Ceralasertib + Trastuzumab Deruxtecan for Solid Tumors

Recruiting at 28 trial locations

Overseen By Babar Bashir

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors, Chloroquine

Disqualifiers: Interstitial lung disease, Myocardial infarction, Uncontrolled infection, others

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

Compensation: Varies

Number of Visits: 5

51 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of two drugs, ceralasertib (a potential cancer treatment) and trastuzumab deruxtecan, to determine their safety and effectiveness in treating certain advanced cancers. The focus is on cancers with a specific change in the HER2 gene or protein, such as colorectal and gastroesophageal cancers, that have metastasized. Participants should have these cancer types and have already tried standard treatments without success. The goal is to find the optimal dose and assess whether this combination works better than trastuzumab deruxtecan alone. As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants a 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 requires a washout period (time without taking certain medications) for some treatments before starting the study. Specifically, you must stop taking strong CYP3A inhibitors and certain other medications for a specified time before enrollment. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that ceralasertib, when used alone, is generally well-tolerated by patients. In previous studies, some individuals experienced mild side effects such as fatigue and nausea, but serious issues were rare. Studies have also found trastuzumab deruxtecan to be safe for patients. It is approved for treating certain cancers, indicating its well-established safety. Common side effects include nausea and low blood cell counts, but most patients manage these effectively. Both treatments have shown promise in treating advanced solid tumors, making them potential options for future therapies. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Ceralasertib combined with Trastuzumab Deruxtecan because they offer a novel approach to treating solid tumors like gastroesophageal and colorectal cancers. Unlike standard chemotherapy, which attacks all rapidly dividing cells, this combination targets cancer cells more precisely. Trastuzumab Deruxtecan is an antibody-drug conjugate that delivers chemotherapy directly to cancer cells, while Ceralasertib inhibits a specific enzyme involved in DNA repair, potentially enhancing the effectiveness of Trastuzumab Deruxtecan. This targeted strategy may lead to fewer side effects and improved outcomes compared to traditional treatments.

What evidence suggests that this trial's treatments could be effective for advanced solid tumors with HER2 mutation?

Studies have shown that trastuzumab deruxtecan effectively targets and destroys cancer cells with the HER2 protein by attaching to these cells and delivering a chemotherapy drug directly to them. Ceralasertib may enhance this effect by blocking enzymes that aid cancer cell growth. Previous patients demonstrated promising results with trastuzumab deruxtecan, particularly for HER2-positive cancers. In this trial, participants will receive a combination of trastuzumab deruxtecan and ceralasertib, which remains under study. The mechanism of these drugs suggests they could form a powerful pair against advanced solid tumors with HER2 mutations. ^{1 4 6 7 8}

Who Is on the Research Team?

Kanwal P. Raghav

Principal Investigator

University of Texas MD Anderson Cancer Center LAO

Are You a Good Fit for This Trial?

Adults with advanced solid tumors expressing HER2, who've tried at least one chemotherapy, can join this trial. They must have a measurable tumor and be able to undergo biopsies. Key health requirements include proper liver and kidney function, controlled HIV if present, no severe heart issues or lung disease like ILD/pneumonitis, and not pregnant.

Inclusion Criteria

Must have life expectancy of at least 3 months

Patients must have a biopsiable lesion and provide consent for on treatment biopsy

I am fully active or restricted in physically strenuous activity but can do light work.

Exclusion Criteria

Patients with psychiatric illness/social situations that would limit compliance with study requirements

You have had strong allergic reactions to the drug or its inactive parts in the past.

Patients with substance abuse or any other medical conditions that would increase the safety risk to the subject or interfere with participation of the subject or evaluation of the clinical study in the opinion of the investigator

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Evaluate safety, tolerability, and recommended phase 2 dose of trastuzumab deruxtecan in combination with ceralasertib in advanced solid tumors with HER2 expression.

21 days per cycle

1 visit per cycle (in-person)

Dose Expansion

Assess differential pharmacodynamic profile of tumor tissue between Top1 inhibition and dual inhibition of Top1 and ATR in patients with colorectal and gastroesophageal cancer with HER2 expression.

21 days per cycle

1 visit per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

5 years

Every 3 months for 2 years, then every 6 months for 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Ceralasertib
• Trastuzumab Deruxtecan

Trial Overview The DASH trial is testing the combination of two drugs: DS-8201a (trastuzumab deruxtecan) which targets HER2 cancer cells with attached chemo drug deruxtecan; and AZD6738 (ceralasertib), which may halt tumor growth by blocking certain enzymes. The study has two phases to determine safety and compare responses in colorectal/gastroesophageal cancers.

How Is the Trial Designed?

Group I: Treatment (trastuzumab deruxtecan, ceralasertib) Experimental Treatment 8 Interventions

Patients receive trastuzumab deruxtecan IV over 30-90 minutes on day 1 of each cycle and ceralasertib PO BID on days 1-7 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. NOTE: During the dose-expansion phase, the first 6 patients in each disease cohort (gastroesophageal cancer \[cohort A\] and colorectal cancer \[cohort B\]) receive only trastuzumab deruxtecan for the first cycle, followed by trastuzumab deruxtecan and ceralasertib together in subsequent cycles. Additionally, patients undergo tissue biopsy on study and blood sample collection, CT or PET/CT and ECHO or MUGA throughout the study.

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

In a phase 1 trial involving 115 patients with HER2-positive breast cancer previously treated with trastuzumab emtansine, trastuzumab deruxtecan demonstrated a manageable safety profile, with 59.5% of patients achieving a confirmed objective response.

