RP-6306 + RP-3500 for Cancer

(MYTHIC Trial)

Recruiting at 37 trial locations

Overseen By Repare Therapeutics Medical Monitor, MD, MBA

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Repare Therapeutics

Must not be taking: Chemotherapy, Antineoplastic agents

Disqualifiers: Pregnancy, Brain metastases, Hypertension, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Variable, until disease progression or unacceptable toxicity

364 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of new cancer treatments, RP-6306 and RP-3500, for individuals with advanced solid tumors. Researchers aim to determine the optimal dose of these treatments and assess their cancer-fighting capabilities. Individuals with difficult-to-treat cancers that have specific genetic traits, such as changes in certain genes, might be suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in humans, offering participants the opportunity to be among the first to receive these new treatments.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that chemotherapy or similar treatments should not have been taken within 21 days before starting the study drugs. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that RP-6306, whether used alone or with RP-3500, is generally safe. In studies, patients with advanced cancers tolerated the combination of RP-6306 and RP-3500 well, even those who had undergone many previous treatments. These studies reported few serious side effects, suggesting it is usually safe to use.

When used alone, RP-6306 also demonstrated good safety results. Studies found that the drug can kill cancer cells without causing major harm to patients. Most patients experienced moderate side effects, and some even showed signs of tumor reduction.

In summary, both RP-6306 alone and with RP-3500 have been tested in people and are considered safe so far. However, since this is a Phase 1 trial, researchers continue to monitor the treatments closely to determine the best dose and ensure safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about RP-6306 and RP-3500 for cancer because these treatments target the DNA damage response in cancer cells, a novel approach compared to traditional chemotherapy that often targets rapidly dividing cells. RP-6306 works by inhibiting a protein involved in cell cycle regulation, potentially stopping cancer cells from repairing themselves and multiplying. Meanwhile, RP-3500 enhances the effects of RP-6306 by inhibiting a different protein involved in DNA repair. This combination could offer a more precise, targeted attack on cancer cells, with the hope of reducing damage to healthy cells and minimizing side effects.

What evidence suggests that this trial's treatments could be effective for advanced solid tumors?

Research shows that using RP-6306 and RP-3500 together may help treat certain cancers. In this trial, one arm will study the combination of RP-6306 and RP-3500, which studies have found to slow tumor growth more effectively together than separately. In some cases, tumors have shrunk, known as a partial response. Another arm will study RP-6306 alone, which lab studies have shown to slow cancer growth and work even better when combined with a common chemotherapy drug. Overall, these early results suggest that these treatments could be helpful, but more research is needed to confirm their benefits. ^{4 5 6 7 8}

Are You a Good Fit for This Trial?

This trial is for people aged 12 and older with advanced solid tumors that are resistant or refractory. They must be able to take oral meds, have recovered from previous treatments, have a certain performance status score, weigh at least 40 kg if under 18, and not be pregnant. A report showing an eligible tumor biomarker is required.

Inclusion Criteria

Negative pregnancy test (serum) for women of childbearing potential (WOCBP) at Screening

Measurable disease as per RECIST v1.1.

I am mostly active and can do most of my daily activities.

Exclusion Criteria

Life-threatening illness, medical condition, active uncontrolled infection, or organ system dysfunction or other reasons which, in the investigator's opinion, could compromise the participating patient's safety

I have not had major surgery in the last 4 weeks.

Patients who are pregnant or breastfeeding

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive RP-6306 alone or in combination with RP-3500 or Debio 0123 until disease progression, unacceptable toxicity, or decision to discontinue

Variable, until disease progression or unacceptable toxicity

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 90 days after last administration of study intervention

Extension

Participants may continue treatment in an open-label extension if they benefit from the study drug

Long-term, as per participant and investigator decision

What Are the Treatments Tested in This Trial?

Interventions

• RP-3500
• RP-6306

Trial Overview The study tests the safety and effectiveness of RP-6306 alone or combined with RP-3500 in treating advanced solid tumors. It aims to find the highest dose patients can tolerate without severe side effects and to see how well these drugs work against the tumors.

How Is the Trial Designed?

