DS-8201a + Olaparib for Endometrial Cancer

Recruiting at 4 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Interstitial lung disease, Severe pulmonary compromise, Myocardial infarction, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 42 days

55 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks to determine the optimal dose and understand the side effects of combining two treatments, DS-8201a (an experimental treatment) and olaparib, for endometrial cancer that has spread or cannot be surgically removed, and for ovarian cancer unresponsive to platinum treatments. Olaparib blocks an enzyme that aids cancer cell repair, while DS-8201a targets cancer cells with the HER2 protein, delivering chemotherapy directly to them. Individuals with HER2-positive tumors or ovarian cancer resistant to platinum treatment may be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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, you cannot take medications that are moderate or strong inhibitors or inducers of CYP3A, and if you are taking chloroquine or hydroxychloroquine, you will need a 14-day washout period (time without taking these medications) before joining the study.

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

Research has shown that trastuzumab deruxtecan (also known as DS-8201a) is generally safe and may help treat cancers with HER2 proteins, such as some breast and stomach cancers. However, some patients have experienced side effects, including interstitial lung disease (ILD).

Olaparib, another drug in this study, is commonly used and usually well-tolerated. In past studies, some patients experienced side effects like nausea or tiredness, but these were mostly mild to moderate.

This study is in its early stages (Phase 1), focusing on learning more about the safety and optimal dosage of these drugs when used together. While previous studies provide insights into safety, different combinations and conditions can lead to varying effects. Discussing participation with a healthcare provider is important to determine if joining this trial is suitable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments DS-8201a (trastuzumab deruxtecan) and olaparib for endometrial cancer because they offer a novel approach compared to existing therapies. Unlike traditional chemotherapy or hormone therapies, trastuzumab deruxtecan is an antibody-drug conjugate that specifically targets cancer cells with HER2 expression and delivers a potent chemotherapy agent directly to them, minimizing impact on healthy cells. Olaparib is a PARP inhibitor that interferes with cancer cell repair mechanisms, potentially enhancing the effectiveness of other treatments. Together, these treatments could provide a more targeted and effective treatment option for endometrial cancer, offering hope for better outcomes.

What evidence suggests that DS-8201a and olaparib might be effective for endometrial cancer?

Research has shown that Trastuzumab Deruxtecan (DS-8201a) effectively treats cancers expressing HER2, with 57.5% of patients experiencing tumor shrinkage or halted growth. In this trial, participants will receive a combination of Trastuzumab Deruxtecan and Olaparib. Olaparib helps prevent cancer from growing after initial treatments and has been shown to double the time cancer remains under control compared to chemotherapy. Together, these treatments target specific functions of cancer cells to shrink or stabilize the cancer. ^{3 4 6 7 8}

Who Is on the Research Team?

Elizabeth K Lee

Principal Investigator

Dana-Farber - Harvard Cancer Center LAO

Are You a Good Fit for This Trial?

This trial is for adults with HER2-expressing cancers that are advanced or can't be surgically removed, and specifically includes those with endometrial cancer. Participants must have tried at least one chemotherapy before, have a good performance status, and meet certain health criteria like normal organ function tests. Pregnant women, patients with recent heart attacks or uncontrolled infections, and those on certain drugs are excluded.

Inclusion Criteria

I have a preserved tissue sample for HER2 testing.

AST/ALT =< 3 x institutional ULN (within 14 days of randomization/enrollment)

INR/PT and aPTT =< 1.5 x ULN (within 14 days of randomization/enrollment)

Exclusion Criteria

You have experienced allergic reactions to similar drugs or compounds like DS-8201a, olaparib or monoclonal antibodies.

I have side effects from cancer treatment that haven't improved to mild or gone back to how they were before treatment.

I have or had lung inflammation that needed steroids, or it can't be ruled out by scans.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive trastuzumab deruxtecan IV and olaparib PO in cycles of 21 days, with blood samples, ECHO or MUGA, and CT scans conducted throughout the trial

Up to 42 days

Multiple visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

30 days

What Are the Treatments Tested in This Trial?

Interventions

• DS-8201a
• Olaparib

Trial Overview

The trial is testing the combination of DS-8201a (an antibody-drug conjugate targeting HER2-positive tumor cells) and olaparib (a drug blocking enzymes involved in DNA repair), to see if they can shrink or stabilize these cancers. It's a phase I study to determine side effects and optimal dosages.

How Is the Trial Designed?

Group I: Treatment (trastuzumab deruxtecan, olaparib) Experimental Treatment 7 Interventions

Patients receive trastuzumab deruxtecan IV over 30-90 minutes on day 1 and olaparib PO BID on days 1-21, days 8-14, or days 3-9 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. All patients undergo collection of blood samples, ECHO or MUGA, CT, and biopsies throughout the trial.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Olaparib is an oral medication that inhibits poly (ADP-ribose) polymerase and is primarily developed for treating BRCA mutation-positive ovarian cancer, with its capsule formulation already approved in the EU and USA.

The drug is currently undergoing extensive clinical trials for various cancers, including breast, gastric, and pancreatic cancers, indicating its potential broad application in oncology beyond ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: first global approval. Deeks, ED.[2020]

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]

Olaparib is an effective oral treatment for patients with BRCA mutation-positive ovarian cancer, approved for maintenance therapy after platinum-based chemotherapy, showing good tolerability with common side effects like nausea, fatigue, and anemia being mild to moderate.

