Olaparib + ASTX727 for BRCA Mutations

Overseen By Early Phase Cancer Clinical Trials

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Pamela Munster

Disqualifiers: MDS, AML, Pregnancy, Breastfeeding, others

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

Compensation: Varies

Number of Visits: Unknown

18 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a single center, phase I/Ib clinical trial evaluating the combination of the poly adenosine diphosphate-ribose polymerase (PARP) inhibitor olaparib with the DNA methyltransferase (DNMT) inhibitor ASTX727, which is an oral formulation of decitabine with cedazuridine (a cytidine deaminase inhibitor that allows for oral administration). The study population consists of adults with advanced/metastatic solid tumor malignancies with germline or somatic mutations in the HRR pathway (i.e., BReast CAncer gene 1 (BRCA1), BReast CAncer gene 2(BRCA2), Partner And Localizer of BRCA2 (PALB2), ATM, and/or Checkpoint kinase 2 (CHEK2) mutations).

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

The trial protocol does not specify if you need to stop taking your current medications. However, if you are taking a prohibited medication that cannot be safely discontinued or substituted, you may not be eligible to participate.

What data supports the effectiveness of the drug Olaparib + ASTX727 for BRCA mutations?

Olaparib, a drug used in this treatment, has shown effectiveness in treating cancers with BRCA mutations, such as ovarian and breast cancer, by targeting specific weaknesses in cancer cells' DNA repair mechanisms. Additionally, Olaparib has demonstrated benefits in other cancers like pancreatic and prostate cancer, suggesting its potential effectiveness in a broader range of BRCA-related conditions. ^{1 2 3 4 5}

Is the combination of Olaparib and ASTX727 safe for humans?

Olaparib, a drug used for certain cancers with BRCA mutations, has been studied and shown to be generally safe, with some side effects like nausea and fatigue. However, specific safety data for the combination of Olaparib and ASTX727 is not available in the provided research. ^{1 3 5 6 7}

What makes the drug combination of Olaparib and ASTX727 unique for treating BRCA mutations?

The combination of Olaparib, a PARP inhibitor that targets cancer cells with DNA repair issues, and ASTX727, which includes Decitabine/Cedazuridine to enhance DNA damage, is unique because it potentially increases the effectiveness of treatment by exploiting the cancer cells' inability to repair DNA, leading to their death. This approach is particularly novel for BRCA-mutated cancers, as it combines two mechanisms to enhance treatment efficacy. ^{3 5 8 9 10}

Research Team

Pamela Munster

Principal Investigator

University of California, San Francisco

Eligibility Criteria

Adults with advanced or metastatic solid tumors that have specific genetic mutations in the HRR pathway, such as BRCA1, BRCA2, PALB2, ATM, and CHEK2. Participants must have a mutation related to their cancer.

Inclusion Criteria

My advanced cancer has specific genetic mutations.

I have tried or cannot tolerate approved treatments for my condition, or I choose not to receive them.

My hepatitis B is under control with treatment.

Exclusion Criteria

Individuals who are pregnant

I haven't had cancer treatments or radiation in the last 3 weeks, or antibody therapy in the last 4 weeks.

I haven't taken part in other clinical trials within the last 3 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Participants receive 300 mg Olaparib orally, twice a day on day 1 and day 14 for each 28-day cycle, along with 35/100mg ASTX727 on days 1 and 3 of the 28-day cycle. Dose escalation may occur if no DLTs are observed.

Indefinite until disease progression or unacceptable toxicity

Phase 1b Treatment

Participants receive the recommended phase 2 dose (RP2D) of Olaparib and ASTX727 based on safety and efficacy profile determined in Phase 1.

Indefinite until disease progression or unacceptable toxicity

Follow-up

Participants are monitored for safety approximately 30 days after discontinuation of study treatment and every 16 weeks for up to 2 years.

Up to 2 years

Treatment Details

Interventions

• ASTX727
• Olaparib

Trial Overview The trial is testing a combination of two drugs: Olaparib (a PARP inhibitor) and ASTX727 (an oral drug combining decitabine with cedazuridine). It's designed to see how well these drugs work together against certain tumor mutations.

