A Dose-escalation Study of the Safety and Pharmacology of DAN-222 in Subjects With Metastatic Breast Cancer

Recruiting at 8 trial locations

Overseen By Kristen Foye

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: Dantari, Inc.

Must not be taking: Antiepileptics, CYP3A4 inhibitors

Disqualifiers: Pregnancy, QT prolongation, others

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

Compensation: Varies

Number of Visits: Unknown

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a new drug called DAN-222 alone and with another drug, niraparib. Niraparib is an oral medication approved for maintenance treatment in ovarian, fallopian tube, or primary peritoneal cancer. It likely targets cancer patients who need new treatment options. DAN-222's effects are being studied, while niraparib helps kill cancer cells by stopping them from repairing their DNA.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take certain medications like enzyme-inducing antiepileptic drugs or those that affect the QT interval. You may need to stop or switch these medications before starting the trial.

What data supports the effectiveness of the drug Niraparib (Zejula) in treating cancer?

Niraparib has been shown to significantly extend the time patients with advanced ovarian cancer live without their disease getting worse, compared to a placebo. It is effective for patients with certain genetic profiles and those without, and it is generally well-tolerated with manageable side effects. ^{1 2 3 4 5}

What safety data exists for Niraparib (also known as DAN-222 or Zejula)?

Niraparib has been studied for safety in various clinical trials, including those for ovarian and breast cancer. No new safety concerns were identified in these studies, suggesting it is generally safe for human use. ^{3 6 7 8 9}

Eligibility Criteria

Inclusion Criteria

A minimum of 2 weeks or 5 half-lives (whichever is longer) will be required from any prior therapy for mBC, including chemotherapy, immunotherapy and/or radiation therapy.

Subjects must have measurable disease as per RECIST v1.1.

Additional Inclusion Criteria for Stage 2: Documentation of DNA repair defects status validated from HRD plasma testing through the central laboratory or from archival tumor tissue or germ line testing. This testing will need to occur prior to enrollment.

Exclusion Criteria

Subject is pregnant or breastfeeding, or expecting to conceive children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment.

Subjects taking medications know to prolong the QT interval or associated with torsades de pointes, unless the subject can safely discontinue these medications or change to comparable medications that do not significantly prolong the QT interval, at least 5 half-lives or 7 days (whichever is longer) prior to the first dose of DAN-222.

Inability to comply with study procedures or unwilling to use adequate birth control.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part A

Dose escalation of single agent DAN-222 administered IV every week

8-12 weeks

Weekly visits (in-person)

Treatment Part B

Dose escalation of DAN-222 in combination with daily oral niraparib

8-12 weeks

Weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• DAN-222
• Niraparib

Participant Groups

Group I: Dose Escalation (DAN-222) Experimental Treatment 1 Intervention

The starting dose of DAN-222 will be administered IV every week (QW) to subjects in the first cohort.

Group II: Dose Escalation (DAN-222 + niraparib) Experimental Treatment 2 Interventions

The starting dose of DAN-222 will be administered IV every week (QW), in combination with daily oral niraparib.

Who Is Running the Clinical Trial?

Dantari, Inc.

Lead Sponsor

Trials

1

Recruited

30+

Findings from Research

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, a recently approved treatment for recurrent platinum-sensitive ovarian cancer, has demonstrated a high oral bioavailability of 72.7% in humans, indicating effective absorption when taken orally.

The study involved six patients who received a therapeutic dose of 300 mg of niraparib, followed by a small intravenous dose to measure its levels in the bloodstream, confirming its potential as a convenient oral treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14C-microtracer and therapeutic dose in cancer patients. van Andel, L., Rosing, H., Zhang, Z., et al.[2019]

Niraparib significantly extends progression-free survival in patients with newly diagnosed advanced ovarian cancer, showing efficacy in both homologous-recombination deficiency positive (HRd) and negative (HRp) populations, based on a phase III trial.