Long-term monitoring is recommended due to a low risk of serious hematological complications, such as anemia and myelodysplastic syndrome, ensuring patient safety during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation of olaparib for treating ovarian cancer. Lheureux, S., Bowering, V., Karakasis, K., et al.[2015]

Olaparib is an effective treatment for patients with platinum-sensitive, relapsed BRCA-mutated high-grade serous ovarian cancer, showing significant improvement in progression-free survival compared to placebo in a study of 265 patients.

The treatment is generally well tolerated, with most side effects being mild to moderate, although fatigue, anemia, and neutropenia were noted as more severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: a review of its use as maintenance therapy in patients with ovarian cancer. Frampton, JE.[2016]

The OPINION study is evaluating the safety and efficacy of olaparib as a maintenance therapy for women with high-grade serous or endometrioid platinum-sensitive relapsed ovarian cancer who do not have BRCA mutations, involving patients who have undergone at least two prior lines of platinum-based chemotherapy.

The primary goal of the study is to assess progression-free survival, which will help determine how effective olaparib is in delaying cancer progression in this specific patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib maintenance monotherapy in platinum-sensitive, relapsed ovarian cancer without germline BRCA mutations: OPINION Phase IIIb study design. Poveda, AM., Davidson, R., Blakeley, C., et al.[2020]

Olaparib is a powerful inhibitor of PARP-1 and PARP-2, showing effectiveness in treating ovarian cancer, particularly in patients with germline BRCA mutations.

Phase III trials are currently evaluating olaparib's efficacy as a maintenance therapy after initial treatment in patients with BRCA mutations, highlighting its potential role in long-term cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: an oral PARP-1 and PARP-2 inhibitor with promising activity in ovarian cancer. Gunderson, CC., Moore, KN.[2016]

Olaparib (Lynparza) is approved for treating adult patients with high-risk early breast cancer that has a germline BRCA mutation, following chemotherapy treatment.

This approval highlights Olaparib's role as an adjuvant therapy, which means it is used after initial treatments to help prevent cancer recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Adjuvant Treatment for High-Risk Early Breast Cancer. Aschenbrenner, DS.[2022]

Olaparib, a PARP inhibitor, showed a 36% objective response rate in women with relapsed ovarian cancer and a germline BRCA1/2 mutation, even after they had undergone multiple lines of chemotherapy, indicating its efficacy in this challenging patient population.

The median duration of response to olaparib was 7.4 months, and the safety profile was consistent across patients who had received three or more lines of prior chemotherapy, with similar rates of serious adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety. Matulonis, UA., Penson, RT., Domchek, SM., et al.[2022]

A 50-year-old woman with stage IVB poorly differentiated endometrial cancer experienced a significant clinical complete response after receiving the PARP inhibitor Olaparib, following the identification of a BRIP1 mutation.

This case represents the first documented instance of a pathologic complete response in high-grade endometrioid endometrial cancer treated with a PARP inhibitor, highlighting the potential for targeted therapies in cases with specific genetic mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complete Pathologic Response to PARP Inhibitor Olaparib in a Patient with Stage IVB Recurrent Endometrioid Endometrial Adenocarcinoma. Senguttuvan, RN., Wei, C., Raoof, M., et al.[2023]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11622448/

Real-world evidence of Trastuzumab Deruxtecan (T-DXd) ...

Trastuzumab-Deruxtecan (T-DXd) has shown substantial efficacy in HER2 overexpressing carcinomas, most prominently in ovarian, endometrial and cervical patients.

2.

sciencedirect.com

sciencedirect.com/science/article/pii/S2352578925002991

Successful treatment of gynecologic malignancy with ...

The objective response rate (ORR) was 57.5 % for endometrial cancer patients, 50.0 % for cervical cancer patients, and 45.0 % for ovarian cancer ...

3.

aacrjournals.org

aacrjournals.org/clincancerres/article/29/12/2239/727075/Co-Clinical-Study-of-fam-Trastuzumab-Deruxtecan

Co-Clinical Study of [fam-] Trastuzumab Deruxtecan ...

Remarkable tumor shrinkage was observed in four of the six PDXs (67%), comparable with the response rate in the STATICE trial. Two patients enrolled in the ...

4.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.23.02005

Efficacy and Safety of Trastuzumab Deruxtecan in Patients ...

Our study demonstrates durable clinical benefit, meaningful survival outcomes, and safety consistent with the known profile (including ILD) in pretreated ...

5.

daiichisankyo.us

daiichisankyo.us/press-releases/-/article/destiny-endometrial01-phase-3-trial-of-enhertu-initiated-as-first-line-therapy-in-patients-with-her2-expressing-primary-advanced-or-recurrent-endometrial-cancer

DESTINY-Endometrial01 Phase 3 Trial of ENHERTU® ...

Endometrial cancer that is recurrent or diagnosed in advanced stages has a median overall survival of up to 30 months. While there have been ...

6.

sciencedirect.com

sciencedirect.com/science/article/pii/S1048891X24118695

PO007LBA/#1550 Efficacy and safety of trastuzumab ...

Trastuzumab deruxtecan (T-DXd) has demonstrated significant survival benefit for patients with HER2-expressing breast and gastric cancers.

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11480158/

Efficacy of Trastuzumab Deruxtecan in HER2-Expressing ...

In patients with IHC 2+ tumors, investigator-assessed ORR was 26.5% (95% CI 19.6, 34.3), and median DOR was 9.8 months (95% CI 4.5, 12.6).

8.

ejgo.org

ejgo.org/src/2024-ASGO/0108.pdf

Efficacy and safety of trastuzumab deruxtecan in patients ...

Conclusion: T-DXd demonstrated durable responses and encouraging survival outcomes in gynecological cohorts, alongside responses across HER2 expression levels, ...