Radiation Therapy for Cancer

Recruiting at 6 trial locations

Overseen By Ezra Rosen, MD,PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Strong CYP3A inhibitors

Disqualifiers: Uncontrolled hypertension, Active infections, Hepatic impairment, others

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

Compensation: Varies

Number of Visits: 5

Duration: 1 week

84 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to test the safety of the study drug, RP-3500 when given in combination with palliative external beam radiotherapy (EBRT) to people who have metastatic solid tumor cancer with a mutation of the ATM gene. The study researchers will do tests to find the highest dose of RP3500 that causes few or mild side effects.

Do I need to stop my current medications for the trial?

The trial requires that you do not take any other systemic therapy during the entire duration of the protocol treatment. You can have other systemic treatments up until the start of the trial and after its completion.

What data supports the effectiveness of the treatment RP-3500 + Radiation Therapy for Cancer?

Research shows that external beam radiation therapy (EBRT) is effective in treating prostate cancer, helping patients live longer and preventing cancer progression. This suggests that EBRT, as part of the RP-3500 + Radiation Therapy treatment, may also be effective for other types of cancer. ^{1 2 3 4 5}

What safety data exists for RP-3500 and External Beam Radiotherapy (EBRT) in humans?

External Beam Radiotherapy (EBRT) is generally used for pain relief in bone metastases, but it can cause a temporary increase in pain, known as pain flare, in 16-41% of patients who haven't taken steroids. Additionally, when combined with hormone therapy for prostate cancer, EBRT can lead to adverse events. ^{6 7 8 9 10}

How is the treatment RP-3500 + Radiation Therapy for Cancer different from other treatments?

The combination of RP-3500 with external beam radiation therapy (EBRT) is unique because it integrates a drug (RP-3500) with radiation, potentially enhancing the effectiveness of radiation therapy by targeting cancer cells more precisely. This approach may offer a novel option for patients, especially if standard treatments are limited or less effective. ^{1 3 10 11 12}

Research Team

Nancy Lee, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for adults with metastatic solid tumors and a specific ATM gene mutation who can swallow pills, have good organ function, and haven't had certain prior treatments. They must not be pregnant or breastfeeding, agree to use contraception, and are expected to live more than 6 months.

Inclusion Criteria

My cancer has spread and can be treated with radiation.

I can swallow pills without difficulty.

I can take care of myself and perform daily activities.

Exclusion Criteria

Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol

Known hypersensitivity to any of the ingredients of RP-3500

I have health conditions that prevent me from receiving radiation therapy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive RP-3500 in combination with standard palliative external beam radiotherapy (EBRT) for 5 days

1 week

5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Long-term follow-up

Participants are monitored for long-term safety and local control rate

2 years

Treatment Details

Interventions

• External Beam Radiotherapy (EBRT)
• RP-3500

Trial Overview The study tests the safety of RP-3500 combined with palliative external beam radiotherapy (EBRT) in treating metastatic solid tumor cancer. Researchers aim to find the highest dose of RP-3500 that causes few or mild side effects.

Participant Groups

Group I: RP-3500 in Combination With Standard Radiation Therapy Experimental Treatment 2 Interventions

Patients with metastatic cancers with identified mutations in ATM will be enrolled. All patients will receive a standard palliative RT (4Gy x 5 fractions) on Days 1-5 in combination with RP-3500 on Days 1-5. In the first phase of the study, a 3+3 study design will be used to identify a safe dose of RP-3500 (starting at 80 mg QD) in combination with palliative RT.

Group II: Pilot subcohort Experimental Treatment 2 Interventions

The primary objective is to assess 6 month local control rate of patients of new metastatic lesions with pathogenic ATM who haves received prior RP-3500 and palliative RT.

External Beam Radiotherapy (EBRT) is already approved in United States, European Union, Canada, Japan, China, Switzerland for the following indications:

Approved in United States as External Beam Radiation Therapy for:

• Various types of cancer including but not limited to breast cancer, lung cancer, prostate cancer, and brain tumors

Approved in European Union as External Beam Radiation Therapy for:

• Various types of cancer including but not limited to breast cancer, lung cancer, prostate cancer, and brain tumors

Approved in Canada as External Beam Radiation Therapy for:

• Various types of cancer including but not limited to breast cancer, lung cancer, prostate cancer, and brain tumors

Approved in Japan as External Beam Radiation Therapy for:

• Various types of cancer including but not limited to breast cancer, lung cancer, prostate cancer, and brain tumors

Approved in China as External Beam Radiation Therapy for:

• Various types of cancer including but not limited to breast cancer, lung cancer, prostate cancer, and brain tumors

Approved in Switzerland as External Beam Radiation Therapy for:

• Various types of cancer including but not limited to breast cancer, lung cancer, prostate cancer, and brain tumors

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Repare Therapeutics

Industry Sponsor

Trials

10

Recruited

1,300+

Findings from Research

External beam radiation therapy (EBRT) is an effective treatment option for localized prostate cancer, which affects one in five Australian men, and recent technological advances have improved patient outcomes.

