AZD9574 for Advanced Solid Tumors

(CERTIS1 Trial)

Recruiting at 28 trial locations

Overseen By AstraZeneca Breast Cancer Study Locator Service

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: AstraZeneca

Must be taking: PARPi, TMZ

Must not be taking: Antiepileptics, Immunosuppressives

Disqualifiers: Severe pancytopenia, Uncontrolled seizures, Severe brain injury, others

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

Compensation: Varies

Number of Visits: 8

695 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and effectiveness of a new treatment called AZD9574, both alone and with other cancer-fighting drugs, for individuals whose cancer has returned or spread. It targets those with advanced cancers such as breast, ovarian, prostate, pancreatic, and certain brain tumors. Ideal candidates include those with these cancers, particularly if previous treatments have failed and their tumors have specific genetic markers. Participants will receive various combinations and doses of AZD9574 to assess its effectiveness and potential side effects. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive it.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that concurrent use of certain medications is prohibited, so it's best to discuss your current medications with the study team to ensure they are not among the restricted ones.

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

Ongoing research aims to determine the safety of AZD9574, both alone and in combination with other treatments. Currently, detailed safety information about AZD9574 alone in humans is unavailable, which is typical at this research stage.

When combined with T-DXd, studies have shown that T-DXd is generally safe, with no new safety concerns identified. This finding is promising for its use with AZD9574.

For the combination of AZD9574 and TMZ, safety information is limited. However, early lab tests suggest that AZD9574 might reach the brain, which is crucial for treating certain brain tumors.

Regarding AZD9574 and Dato-DXd, specific safety information is not yet available, but ongoing studies will determine their safety and optimal doses.

Overall, these treatments are still under investigation to gather more detailed safety information. Participants should be aware that the full safety profile is not yet established. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about AZD9574 because it offers a novel approach to treating advanced solid tumors by targeting specific genetic mutations like BRCA1, BRCA2, PALB2, RAD51C, and RAD51D. Unlike traditional chemotherapy that broadly attacks all rapidly dividing cells, AZD9574 is a PARP inhibitor, which specifically interferes with cancer cells' ability to repair DNA, leading to their destruction. This targeted action could mean fewer side effects and improved effectiveness for patients with these genetic markers. Additionally, when combined with drugs like T-DXd and TMZ, it has the potential to enhance treatment outcomes by attacking cancer cells from multiple angles.

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

Research has shown that AZD9574 could be a promising cancer treatment. It stops cancer cells from repairing their DNA, increasing the likelihood of cell death. In this trial, participants in different arms will receive AZD9574 with other treatments. For instance, some participants will receive AZD9574 with the chemotherapy drug temozolomide (TMZ), which may enhance TMZ's effectiveness, particularly for certain brain cancers like gliomas. Others will receive AZD9574 combined with T-DXd, which has been effective in treating some types of breast cancer. Additionally, AZD9574 used with Dato-DXd has shown potential in improving survival in some lung cancer cases. These findings suggest that AZD9574 could be a strong option for treating various advanced cancers. ^{1 2 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults with advanced solid tumors that have worsened despite previous treatments. They must be in stable condition, not planning to conceive, and have specific genetic mutations related to cancer growth. People who've had certain prior therapies or severe reactions to similar drugs, uncontrolled diseases, or are unable to take oral medications cannot join.

Inclusion Criteria

I am not breastfeeding and won't donate or use my eggs for 6 months after the study ends.

Participants must be capable of eating a high fat meal and adhering to fasting restrictions

My condition worsened after treatment for advanced cancer and I have no other good treatment options.

Exclusion Criteria

I have had a severe brain injury or stroke.

I cannot take AZD9574 due to severe nausea, vomiting, gut diseases, swallowing issues, or major bowel surgery.

I cannot have MRI with gadolinium or cannot keep my steroid dose stable.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive AZD9574 as monotherapy or in combination with anti-cancer agents in dose-escalation cohorts to assess safety and tolerability.

Cycle 0 (7 days) and Cycle 1 (28 days)

Multiple visits for dose administration and monitoring

Dose Expansion

Participants are enrolled in dose-expansion cohorts to further evaluate safety, tolerability, and preliminary efficacy.

Approximately 3 years

Visits every 8 weeks for assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 3 years

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• AZD9574
• Temozolomide

Trial Overview The study tests AZD9574 alone and combined with other anti-cancer agents (Trastuzumab Deruxtecan, Datopotamab Deruxtecan, Temozolomide) on 490 participants. It aims to evaluate safety and early signs of effectiveness while monitoring how the body processes these drugs.

