Combination Drug Therapy for Cancer

(DIDO Trial)

Overseen By Amanda Fletcher, RN

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: West Cancer Center

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Prostate cancer, Ovarian cancer, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an open-label, single-arm, Phase 2 study which will evaluate the efficacy and safety of niraparib and dostarlimab (TSR-042) combination in patients with metastatic, recurrent, or unresectable solid tumor with a pathogenic, or presumed pathogenic, somatic homologous recombination deficiency (HRD) gene mutation

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, certain conditions like recent surgery, radiation, or investigational therapy might require a waiting period before starting the trial. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination of Niraparib and Dostarlimab for cancer treatment?

A Phase II study showed that the combination of Niraparib and Dostarlimab was effective in treating patients with recurrent platinum-resistant ovarian cancer, improving their health-related quality of life. ^{1 2 3 4 5}

Is the combination of Niraparib and Dostarlimab generally safe for humans?

Niraparib has been studied for safety in various trials, showing common side effects like low blood cell counts, stomach issues, tiredness, and heart-related issues. Dostarlimab is being studied in combination with Niraparib for safety in certain lung and mesothelioma cancers, but specific safety results for this combination are not yet available. ^{6 7 8 9 10}

How is the combination drug therapy of Niraparib and Dostarlimab unique for cancer treatment?

This combination therapy is unique because it uses Niraparib, which targets cancer cells with DNA repair issues, alongside Dostarlimab, an immune checkpoint inhibitor, to enhance the immune system's ability to fight cancer. This dual approach is particularly aimed at cancers with specific genetic markers, making it a targeted and potentially more effective treatment for certain patients. ^{2 3 7 11 12}

Research Team

Gregory Vidal, MD

Principal Investigator

West Cancer Center

Eligibility Criteria

Adults with certain unresectable or metastatic solid tumors containing specific HRD gene mutations, who are in good physical condition (ECOG ≤ 1), and have proper organ function. Participants must agree to use effective contraception and not donate blood during the study. HIV-positive patients on successful treatment can join. Those with recent major surgery, other cancer treatments, or certain medical conditions are excluded.

Inclusion Criteria

I am not pregnant and agree to use effective birth control during the study.

My cancer has spread, can't be removed by surgery, and has specific genetic changes.

My blood tests show my organs are working well.

Exclusion Criteria

I have active hepatitis B or C.

I haven't had a blood transfusion in the last 4 weeks.

I do not have brain metastases or any signs of bleeding in the brain.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive niraparib and dostarlimab combination therapy

16 weeks

Regular visits as per protocol

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Treatment Details

Interventions

• Niraparib and Dostarlimab

Trial Overview The trial is testing a combination of niraparib and dostarlimab for effectiveness and safety in treating solid tumors with HRD gene mutations. It's an open-label, single-arm Phase 2 study where all participants receive the same drug combo without a comparison group.

Participant Groups

Group I: Experimental Experimental Treatment 1 Intervention

niraparib and dostarlimab

Who Is Running the Clinical Trial?

West Cancer Center

Lead Sponsor

Trials

5

Recruited

600+

Findings from Research

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]

The combination of everolimus and niraparib in a Phase 1 trial showed significant toxicity, particularly severe hypertension and thrombocytopenia, leading to the conclusion that this treatment regimen is not feasible for patients with advanced ovarian and breast cancers.

Despite the high toxicity, the treatment resulted in a modest progression-free survival (PFS) of 6 months and an overall survival (OS) of approximately 18 months, with three patients still alive, suggesting that further research into this combination therapy may be warranted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 evaluation of the safety and tolerability of niraparib in combination with everolimus in advanced ovarian and breast cancers. Starks, D., Rojas-Espaillat, L., Meissner, T., et al.[2023]

The combination treatment of dostarlimab and niraparib in patients with recurrent platinum-resistant ovarian cancer showed a low objective response rate of only 7.3%, leading to the early termination of the study due to insufficient efficacy.

Despite the treatment being generally safe with no new safety issues identified, 95.1% of patients experienced treatment-related adverse events, and health-related quality of life worsened over time, indicating a need for more effective therapies for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib and dostarlimab for the treatment of recurrent platinum-resistant ovarian cancer: results of a Phase II study (MOONSTONE/GOG-3032). Randall, LM., O'Malley, DM., Monk, BJ., et al.[2023]

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]

Niraparib significantly prolongs progression-free survival (PFS) in patients with platinum-sensitive recurrent ovarian cancer, with a median PFS of 18.3 months compared to 5.4 months for placebo, indicating a 68% reduction in the risk of disease progression or death.

The treatment was generally safe, though 50.8% of patients experienced grade ≥3 adverse events, with the most common being decreased neutrophil count and anemia, highlighting the importance of monitoring for side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer using an individualized starting dose (NORA): a randomized, double-blind, placebo-controlled phase III trial☆. Wu, XH., Zhu, JQ., Yin, RT., et al.[2021]

Niraparib, a PARP inhibitor for recurrent ovarian cancer, showed no significant changes in its pharmacokinetics when taken with a high-fat meal compared to fasting, indicating it can be safely taken with or without food.

