RP-6306 + RP-3500 for Cancer (MYTHIC Trial)
Recruiting in Palo Alto (17 mi)
+18 other locations
Age: Any Age
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Repare Therapeutics
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial is testing a new drug called RP-6306 alone and with two other drugs in patients with advanced solid tumors. The goal is to see if these drugs are safe, well-tolerated, and effective at reducing tumors.
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.
What data supports the idea that RP-6306 + RP-3500 for Cancer is an effective treatment?
The available research does not provide specific data on the effectiveness of RP-6306 + RP-3500 for Cancer. Instead, it focuses on other treatments for prostate cancer, such as docetaxel, sipuleucel-T, and enzalutamide, which have shown positive outcomes in clinical trials. These treatments have been associated with improved survival rates for patients with castration-resistant prostate cancer. However, there is no direct comparison or data available for RP-6306 + RP-3500 in the provided information.
12345Is the combination of RP-6306 and RP-3500 safe for humans?
RP-3500 has been studied in preclinical models and shows potential for tumor growth inhibition with manageable side effects, such as reversible red blood cell depletion. This suggests it may be generally safe, but more clinical data is needed to confirm its safety in humans.
678910What makes the drug RP-6306 + RP-3500 unique for cancer treatment?
The drug RP-6306 + RP-3500 is unique because it targets synthetic lethal interactions, which means it aims to exploit specific genetic vulnerabilities in cancer cells that are not present in normal cells, potentially leading to more effective and targeted cancer treatment.
1112131415Eligibility Criteria
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
I am mostly active and can do most of my daily activities.
My tumor has a specific marker found by advanced testing.
I can swallow and keep down pills.
I am under 18 and weigh at least 40 kg.
My cancer is advanced, has spread, and doesn’t respond to treatment.
I am under 18 and weigh at least 40 kg.
My cancer is advanced, has spread, and is not responding to treatment.
I am mostly active and can do most of my daily activities on my own.
My tumor has a specific marker found by advanced genetic testing.
I can provide tumor tissue or am willing to undergo a biopsy if it's safe.
I can swallow and keep down pills.
Exclusion Criteria
My high blood pressure is not under control.
I have brain metastases that are not managed and cause symptoms.
I haven't had chemotherapy or cancer drugs within the last 21 days or less than 5 half-lives of the drug.
Participant Groups
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.
3Treatment groups
Experimental Treatment
Group I: Phase 1: RP-6306 in combination with RP-3500, Dose Escalation StudyExperimental Treatment2 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 StudyExperimental Treatment2 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 StudyExperimental Treatment1 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.
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Participating Site, # 1027Charlottesville, VA
Participating Site # 1030Providence, RI
Participating Site # 1008New York, NY
Participating Site # 1004New York, NY
More Trial Locations
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Who is running the clinical trial?
Repare TherapeuticsLead Sponsor
Debiopharm International SAIndustry Sponsor
References
A real-world retrospective analysis of the management of metastatic castrate-resistant prostate cancer in Ontario, Canada from 2010 - 2018. [2023]We sought to quantify mCRPC patient treatment patterns and survival across multiple lines of therapy after prior androgen-receptor-axis-targeted therapy (ARAT) failure.
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. [2022]This multinational, double-blind, randomized, placebo-controlled, phase III trial assessed the efficacy and tolerability of the oral platinum analog satraplatin in patients with metastatic castrate-refractory prostate cancer (CRPC) experiencing progression after one prior chemotherapy regimen.
Novel and bone-targeted agents for CRPC. [2020]Clearly, no neoplasm other than prostate cancer has benefited from so many breakthroughs since the beginning of this decade: the past two years can be considered exceptional due to the number of emerging agents against castration-resistant prostate cancer (CRPC), which have demonstrated positive outcomes in phase III trials. Until 2010, docetaxel (Taxotere) was the only agent capable of improving survival in patients with metastatic CRPC. Since then, positive results from phase III trials have been reported for sipuleucel-T, cabazitaxel, denosumab, abiraterone, radium-223, and enzalutamide, while other promising agents including notably orteronel, ipilimumab and cabozantinib are currently under study. Taken together, the incorporation of these agents in the routine management of patients with CRPC is likely to expand their median life expectancy, which was only ∼1 year until the early 2000, to >30 months in the near future. The availability of these agents will lead to new challenges and questions, such as: Can our societies afford the costs? Should we use these agents sequentially or in combination with an incremental benefit? Can we personalise treatment based on the biology of the individual's disease? How will we develop new active compounds in the context where a half dozen approved agents may confound their potential overall survival effect?
The association between radiographic response and overall survival in men with metastatic castration-resistant prostate cancer receiving chemotherapy. [2021]In men with metastatic castration-resistant prostate cancer (CRPC), the association of measurable tumor responses with overall survival (OS) is unknown. The authors retrospectively evaluated the TAX327 phase 3 trial to study this relation.