How Is the Trial Designed?

Group I: Module 5 Part A : Dose escalation (AZD9574 + Dato-DXd) Experimental Treatment 2 Interventions

Participants with advanced, unresectable, or metastatic solid tumours in different types of cancers will receive a combination of AZD9574 and Dato-DXd at escalating cohorts.

Group II: Module 4 Part B : Dose expansion (AZD9574 + T-DXd) Experimental Treatment 2 Interventions

Participants with HER2-low/ultralow, HR positive breast cancer will receive a combination of different doses of AZD9574 and T-DXd at expanding cohorts.

Group III: Module 4 Part A: Dose escalation (AZD9574 + T-DXd) Experimental Treatment 2 Interventions

Participants with advanced, unresectable, or metastatic solid tumours that are HER2-positive will receive a combination of AZD9574 and T-DXd at at escalating cohorts.

Group IV: Module 3 Panel 3: AZD9574 monotherapy (Sweden only) Experimental Treatment 2 Interventions

Participants with breast cancer (without BM).

Group V: Module 3 Panel 2: AZD9574 + TMZ (Sweden only) Experimental Treatment 3 Interventions

Participants with IDH 1/2-mutant glioma who are PARPi naive will receive AZD9574 and TMZ at escalating cohorts.

Group VI: Module 3 Panel 1: AZD9574 monotherapy (Sweden only) Experimental Treatment 2 Interventions

Participants with advanced/relapsed HER2-negative breast, ovarian, prostate, or pancreatic cancer and expressing BRCA1m, BRCA2m, PALB2m, RAD51Cm or RAD51Dm.

Group VII: Module 2 Part A: Dose escalation Experimental Treatment 2 Interventions

Participants with IDH 1/2-mutant glioma who are PARPi naive will receive AZD9574 and TMZ at escalating cohorts.

Group VIII: Module 1 Part B: Dose expansion Experimental Treatment 1 Intervention

Participants with breast cancer who are PARPi naive at doses determined in dose-escalation.

Group IX: Module 1 Part A: Dose escalation Experimental Treatment 1 Intervention

Participants with advanced/relapsed ovarian, breast, pancreatic, or prostate cancer who are deemed suitable for a PARPi will receive AZD9574 monotherapy at escalating cohorts.

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Published Research Related to This Trial

The study confirmed that the generic temozolomide capsules (TOZ039) are bioequivalent to the brand Temodal® capsules, with pharmacokinetic parameters falling within the acceptable range for both 20-mg and 100-mg doses in 29 patients with brain tumors.

The treatment was found to be safe, with no treatment-related severe adverse events or mortality reported, although 82.8% of patients experienced some adverse effects, highlighting the importance of monitoring patient responses during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioequivalence study of 20-mg and 100-mg temozolomide capsules (TOZ309 and Temodal®) in glioma patients in China. Hu, C., Lin, Q., Liu, C., et al.[2021]

Temozolomide (TMZ) is an effective DNA-methylating agent with nearly 100% oral bioavailability, allowing it to cross the blood-brain barrier and be rapidly absorbed, making it a promising treatment for brain tumors.

While TMZ shows limited effectiveness against pediatric brain tumors on its own, combining it with other treatments and assessing the methylation status of specific genes may enhance its efficacy and should be explored in future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of temozolomide in pediatric brain tumors. Barone, G., Maurizi, P., Tamburrini, G., et al.[2022]

In a phase II trial involving 26 patients with advanced mycosis fungoides/Sézary syndrome, temozolomide (TMZ) showed an overall response rate of 27%, with 8% achieving complete remission and 19% partial remission, indicating its potential efficacy in this patient population.

Despite the low levels of MGMT in malignant CD4(+) T cells, which suggested sensitivity to TMZ, the study found that pretreatment levels of MGMT and mismatch repair proteins did not predict treatment response, indicating that other resistance mechanisms may be at play.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter phase II trial of temozolomide in mycosis fungoides/sezary syndrome: correlation with O⁶-methylguanine-DNA methyltransferase and mismatch repair proteins. Querfeld, C., Rosen, ST., Guitart, J., et al.[2021]

A review of 5,127 reports on temozolomide (TMZ) revealed 112 cases of major hematologic adverse events (HAEs), with a significant number of these cases leading to death, highlighting the serious risks associated with this medication.

