What is the mechanism of action of this treatment?

Antibody-Drug Conjugates (ADCs) and PARP inhibitors are pivotal in treating solid tumors due to their targeted mechanisms of action. ADCs, like DS-8201a, use an antibody to deliver a cytotoxic drug directly to tumor cells expressing specific antigens (e.g., HER2), thereby sparing normal cells and reducing side effects. PARP inhibitors, such as Olaparib, block the PARP enzyme essential for DNA repair, causing cancer cells with DNA repair deficiencies to accumulate damage and die. These targeted therapies enhance treatment efficacy and minimize collateral damage, offering significant benefits for solid tumor patients.

What side effects are associated with this type of intervention?

The most common side effects of treatments for solid tumors, particularly those similar to DS-8201a (an antibody-drug conjugate targeting HER2) and Olaparib (a PARP inhibitor), include nausea, fatigue, and hematologic toxicities such as anemia and neutropenia. These treatments may also cause other non-hematologic side effects like vomiting and anorexia. Managing these side effects often involves dose modifications and supportive care.

What prior FDA approvals exist?

The FDA has approved several treatments for solid tumors that are similar to DS-8201a and Olaparib. DS-8201a, known as trastuzumab deruxtecan, is an antibody-drug conjugate targeting HER2 and has been approved for HER2-positive breast cancer. Olaparib, a PARP inhibitor, has been approved for BRCA-mutated ovarian, breast, pancreatic, and prostate cancers. These drugs work by targeting specific proteins involved in tumor growth and DNA repair, offering targeted treatment options for patients with these genetic profiles.

What other types of research exist?

Promising alternatives to DS-8201a and Olaparib for solid tumors include: 1) Trastuzumab Deruxtecan (another HER2-targeting ADC), 2) Talazoparib (another PARP inhibitor), 3) Niraparib (a PARP inhibitor showing efficacy in HRR-deficient cancers), and 4) Pembrolizumab (an immune checkpoint inhibitor for tumors with high mutational burden). These therapies are in advanced stages of clinical trials or have shown significant efficacy in specific solid tumors.

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Antibody-drug Conjugate

DS-8201a + Olaparib for Endometrial Cancer

Phase 1

Waitlist Available

Led By Jennifer L Veneris

Research Sponsored by National Cancer Institute (NCI)

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Patients must have archival FFPE tissue available for central confirmation of HER2 testing

Dose Escalation and Dose Expansion Phases: Patients must have had at least one prior line of cytotoxic chemotherapy

Must not have

Patients with unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to grade =< 1 or baseline

Patients with a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 42 days

Awards & highlights

No Placebo-Only Group

Summary

This trial tests the safety and best dose of two drugs, DS-8201a and olaparib, in patients with certain advanced cancers. DS-8201a targets and kills cancer cells with a specific protein, and olaparib stops cancer cells from fixing their DNA. The goal is to see if these drugs can shrink or control the cancer.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Potential side effects include reactions related to the immune system attacking normal organs due to the antibody component of DS-8201a; damage from blocked DNA repair mechanisms caused by olaparib; fatigue; blood disorders; increased risk of infection; as well as specific risks associated with each drug.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I have a preserved tissue sample for HER2 testing.

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I have had at least one round of chemotherapy before.

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I have a confirmed diagnosis of uterine serous carcinoma and at least one tumor that can be safely biopsied.

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My tumor is HER2-positive, confirmed by a certified lab.

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I have a preserved tissue sample available for HER2 testing.

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My hepatitis C is cured or currently undetectable.

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I agree to use effective birth control during and for 7 months after the study.

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I am a woman who cannot become pregnant due to surgery or menopause.

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I am 18 years old or older.

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I have received chemotherapy before.

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My hepatitis B virus load is undetectable with treatment.

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I am mostly able to care for myself and perform daily activities.

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My cancer is advanced, cannot be surgically removed, and standard treatments are not effective.

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My cancer is advanced, cannot be surgically removed, and standard treatments are not effective.

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My cancer can be measured or evaluated using specific criteria.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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

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

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I haven't had a heart attack or severe heart failure in the last 6 months.

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I have severe lung problems due to other illnesses or autoimmune conditions.

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I have not had radiation therapy in the last 4 weeks.

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I have previously taken PARP inhibitors.

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I haven't taken chloroquine or hydroxychloroquine in the last 14 days.

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I had major surgery less than 4 weeks ago.

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I do not have an infection needing IV drugs.

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I am not taking any strong or moderate drugs that affect liver enzymes.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 30 days post treatment

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 30 days post treatment

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 30 days post treatment for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Maximum tolerated dose/recommended phase 2 dose

Secondary study objectives

Clinical benefit rate (CBR)

Duration of response (DOR)

Markers of deoxyribonucleic acid (DNA) damage response (DDR)

+2 more

Other study objectives

Biomarkers of response and resistance

Changes in HER2 expression

Formation of TOP1cc in tumor specimens

+2 more

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

1Treatment groups

Experimental Treatment

Group I: Treatment (trastuzumab deruxtecan, olaparib)Experimental Treatment6 Interventions

Patients receive trastuzumab deruxtecan IV over 30-90 minutes on day 1 and olaparib PO BID on days 1-21 or days 8-14 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients taking olaparib BID on days 1-21 undergo collection of blood samples at the following times: baseline, days 1, 2, 8, and 15 of cycle 1, day 1 of cycle 2, days 1, 8, and 15 of cycle 3, day 1 of cycle 4, day 1 of every fourth cycle after cycle 4 and then at treatment end. Patients taking olaparib BID on days 8-14 undergo collection of blood samples at the following times: baseline, days 1, 2, 8, 9, and 15 of cycle 1, days 1 and 8 of cycle 2, days 1, 8, and 15 of cycle 3, day 1 of cycle 4, day 1 of every fourth cycle after that, and at treatment end. Patients undergo biopsy at baseline, and then on day 3 or day 10 of cycle 1. Patients also undergo echocardiography and CT throughout the trial.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Echocardiography

2013

Completed Phase 4

~11580

Trastuzumab Deruxtecan

2021

Completed Phase 2

~100

Olaparib

2007

Completed Phase 4

~2190

Biopsy

2014

Completed Phase 4

~1090

Biospecimen Collection

2004

Completed Phase 3

~2020

Computed Tomography

2017

Completed Phase 2

~2740

0 / 25Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Antibody-Drug Conjugates (ADCs) and PARP inhibitors are pivotal in treating solid tumors due to their targeted mechanisms of action. ADCs, like DS-8201a, use an antibody to deliver a cytotoxic drug directly to tumor cells expressing specific antigens (e.g., HER2), thereby sparing normal cells and reducing side effects. PARP inhibitors, such as Olaparib, block the PARP enzyme essential for DNA repair, causing cancer cells with DNA repair deficiencies to accumulate damage and die. These targeted therapies enhance treatment efficacy and minimize collateral damage, offering significant benefits for solid tumor patients.