Niraparib + Irinotecan for Breast Cancer

Overseen By Early Phase Cancer Clinical Trials Recruitment

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of California, San Francisco

Must not be taking: Investigational agents

Disqualifiers: Unstable brain metastases, Hypertension, others

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

Compensation: Varies

Number of Visits: 34

Duration: Up to 2 years

24 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this phase 1 clinical trials is to determine whether niraparib (a Poly (ADP-ribose) polymerase inhibitor (PARPi)) can be safely combined with irinotecan with manageable toxicity and reasonable efficacy. Emerging evidence suggest that PARPi is an effective therapeutic strategy in a wider subset of solid tumors that may have defective homologous recombination (HR) or DNA repair gene mutations. BReast CAncer gene (BRCA), partner and localizer of BRCA2 (PALB2), and various other DNA repair germline mutations predispose carriers to cancers of the breast, ovaries, pancreas, prostate and melanoma. A number of preclinical studies have demonstrated that PARP inhibitors can work as chemopotentiators. There is significant interest in this combination, and the recommended phase II dose will be used in the upcoming NCI ComboMatch trial.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) of at least 3 weeks or 5 half-lives, whichever is shorter, since the last anticancer therapy. This means you may need to stop taking your current cancer medications before starting the trial.

What data supports the effectiveness of the drug combination Niraparib and Irinotecan for breast cancer?

Irinotecan, one of the drugs in the combination, has shown effectiveness in treating other types of cancer, such as colorectal cancer, by inhibiting DNA synthesis in cancer cells. Although this is not direct evidence for breast cancer, it suggests potential effectiveness in targeting cancer cells. ^{1 2 3 4 5}

Is the combination of Niraparib and Irinotecan safe for humans?

Irinotecan, also known as CPT-11 or Camptosar, has been studied in various cancers and is known to cause some side effects like low blood cell counts (neutropenia and thrombocytopenia) and diarrhea. These side effects have been observed in different studies, but the overall safety profile shows it can be used with careful monitoring. There is no specific safety data available for the combination of Niraparib and Irinotecan in humans. ^{3 6 7 8 9}

How is the drug combination of Niraparib and Irinotecan unique for breast cancer treatment?

The combination of Niraparib and Irinotecan is unique because it pairs a PARP inhibitor (Niraparib) with a topoisomerase inhibitor (Irinotecan), potentially offering a novel mechanism of action by targeting DNA repair pathways and DNA replication in cancer cells, which is different from standard breast cancer treatments. ^{2 3 6 7 10}

Research Team

Pamela Munster

Principal Investigator

University of California, San Francisco

Eligibility Criteria

Adults with advanced solid tumors that can't be cured and have specific DNA repair gene mutations (BRCA1, BRCA2, ATM, PALB2) are eligible. They should not have had cancer treatment recently and must be in good physical condition with well-functioning organs. Pregnant women or those who may become pregnant must use effective contraception.

Inclusion Criteria

It's been over 3 weeks or 5 half-lives since my last cancer treatment.

My cancer type responds to specific drugs, and I have certain genetic mutations.

My cancer is advanced and cannot be cured with current treatments.

Exclusion Criteria

Individuals with known toxicity to irinotecan (e.g., grade 3 or 4 neutropenia) or suspected sensitivity

I am allergic to PARP inhibitors or irinotecan.

I have a genetic variation that increases my risk of side effects from irinotecan.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive niraparib and irinotecan in 21-day cycles until unacceptable toxicity, disease progression, or withdrawal

Up to 2 years

Every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days after last dose

1 visit (in-person)

Long-term follow-up

Participants are followed every 12 weeks for up to 2 years for disease progression or death

Up to 2 years

Every 12 weeks

Treatment Details

Interventions

• Irinotecan
• Niraparib

Trial Overview The trial is testing the combination of niraparib, a drug targeting enzymes involved in DNA repair, with irinotecan, a chemotherapy agent. The goal is to see if this combo is safe and works against cancers due to faulty DNA repair genes.

Participant Groups

Group I: Cohort 4b (Niraparib, Irinotecan) Experimental Treatment 2 Interventions

Participants weighing \>= 77 kg will receive a starting dose of 300 mg of niraparib on days 1-7 each 21-day cycle, and 150 mg/m\^2 of irinotecan on day 1 of each 21 day cycle until unacceptable toxicity, disease progression or participant withdrawal.

Group II: Cohort 4a (Niraparib, Irinotecan) Experimental Treatment 2 Interventions

Participants weighing \< 77 kg will receive a starting dose of 200 mg of niraparib on days 1-7 each 21-day cycle, and 150 mg/m\^2 of irinotecan on day 1 of each 21 day cycle until unacceptable toxicity, disease progression or participant withdrawal.