The treatment has a manageable safety profile, with myelosuppression as the main concern, which can be effectively managed through monitoring and individualized dosing based on weight and platelet count.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib: A Review in First-Line Maintenance Therapy in Advanced Ovarian Cancer. Lee, A.[2022]

Niraparib at a dose of 200 mg/day was determined to be the recommended phase 2 dose when combined with abiraterone acetate plus prednisone (AAP) for patients with metastatic castration-resistant prostate cancer (mCRPC), as it showed a tolerable safety profile with no new safety signals.

The combination of niraparib with apalutamide resulted in a higher incidence of dose-limiting toxicities, leading to the decision not to further evaluate this combination, highlighting the importance of monitoring drug interactions in treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib with androgen receptor-axis-targeted therapy in patients with metastatic castration-resistant prostate cancer: safety and pharmacokinetic results from a phase 1b study (BEDIVERE). Saad, F., Chi, KN., Shore, ND., et al.[2021]

In a pilot study of 21 patients with localized HER2-negative, BRCA-mutated breast cancer, neoadjuvant treatment with niraparib showed a high tumor response rate of 90.5% after 2 cycles, indicating strong antitumor activity.

Among those who continued treatment for 2-6 cycles, 40% achieved a pathological complete response, and no new safety concerns were reported, suggesting that niraparib is both effective and safe for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant study of niraparib in patients with HER2-negative, BRCA-mutated, resectable breast cancer. Spring, LM., Han, H., Liu, MC., et al.[2022]

In a Phase 2 study involving 19 Japanese patients with platinum-sensitive, relapsed ovarian cancer, niraparib at a dose of 300 mg/day was found to have a safety profile consistent with previous studies, with 31.6% of patients experiencing grade 3 or 4 thrombocytopenia-related events within 30 days of treatment.

The overall safety profile of niraparib was deemed acceptable, with common treatment-emergent adverse events including nausea and decreased blood cell counts, but no significant improvements in tumor response were observed in the small cohort.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 single-arm study on the safety of maintenance niraparib in Japanese patients with platinum-sensitive relapsed ovarian cancer. Takehara, K., Matsumoto, T., Hamanishi, J., 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]

Niraparib, administered at doses of 200 mg and 300 mg daily, was found to be tolerable in Japanese patients with advanced solid tumors, with only one case of dose-limiting toxicity observed.

The study demonstrated a favorable pharmacokinetic profile for niraparib, with dose-proportional increases in drug levels and some patients showing a partial response to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety, tolerability and pharmacokinetics of niraparib in Japanese patients with solid tumours: results of a phase I dose-escalation study. Yonemori, K., Shimizu, T., Kondo, S., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Quality-adjusted time without symptoms of disease or toxicity and quality-adjusted progression-free survival with niraparib maintenance in first-line ovarian cancer in the PRIMA trial. [2022]

2. 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]

3. Germany pubmed.ncbi.nlm.nih.gov

Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14C-microtracer and therapeutic dose in cancer patients. [2019]

4. France pubmed.ncbi.nlm.nih.gov

Niraparib: A Review in First-Line Maintenance Therapy in Advanced Ovarian Cancer. [2022]

5. Germany pubmed.ncbi.nlm.nih.gov

Niraparib with androgen receptor-axis-targeted therapy in patients with metastatic castration-resistant prostate cancer: safety and pharmacokinetic results from a phase 1b study (BEDIVERE). [2021]

6. England pubmed.ncbi.nlm.nih.gov

Neoadjuvant study of niraparib in patients with HER2-negative, BRCA-mutated, resectable breast cancer. [2022]

7. Korea (South) pubmed.ncbi.nlm.nih.gov

Phase 2 single-arm study on the safety of maintenance niraparib in Japanese patients with platinum-sensitive relapsed ovarian cancer. [2021]

8. 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]

9. England pubmed.ncbi.nlm.nih.gov

The safety, tolerability and pharmacokinetics of niraparib in Japanese patients with solid tumours: results of a phase I dose-escalation study. [2021]