The study demonstrated that niraparib was well-tolerated and had similar adverse events regardless of the meal condition, confirming its safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of food on the pharmacokinetics of niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, in patients with recurrent ovarian cancer. Moore, K., Zhang, ZY., Agarwal, S., et al.[2019]

The study investigates the safety and effectiveness of combining niraparib, a PARP inhibitor, with dostarlimab, an immune checkpoint inhibitor, in treating advanced non-small-cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM) in patients with homologous recombination deficiency (HRD) and PD-L1 expression of 1% or higher.

A total of 700 to 1000 patients will be screened to find 70 eligible participants, with the primary goal of assessing progression-free survival, while also evaluating overall survival and safety, highlighting the potential for this combination therapy to enhance cancer treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Prospective Phase II Single-arm Study of Niraparib Plus Dostarlimab in Patients With Advanced Non-small-cell Lung Cancer and/or Malignant Pleural Mesothelioma, Positive for PD-L1 Expression and Germline or Somatic Mutations in the DNA Repair Genes: Rationale and Study Design. Passiglia, F., Bironzo, P., Righi, L., et al.[2021]

Niraparib, a PARP inhibitor, significantly improves progression-free survival in patients with advanced epithelial ovarian cancer, but nearly all patients (≥99%) experience treatment-emergent adverse events, with 51-74% experiencing severe (grade ≥3) events.

An individualized starting dose of niraparib based on body weight and platelet count leads to fewer severe adverse events and dose modifications, suggesting a tailored approach can enhance safety while maintaining treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and management of niraparib monotherapy in ovarian cancer clinical trials. Monk, BJ., González-Martin, A., Buckley, L., et al.[2023]

Niraparib is an FDA and EMA-approved oral PARP inhibitor for maintenance treatment in women with recurrent ovarian cancer who have responded to platinum-based chemotherapy, showing efficacy in both BRCA mutated and wild-type cancers.

While niraparib is effective, it can cause significant hematologic toxicities, such as thrombocytopenia and anemia, necessitating dose adjustments for certain patients to minimize these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The poly (ADP ribose) polymerase inhibitor niraparib: Management of toxicities. Moore, KN., Mirza, MR., Matulonis, UA.[2019]

Niraparib, a treatment for recurrent ovarian cancer, has a high dose reduction rate of 68.9% due to treatment-emergent adverse events, with thrombocytopenia being a notable cause for 3.3% of patients.

Baseline body weight and platelet count are significant predictors for the risk of severe thrombocytopenia, suggesting that patients with a body weight under 77 kg or platelet count below 150,000/µl may benefit from starting at a lower dose of 200 mg/day without compromising progression-free survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and dose modification for patients receiving niraparib. Berek, JS., Matulonis, UA., Peen, U., et al.[2021]

In a clinical trial involving 55 patients with advanced solid tumors, the PD-1 inhibitor dostarlimab was found to be well tolerated in both doublet and triplet combination therapies, with no new safety concerns arising.

The triplet combinations showed higher disease control rates compared to doublets, with preliminary antitumor activity observed in various combinations, indicating potential for improved efficacy in treating advanced cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IOLite: phase 1b trial of doublet/triplet combinations of dostarlimab with niraparib, carboplatin-paclitaxel, with or without bevacizumab in patients with advanced cancer. Yap, TA., Bessudo, A., Hamilton, E., et al.[2022]

Niraparib (NIRA) is an effective treatment for patients with metastatic castration-resistant prostate cancer who have specific genetic alterations, showing promising results in a Phase II study.

When combined with abiraterone acetate and prednisone, NIRA demonstrated a manageable safety profile while effectively disrupting cancer cell signaling pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib with Abiraterone Acetate and Prednisone for Metastatic Castration-Resistant Prostate Cancer: Phase II QUEST Study Results. Chi, KN., Fleshner, N., Chiuri, VE., et al.[2023]

References

1. United States 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. [2022]

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

A phase 1 evaluation of the safety and tolerability of niraparib in combination with everolimus in advanced ovarian and breast cancers. [2023]

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

Niraparib and dostarlimab for the treatment of recurrent platinum-resistant ovarian cancer: results of a Phase II study (MOONSTONE/GOG-3032). [2023]

4. Korea (South) 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. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Niraparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer using an individualized starting dose (NORA): a randomized, double-blind, placebo-controlled phase III trial☆. [2021]

6. Germany pubmed.ncbi.nlm.nih.gov

The effect of food on the pharmacokinetics of niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, in patients with recurrent ovarian cancer. [2019]

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

A Prospective Phase II Single-arm Study of Niraparib Plus Dostarlimab in Patients With Advanced Non-small-cell Lung Cancer and/or Malignant Pleural Mesothelioma, Positive for PD-L1 Expression and Germline or Somatic Mutations in the DNA Repair Genes: Rationale and Study Design. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Safety and management of niraparib monotherapy in ovarian cancer clinical trials. [2023]

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

The poly (ADP ribose) polymerase inhibitor niraparib: Management of toxicities. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Safety and dose modification for patients receiving niraparib. [2021]

11. England pubmed.ncbi.nlm.nih.gov

IOLite: phase 1b trial of doublet/triplet combinations of dostarlimab with niraparib, carboplatin-paclitaxel, with or without bevacizumab in patients with advanced cancer. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Niraparib with Abiraterone Acetate and Prednisone for Metastatic Castration-Resistant Prostate Cancer: Phase II QUEST Study Results. [2023]