Technological innovations in EBRT, such as image guidance and intensity-modulated radiation therapy, enhance the precision of treatment, making it a viable alternative to surgery for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in radiotherapy technology for prostate cancer: What every GP should know. Gorayski, P., Pinkham, MB., Lehman, M.[2018]

In a study of 142 patients with unfavorable prostate cancer, combining external beam radiation therapy (EBRT) with high-dose-rate (HDR) brachytherapy resulted in an impressive 89% biochemical control rate at 2 years and 63% at 5 years, indicating strong efficacy despite poor prognostic factors.

The treatment was associated with minimal morbidity, showing a low 5-year rate of severe complications (9% for Grade 3), and no patients experienced severe acute or late toxicity, highlighting the safety of this combined approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interim report of image-guided conformal high-dose-rate brachytherapy for patients with unfavorable prostate cancer: the William Beaumont phase II dose-escalating trial. Martinez, AA., Kestin, LL., Stromberg, JS., et al.[2019]

In a systematic review of 27 studies, external beam radiation therapy (EBRT) alone was found to have significantly worse overall survival (OS) and cancer-specific survival (CSS) compared to radical prostatectomy (RP) for patients with high-risk localized prostate cancer, indicating that EBRT alone may not be sufficient for effective cancer control.

However, when brachytherapy (BT) was added to EBRT, there was no significant difference in OS and CSS compared to RP, suggesting that combining BT with EBRT could be an effective treatment strategy for high-risk prostate cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation therapy compared to radical prostatectomy as first-line definitive therapy for patients with high-risk localised prostate cancer: An updated systematic review and meta-analysis. Aydh, A., Motlagh, RS., Abufaraj, M., et al.[2022]

Between 1996 and 2005, there was a notable trend in Japan towards treating more patients with early-stage prostate cancer (T1 to T2) and administering higher radiation doses, increasing from a median of 65.0 Gy to 70 Gy.

The use of advanced conformal therapy significantly rose from 49.1% to 84.9% during the same period, indicating improvements in treatment technology and techniques, while the percentage of patients receiving hormone therapy remained stable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radical external beam radiotherapy for clinically localized prostate cancer in Japan: changing trends in the patterns of care process survey. Ogawa, K., Nakamura, K., Sasaki, T., et al.[2019]

External-beam radiotherapy (EBRT) has been effectively used for over 30 years to treat prostate adenocarcinoma, demonstrating significant improvements in cause-specific survival and freedom from PSA progression.

Recent advancements in radiation techniques have enhanced the safety and efficacy of EBRT, making it a viable treatment option for early-stage, locally advanced, and metastatic prostate cancer, while managing side effects effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

External-beam radiotherapy in the management of carcinoma of the prostate. Zlotecki, RA.[2017]

In a phase 3 trial involving 1532 prostate cancer patients, escalating the dose of external beam radiation therapy (EBRT) from 70.2 Gy to 79.2 Gy did not significantly impact patient-reported outcomes (PROs) such as erectile function and quality of life over 24 months.

Despite the higher radiation dose, there was no significant difference in the rates of erectile dysfunction between the two treatment groups, indicating that higher doses of EBRT may not lead to worse patient experiences in terms of these specific outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality of Life Implications of Dose-Escalated External Beam Radiation for Localized Prostate Cancer: Results of a Prospective Randomized Phase 3 Clinical Trial, NRG/RTOG 0126. Hall, WA., Deshmukh, S., Bruner, DW., et al.[2023]

In a study of 173 patients with high-risk localized prostate cancer, long-term androgen deprivation therapy (ADT) for 36 months or more combined with external-beam radiotherapy (EBRT) significantly improved five-year progression-free survival rates (92.8%) compared to short-term ADT (72.9%).

Patients receiving short-term ADT experienced a higher incidence of cardiovascular toxicity (grade II or above) compared to those on long-term ADT, indicating that longer ADT may not only enhance survival but also have a more favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of the duration of hormonal therapy following radiotherapy for localized prostate cancer. Okubo, M., Nakayama, H., Itonaga, T., et al.[2022]

In a study of 32 patients receiving External Beam Radiotherapy (EBRT) for bone metastases, 41% experienced a pain flare, which is defined as a significant increase in pain or analgesia intake, with a median duration of 3 days.