Group III: Cohort 3b (Niraparib, Irinotecan) Experimental Treatment 2 Interventions

Participants weighing \>= 77 kg will receive a starting dose of 300 mg of niraparib on days 1-7 each 21-day cycle, and 100 mg/m\^2 of irinotecan on day 1 of each 21 day cycle until unacceptable toxicity, disease progression or participant withdrawal.

Group IV: Cohort 3a (Niraparib, Irinotecan) Experimental Treatment 2 Interventions

Participants weighing \< 77 kg will receive a starting dose of 200 mg of niraparib on days 1-7 each 21-day cycle, and 100 mg/m\^2 of irinotecan on day 1 of each 21 day cycle until unacceptable toxicity, disease progression or participant withdrawal.

Group V: Cohort 2 (Niraparib, Irinotecan) Experimental Treatment 2 Interventions

Participants will receive a starting dose of 200 mg of niraparib on days 1-7 each 21-day cycle, and 100 mg/m\^2 of irinotecan on day 1 of each 21 day cycle until unacceptable toxicity, disease progression or participant withdrawal.

Group VI: Cohort 1 (Niraparib, Irinotecan) Experimental Treatment 2 Interventions

Participants will receive a starting dose of 100 mg of niraparib on days 1-7 each 21-day cycle, and 100 mg/m\^2 of irinotecan on day 1 of each 21 day cycle until unacceptable toxicity, disease progression or participant withdrawal.

Irinotecan is already approved in United States, European Union, Japan, Canada for the following indications:

Approved in United States as Camptosar for:

• Colorectal cancer

Approved in European Union as Irinotecan for:

• Colorectal cancer

Approved in Japan as Topotecin for:

• Colorectal cancer
• Small cell lung cancer

Approved in Canada as Irinotecan for:

• Colorectal cancer

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

GlaxoSmithKline

Industry Sponsor

Trials

4,834

Recruited

8,389,000+

Headquarters

London, UK

Known For

Vaccines & Medicines

Top Products

**Advair (salmeterol, fluticasone propionate)**, **Shingrix (shingles vaccine)**, **Augmentin (amoxicillin/clavulanate potassium)**, **Ventolin (salbutamol sulfate)

Dame Emma Walmsley

GlaxoSmithKline

Chief Executive Officer since 2017

MA in Classics and Modern Languages from Oxford University

Dr. Hal Barron

GlaxoSmithKline

Chief Medical Officer since 2018

MD from Harvard Medical School

Findings from Research

Irinotecan is approved as a second-line treatment for metastatic colorectal cancer and has shown promising single-agent activity in Phase II studies for first-line treatment, with response rates comparable to standard regimens.

Due to its high cost and lack of definitive evidence showing superiority over current first-line treatments, routine use of irinotecan as a single agent may not be justified, although combination therapies with fluorouracil and molecular markers could help identify suitable patients for its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan in the first-line treatment of colorectal cancer. Saltz, LB.[2018]

ZBH-1207, a novel derivative of irinotecan, shows significantly higher cytotoxicity against colorectal cancer (CRC) cells compared to its parent compound CPT-11 and its active metabolite SN38, as demonstrated through in vitro studies on seven tumor cell lines.

The mechanism of action for ZBH-1207 involves inducing apoptosis and cell cycle arrest in CRC cells, with increased expression of active caspase-3 and PARP, indicating a robust activation of the apoptosis signaling pathway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel irinotecan derivative ZBH-1207 with different anti-tumor mechanism from CPT-11 against colon cancer cells. Zhao, D., Wu, D., Zhang, G., et al.[2022]

Irinotecan (CPT-11) demonstrated activity in treating recurrent malignant gliomas, with 15% of patients showing a confirmed partial response and 55% achieving stable disease for over 12 weeks, based on a study of 60 patients.

The treatment was associated with limited toxicity, primarily mild side effects like neutropenia and nausea, but the low plasma concentrations of the drug suggest that concurrent use of anticonvulsants and dexamethasone may reduce its effectiveness by enhancing drug clearance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan therapy in adults with recurrent or progressive malignant glioma. Friedman, HS., Petros, WP., Friedman, AH., et al.[2022]

Camptothecins (CPTs) are effective chemotherapeutic agents that work by inhibiting topoisomerase I, which is crucial for DNA synthesis, and newer analogues like irinotecan and topotecan have been developed to improve water solubility and reduce toxicity.

The review highlights the clinical pharmacology of these CPT analogues, focusing on their absorption, variability in pharmacokinetics and pharmacodynamics, metabolism, and considerations for use in special populations, indicating their potential for tailored cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical pharmacology of camptothecins. Iyer, L., Ratain, MJ.[2019]

The combination therapy of cisplatin and irinotecan hydrochloride via intra-arterial infusion showed promising results in patients with gynecological cancer, leading to tumor reduction and improved tumor marker levels without serious adverse reactions, except for one case of grade 3 diarrhea.