Despite some serious treatment-emergent adverse events, including cases of interstitial lung disease and pneumonitis, the preliminary efficacy results suggest that trastuzumab deruxtecan is a promising treatment option, warranting further investigation in larger clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study. Tamura, K., Tsurutani, J., Takahashi, S., et al.[2020]

In a phase 1 trial involving 44 patients with HER2-positive gastric or gastro-oesophageal junction cancer, trastuzumab deruxtecan demonstrated a manageable safety profile, with the most common serious side effects being anemia and decreases in blood cell counts, but no drug-related deaths were reported.

The treatment showed promising preliminary activity, with 43.2% of patients achieving a confirmed objective response, indicating its potential effectiveness in patients who had previously been treated with trastuzumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study. Shitara, K., Iwata, H., Takahashi, S., et al.[2020]

In a phase 2 study involving 184 patients with HER2-positive metastatic breast cancer who had previously been treated with trastuzumab emtansine, trastuzumab deruxtecan demonstrated a significant response rate of 60.9%, with a median response duration of 14.8 months.

While trastuzumab deruxtecan showed promising efficacy, it was associated with notable adverse effects, including interstitial lung disease in 13.6% of patients, highlighting the need for careful monitoring of pulmonary symptoms during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. Modi, S., Saura, C., Yamashita, T., et al.[2021]

Trastuzumab deruxtecan (ENHERTU®) is an innovative treatment that combines an antibody targeting HER2 with a DNA topoisomerase I inhibitor, specifically designed for HER2-expressing solid tumors, including various types of cancer.

It received accelerated approval in the USA based on the promising results from the phase 2 DESTINY-Breast01 trial, which focused on patients with advanced HER2-positive breast cancer who had already undergone multiple treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: First Approval. Keam, SJ.[2020]

Trastuzumab deruxtecan (Enhertu®) has been shown to significantly improve progression-free survival in adults with unresectable or metastatic HER2-positive breast cancer compared to the previous standard treatment, trastuzumab emtansine, in a pivotal phase 3 trial.

The treatment has a generally manageable safety profile, although it is associated with common adverse events like hematological and gastrointestinal disorders, and requires careful monitoring for interstitial lung disease (ILD)/pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: A Review in Unresectable or Metastatic HER2-Positive Breast Cancer. Nie, T., Blair, HA.[2023]

Trastuzumab deruxtecan (Enhertu®) has been shown to be significantly more effective than standard chemotherapy in improving overall survival and achieving objective responses in adults with advanced HER2-positive gastric or gastro-oesophageal junction adenocarcinoma, based on results from the phase II DESTINY-Gastric01 trial.

The treatment is generally well-tolerated, with common side effects including nausea and fatigue, but it does carry important safety warnings for interstitial lung disease and embryo-foetal toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: A Review in Gastric or Gastro-Oesophageal Junction Adenocarcinoma. Kang, C.[2023]

Trastuzumab deruxtecan has shown efficacy in treating patients with unresectable or metastatic HER2-mutated non-small-cell lung cancer (NSCLC), as demonstrated in the DESTINY-Lung01 and DESTINY-Lung02 trials.

This report presents the first case of a patient with metastatic HER2-amplified NSCLC who achieved a durable response to trastuzumab deruxtecan, suggesting potential effectiveness in this specific patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metastatic HER2-amplified non-small-cell lung cancer treated with trastuzumab deruxtecan. Yun, KM., Bazhenova, L.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04704661

Study Details | NCT04704661 | Testing the Combination of ... Ceralasertib and trastuzumab deruxtecan may be safe, tolerable and effective in treating patients with advanced solid tumors expressing the HER2 protein or gene ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04704661

Study Details | NCT04704661 | Testing the Combination of ... Ceralasertib and trastuzumab deruxtecan may be safe, tolerable and effective in treating patients with advanced solid tumors expressing the HER2 protein or gene ...

3. clinicaltrials.gov clinicaltrials.gov/ct2/show/study/NCT04704661

Testing the Combination of Two Anti-cancer Drugs, DS ... Ceralasertib and trastuzumab deruxtecan may be safe, tolerable and effective in treating patients with advanced solid tumors expressing the HER2 protein or gene ...

4. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2021-0017.html

10358; Phase 1/1B Study of DS-8201a in Combination with ... Ceralasertib and trastuzumab deruxtecan may be safe, tolerable and effective in treating patients with advanced solid tumors expressing the HER2 protein or gene ...

5. withpower.com withpower.com/trial/phase-1-carcinoma-2-2021-79b08

Ceralasertib + Trastuzumab Deruxtecan for Solid Tumors Trastuzumab attaches to HER2 positive cancer cells in a targeted way and delivers deruxtecan to kill them. Ceralasertib and trastuzumab deruxtecan may be safe, ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35790315/

Phase II study of ceralasertib (AZD6738) in combination ... Ceralasertib plus durvalumab has promising antitumor activity, with durable responses in patients with refractory AGC. Thus, a biomarker-driven trial is ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9401487/

Ceralasertib (AZD6738), an Oral ATR Kinase Inhibitor, in ... This study reports the safety, tolerability, MTD, recommended phase II dose (RP2D), pharmacokinetic/pharmacodynamic profile, and preliminary antitumor activity

8. aacrjournals.org aacrjournals.org/cancerres/article/84/7_Supplement/CT222/742542/Abstract-CT222-Efficacy-and-safety-of-ceralasertib

Abstract CT222: Efficacy and safety of ceralasertib in the ... Efficacy and safety of ceralasertib in the PLANETTE study in patients (pts) with ATM-altered advanced solid tumors (ASTs) or metastatic castration-resistant ...