The incidence and duration of pain flare observed in this study align with findings from international studies, indicating that pain flare is a common side effect of EBRT for bone metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An investigation into the incidence of pain flare in patients undergoing radiotherapy for symptomatic bone metastases. Goldfinch, R., White, N.[2018]

In a study of 254 patients (150 undergoing robot-assisted prostatectomy and 104 receiving external beam radiotherapy), the PBS-90 method showed that 69% of EBRT patients and 34% of RALP patients regained 90% of their baseline urinary function after 24 months, indicating better recovery with EBRT.

The Generalized Estimating Equation (GEE) analysis revealed that function scores at 6 months were predictive of outcomes at 24 months, highlighting the importance of early assessment in determining long-term recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methods for prospective studies of adverse effects as applied to prostate cancer patients treated with surgery or radiotherapy without hormones. Stensvold, A., Dahl, AA., Brennhovd, B., et al.[2012]

In a study of 583 high-risk prostate cancer patients treated between 2005 and 2015, both external beam radiotherapy (EBRT) and radical prostatectomy (RP) showed similar long-term outcomes in prostate cancer-specific survival (PCSS) and distant metastasis-free survival (DMFS).

The estimated 10-year PCSS was 97.0% for RP and 95.9% for EBRT, indicating that both treatment options are effective, with no significant differences in survival rates, even after adjusting for confounding variables.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of radical prostatectomy and external beam radiotherapy in high-risk prostate cancer. Chun, SJ., Kim, JH., Ku, JH., et al.[2021]

In a study of 335 patients with high-risk localized prostate cancer, those who underwent external beam radiotherapy (EBRT) had significantly better biochemical progression-free survival (BPFS) rates compared to those who had radical prostatectomy (RP), with 3-year BPFS rates of 86% for EBRT versus 42% for RP.

While cancer-specific survival (CSS) and overall survival (OS) rates were similar for both treatments (98% CSS and 97% OS for RP vs. 98% CSS and 94% OS for EBRT), RP patients experienced higher rates of biochemical failure and required more adjuvant or salvage therapies (58% after RP vs. 20% after EBRT).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oncologic outcome of radical prostatectomy versus radiotherapy as primary treatment for high and very high risk localized prostate cancer. Emam, A., Hermann, G., Attwood, K., et al.[2022]

In a study of 29 patients with oligometastatic hormone-sensitive prostate cancer treated with external beam radiation therapy (EBRT) and androgen deprivation therapy, the median overall survival was 9.7 years, indicating promising long-term outcomes for this treatment approach.

Patients with de novo metastases experienced significantly better progression-free survival (2.0 years) compared to those with oligorecurrent disease (1.8 years), suggesting that the timing and nature of metastases may influence treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Outcomes of Patients on a Phase II Prospective Trial of Oligometastatic Hormone-Sensitive Prostate Cancer Treated With Androgen Deprivation and External Beam Radiation. Hao, C., Ladbury, C., Lyou, Y., et al.[2022]

References

1. Australia pubmed.ncbi.nlm.nih.gov

Advances in radiotherapy technology for prostate cancer: What every GP should know. [2018]

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

Interim report of image-guided conformal high-dose-rate brachytherapy for patients with unfavorable prostate cancer: the William Beaumont phase II dose-escalating trial. [2019]

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

Radiation therapy compared to radical prostatectomy as first-line definitive therapy for patients with high-risk localised prostate cancer: An updated systematic review and meta-analysis. [2022]

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

Radical external beam radiotherapy for clinically localized prostate cancer in Japan: changing trends in the patterns of care process survey. [2019]

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

External-beam radiotherapy in the management of carcinoma of the prostate. [2017]

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

Quality of Life Implications of Dose-Escalated External Beam Radiation for Localized Prostate Cancer: Results of a Prospective Randomized Phase 3 Clinical Trial, NRG/RTOG 0126. [2023]

7. Greece pubmed.ncbi.nlm.nih.gov

Impact of the duration of hormonal therapy following radiotherapy for localized prostate cancer. [2022]

8. Netherlands pubmed.ncbi.nlm.nih.gov

An investigation into the incidence of pain flare in patients undergoing radiotherapy for symptomatic bone metastases. [2018]

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

Methods for prospective studies of adverse effects as applied to prostate cancer patients treated with surgery or radiotherapy without hormones. [2012]

10. Korea (South) pubmed.ncbi.nlm.nih.gov

Comparison of radical prostatectomy and external beam radiotherapy in high-risk prostate cancer. [2021]

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

Oncologic outcome of radical prostatectomy versus radiotherapy as primary treatment for high and very high risk localized prostate cancer. [2022]

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

Long-Term Outcomes of Patients on a Phase II Prospective Trial of Oligometastatic Hormone-Sensitive Prostate Cancer Treated With Androgen Deprivation and External Beam Radiation. [2022]