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). [2018]This multicentre, randomised, open label, phase II/III study aimed to investigate the potential benefit of adding risedronate (R) to docetaxel (D) in patients with metastatic Castration Resistant Prostate Cancer (CRPC).
RP-3500: A Novel, Potent, and Selective ATR Inhibitor that is Effective in Preclinical Models as a Monotherapy and in Combination with PARP Inhibitors. [2023]Ataxia telangiectasia and Rad3-related (ATR) kinase protects genome integrity during DNA replication. RP-3500 is a novel, orally bioavailable clinical-stage ATR kinase inhibitor (NCT04497116). RP-3500 is highly potent with IC50 values of 1.0 and 0.33 nmol/L in biochemical and cell-based assays, respectively. RP-3500 is highly selective for ATR with 30-fold selectivity over mammalian target of rapamycin (mTOR) and more than 2,000-fold selectivity over ataxia telangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK), and phosphatidylinositol 3-kinase alpha (PI3Kα) kinases. In vivo, RP-3500 treatment results in potent single-agent efficacy and/or tumor regression in multiple xenograft models at minimum effective doses (MED) of 5 to 7 mg/kg once daily. Pharmacodynamic assessments validate target engagement, with dose-proportional tumor inhibition of phosphorylated checkpoint kinase 1 (pCHK1) (IC80 = 18.6 nmol/L) and induction of phosphorylated H2A.X variant histone (γH2AX), phosphorylated DNA-PK catalytic subunit (pDNA-PKcs), and phosphorylated KRAB-associated protein 1 (pKAP1). RP-3500 exposure at MED indicates that circulating free plasma levels above the in vivo tumor IC80 for 10 to 12 hours are sufficient for efficacy on a continuous schedule. However, short-duration intermittent (weekly 3 days on/4 days off) dosing schedules as monotherapy or given concomitantly with reduced doses of olaparib or niraparib, maximize tumor growth inhibition while minimizing the impact on red blood cell depletion, emphasizing the reversible nature of erythroid toxicity with RP-3500 and demonstrating superior efficacy compared with sequential treatment. These results provide a strong preclinical rationale to support ongoing clinical investigation of the novel ATR inhibitor, RP-3500, on an intermittent schedule as a monotherapy and in combination with PARP inhibitors as a potential means of maximizing clinical benefit.
Guidelines for Management of Treatment-Emergent Adverse Events During Rucaparib Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer. [2022]Label="PURPOSE" NlmCategory="OBJECTIVE">The US Food and Drug Administration has recently granted accelerated approval of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib as treatment for men with metastatic castration-resistant prostate cancer (mCRPC) associated with a deleterious germline or somatic BRCA1 or BRCA2 (BRCA) alteration. As the safety profile of this new addition to the mCRPC treatment landscape may be unfamiliar to clinicians and patients, we summarize the data from the literature and provide practical guidelines for the management of treatment-emergent adverse events (TEAEs) that may occur during rucaparib treatment.
Incidence of grade 3-4 adverse events, dose reduction, and treatment discontinuation in castration-resistant prostate cancer patients receiving PARP inhibitors: a meta-analysis. [2022]PARP inhibitors (PARPi) have recently emerged as a new treatment option for several solid tumors, including metastatic castration-resistant prostate cancer (mCRPC). However, several grade 3-4 adverse events have been reported during PARPi administration, leading to limitations in treatment adherence.
In Vivo Targeting Replication Protein A for Cancer Therapy. [2023]Replication protein A (RPA) plays essential roles in DNA replication, repair, recombination, and the DNA damage response (DDR). Retrospective analysis of lung cancer patient data demonstrates high RPA expression as a negative prognostic biomarker for overall survival in smoking-related lung cancers. Similarly, relative expression of RPA is a predictive marker for response to chemotherapy. These observations are consistent with the increase in RPA expression serving as an adaptive mechanism that allows tolerance of the genotoxic stress resulting from carcinogen exposure. We have developed second-generation RPA inhibitors (RPAis) that block the RPA-DNA interaction and optimized formulation for in vivo analyses. Data demonstrate that unlike first-generation RPAis, second-generation molecules show increased cellular permeability and induce cell death via apoptosis. Second-generation RPAis elicit single-agent in vitro anticancer activity across a broad spectrum of cancers, and the cellular response suggests existence of a threshold before chemical RPA exhaustion induces cell death. Chemical RPA inhibition potentiates the anticancer activity of a series of DDR inhibitors and traditional DNA-damaging cancer therapeutics. Consistent with chemical RPA exhaustion, we demonstrate that the effects of RPAi on replication fork dynamics are similar to other known DDR inhibitors. An optimized formulation of RPAi NERx 329 was developed that resulted in single-agent anticancer activity in two non-small cell lung cancer models. These data demonstrate a unique mechanism of action of RPAis eliciting a state of chemical RPA exhaustion and suggest they will provide an effective therapeutic option for difficult-to-treat lung cancers.
