Tuvusertib + Niraparib/Lartesertib for Ovarian Cancer

Not currently recruiting at 100 trial locations

Overseen By Communication Center

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: EMD Serono Research & Development Institute, Inc.

Disqualifiers: Platinum-refractory, Recent malignancy, Brain metastases, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatment options for individuals with certain types of ovarian cancer. It evaluates the effectiveness and safety of combining tuvusertib (an experimental drug) with either niraparib or lartesertib. Researchers focus on tumor response and any side effects. The trial seeks participants whose ovarian cancer has progressed despite prior treatment with a PARP inhibitor and who have specific genetic markers, such as BRCA1 or BRCA2 mutations, linked to their cancer. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group of participants.

Do I have to stop taking my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. However, it does mention that participants should have progressed on PARP inhibitors before joining, which suggests that you may need to stop those specific medications. It's best to discuss your current medications with the trial coordinators.

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

Research has shown that tuvusertib is generally well-tolerated. Studies have found that when used alone, tuvusertib has a manageable safety profile, with most people not experiencing severe side effects.

Niraparib, often used for ovarian cancer, has undergone extensive study. It is considered safe as a maintenance treatment, though some people might experience side effects.

Lartesertib is another treatment option currently under investigation for safety. Early studies suggest it could be effective, but more research is needed to fully understand its side effects.

This trial is in Phase 2, meaning researchers are still gathering detailed information about the safety and effectiveness of these treatments when used together. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for ovarian cancer because they explore a novel approach by combining tuvusertib with either niraparib or lartesertib. Tuvusertib is unique as it targets cancer cells through a different mechanism, potentially enhancing the effectiveness of existing PARP inhibitors like niraparib. This combination aims to improve treatment outcomes by exploiting vulnerabilities in cancer cell DNA repair processes more efficiently than current standards of care. Additionally, examining different dosing regimens could optimize effectiveness and minimize side effects, offering a promising new strategy for managing ovarian cancer.

What evidence suggests that this trial's treatments could be effective for ovarian cancer?

Research has shown that tuvusertib can help fight cancer cells. One study found that about 15.6% of patients with ovarian cancer responded well to tuvusertib, with their tumors either shrinking or disappearing. In this trial, participants will receive a randomized combination of tuvusertib with either niraparib or lartesertib. Combining tuvusertib with niraparib appears promising, particularly for overcoming resistance to PARP inhibitors, which treat ovarian cancer. Researchers are also exploring the combination of tuvusertib with lartesertib, as this may enhance cancer treatment by targeting cancer cells in different ways. Although early results are encouraging, further research is necessary to confirm these findings. ^{1 2 6 7 8}

Who Is on the Research Team?

Medical Responsible

Principal Investigator

EMD Serono Research & Development Institute, Inc.

Are You a Good Fit for This Trial?

This trial is for individuals with epithelial ovarian cancer who have previously not responded well to treatment with a PARP inhibitor. Specific eligibility details are not provided, but typically participants must meet certain health standards and may be excluded based on other medical conditions or treatments.

Inclusion Criteria

My tumor has harmful BRCA1/2 mutations or is HRD positive.

My cancer progressed after first-line PARPi treatment, and I've had only one platinum-based chemotherapy before this study.

I have not received any cancer treatments after my second-line PARPi therapy.

Exclusion Criteria

I do not have any active or uncontrolled infections.

My brain metastases are stable.

I have had an organ or stem cell transplant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive treatment with tuvusertib combined with either niraparib or lartesertib

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Lartesertib
• Niraparib
• Tuvusertib

Trial Overview The study tests the effectiveness and safety of tuvusertib in combination with either niraparib or lartesertib in those with epithelial ovarian cancer. It aims to see if these combinations can reduce tumor size or stop tumor growth after previous treatments haven't worked.

How Is the Trial Designed?

Group I: Part B: Tuvusertib Monotherapy Experimental Treatment 1 Intervention

In Part B, the most favorable combination treatment from Part A will be further explored at 2 different dosing regimens and compared to tuvusertib monotherapy.

Group II: Part B (dose optimization), dosing regimen 2: Tuvusertib + Niraparib or Tuvusertib + Lartesertib Experimental Treatment 3 Interventions

In Part B, the most favorable combination treatment from Part A will be further explored at 2 different dosing regimens and compared to tuvusertib monotherapy.

Group III: Part B (dose optimization), dosing regimen 1 :Tuvusertib+Niraparib or Tuvusertib +Lartesertib Experimental Treatment 3 Interventions

In Part B, the most favorable combination treatment from Part A will be further explored at 2 different dosing regimens and compared to tuvusertib monotherapy.

Group IV: Part A, Arm 2: Tuvusertib with Lartesertib Experimental Treatment 2 Interventions

In Part A, participants will be randomized to one of 2 arms to receive tuvusertib in combination with either niraparib or lartesertib.

