RP-3500 for Solid Cancers

(TRESR Trial)

No longer recruiting at 26 trial locations

Overseen By Gabriela Gomez, MD, MBA

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Repare Therapeutics

Must not be taking: QT-prolonging medications

Disqualifiers: Uncontrolled infection, Brain metastases, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called RP-3500 (camonsertib) to determine the right dose and assess its safety and effectiveness for people with advanced solid tumors. The study tests RP-3500 alone and in combination with other drugs, talazoparib or gemcitabine (Gemzar), to evaluate their effectiveness against tumors. It suits those with solid tumors unresponsive to standard treatments and who can take oral medication. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive it.

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

The trial requires that you stop chemotherapy, small molecule anticancer, or biologic anticancer therapy at least 14 days before starting the study drug. If you are on medications that prolong the QT interval, you may also need to stop those. Other medications are not specifically mentioned, so consult with the trial team for guidance.

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

The trial requires that you stop chemotherapy, small molecule anticancer, or biologic anticancer therapy at least 14 days before starting the study drug. Other medications are not specifically mentioned, so 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-3500 (camonsertib) maintains a manageable safety profile in early studies involving patients with advanced solid tumors. Patients generally tolerated the treatment well, whether administered alone or with other drugs like talazoparib or gemcitabine.

For camonsertib alone, studies found it safe, with manageable side effects that allowed patients to continue treatment.

When combined with talazoparib, camonsertib also proved safe. The combination was effective for some patients, and side effects were similar to those with camonsertib alone.

Combining camonsertib with gemcitabine also demonstrated safety. Side effects occurred but were not severe enough to halt treatment.

Overall, the data suggest these treatments are generally well-tolerated. However, as this study is in the early stages, further research is needed to fully understand the safety and side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for solid cancers typically involve chemotherapy, radiation, or targeted therapies like PARP inhibitors. RP-3500 (camonsertib) is unique because it targets the DNA damage response pathway, potentially enhancing the effectiveness of existing treatments like gemcitabine and talazoparib. This targeted approach aims to exploit cancer cells' vulnerabilities in DNA repair mechanisms, possibly leading to more effective and personalized cancer treatment strategies. Researchers are excited about RP-3500 because it offers a new mechanism of action that could provide better outcomes for patients with solid tumors, particularly those resistant to current treatments.

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

Research has shown that RP-3500 (camonsertib) may help treat advanced solid tumors. In earlier studies, RP-3500 benefited 43% of patients, with nearly half experiencing positive effects. Specifically, for ovarian cancer, RP-3500 helped 75% of patients, and 25% saw significant tumor shrinkage. In this trial, some participants will receive RP-3500 alone, while others will receive it with talazoparib or gemcitabine. When combined with talazoparib, RP-3500 has shown good results, especially for patients who did not respond to previous treatments called PARP inhibitors. Research on combining RP-3500 with gemcitabine is ongoing, but early results are promising. Overall, RP-3500 appears effective for tumors with certain genetic changes. ^{1 5 6 7 8}

Who Is on the Research Team?

Timothy Yap

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults with advanced solid tumors and specific ATR inhibitor-sensitizing mutations can join this trial. They must have measurable disease, be in good physical condition (ECOG score of 0 or 1), and able to swallow pills. Participants need proper organ function, acceptable blood counts, and a negative pregnancy test if applicable. Contraception is required during the study and for six months after.

Inclusion Criteria

I have recovered from all side effects of my previous cancer treatments or surgeries.

My cancer does not respond to standard treatments or I cannot tolerate them.

My cancer's biomarker profile is available from a certified lab test.

Exclusion Criteria

I do not have any active, uncontrolled infections including HBV, HCV, HIV, or AIDS.

I have been treated with ATR or DNA-PK inhibitors before.

My liver function is moderately or severely impaired.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Evaluate the safety profile and MTD of RP-3500 (camonsertib) when administered orally, alone and in combination with talazoparib or gemcitabine

Up to 90 days

Expansion Cohorts

Expansion cohorts with RP-3500 (camonsertib) to study the anti-tumor effect and further examine the safety and PK at the RP2D

About 1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 90 days after last administration of study intervention

What Are the Treatments Tested in This Trial?

Interventions

• Gemcitabine Injection [Gemzar]
• RP-3500 (camonsertib)
• Talazoparib

Trial Overview The trial tests RP-3500 (camonsertib) alone or combined with talazoparib or gemcitabine to find the safest high dose for Phase 2 trials. It will assess safety, how the body processes these drugs, their effects on tumors, and overall anti-tumor activity.