Participant Groups

Group I: Phase 1b: RP2D (Olaparib, ASTX727) - Dose Expansion Experimental Treatment 2 Interventions

Participants enrolled in this cohort will receive the RP2D based on the safety and efficacy profile determined in the Phase 1 cohorts. Participants will receive the RP2D dose of olaparib orally, twice a day (BID) on day 1 and day 14 for each 28-day cycle. Participants will also receive 35/100mg ASTX727 at the RP2D for the 28-day cycle. Participants may continue study treatment indefinitely until disease progression unacceptable toxicity, withdrawal, or study closure; whichever comes first.

Group II: Phase 1: Olaparib, ASTX727 (D1,D3)-Starting Dose Experimental Treatment 2 Interventions

Participants enrolled in the starting dose cohort will receive 300 mg Olaparib orally, twice a day (BID) on day 1 and day 14 for each 28-day cycle. Participants will also receive 35/100mg ASTX727 on days 1, and 3 of the 28-day cycle. Participants may continue study treatment indefinitely until disease progression unacceptable toxicity, withdrawal, or study closure; whichever comes first. If no DLTs are reported for the first 3 participants, an additional dose escalation cohort may open at the next dose level.

Group III: Phase 1: Olaparib + ASTX727 (D1,D3,D5) Experimental Treatment 2 Interventions

If no DLTs are reported in the previous dose level, participants enrolled in this cohort will receive 300 mg olaparib orally, twice a day (BID) on day 1 and day 14 for each 28-day cycle. Participants will also receive 35/100mg ASTX727 on days 1, 3 and 5 of the 28-day cycle. Participants may continue study treatment indefinitely until disease progression unacceptable toxicity, withdrawal, or study closure; whichever comes first.

ASTX727 is already approved in United States, European Union for the following indications:

Approved in United States as Inqovi for:

• Myelodysplastic Syndromes (MDS)

Approved in European Union as Inqovi for:

• Myelodysplastic Syndromes (MDS)

Who Is Running the Clinical Trial?

Pamela Munster

Lead Sponsor

Trials

8

Recruited

180+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

PARP inhibitors, like olaparib, have shown promising efficacy in treating ovarian cancer, particularly in patients with BRCA mutations, where 28% of patients achieved an objective response, and also in 'BRCAness' patients who lack BRCA mutations but have similar DNA repair deficiencies.

The ongoing research aims to better identify 'BRCAness' patients and optimize treatment regimens involving PARP inhibitors, including their combination with other therapies, to enhance clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on PARP1 inhibitors in ovarian cancer. Sessa, C.[2020]

The study developed an antisense strategy to downregulate BRCA2 in tumor cells, which sensitized them to the PARP-1 inhibitor olaparib, effectively increasing the drug's efficacy against tumors that are typically resistant due to functional homologous recombination repair (HRR).

Combining BRCA2 inhibition with olaparib treatment not only prevented the emergence of resistant HRR-proficient cells but also significantly reduced tumor growth in ovarian cancer models in mice, suggesting a promising approach to enhance the effectiveness of olaparib in diverse cancer populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reciprocal positive selection for weakness - preventing olaparib resistance by inhibiting BRCA2. Rytelewski, M., Maleki Vareki, S., Mangala, LS., et al.[2023]

A phase II study of the PARP inhibitor olaparib confirmed its clinical benefits for cancer patients with inherited BRCA1 and BRCA2 mutations, particularly in advanced breast and ovarian cancers.

The study also provided evidence that olaparib is effective against pancreatic and prostate cancers, expanding its potential use in treating various cancer types associated with these genetic mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib shows promise in multiple tumor types. [2014]

Olaparib and talazoparib, both PARP inhibitors, have been approved for treating breast cancer in patients with BRCA mutations, showing significant benefits in progression-free survival compared to chemotherapy in phase 3 trials.

PARP inhibitors are being explored for broader applications, including early-stage breast cancer and combinations with immune checkpoint inhibitors, highlighting their potential beyond just advanced cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Overview of PARP Inhibitors for the Treatment of Breast Cancer. Cortesi, L., Rugo, HS., Jackisch, C.[2023]

Olaparib is particularly effective for patients with BRCA-mutated ovarian cancer, but it also benefits a subset of patients with BRCA wild-type tumors that have loss-of-function mutations in DNA repair genes, showing similar treatment outcomes.