Group V: Part A, Arm 1: Tuvusertib with Niraparib Experimental Treatment 2 Interventions

In Part A, participants will be randomized to one of 2 arms to receive tuvusertib in combination with either niraparib or lartesertib.

Who Is Running the Clinical Trial?

EMD Serono Research & Development Institute, Inc.

Lead Sponsor

Trials

86

Recruited

22,700+

Miguel Fernández Alcalde

EMD Serono Research & Development Institute, Inc.

Chief Executive Officer

Bachelor’s Degree in Pharmacy from the University Complutense in Madrid, MBA from the University of Alcalá de Henares, Master’s Degree in Management from IESE Business School

Danny Bar-Zohar

EMD Serono Research & Development Institute, Inc.

Chief Medical Officer since 2022

MD

Merck KGaA, Darmstadt, Germany

Industry Sponsor

Trials

449

Recruited

122,000+

Danny Bar-Zohar

Merck KGaA, Darmstadt, Germany

Chief Medical Officer since 2022

MD

Belén Garijo

Merck KGaA, Darmstadt, Germany

Chief Executive Officer since 2021

MD

Published Research Related to This Trial

Adavosertib, when combined with carboplatin, showed a high overall response rate of 66.7% in patients with platinum-resistant ovarian cancer, indicating promising efficacy for this treatment combination.

However, the combination therapy resulted in significant hematologic toxicities, such as neutropenia and anemia, suggesting that while adavosertib is effective, careful monitoring and further optimization of treatment protocols are necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adavosertib with Chemotherapy in Patients with Primary Platinum-Resistant Ovarian, Fallopian Tube, or Peritoneal Cancer: An Open-Label, Four-Arm, Phase II Study. Moore, KN., Chambers, SK., Hamilton, EP., et al.[2022]

In a Phase 2 study involving 20 Japanese women with heavily pretreated ovarian cancer, niraparib demonstrated an objective response rate of 35%, indicating that it can effectively reduce tumor size in some patients.

The treatment was generally well-tolerated, with a high disease control rate of 90%, although common side effects included anemia and nausea, and 70% of patients experienced dose reductions or interruptions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 single-arm study on the efficacy and safety of niraparib in Japanese patients with heavily pretreated, homologous recombination-deficient ovarian cancer. Okamoto, A., Kondo, E., Nakamura, T., et al.[2021]

In the ENGOT-OV16/NOVA trial, patients aged 70 and older with recurrent ovarian cancer who received niraparib showed significant progression-free survival (PFS) benefits, with non-gBRCAmut patients achieving a median PFS of 11.3 months compared to 3.8 months for those on placebo.

The safety profile of niraparib in older patients was similar to that in younger patients, with common adverse events being hematologic issues like thrombocytopenia and anemia, suggesting that niraparib is a viable treatment option for older patients with recurrent ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of niraparib as maintenance treatment in older patients (≥ 70 years) with recurrent ovarian cancer: Results from the ENGOT-OV16/NOVA trial. Fabbro, M., Moore, KN., Dørum, A., et al.[2019]

In a study of 331 patients with recurrent ovarian cancer, niraparib maintenance therapy significantly improved progression-free survival (PFS) in patients with somatic BRCA mutations and those with BRCA wild-type tumors, indicating its efficacy across different genetic backgrounds.

Patients with BRCA wild-type tumors that had other homologous recombination repair (HRR) mutations, as well as those without any HRR mutations, also experienced PFS benefits from niraparib, suggesting its potential as a treatment option regardless of specific mutation status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ad hoc Analysis of the Phase III ENGOT-OV16/NOVA Study: Niraparib Efficacy in Germline BRCA Wild-type Recurrent Ovarian Cancer with Homologous Recombination Repair Defects. Mirza, MR., Lindahl, G., Mahner, S., et al.[2023]

Niraparib maintenance therapy significantly prolonged progression-free survival (PFS) in patients with newly diagnosed advanced ovarian cancer, with a median PFS of 24.8 months compared to 8.3 months for placebo, demonstrating its efficacy across various patient subgroups.

The individualized starting dose (ISD) of niraparib was found to be both effective and safe, with similar rates of treatment discontinuation due to adverse events between niraparib (6.7%) and placebo (5.4%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment With Niraparib Maintenance Therapy in Patients With Newly Diagnosed Advanced Ovarian Cancer: A Phase 3 Randomized Clinical Trial. Li, N., Zhu, J., Yin, R., et al.[2023]

Niraparib is the first FDA- and EMA-approved PARP inhibitor for maintenance therapy in platinum-sensitive ovarian cancer, effective regardless of BRCA status in first-line treatment.

The review highlights niraparib's pharmacological properties and summarizes efficacy and safety data from key trials, indicating its significant role in improving treatment outcomes for ovarian cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib and Advanced Ovarian Cancer: A Beacon in the Non-BRCA Mutated Setting. Maiorano, MFP., Maiorano, BA., Biancofiore, A., et al.[2023]

Niraparib, a PARP inhibitor, showed tumor regression in certain patient-derived xenograft (PDX) models of high-grade serous ovarian carcinoma (HGSOC), particularly in those with BRCA2 mutations, indicating its potential efficacy in specific genetic contexts.