Poly(adenosine diphosphate-ribose) polymerase inhibitor combinations in first-line metastatic castrate-resistant prostate cancer setting: a systematic review and meta-analysis. [2023]To compare radiographic progression-free survival (rPFS), overall survival (OS), and treatment-emergent adverse events (TEAEs) among patients with metastatic castrate-resistant prostate cancer (mCRPC) receiving a combination of first-line poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) plus androgen receptor axis-targeted agents (ARAT) vs placebo/ARAT.
Characterizing the tumor response to treatment with combretastatin A4 phosphate. [2019]To examine the pathophysiologic impact of treatment with combretastatin A4 phosphate (CA4P) in regions of tumors that ultimately either necrose or survive treatment with this agent.
Response of a chemo-resistant triple-negative breast cancer patient to a combination of p62-encoding plasmid, Elenagen, and CMF chemotherapy. [2020]Triple-negative breast cancers are often characterized by aggressive behavior and short clinical course once they become chemotherapy-resistant. We describe below a patient who has shown a response to combination of chemotherapy with Elenagen, a plasmid encoding p62. Elenagen was tested in a previous phase I/II study in patients with refractory solid tumors and shown to be safe. Also, plasmid ability to halt tumor progression and restore sensitivity to chemotherapy was found. Preclinical data supports effects on tumor grade and change the tumor's microenvironment in spontaneous canine breast cancers. We describe here a 48-year old female with triple-negative and BRCA1/2-negative breast cancer who had a primary resistance to chemotherapy and negative dynamics despite the use of multiple lines of treatments. Elenagen was applied intramuscularly at a dose of 1 mg weekly in combination with standard chemotherapy scheme CMF (cyclophosphamide, methotrexate, fluorouracil). In this patient we observed partial tumor regression (by 33%) and 19 weeks of progression-free survival. This first observed objective response to a combination of Elenagen with chemotherapy demonstrates that even in heavily pretreated chemo-resistant triple-negative tumor, the addition of Elenagen to a chemotherapy regimen can cause an objective response and increase in progression-free survival. Such a regimen is worthy of further study in a larger number of patients.
CX-5461 Enhances the Efficacy of APR-246 via Induction of DNA Damage and Replication Stress in Triple-Negative Breast Cancer. [2021]Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer lacking targeted therapy. Here, we evaluated the anti-cancer activity of APR-246, a P53 activator, and CX-5461, a RNA polymerase I inhibitor, in the treatment of TNBC cells. We tested the efficacy of individual and combination therapy of CX-5461 and APR-246 in vitro, using a panel of breast cancer cell lines. Using publicly available breast cancer datasets, we found that components of RNA Pol I are predominately upregulated in basal-like breast cancer, compared to other subtypes, and this upregulation is associated with poor overall and relapse-free survival. Notably, we found that the treatment of breast cancer cells lines with CX-5461 significantly hampered cell proliferation and synergistically enhanced the efficacy of APR-246. The combination treatment significantly induced apoptosis that is associated with cleaved PARP and Caspase 3 along with Annexin V positivity. Likewise, we also found that combination treatment significantly induced DNA damage and replication stress in these cells. Our data provide a novel combination strategy by utilizing APR-246 in combination CX-5461 in killing TNBC cells that can be further developed into more effective therapy in TNBC therapeutic armamentarium.
A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions. [2021]A synthetic lethal interaction between two genes is given when knock-out of either one of the two genes does not affect cell viability but knock-out of both synthetic lethal interactors leads to loss of cell viability or cell death. The best studied synthetic lethal interaction is between BRCA1/2 and PARP1, with PARP1 inhibitors being used in clinical practice to treat patients with BRCA1/2 mutated tumors. Large genetic screens in model organisms but also in haploid human cell lines have led to the identification of numerous additional synthetic lethal interaction pairs, all being potential targets of interest in the development of novel tumor therapies. One approach is to therapeutically target genes with a synthetic lethal interactor that is mutated or significantly downregulated in the tumor of interest. A second approach is to formulate drug combinations addressing synthetic lethal interactions. In this article, we outline a data integration workflow to evaluate and identify drug combinations targeting synthetic lethal interactions. We make use of available datasets on synthetic lethal interaction pairs, homology mapping resources, drug-target links from dedicated databases, as well as information on drugs being investigated in clinical trials in the disease area of interest. We further highlight key findings of two recent studies of our group on drug combination assessment in the context of ovarian and breast cancer.
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. [2021]Synthetic lethal therapeutic strategy using poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor olaparib in carriers of BRCA1 or BRCA2 mutation has shown promise in clinical settings. Since