Group I: Phase 1: RP-6306 in combination with RP-3500, Dose Escalation Study Experimental Treatment 2 Interventions

Patients receive RP-6306 with RP-3500 orally until disease progression, unacceptable toxicity, or investigator/patient decision. Dose escalation will proceed until a maximum tolerated dose is identified.

Group II: Phase 1: RP-6306 in combination with Debio 0123, Dose Escalation Study Experimental Treatment 2 Interventions

Patients receive RP-6306 with Debio 0123 orally until disease progression, unacceptable toxicity, or investigator/patient decision. Dose escalation will proceed until a maximum tolerated dose is identified.

Group III: Phase 1: RP-6306 Single-Agent, Dose Escalation and Food-effect Study Experimental Treatment 1 Intervention

Patients receive RP-6306 orally until disease progression, unacceptable toxicity, or investigator/patient decision. Dose escalation will proceed until a maximum tolerated dose is identified.

Who Is Running the Clinical Trial?

Repare Therapeutics

Lead Sponsor

Trials

10

Recruited

1,300+

Debiopharm International SA

Industry Sponsor

Trials

53

Recruited

7,300+

Published Research Related to This Trial

Treatment with combretastatin A4 phosphate (CA4P) leads to a temporary decrease in blood flow (perfusion) in tumor regions, which could impact the effectiveness of other cancer therapies that rely on good blood supply.

While CA4P reduces tumor cell proliferation, the transient nature of its effects on perfusion suggests that careful timing is crucial when combining CA4P with standard anticancer treatments to ensure optimal drug delivery and oxygenation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterizing the tumor response to treatment with combretastatin A4 phosphate. Salmon, BA., Siemann, DW.[2019]

High expression of Replication Protein A (RPA) in lung cancer patients is linked to poor survival outcomes and can predict chemotherapy response, indicating its role as a negative prognostic biomarker.

Second-generation RPA inhibitors (RPAis) have been developed that effectively induce cancer cell death through apoptosis and enhance the efficacy of other cancer treatments, showing promise as a therapeutic option for challenging lung cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In Vivo Targeting Replication Protein A for Cancer Therapy. VanderVere-Carozza, PS., Gavande, NS., Jalal, SI., et al.[2023]

In a study of 412 men with metastatic castration-resistant prostate cancer (CRPC) receiving chemotherapy, those with a complete or partial tumor response had a significantly longer median overall survival (29.0 months) compared to those with stable disease (22.1 months) or progressive disease (10.8 months).

The study found that a measurable tumor response is a valuable prognostic factor for overall survival, complementing prostate-specific antigen (PSA) assessments, as a significant association was observed between tumor response and declines in PSA levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The association between radiographic response and overall survival in men with metastatic castration-resistant prostate cancer receiving chemotherapy. Sonpavde, G., Pond, GR., Berry, WR., et al.[2021]

A 48-year-old woman with chemotherapy-resistant triple-negative breast cancer showed a 33% reduction in tumor size and 19 weeks of progression-free survival after receiving Elenagen combined with standard chemotherapy, indicating potential efficacy in difficult-to-treat cases.

Elenagen, a plasmid encoding p62, has previously been shown to be safe and effective in halting tumor progression and restoring chemotherapy sensitivity, suggesting it could be a valuable addition to treatment regimens for aggressive breast cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response of a chemo-resistant triple-negative breast cancer patient to a combination of p62-encoding plasmid, Elenagen, and CMF chemotherapy. Ponomarenko, DM., Gabai, VL., Sufianov, AA., et al.[2020]

The combination of APR-246, a P53 activator, and CX-5461, an RNA polymerase I inhibitor, shows promising anti-cancer activity against triple-negative breast cancer (TNBC) cells, significantly hampering cell proliferation and inducing apoptosis.

This combination therapy not only enhances the efficacy of each drug but also induces DNA damage and replication stress in TNBC cells, suggesting a novel strategy for more effective treatment options in this aggressive cancer subtype.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CX-5461 Enhances the Efficacy of APR-246 via Induction of DNA Damage and Replication Stress in Triple-Negative Breast Cancer. Makhale, A., Nanayakkara, D., Raninga, P., et al.[2021]

RP-3500 is a highly potent and selective ATR kinase inhibitor that shows significant tumor regression in various xenograft models at low doses (5 to 7 mg/kg), indicating its potential as an effective cancer treatment.