How Is the Trial Designed?

Group I: RP-3500 (camonsertib) with Talazoparib or Gemcitabine Experimental Treatment 3 Interventions

Phase 1: Multiple doses of RP-3500 (camonsertib) for oral administration in combination with talazoparib or gemcitabine

Group II: RP-3500 (camonsertib) alone Experimental Treatment 1 Intervention

Phase 1: Multiple doses of RP-3500 (camonsertib) for oral administration alone

Group III: Expansion cohorts with RP-3500 (camonsertib) Experimental Treatment 1 Intervention

Phase 2: Expansion cohorts with RP-3500 (camonsertib)

Gemcitabine Injection [Gemzar] is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Non-small cell lung cancer
• Ovarian cancer

Approved in United States as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Non-small cell lung cancer
• Ovarian cancer

Approved in Canada as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Non-small cell lung cancer
• Ovarian cancer

Approved in Japan as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Non-small cell lung cancer
• Ovarian cancer

Who Is Running the Clinical Trial?

Repare Therapeutics

Lead Sponsor

Trials

10

Recruited

1,300+

Roche Pharma AG

Industry Sponsor

Trials

413

Recruited

430,000+

Dr. Thomas Schinecker

Roche Pharma AG

Chief Executive Officer since 2023

PhD in Molecular Biology from New York University

Dr. Levi Garraway

Roche Pharma AG

Chief Medical Officer since 2019

MD from University of California, San Francisco

Published Research Related to This Trial

In a phase I clinical trial involving 13 patients with metastatic renal cell carcinoma, the combination of gemcitabine and rHuIFN-alpha2b showed significant hematologic toxicity, particularly at higher doses, including severe anemia and neutropenia.

The study determined that the maximal tolerated dose was gemcitabine 600 mg/m2 weekly and rHuIFN-alpha2b 1.0 MU/m2 three times a week, leading to the conclusion that further investigation of this combination is not recommended due to the associated toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of weekly gemcitabine and subcutaneous interferon alpha in patients with refractory renal cell carcinoma. Perez-Zincer, F., Olencki, T., Budd, GT., et al.[2022]

Gemcitabine, a nucleoside analogue, shows promise in treating non-small cell lung cancer (NSCLC) and has been evaluated in economic studies across multiple countries, indicating it may be cost-effective compared to other treatments.

The economic evaluations suggest that gemcitabine can be administered safely in an outpatient setting with a lower side-effect profile, which contributes to its potential cost savings in NSCLC treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of the pharmacoeconomic research on gemcitabine in the treatment of advanced non-small cell lung cancer. Minshall, ME., Liepa, AM.[2022]

Gemcitabine was initially approved for treating advanced non-small-cell lung cancer (NSCLC) in combination with cisplatin, but research has shifted towards combining it with newer drugs that may offer better efficacy and fewer side effects.

The article reviews the effectiveness of non-cisplatin-based combinations of gemcitabine with other agents, highlighting the ongoing evolution in treatment strategies for advanced NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in treatment of inoperable NSCLC: gemcitabine doublets--a promising alternative. Cappuzzo, F., Rocha Lima, CM., Sherman, CA., et al.[2022]

Gemcitabine (Gemzar) has shown significant antitumor activity in breast cancer treatment, providing better outcomes without excessive toxicity, making it a promising option for patients.

In combination with paclitaxel, gemcitabine has established itself as a first-line treatment, improving response rates and survival, and is currently being investigated for its role in early-stage breast cancer as part of neoadjuvant therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Integrating gemcitabine into breast cancer therapy. Yardley, DA.[2022]

In a study involving 39 chemotherapy-naive patients with stage IIIB breast cancer, the combination of gemcitabine and doxorubicin as neoadjuvant therapy resulted in a high overall response rate of 95%, with 18% achieving a complete response and 77% a partial response.

The treatment was associated with moderate toxicity, including hematologic issues like neutropenia and leukopenia, but overall, 83% of treatment cycles were administered at full dose, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of neoadjuvant gemcitabine plus doxorubicin in stage IIIB breast cancer: a preliminary report. Gomez, H., Kahatt, C., Falcon, S., et al.[2022]

Combining gemcitabine with carboplatin has shown promising efficacy in treating advanced non-small-cell lung cancer, with recent studies indicating improved toxicity profiles compared to older regimens that used cisplatin.

