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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination treatment for individuals with advanced solid tumors and specific genetic mutations, such as BRCA1 or BRCA2. The treatment combines two drugs, olaparib (Lynparza) and ASTX727 (Decitabine/Cedazuridine), to determine if they are more effective together against these cancers. Suitable participants have a prior diagnosis of advanced solid tumors and specific genetic mutations. They must also be able to take oral medication and have not experienced serious side effects from similar treatments in the past. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this new combination therapy.

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.

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

Research has shown that olaparib, a drug used for some cancers with BRCA mutations, is generally safe. Some patients have experienced side effects like nausea and tiredness, but these are usually manageable. The main goal of combining it with ASTX727 is to determine if the two drugs can work better together to kill more cancer cells.

The combination is still being tested to assess its tolerability. Researchers are monitoring for any bothersome side effects. Since this trial is in an early stage, the primary aim is to ensure the treatment's safety and to find the best dose for future studies. Evidence from similar studies suggests that this combination could be safe, but more information is needed to confirm this. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Olaparib and ASTX727 for treating BRCA mutations because they target cancer cells at the genetic level. Unlike traditional chemotherapy, which attacks rapidly dividing cells indiscriminately, Olaparib is a PARP inhibitor that specifically disrupts cancer cell DNA repair mechanisms, potentially leading to cancer cell death while sparing healthy cells. ASTX727, a novel oral formulation combining decitabine and cedazuridine, enhances the effectiveness of DNA-targeting treatments by inhibiting DNA methylation. This combination could offer a more targeted and potentially less toxic alternative to existing treatments for patients with BRCA mutations.

What evidence suggests that this trial's treatments could be effective for BRCA mutations?

Research has shown that olaparib, a PARP inhibitor, effectively treats cancers with BRCA gene changes. It can slow tumor growth in individuals with these genetic alterations. In this trial, participants will receive a combination of olaparib and ASTX727. Studies suggest that combining olaparib with ASTX727 might enhance its effectiveness, leading to increased cancer cell death. ASTX727 contains decitabine, which can make cancer cells more responsive to treatment. Early results indicate that this combination is generally safe, with manageable side effects such as nausea and tiredness. This evidence supports the potential effectiveness of this treatment for patients with advanced cancers and specific genetic changes. ^{2 3 4 5 6}

Who Is on the Research Team?

Pamela Munster

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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 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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06177171

NCT06177171 | Olaparib and ASTX727 in BRCA1/2 ... To evaluate the preliminary efficacy of the recommended dose level of olaparib and ASTX727 in patients with solid tumor malignancies and germline or somatic ...

2. withpower.com withpower.com/trial/phase-1-atm-gene-mutation-3-2024-6c385

Olaparib + ASTX727 for BRCA Mutations 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.

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-10542

Olaparib and ASTX727 for the Treatment of Patients with ... Olaparib in combination with ASTX727 may kill more tumor cells in patients with BRCA 1/2 and HRD mutated advanced tumors.

4. researchgate.net researchgate.net/publication/392303669_A_phase_IIb_study_of_olaparib_and_ASTX727_in_BRCA_12-_and_HRD-mutated_tumors

A phase I/Ib study of olaparib and ASTX727 in BRCA 1/2 This phase I study aims to assess the safety and tolerability of olaparib and AST727 in HRR-mutated patients and establish the RP2D for a phase ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9047307/

Perspectives on PARP inhibitors as pharmacotherapeutic ... Several studies have evaluated efficacy of platinum in patients with germline BRCA mutations. A phase 2 trial showed 80% response rate among 20 patients with ...

6. clinicaltrials.ucsf.edu clinicaltrials.ucsf.edu/trial/NCT06177171

Olaparib and ASTX727 in BRCA1/2- and Homologous ... To assess the safety and tolerability of olaparib and ASTX7272 in patients with advanced solid tumors and germline or somatic mutations in the ...