Intermittent dosing schedules of RP-3500, either alone or in combination with reduced doses of PARP inhibitors like olaparib or niraparib, enhance tumor growth inhibition while reducing side effects like red blood cell depletion, suggesting a safer and more effective treatment strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RP-3500: A Novel, Potent, and Selective ATR Inhibitor that is Effective in Preclinical Models as a Monotherapy and in Combination with PARP Inhibitors. Roulston, A., Zimmermann, M., Papp, R., et al.[2023]

In a study of 5,588 men with metastatic castration-resistant prostate cancer (mCRPC) in Ontario, both androgen-receptor-axis-targeted therapies (ARATs) and taxanes showed similar survival rates across first, second, and third lines of treatment, suggesting comparable efficacy.

Survival times for patients treated with ARATs were 13.0 months for first-line, 11.5 months for second-line, and 8.9 months for third-line therapy, while taxane treatments had survival times of 16.7 months for first-line, 11.3 months for second-line, and 7.8 months for third-line, indicating that both treatment types can be effective options in managing mCRPC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A real-world retrospective analysis of the management of metastatic castrate-resistant prostate cancer in Ontario, Canada from 2010 - 2018. Moldaver, DM., Hassan, S., Seung, SJ., et al.[2023]

In a phase III trial involving 950 patients with metastatic castrate-refractory prostate cancer, oral satraplatin significantly reduced the risk of disease progression or death by 33% compared to placebo, indicating its efficacy in delaying disease progression.

While satraplatin did not improve overall survival compared to placebo, it effectively delayed pain progression and was generally well tolerated, although some patients experienced more frequent side effects like myelosuppression and gastrointestinal disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multinational, double-blind, phase III study of prednisone and either satraplatin or placebo in patients with castrate-refractory prostate cancer progressing after prior chemotherapy: the SPARC trial. Sternberg, CN., Petrylak, DP., Sartor, O., et al.[2022]

The study demonstrates that a BRCA1 inhibitor peptide (inhibitor 2) can effectively mimic BRCA1 mutations, enhancing the sensitivity of certain cancer cell lines (HeLa and MDA-MB-231) to the PARP inhibitor olaparib, which is a promising strategy for treating cancers in non-BRCA mutation carriers.

Inhibition of BRCA1 by this peptide leads to increased growth inhibition and apoptosis in specific cancer cell lines, suggesting that developing high-affinity BRCT(BRCA1) inhibitors could be a valuable approach for treating sporadic breast and ovarian cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of BRCT(BRCA1)-phosphoprotein interaction enhances the cytotoxic effect of olaparib in breast cancer cells: a proof of concept study for synthetic lethal therapeutic option. Pessetto, ZY., Yan, Y., Bessho, T., et al.[2021]

Synthetic lethal interactions, such as the well-known BRCA1/2 and PARP1 relationship, can be exploited for cancer treatment, particularly in tumors with specific genetic mutations, leading to targeted therapies.

The article presents a data integration workflow to identify and evaluate drug combinations that target synthetic lethal interactions, which could enhance treatment strategies for ovarian and breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions. Marhold, M., Heinzel, A., Merchant, A., et al.[2021]

The combination of poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) and androgen receptor axis-targeted agents (ARAT) significantly improves radiographic progression-free survival (rPFS) by 35% in patients with metastatic castrate-resistant prostate cancer (mCRPC), especially in those with BRCA1/2 mutations, indicating a strong efficacy of this treatment approach.

While the combination therapy shows potential overall survival (OS) benefits, particularly in homologous recombination repair-mutated patients, it also leads to a significant increase in treatment-emergent adverse events (TEAEs), including a notable rise in severe anemia, suggesting that careful patient selection is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Poly(adenosine diphosphate-ribose) polymerase inhibitor combinations in first-line metastatic castrate-resistant prostate cancer setting: a systematic review and meta-analysis. Sayyid, RK., Klaassen, Z., Berlin, A., et al.[2023]

Recent advancements in treatments for castration-resistant prostate cancer (CRPC) have led to multiple new agents showing positive outcomes in phase III trials, significantly improving patient survival rates.