Aplastic anemia (AA) and leukemia were the most common major HAEs linked to TMZ, indicating a unique toxicity profile compared to other alkylating agents, and suggesting that patients should be informed about these risks, especially since AA can develop after a short duration of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematologic adverse events associated with temozolomide. Villano, JL., Letarte, N., Yu, JM., et al.[2018]

In a phase II trial involving 46 patients with progressive low-grade glioma, Temozolomide (Temodar) demonstrated a 61% objective response rate, with 24% achieving complete response and 37% achieving partial response.

The treatment showed promising safety, with limited toxicity observed; however, one patient experienced severe complications, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of temozolomide in patients with progressive low-grade glioma. Quinn, JA., Reardon, DA., Friedman, AH., et al.[2022]

Temozolomide (TMZ) has been established as an effective treatment for primary brain tumors like glioblastoma and oligodendroglioma, and it has also shown efficacy in melanoma, with multiple studies supporting its use as both a monotherapy and adjuvant chemotherapy.

Recent clinical trials suggest that TMZ may be beneficial in treating a variety of other cancers, including brain metastases, lymphomas, and neuroendocrine tumors, indicating its potential as a versatile cancer treatment beyond its formal indications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide and unusual indications: review of literature. Tatar, Z., Thivat, E., Planchat, E., et al.[2022]

Temozolomide (TMZ), a treatment for malignant glioma, can lead to therapy-induced myelodysplasia (T-MDS) in patients, with a cumulative dose threshold of approximately 18,000 to 20,000 mg/sq m identified as a risk factor.

Despite its effectiveness, TMZ is considered potentially leukemogenic, similar to other alkylating agents, highlighting the need for careful monitoring during long-term treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide-induced myelodysplasia. Natelson, EA., Pyatt, D.[2020]

Temozolomide is an effective oral chemotherapy drug approved for treating newly diagnosed glioblastoma, especially when used with radiotherapy, based on pivotal Phase III trial results.

The drug is generally safe with mild-to-moderate side effects, primarily reversible myelosuppression, and is most effective in patients with tumors that have a specific genetic marker (methylated MGMT), which helps them respond better to the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide: a milestone in neuro-oncology and beyond? Mutter, N., Stupp, R.[2018]

Temozolomide is primarily used for treating refractory central nervous system cancers like anaplastic astrocytoma and glioblastoma, but ongoing clinical trials are exploring its efficacy and safety in newly diagnosed gliomas and other types of tumors.

Research is also investigating different dosing schedules and combinations with other treatments, suggesting that temozolomide could be a versatile option in cancer therapy beyond its current approved uses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future directions for temozolomide therapy. Yung, WK.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05417594

NCT05417594 | Study of AZD9574 as Monotherapy and in ... This study will assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of AZD9574 individually and in ...

2. astrazenecaclinicaltrials.com astrazenecaclinicaltrials.com/study/D8410C00001

Study of AZD9574 as monotherapy and in combination ... This study will assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of AZD9574 individually and in ...

3. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05417594/study-of-azd9574-as-monotherapy-and-in-combination-with-anti-cancer-agents-in-participants-with-advanced-solid-malignancies

Study of AZD9574 as Monotherapy and in Combination ... This study will assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of AZD9574 ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11125602/

Progress and Innovative Combination Therapies in Trop-2 ... The results from the TROPION-Lung01 study suggest that Dato-DXd monotherapy improves survival outcomes in locally advanced/metastatic NSCLC patients, regardless ...

5. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-05317

Study of AZD9574 as Monotherapy and in Combination ... This study will assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of AZD9574 individually and in ...

6. astrazeneca.com astrazeneca.com/content/dam/az/PDF/2024/9mq3/9M-and-Q3-2024-results-clinical-trials-appendix.pdf

Clinical Trials Appendix Dato-DXd – NSCLC (non-squamous 2L and 3L) (TROPION-Lung01) (EU) ... Advanced/metastatic solid tumors. 60. • Platform, multi-center study.

7. cdek.pharmacy.purdue.edu cdek.pharmacy.purdue.edu/trial/NCT05417594/

Trial | NCT05417594 This study will assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of AZD9574 individually and in ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT05417594?term=AREA%5BNCTIdSearch%5D(NCT00412503%20OR%20NCT01193140%20OR%20NCT02813135%20OR%20NCT04164199%20OR%20NCT04238819%20OR%20NCT04610736%20OR%20NCT05004116%20OR%20NCT05417594)&rank=1

Study of AZD9574 as Monotherapy and in Combination ... Also called a data safety and monitoring board, or DSMB. Early Phase 1 (formerly listed as Phase 0). A phase of research used to describe exploratory trials ...