The study suggests that patients with specific HRR gene mutations, even without BRCA mutations, can be identified as a group that may respond well to olaparib, indicating a potential for broader use of this treatment in ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes. Hodgson, DR., Dougherty, BA., Lai, Z., et al.[2020]

PARP inhibitors, such as olaparib and talozaparib, are effective treatments for advanced breast cancer in patients with germline BRCA 1 or BRCA 2 variants, showing improved progression-free survival compared to standard treatments in phase III trials.

These medications work by inducing synthetic lethality in cancer cells with impaired DNA damage repair, specifically targeting the vulnerabilities created by these genetic mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perspectives on PARP inhibitors as pharmacotherapeutic strategies for breast cancer. Oh, SY., Rahman, S., Sparano, JA.[2022]

In a phase 3 trial involving 295 patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation, olaparib significantly improved median progression-free survival to 19.1 months compared to 5.5 months for placebo, indicating its efficacy as a maintenance treatment.

While olaparib was associated with higher rates of grade 3 or worse adverse events like anemia (19% vs 2% in placebo), most toxicities were manageable and did not negatively impact the patients' quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Pujade-Lauraine, E., Ledermann, JA., Selle, F., et al.[2022]

Olaparib, a PARP inhibitor, has received FDA approval as the first treatment of its kind for fourth-line therapy in patients with ovarian cancer that has germline BRCA1/2 mutations, marking a significant advancement in cancer treatment.

The drug works by exploiting the vulnerabilities of cancer cells with DNA repair deficiencies, leading to cell death through a mechanism known as synthetic lethality, particularly effective in high-grade serous ovarian carcinomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of Olaparib for BRCA-Deficient Recurrent Epithelial Ovarian Cancer. Tewari, KS., Eskander, RN., Monk, BJ.[2022]

In a study of 24 patients with various tumor types and BRCA1/2 mutations, 58% experienced clinical benefit from olaparib treatment, indicating its efficacy in this patient population.

Whole-genome sequencing (WGS) helped identify additional oncogenic drivers in some patients who developed resistance to olaparib, suggesting that understanding tumor genetics can enhance treatment strategies and outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patients with Biallelic BRCA1/2 Inactivation Respond to Olaparib Treatment Across Histologic Tumor Types. van der Wijngaart, H., Hoes, LR., van Berge Henegouwen, JM., et al.[2022]

In preclinical models of BRCA1/2-mutated breast and ovarian cancers, combining olaparib (a PARP inhibitor) with PSPC1 small interfering RNA (siRNA) significantly enhanced the sensitivity of cancer cells to treatment, leading to greater anti-proliferative effects.

Mechanistically, the combination therapy increased DNA double-strand breaks and induced apoptosis by disrupting the DNA damage response, suggesting that targeting PSPC1 could be a promising strategy to overcome resistance to PARP inhibitors like olaparib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PSPC1 Inhibition Synergizes with Poly(ADP-ribose) Polymerase Inhibitors in a Preclinical Model of BRCA-Mutated Breast/Ovarian Cancer. Ghosh, M., Kang, MS., Katuwal, NB., et al.[2023]

References

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

Update on PARP1 inhibitors in ovarian cancer. [2020]

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

Reciprocal positive selection for weakness - preventing olaparib resistance by inhibiting BRCA2. [2023]

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

Olaparib shows promise in multiple tumor types. [2014]

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

An Overview of PARP Inhibitors for the Treatment of Breast Cancer. [2023]

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

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes. [2020]

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

Perspectives on PARP inhibitors as pharmacotherapeutic strategies for breast cancer. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. [2022]

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

Development of Olaparib for BRCA-Deficient Recurrent Epithelial Ovarian Cancer. [2022]

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

Patients with Biallelic BRCA1/2 Inactivation Respond to Olaparib Treatment Across Histologic Tumor Types. [2022]

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

PSPC1 Inhibition Synergizes with Poly(ADP-ribose) Polymerase Inhibitors in a Preclinical Model of BRCA-Mutated Breast/Ovarian Cancer. [2023]