The new regimen allowed for a higher conversion rate of irinotecan to its active metabolite SN 38 (10% compared to 3% with standard intravenous infusion), and significantly increased the area under the curve (AUC) of free platinum, suggesting enhanced efficacy and localized treatment benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Improvement in the regimen for combined CDDP and CPT-11 chemotherapy]. Shimizu, A., Sugitoh, Y., Hasegawa, A., et al.[2013]

Irinotecan (CPT-11) demonstrated a 21% overall response rate in 42 patients with refractory squamous cell cancer of the cervix, with a median survival of 6.4 months, and a significant survival advantage for those who responded to treatment (12.6 months vs. 5.1 months).

The treatment was associated with notable toxicities, including severe nausea and vomiting (45%), diarrhea (24%), and anemia (62%), indicating the need for careful monitoring of gastrointestinal and hematologic side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of irinotecan in prior chemotherapy-treated squamous cell carcinoma of the cervix. Verschraegen, CF., Levy, T., Kudelka, AP., et al.[2018]

Irinotecan (CPT-11) has shown response rates of 13% to 20% in treating refractory or recurrent cervical cancer, indicating some level of efficacy in this challenging condition.

The combination of irinotecan with cisplatin has been studied, but the treatment is associated with significant hematologic and gastrointestinal toxicities, highlighting the need for further research to optimize safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan in cervical cancer. Kavanagh, JJ., Verschraegen, CF., Kudelka, AP.[2018]

Irinotecan, administered weekly to 19 patients with advanced non-small cell lung cancer (NSCLC) who were resistant to previous chemotherapy, demonstrated a 16% overall clinical response rate, indicating some effectiveness as a treatment option.

The treatment was associated with manageable side effects, primarily grade 3 neutropenia and diarrhea in 10% of patients, and grade 4 thrombocytopenia in 5%, suggesting that irinotecan has a favorable safety profile in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of weekly irinotecan (CPT-11) in patients with advanced non-small cell lung cancer pretreated with platinum and taxanes. Sánchez, R., Esteban, E., Palacio, I., et al.[2019]

In a study of 36 patients with advanced non-small cell lung cancer (NSCLC), the combination of irinotecan and cisplatin showed a partial response rate of 22.9% and a stable disease rate of 60%, indicating its efficacy in this patient population.

The treatment was associated with manageable adverse events, with grade III/IV side effects occurring in a minority of patients, including neutropenia (16.7%) and alopecia (13.9%), suggesting that the regimen is tolerable for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Irinotecan plus cisplatin for the treatment of advanced non-small cell lung cancer]. Zhang, XR., Zhu, YZ., Xiu, QY., et al.[2018]

In a phase I/II study involving 24 patients with advanced non-small cell lung cancer (NSCLC), the combination of paclitaxel (Pac) and irinotecan (CPT) demonstrated a significant objective response rate of 58.3% and a median survival time of 370 days.

The study identified pneumonitis as the dose-limiting toxicity, with a maximum-tolerated dose of Pac at 160 mg/m² and CPT at 60 mg/m² recommended for further phase II trials, indicating a manageable safety profile for this chemotherapy combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose escalation study of paclitaxel in combination with fixed-dose irinotecan in patients with advanced non-small cell lung cancer (JCOG 9807). Yamada, K., Ikehara, M., Tanaka, G., et al.[2018]

References

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

Irinotecan in the first-line treatment of colorectal cancer. [2018]

2. Netherlands pubmed.ncbi.nlm.nih.gov

A novel irinotecan derivative ZBH-1207 with different anti-tumor mechanism from CPT-11 against colon cancer cells. [2022]

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

Irinotecan therapy in adults with recurrent or progressive malignant glioma. [2022]

4. Germany pubmed.ncbi.nlm.nih.gov

Clinical pharmacology of camptothecins. [2019]

5. Japan pubmed.ncbi.nlm.nih.gov

[Improvement in the regimen for combined CDDP and CPT-11 chemotherapy]. [2013]

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

Phase II study of irinotecan in prior chemotherapy-treated squamous cell carcinoma of the cervix. [2018]

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

Irinotecan in cervical cancer. [2018]

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

Activity of weekly irinotecan (CPT-11) in patients with advanced non-small cell lung cancer pretreated with platinum and taxanes. [2019]

9. China pubmed.ncbi.nlm.nih.gov

[Irinotecan plus cisplatin for the treatment of advanced non-small cell lung cancer]. [2018]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Dose escalation study of paclitaxel in combination with fixed-dose irinotecan in patients with advanced non-small cell lung cancer (JCOG 9807). [2018]