The median life expectancy for patients with metastatic CRPC is expected to increase from about 1 year to over 30 months due to the incorporation of these new therapies, raising important questions about treatment strategies and healthcare costs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel and bone-targeted agents for CRPC. Fizazi, K., Albiges, L., Massard, C., et al.[2020]

In a study involving 592 men with metastatic Castration Resistant Prostate Cancer, adding risedronate to docetaxel chemotherapy did not improve time to progression (TTP), which was 7.4 months for docetaxel alone compared to 6.5 months for the combination (p=0.75).

The overall survival rates were also similar between the two groups, with 18.4 months for docetaxel alone and 19.2 months for the combination, indicating that risedronate did not enhance the efficacy of docetaxel treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomised phase II/III study of docetaxel with or without risedronate in patients with metastatic Castration Resistant Prostate Cancer (CRPC), the Netherlands Prostate Study (NePro). Meulenbeld, HJ., van Werkhoven, ED., Coenen, JL., et al.[2018]

Rucaparib, a PARP inhibitor, has been granted accelerated approval for treating men with metastatic castration-resistant prostate cancer (mCRPC) who have BRCA1 or BRCA2 mutations, based on safety data from clinical trials involving 193 participants.

Common treatment-emergent adverse events (TEAEs) include gastrointestinal issues, fatigue, and anemia, with most being self-limiting; effective management of these TEAEs is crucial to maximize the benefits of rucaparib treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Guidelines for Management of Treatment-Emergent Adverse Events During Rucaparib Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer. Labadie, BW., Morris, DS., Bryce, AH., et al.[2022]

A meta-analysis of six trials involving 752 patients with metastatic castration-resistant prostate cancer (mCRPC) revealed that anemia was the most common severe adverse event associated with PARP inhibitors, occurring in 24.1% of patients.

The study also found that dose reductions and treatment discontinuations were significant issues, with rates of 26.9% and 14.1%, respectively, highlighting the need for careful monitoring of patients undergoing PARP inhibitor therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence of grade 3-4 adverse events, dose reduction, and treatment discontinuation in castration-resistant prostate cancer patients receiving PARP inhibitors: a meta-analysis. Rizzo, A., Mollica, V., Merler, S., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04855656

NCT04855656 | Study of RP-6306 Alone or in Combination ... The primary purpose of this study is to assess the safety and tolerability of RP-6306 alone and in combination with RP-3500 or in combination with Debio 0123

2. ir.reparerx.com ir.reparerx.com/news-releases/news-release-details/repare-therapeutics-reports-proof-concept-lunresertib-rp-6306

Repare Therapeutics | Precision Oncology Preliminary anti-tumor activity was observed, including moderate tumor shrinkages and a confirmed partial response per RECIST 1.1 criteria. Several patients ...

3. onclive.com onclive.com/view/lunresertib-plus-camonsertib-produces-durable-responses-in-advanced-endometrial-ovarian-cancer

Lunresertib Plus Camonsertib Produces Durable ... In evaluable patients with platinum-resistant ovarian cancer (n = 24), lunresertib plus camonsertib generated an ORR of 37.5% and a CBR of 79%.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11962063/

Targeting CCNE1 amplified ovarian and endometrial ... The combination of RP-6306 and RP-3500 showed increased growth inhibition than the respective monotherapies in WO-58, WO-19 and WO-77 organoids ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05605509

NCT05605509 | RP-6306 in Patients With Advanced Cancer This study is being done to answer the following questions: Is the new drug, RP-6306, safe to use, and what effects does it have on cancer when given with ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04855656

NCT04855656 | Study of RP-6306 Alone or in Combination ... The primary purpose of this study is to assess the safety and tolerability of RP-6306 alone and in combination with RP-3500 or in combination with Debio ...

7. dana-farber.org dana-farber.org/clinical-trials/21-311

Phase 1/1b Study of the Safety, Pharmacokinetics, ... The primary purpose of this study is to assess the safety and tolerability of RP-6306 alone and in combination with RP-3500 or in combination with Debio 0123

8. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2021-04132

Study of RP-6306 Alone or in Combination With RP-3500 ... The primary purpose of this study is to assess the safety and tolerability of RP-6306 alone and in combination with RP-3500 or in combination with Debio 0123