New dosing schedules for gemcitabine, specifically administering it only on days 1 and 8 of a 21-day cycle, have reduced the risk of thrombocytopenia while maintaining effectiveness, making this combination a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine in combination with new platinum compounds: an update. Gandara, DR., Edelman, MJ., Lara, PN., et al.[2022]

Gemcitabine has shown promising results as a single-agent treatment for platinum-resistant ovarian cancer, achieving remission rates of nearly 20% with a favorable safety profile.

Combining gemcitabine with carboplatin has been explored in phase I and II trials, showing potential for improved efficacy in treating ovarian cancer, and further combinations with other agents are being actively researched.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine in ovarian cancer. Orlando, M., Mandachain, M.[2022]

The combination of carboplatin (CBDCA) and gemcitabine (GEM) is effective and safe for treating stage IV non-small-cell lung cancer (NSCLC), with a response rate of 35% in a study of 88 chemotherapy-naïve patients.

Administering CBDCA before GEM resulted in better patient outcomes, including a median survival of 13 months compared to 9 months for those receiving GEM first, highlighting the importance of treatment sequencing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical and clinical evaluation of four gemcitabine plus carboplatin schedules as front-line treatment for stage IV non-small-cell lung cancer. Bajetta, E., Stani, SC., De Candis, D., et al.[2022]

Gemcitabine, a nucleoside analog, inhibits DNA synthesis and shows potential synergy with other antimetabolites like 5-fluorouracil, making it a promising treatment for solid tumors.

In a phase I study involving eight patients, the main side effect observed was myelosuppression, and the study aims to establish the maximum tolerated doses of gemcitabine when combined with UFT and oral calcium folinate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine and UFT plus oral calcium folinate: phase I study. Philip, PA., Ibrahim, D., Zalupski, M., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37277454/

Camonsertib in DNA damage response-deficient advanced ... Here we report the results from module 1 of an ongoing phase 1 trial of the ATRi camonsertib (RP-3500) in 120 patients with advanced solid tumors.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04497116

Study of RP-3500, Camonsertib, in Advanced Solid Tumors This study will also evaluate the safety and tolerability of RP-3500 (camonsertib) alone or in combination with talazoparib or gemcitabine, examine both the ...

3. ir.reparerx.com ir.reparerx.com/news-releases/news-release-details/repare-therapeutics-presents-updated-clinical-data-ongoing-phase

Repare Therapeutics Presents Updated Clinical Data from ... RP-3500 shows robust activity in ovarian cancer demonstrating 75% CBR, with 25% ORR and mPFS of 35 weeks. Updated monotherapy results show 43% CBR in solid ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9398170/

RP-3500: A Novel, Potent, and Selective ATR Inhibitor that ... RP-3500 is efficacious as a single agent in ATM-deficient tumor models. A, LoVo tumor xenograft volume in mice treated with RP-3500 orally once daily × 17 days.

5. targetedonc.com targetedonc.com/view/rp-3500-shows-early-activity-safety-in-advanced-solid-tumors-with-ddr-pathway-alterations

RP-3500 Shows Early Activity/Safety in Advanced Solid ... Results from the monotherapy cohort of the study show that RP-3500 was safe and well-tolerated, with compelling early efficacy signals. The ...

6. nature.com nature.com/articles/s41591-023-02399-0

Camonsertib in DNA damage response-deficient advanced ... Here we report the results from module 1 of an ongoing phase 1 trial of the ATRi camonsertib (RP-3500) in 120 patients with advanced solid tumors.

7. ir.reparerx.com ir.reparerx.com/news-releases/news-release-details/repare-therapeutics-present-data-phase-12-tresr-clinical-trial

Repare Therapeutics to Present Data from Phase 1/2 ... The study evaluated safety, pharmacokinetics and identify preliminary anti-tumor activity associated with camonsertib monotherapy in patients with solid tumors.

8. onclive.com onclive.com/view/rp-3500-shows-promising-safety-clinical-activity-in-solid-tumors-with-synthetic-lethal-genomic-alterations

RP-3500 Shows Promising Safety, Clinical Activity in Solid ... The ATR inhibitor RP-3500 demonstrated a manageable safety profile and promising early antitumor efficacy in patients whose tumors harbor select genomic ...