The study found that while niraparib did not significantly enhance the effectiveness of carboplatin/paclitaxel chemotherapy, it did delay disease progression in a BRCA2-deficient model when used as maintenance therapy, highlighting the importance of genetic markers in predicting treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo anti-tumor activity of the PARP inhibitor niraparib in homologous recombination deficient and proficient ovarian carcinoma. AlHilli, MM., Becker, MA., Weroha, SJ., et al.[2023]

In a study of 105 patients with newly diagnosed advanced ovarian cancer, the combination of niraparib and bevacizumab as first-line maintenance therapy resulted in a promising progression-free survival (PFS) rate of 62% at 18 months, with even higher rates in patients with homologous recombination deficiency (76%).

The safety profile of this combination therapy was consistent with the known side effects of the individual drugs, with common treatment-related adverse events including thrombocytopenia, fatigue, and anemia, indicating that the treatment is manageable for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

OVARIO phase II trial of combination niraparib plus bevacizumab maintenance therapy in advanced ovarian cancer following first-line platinum-based chemotherapy with bevacizumab. Hardesty, MM., Krivak, TC., Wright, GS., et al.[2022]

In a study of 553 patients with recurrent ovarian cancer, niraparib treatment led to a significant increase in mean progression-free survival (PFS) of 3.23 years for those with a germline BRCA mutation and 1.44 years for those without, compared to routine surveillance.

Niraparib also resulted in a greater time without symptoms or toxicity (TWiST), providing a benefit of 2.95 years for the gBRCAmut cohort and 1.34 years for the non-gBRCAmut cohort, indicating that patients experienced more time free from adverse effects compared to those receiving routine surveillance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib Maintenance Treatment Improves Time Without Symptoms or Toxicity (TWiST) Versus Routine Surveillance in Recurrent Ovarian Cancer: A TWiST Analysis of the ENGOT-OV16/NOVA Trial. Matulonis, UA., Walder, L., Nøttrup, TJ., et al.[2020]

The combination of navicixizumab and paclitaxel demonstrated lasting effectiveness in treating patients with platinum-resistant ovarian cancer, indicating a potential new treatment strategy.

This finding suggests that navicixizumab may enhance the therapeutic impact of paclitaxel in a challenging patient population, although specific details on the number of subjects and study duration were not provided.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Navicixizumab plus Paclitaxel Shows Clinical Benefit in Platinum-Resistant Ovarian Cancer. [2022]

Niraparib, a PARP inhibitor approved in 2020, provides an effective maintenance treatment for ovarian cancer, showing promise regardless of patients' genetic profiles, which is significant given the low survival rates associated with late-stage diagnoses.

The treatment has a low side effect profile and is administered orally, making it a convenient option for patients, while ongoing trials are exploring new combination therapies that could enhance its efficacy further.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib in the maintenance treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: safety and efficacy. Liu, MC., Sutedja, J., Tewari, KS.[2022]

Citations

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First-in-Human Study of the Ataxia Telangiectasia and Rad3 ... Tuvusertib demonstrated manageable safety and exposure-related target engagement. Further clinical evaluation of tuvusertib is ongoing.

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A phase I study of highly potent oral ATR inhibitor (ATRi) ... Preliminary efficacy data show 5 (15.6%) responses (3 confirmed) by RECIST v1.1 in 32 evaluable patients: 2 in patients with epithelial ovarian ...

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The Novel ATR Inhibitor Tuvusertib (M1774) Induces ... Together, these results demonstrate that M1774-induced cancer cell death in combination results from lack of cell cycle arrest and persistent DNA replication, ...

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First-in-Human Study of the Ataxia Telangiectasia and Rad3 ... This first-in-human study demonstrates that ataxia telangiectasia and Rad3-related inhibitor tuvusertib as monotherapy is well tolerated, has a manageable ...

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ATR Inhibitors in Platinum-Resistant Ovarian Cancer Nearly 80% of patients with HGSOC were diagnosed with advanced disease, and the 5-year survival rate was approximately 32.1% [2,3]. The standard ...

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First-in-Human Study of the Ataxia Telangiectasia and Rad3 ... This first-in-human study demonstrates that ataxia telangiectasia and Rad3-related inhibitor tuvusertib as monotherapy is well tolerated, has a manageable ...

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DDRIVER: A study of Tuvusertib combined with Niraparib ... This trial is for those with a diagnosis of high grade serous or endometrioid ovarian cancer that has progressed while on a Parp inhibitor.

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Tuvusertib Combined With Niraparib or Lartesertib in ... The purpose of this study is to measure the effect and safety of treatment with tuvusertib combined with either niraparib or lartesertib in participants ...